NEJM Readers’ Choice Clinical Care Collection

A COLLECTION OF THE MOST POPULAR CLINICAL CARE ARTICLES OF 2013

 February 2014

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• Severe Sepsis and Septic Shock
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• Infective Endocarditis
• Herpes Zoster
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Table of Contents
4 PERSPECTIVE
Dead Man Walking

6 ORIGINAL ARTICLE
Primary Prevention of Cardiovascular Disease
with a Mediterranean Diet

18 ORIGINAL ARTICLE
Duodenal Infusion of Donor Feces for Recurrent
Clostridium difficile

27 REVIEW ARTICLE
Critical Care Medicine: Severe Sepsis and
Septic Shock

39 CLINICAL PRACTICE
Vitamin B12 Deficiency

51 CLINICAL PRACTICE
Infective Endocarditis

60 CLINICAL PRACTICE
Herpes Zoster

69 CLINICAL PRACTICE
Carotid Stenosis

77 CLINICAL PROBLEM-SOLVING
A Patient with Syncope

84 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

Case 23-2013: A 54-Year-Old Woman with
Abdominal Pain, Vomiting, and Confusion

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4 nejm readers’ choice clinical care collection
The NEW ENGLA ND JOURNAL
Dead Man Walking
Michael Stillman, M.D., and Monalisa Tailor, M.D.
“S hocked” wouldn’t be accu­
rate, since we were accus­
tomed to our uninsured patients’
receiving inadequate medical care.
“Saddened” wasn’t right, either,
only pecking at the edge of our
response. And “disheartened” just
smacked of victimhood. After
hearing this story, we were neither
shocked nor saddened nor disheart­
ened. We were simply appalled.
We met Tommy Davis in our
hospital’s clinic for indigent per­
sons in March 2013 (the name
and date have been changed to
protect the patient’s privacy). He
and his wife had been chroni­
cally uninsured despite working
full­time jobs and were now fac­
ing disastrous consequences.
The week before this appoint­
ment, Mr. Davis had come to our
emergency department with ab­
dominal pain and obstipation. His
examination, laboratory tests, and
CT scan had cost him $10,000
(his entire life savings), and at
evening’s end he’d been sent home
with a diagnosis of metastatic
colon cancer.
The year before, he’d had sim­
ilar symptoms and visited a pri­
n engl j med 369;20
Back to Table of Contents
Perspective
mary care physician, who had tak­
en a cursory history, told Mr. Davis
he’d need insurance to be ade­
quately evaluated, and billed him
$200 for the appointment. Since
Mr. Davis was poor and ineligible
for Kentucky Medicaid, however,
he’d simply used enemas until he
was unable to defecate. By the
time of his emergency department
evaluation, he had a fully obstruct­
ed colon and widespread disease
and chose to forgo treatment.
Mr. Davis had had an inkling
that something was awry, but he’d
been unable to pay for an evalua­
tion. As his wife sobbed next to
him in our examination room, he
recounted his months of weight
loss, the unbearable pain of his
bowel movements, and his gnaw­
ing suspicion that he had cancer.
“If we’d found it sooner,” he con­
tended, “it would have made a dif­
ference. But now I’m just a dead
man walking.”
For many of our patients, pov­
erty alone limits access to care.
We recently saw a man with AIDS
and a full­body rash who couldn’t
afford bus fare to a dermatology
appointment. We sometimes pay
nejm.org november 14, 2013
of MEDICINE
november 14, 2013
for our patients’ medications be­
cause they are unable to cover even
a $4 copayment. But a fair number
of our patients — the medical
“have­nots” — are denied basic
services simply because they lack
insurance, and our country’s re­
sponse to this problem has, at
times, seemed toothless.
In our clinic, uninsured patients
frequently find necessary care un­
obtainable. An obese 60­year­old
woman with symptoms and signs
of congestive heart failure was re­
cently evaluated in the clinic. She
couldn’t afford the echocardio­
gram and evaluation for ischemic
heart disease that most internists
would have ordered, so furose­
mide treatment was initiated and
adjusted to relieve her symptoms.
This past spring, our colleagues
saw a woman with a newly dis­
covered lung nodule that was
highly suspicious for cancer. She
was referred to a thoracic surgeon,
but he insisted that she first have
a PET scan — a test for which
she couldn’t possibly pay.
However unconscionable we
may find the story of Mr. Davis,
a U.S. citizen who will die because
1880
PERS PEC T IV E
he was uninsured, the literature
suggests that it’s a common tale.
A 2009 study revealed a direct
correlation between lack of in­
surance and increased mortality
and suggested that nearly 45,000
American adults die each year
because they have no medical
coverage.1 And although we can’t
confidently argue that Mr. Davis
would have survived had he been
insured, research suggests that
possibility; formerly uninsured
adults given access to Oregon
Medicaid were more likely than
those who remained uninsured
to have a usual place of care and
a personal physician, to attend
outpatient medical visits, and to
receive recommended preventive
care.2 Had Mr. Davis been in­
sured, he might well have been
offered timely and appropriate
screening for colorectal cancer,
and his abdominal pain and ob­
stipation would surely have been
urgently evaluated.
Elected officials bear a great
deal of blame for the appalling vul­
nerability of the 22% of American
adults who currently lack insur­
ance. The Affordable Care Act
(ACA) — the only legitimate legis­
lative attempt to provide near­uni­
versal health coverage — remains
under attack from some members
of Congress, and our own two sen­
ators argue that enhancing mar­
ketplace competition and enacting
tort reform will provide security
enough for our nation’s poor.
In discussing (and grieving
over) what has happened to Mr.
Davis and our many clinic patients
whose health suffers for lack of
insurance, we have considered our
own obligations. As some con­
gresspeople attempt to defund
Obamacare, and as some states’
governors and attorneys general
deliberate over whether to imple­
ment health insurance exchanges
1881 n engl j med 369;20
and expand Medicaid eligibility,
how can we as physicians ensure
that the needs of patients like Mr.
Davis are met?
First, we can honor our funda­
mental professional duty to help.
Some have argued that the onus
for providing access to health care
rests on society at large rather
than on individual physicians,3
yet the Hippocratic Oath compels
us to treat the sick according to
our ability and judgment and to
keep them from harm and injus­
tice. Even as we continue to hope
for and work toward a future in
which all Americans have health
insurance, we believe it’s our indi­
vidual professional responsibility
to treat people in need.
Second, we can familiarize our­
selves with legislative details and
educate our patients about pro­
posed health care reforms. During
our appointment with Mr. Davis,
he worried aloud that under the
ACA, “the government would tax
him for not having insurance.”
He was unaware (as many of our
poor and uninsured patients may
be) that under that law’s final rule,
he and his family would meet the
eligibility criteria for Medicaid
and hence have access to compre­
hensive and affordable care.
Finally, we can pressure our
professional organizations to de­
mand health care for all. The
American College of Physicians,
the American Medical Association,
and the Society of General Internal
Medicine have endorsed the prin­
ciple of universal health care cov­
erage yet have generally remained
silent during years of political
debate. Lack of insurance can be
lethal, and we believe our profes­
sional community should treat
inaccessible coverage as a public
health catastrophe and stand be­
hind people who are at risk.
Seventy percent of our clinic
nejm.org november 14, 2013
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nejm.org
Dead Man Walking 5
patients have no health insurance,
and they are all frighteningly vul­
nerable; their care is erratic, they
are disqualified from receiving
certain preventive and screening
measures, and their lack of re­
sources prevents them from par­
ticipating in the medical system.
And this is not a community­ or
state­specific problem. A recent
study showed that underinsured
patients have higher mortality
rates after myocardial infarction,4
and it is well documented that
our country’s uninsured present
with later­stage cancers and more
poorly controlled chronic diseases
than do patients with insurance.5
We find it terribly and tragically
inhumane that Mr. Davis and tens
of thousands of other citizens of
this wealthy country will die this
year for lack of insurance.
Disclosure forms provided by the authors
are available with the full text of this article
at NEJM.org.
From the Department of Medicine, Univer­
sity of Louisville School of Medicine, Louis­
ville, KY.
This article was published on October 23,
2013, at NEJM.org.
1. Wilper AP, Woolhandler S, Lasser KE, Mc­
Cormick D, Bor DH, Himmelstein DU.
Health insurance and mortality in US adults.
Am J Public Health 2009;99:2289­95.
2. Finkelstein A, Taubman S, Wright B, et al.
The Oregon health insurance experiment:
evidence from the first year. Q J Econ 2012;
127:1057­106.
3. Huddle TS, Centor RM. Retainer medi­
cine: an ethically legitimate form of practice
that can improve primary care. Ann Intern
Med 2011;155:633­5.
4. Ng DK, Brotman DJ, Lau B, Young JH.
Insurance status, not race, is associated with
mortality after an acute cardiovascular event
in Maryland. J Gen Intern Med 2012;27:1368­
76.
5. Institute of Medicine. America’s unin­
sured crisis: consequences for health and
health care. Consensus report. Washington,
DC: National Academies Press, February 23,
2009 (http://www.iom.edu/Reports/2009/
Americas­Uninsured­Crisis­Consequences
­for­Health­and­Health­Care.aspx).
DOI: 10.1056/NEJMp1312793
Copyright © 2013 Massachusetts Medical Society.
6 nejm readers’ choice clinical care collection
Mediterr anean Diet and Cardiovascular Events

ORIGINAL ARTICLE

Primary Prevention of Cardiovascular Disease

with a Mediterranean Diet
Ramón Estruch, M.D., Ph.D., Emilio Ros, M.D., Ph.D., Jordi Salas-Salvadó, M.D., Ph.D.,
Maria-Isabel Covas, D.Pharm., Ph.D., Dolores Corella, D.Pharm., Ph.D., Fernando Arós, M.D., Ph.D.,
Enrique Gómez-Gracia, M.D., Ph.D., Valentina Ruiz-Gutiérrez, Ph.D., Miquel Fiol, M.D., Ph.D.,
José Lapetra, M.D., Ph.D., Rosa Maria Lamuela-Raventos, D.Pharm., Ph.D., Lluís Serra-Majem, M.D., Ph.D.,
Xavier Pintó, M.D., Ph.D., Josep Basora, M.D., Ph.D., Miguel Angel Muñoz, M.D., Ph.D., José V. Sorlí, M.D., Ph.D.,
José Alfredo Martínez, D.Pharm, M.D., Ph.D., and Miguel Angel Martínez-González, M.D., Ph.D.,
for the PREDIMED Study Investigators*

A bs t r ac t

Background
Observational cohort studies and a secondary prevention trial have shown an in- The authors’ affiliations are listed in the
verse association between adherence to the Mediterranean diet and cardiovascular Appendix. Address reprint requests to
Dr. Estruch at the Department of Internal
risk. We conducted a randomized trial of this diet pattern for the primary preven- Medicine, Hospital Clinic, Villarroel 170,
tion of cardiovascular events. 08036 Barcelona, Spain, or at restruch@
clinic.ub.es, or to Dr. Martínez-González
Methods at the Department of Preventive Medi-
In a multicenter trial in Spain, we randomly assigned participants who were at high cine and Public Health, Facultad de Me-
dicina–Clínica Universidad de Navarra,
cardiovascular risk, but with no cardiovascular disease at enrollment, to one of Irunlarrea 1, 31008 Pamplona, Spain, or
three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Medi- at mamartinez@unav.es.
terranean diet supplemented with mixed nuts, or a control diet (advice to reduce
* The PREDIMED (Prevención con Dieta
dietary fat). Participants received quarterly individual and group educational ses- Mediterránea) study investigators are
sions and, depending on group assignment, free provision of extra-virgin olive oil, listed in the Supplementary Appendix,
mixed nuts, or small nonfood gifts. The primary end point was the rate of major available at NEJM.org.

cardiovascular events (myocardial infarction, stroke, or death from cardiovascular Drs. Estruch and Martínez-González con-
causes). On the basis of the results of an interim analysis, the trial was stopped tributed equally to this article.
after a median follow-up of 4.8 years.
This article was published on February 25,
Results 2013, at NEJM.org.

A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. N Engl J Med 2013;368:1279-90.
The two Mediterranean-diet groups had good adherence to the intervention, ac- DOI: 10.1056/NEJMoa1200303
Copyright © 2013 Massachusetts Medical Society.
cording to self-reported intake and biomarker analyses. A primary end-point event
occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70
(95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the
group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and
the group assigned to a Mediterranean diet with nuts (83 events), respectively, ver-
sus the control group (109 events). No diet-related adverse effects were reported.
Conclusions
Among persons at high cardiovascular risk, a Mediterranean diet supplemented
with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular
events. (Funded by the Spanish government’s Instituto de Salud Carlos III and oth-
ers; Controlled-Trials.com number, ISRCTN35739639.)

n engl j med 368;14 nejm.org april 4, 2013 1279

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 The n e w e ng l a n d j o u r na l
T
he traditional Mediterranean diet
is characterized by a high intake of olive
oil, fruit, nuts, vegetables, and cereals; a
moderate intake of fish and poultry; a low intake
of dairy products, red meat, processed meats,
and sweets; and wine in moderation, consumed
with meals.1 In observational cohort studies2,3
and a secondary prevention trial (the Lyon Diet
Heart Study),4 increasing adherence to the Medi-
terranean diet has been consistently beneficial
with respect to cardiovascular risk.2-4 A system-
atic review ranked the Mediterranean diet as the
most likely dietary model to provide protection
against coronary heart disease.5 Small clinical
trials have uncovered plausible biologic mecha-
nisms to explain the salutary effects of this food
pattern.6-9 We designed a randomized trial to
test the efficacy of two Mediterranean diets (one
supplemented with extra-virgin olive oil and an-
other with nuts), as compared with a control diet
(advice on a low-fat diet), on primary cardiovas-
cular prevention.
Me thods
Study design
The PREDIMED trial (Prevención con Dieta Med-
iterránea) was a parallel-group, multicenter, ran-
domized trial. Details of the trial design are pro-
vided elsewhere.10-12 The trial was designed and
conducted by the authors, and the protocol was
approved by the institutional review boards at all
study locations. The authors vouch for the accu-
racy and completeness of the data and all analy-
ses and for the fidelity of this report to the pro-
tocol, which is available with the full text of this
article at NEJM.org.
Supplemental foods were donated, including
extra-virgin olive oil (by Hojiblanca and Patrimo-
nio Comunal Olivarero, both in Spain), walnuts
(by the California Walnut Commission), al-
monds (by Borges, in Spain), and hazelnuts (by
La Morella Nuts, in Spain). None of the sponsors
had any role in the trial design, data analysis, or
reporting of the results.
Participant Selection and Randomization
Eligible participants were men (55 to 80 years of
age) and women (60 to 80 years of age) with no
cardiovascular disease at enrollment, who had
either type 2 diabetes mellitus or at least three
of the following major risk factors: smoking,
hypertension, elevated low-density lipoprotein
280 n engl j med 368;14
of m e dic i n e nejm.org 7
cholesterol levels, low high-density lipoprotein
cholesterol levels, overweight or obesity, or a
family history of premature coronary heart dis-
ease. Detailed enrollment criteria are provided
in the Supplementary Appendix, available at NEJM
.org. All participants provided written informed
consent.
Beginning on October 1, 2003, participants
were randomly assigned, in a 1:1:1 ratio, to one
of three dietary intervention groups: a Mediter-
ranean diet supplemented with extra-virgin olive
oil, a Mediterranean diet supplemented with
nuts, or a control diet. Randomization was per-
formed centrally by means of a computer-gener-
ated random-number sequence.
Interventions and Measurements
The dietary intervention8,10-13 is detailed in the
Supplementary Appendix. The specific recom-
mended diets are summarized in Table 1. Par-
ticipants in the two Mediterranean-diet groups
received either extra-virgin olive oil (approxi-
mately 1 liter per week) or 30 g of mixed nuts per
day (15 g of walnuts, 7.5 g of hazelnuts, and
7.5 g of almonds) at no cost, and those in the
control group received small nonfood gifts. No
total calorie restriction was advised, nor was
physical activity promoted.
For participants in the two Mediterranean-
diet groups, dietitians ran individual and group
dietary-training sessions at the baseline visit and
quarterly thereafter. In each session, a 14-item
dietary screener was used to assess adherence to
the Mediterranean diet8,14 (Table S1 in the Sup-
plementary Appendix) so that personalized ad-
vice could be provided to the study participants
in these groups.
Participants in the control group also re-
ceived dietary training at the baseline visit and
completed the 14-item dietary screener used to
assess baseline adherence to the Mediterranean
diet. Thereafter, during the first 3 years of the
trial, they received a leaflet explaining the low-
fat diet (Table S2 in the Supplementary Appen-
dix) on a yearly basis. However, the realization
that the more infrequent visit schedule and less
intense support for the control group might be
limitations of the trial prompted us to amend
the protocol in October 2006. Thereafter, par-
ticipants assigned to the control diet received
personalized advice and were invited to group
sessions with the same frequency and intensity
as those in the Mediterranean-diet groups, with
nejm.org april 4, 2013
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8 nejm readers’ choice clinical
Mediterr aneancare
Dietcollection
and Cardiovascular Events

the use of a separate 9-item dietary screener

Table 1. Summary of Dietary Recommendations to Participants in the
(Table S3 in the Supplementary Appendix). Mediterranean-Diet Groups and the Control-Diet Group.
A general medical questionnaire, a 137-item
validated food-frequency questionnaire,15 and Food Goal
the Minnesota Leisure-Time Physical Activity Mediterranean diet
Questionnaire were administered on a yearly Recommended
basis.10 Information from the food-frequency Olive oil* ≥4 tbsp/day
questionnaire was used to calculate intake of Tree nuts and peanuts† ≥3 servings/wk
energy and nutrients. Weight, height, and waist Fresh fruits ≥3 servings/day
circumference were directly measured.16 Bio-
Vegetables ≥2 servings/day
markers of compliance, including urinary hy-
Fish (especially fatty fish), seafood ≥3 servings/wk
droxytyrosol levels (to confirm compliance in
the group receiving extra-virgin olive oil) and Legumes ≥3 servings/wk
plasma alpha-linolenic acid levels (to confirm Sofrito‡ ≥2 servings/wk
compliance in the group receiving mixed nuts), White meat Instead of red meat
were measured in random subsamples of par- Wine with meals (optionally, only for habitual ≥7 glasses/wk
ticipants at 1, 3, and 5 years (see the Supplemen- drinkers)
tary Appendix). Discouraged
Soda drinks <1 drink/day
End Points Commercial bakery goods, sweets, and pastries§ <3 servings/wk
The primary end point was a composite of myo- Spread fats <1 serving/day
cardial infarction, stroke, and death from cardio- Red and processed meats <1 serving/day
vascular causes. Secondary end points were
Low-fat diet (control)
stroke, myocardial infarction, death from cardio-
Recommended
vascular causes, and death from any cause. We
used four sources of information to identify end Low-fat dairy products ≥3 servings/day
points: repeated contacts with participants, con- Bread, potatoes, pasta, rice ≥3 servings/day
tacts with family physicians, a yearly review of Fresh fruits ≥3 servings/day
medical records, and consultation of the Nation- Vegetables ≥2 servings/wk
al Death Index. All medical records related to Lean fish and seafood ≥3 servings/wk
end points were examined by the end-point adju- Discouraged
dication committee, whose members were un- Vegetable oils (including olive oil) ≤2 tbsp/day
aware of the study-group assignments. Only end
Commercial bakery goods, sweets, and pastries§ ≤1 serving/wk
points that were confirmed by the adjudication
Nuts and fried snacks ≤1 serving /wk
committee and that occurred between October 1,
2003, and December 1, 2010, were included in Red and processed fatty meats ≤1 serving/wk
the analyses. The criteria for adjudicating pri- Visible fat in meats and soups¶ Always remove
mary and secondary end points are detailed in Fatty fish, seafood canned in oil ≤1 serving/wk
the Supplementary Appendix. Spread fats ≤1 serving/wk
Sofrito‡ ≤2 servings/wk
Statistical Analysis
We initially estimated that a sample of 9000 par- * The amount of olive oil includes oil used for cooking and salads and oil con-
sumed in meals eaten outside the home. In the group assigned to the Medi-
ticipants would be required to provide statistical terranean diet with extra-virgin olive oil, the goal was to consume 50 g (ap-
power of 80% to detect a relative risk reduction proximately 4 tbsp) or more per day of the polyphenol-rich olive oil supplied,
of 20% in each Mediterranean-diet group versus instead of the ordinary refined variety, which is low in polyphenols.
† For participants assigned to the Mediterranean diet with nuts, the recommend-
the control-diet group during a 4-year follow-up ed consumption was one daily serving (30 g, composed of 15 g of walnuts,
period, assuming an event rate of 12% in the 7.5 g of almonds, and 7.5 g of hazelnuts).
control group.10,17 In April 2008, on the advice of ‡ Sofrito is a sauce made with tomato and onion, often including garlic and aro-
matic herbs, and slowly simmered with olive oil.
the data and safety monitoring board and on the § Commercial bakery goods, sweets, and pastries (not homemade) included
basis of lower-than-expected rates of end-point cakes, cookies, biscuits, and custard.
events, the sample size was recalculated as 7400 ¶ Participants were advised to remove the visible fat (or the skin) of chicken,
duck, pork, lamb, or veal before cooking and the fat of soups, broths, and
participants, with the assumption of a 6-year cooked meat dishes before consumption.
follow-up period and underlying event rates of

n engl j med 368;14 nejm.org april 4, 2013 1281

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 9

8.8% and 6.6% in the control and intervention
groups, respectively. Power curves under several
assumptions can be found in Figure S1 in the
Supplementary Appendix.
Yearly interim analyses began after a median
of 2 years of follow-up. With the use of O’Brien–
Fleming stopping boundaries, the P values for
stopping the trial at each yearly interim analysis
were 5×10−6, 0.001, 0.009, and 0.02 for benefit
and 9×10−5, 0.005, 0.02, and 0.05 for adverse ef-
fects.18 The stopping boundary for the benefit of
the Mediterranean diets with respect to the pri-
mary end point was crossed at the fourth inter-
im evaluation; on July 22, 2011, the data and
safety monitoring board recommended stopping
the trial on the basis of end points documented
through December 1, 2010.
All primary analyses were performed on an
intention-to-treat basis by two independent ana-
lysts. Time-to-event data were analyzed with the
use of Cox models with two dummy variables
(one for the Mediterranean diet with extra-virgin
olive oil and another for the Mediterranean diet
with nuts) to obtain two hazard ratios for the
comparison with the control group. To account
for small imbalances in risk factors at baseline
among the groups, Cox regression models were
used to adjust for sex, age, and baseline risk fac-
tors. We tested the proportionality of hazards
with the use of time-varying covariates. All
analyses were stratified according to center. Pre-
specified subgroup analyses were conducted ac-
cording to sex, age, body-mass index (BMI),
cardiovascular-risk-factor status, and baseline
adherence to the Mediterranean diet. Sensitivity
analyses were conducted under several assump-
tions, including imputation of data for missing
values and participants who dropped out (see the
Supplementary Appendix).
R e sult s
Baseline Characteristics of the Study
Participants
From October 2003 through June 2009, a total of
8713 candidates were screened for eligibility, and

Table 2. Baseline Characteristics of the Participants According to Study Group.*

Mediterranean Mediterranean
Diet with EVOO Diet with Nuts Control Diet
Characteristic (N = 2543) (N = 2454) (N = 2450)
Female sex — no. (%)† 1493 (58.7) 1326 (54.0) 1463 (59.7)
Age — yr† 67.0±6.2 66.7±6.1 67.3±6.3
Race or ethnic group — no. (%)
White, from Europe 2470 (97.1) 2390 (97.4) 2375 (96.9)
Hispanic, from Central or South America 35 (1.4) 29 (1.2) 38 (1.6)
Other 38 (1.5) 35 (1.4) 37 (1.5)
Smoking status — no. (%)
Never smoked 1572 (61.8) 1465 (59.7) 1527 (62.3)
Former smoker 618 (24.3) 634 (25.8) 584 (23.8)
Current smoker 353 (13.9) 355 (14.5) 339 (13.8)
Body-mass index†‡
Mean 29.9±3.7 29.7±3.8 30.2±4.0
<25 — no. (%) 195 (7.7) 204 (8.3) 164 (6.7)
25–30 — no. (%) 1153 (45.3) 1163 (47.4) 1085 (44.3)
>30 — no. (%) 1195 (47.0) 1087 (44.3) 1201 (49.0)
Waist circumference — cm 100±10 100±11 101±11
Waist-to-height ratio†§ 0.63±0.06 0.63±0.06 0.63±0.07
Hypertension — no. (%)¶ 2088 (82.1) 2024 (82.5) 2050 (83.7)
Type 2 diabetes — no. (%)†‖ 1282 (50.4) 1143 (46.6) 1189 (48.5)
Dyslipidemia — no. (%)** 1821 (71.6) 1799 (73.3) 1763 (72.0)
Family history of premature CHD — no. (%)†† 576 (22.7) 532 (21.7) 560 (22.9)

282 n engl j med 368;14 nejm.org april 4, 2013

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10 nejm readers’ choice clinical Mediterr
care collection
anean Diet and Cardiovascular Events

Table 2. (Continued.)

Mediterranean Mediterranean
Diet with EVOO Diet with Nuts Control Diet
Characteristic (N = 2543) (N = 2454) (N = 2450)
Medication use — no. (%)
ACE inhibitors 1236 (48.6) 1223 (49.8) 1216 (49.6)
Diuretics† 534 (21.0) 477 (19.4) 562 (22.9)
Other antihypertensive agents 725 (28.5) 710 (28.9) 758 (30.9)
Statins 1039 (40.9) 964 (39.3) 983 (40.1)
Other lipid-lowering agents 121 (4.8) 145 (5.9) 126 (5.1)
Insulin 124 (4.9) 126 (5.1) 134 (5.5)
Oral hypoglycemic agents† 768 (30.2) 680 (27.7) 757 (30.9)
Antiplatelet therapy 475 (18.7) 490 (20.0) 513 (20.9)
Hormone-replacement therapy‡‡ 42 (2.8) 35 (2.6) 39 (2.7)
Score for adherence to Med diet§§ 8.7±2.0 8.7±2.0 8.4±2.1

* Plus–minus values are means ±SD. ACE denotes angiotensin-converting enzyme, and EVOO extra-virgin olive oil.
† P<0.05 for comparisons between groups.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ The waist-to-height ratio (an index of central obesity) is the waist circumference divided by height.
¶ Hypertension was defined as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of
90 mm Hg or higher, or the use of antihypertensive therapy.
‖ Diabetes was defined as a fasting blood glucose level of 126 mg per deciliter (7.0 mmol per liter) or higher on two
occasions, a 2-hour plasma glucose level of 200 mg per deciliter (11 mmol per liter) or higher during a 75-g oral glu-
cose-tolerance test, or the use of antidiabetic medication.
** Dyslipidemia was defined as a low-density lipoprotein cholesterol level higher than 160 mg per deciliter (4.1 mmol
per liter), a high-density lipoprotein cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or lower in men or 50 mg
per deciliter (1.3 mmol per liter) or lower in women, or the use of lipid-lowering therapy.
†† A family history of premature coronary heart disease (CHD) was defined as a diagnosis of the disease in a male first-
degree relative younger than 55 years of age or in a female first-degree relative younger than 65 years of age.
‡‡ The values for hormone-replacement therapy are for women only.
§§ The score for adherence to the Mediterranean diet is based on the 14-item dietary screener shown in Table S1 in the
Supplementary Appendix (a score of 0 indicates minimum adherence, and a score of 14 indicates maximum adherence).

7447 were randomly assigned to one of the three
study groups (Fig. S2 in the Supplementary Ap-
pendix). Their baseline characteristics according
to study group are shown in Table 2. Drug-treat-
ment regimens were similar for participants in
the three groups, and they continued to be bal-
anced during the follow-up period (Table S4 in
the Supplementary Appendix).
Participants were followed for a median of
4.8 years (interquartile range, 2.8 to 5.8). After
the initial assessment, 209 participants (2.8%)
chose not to attend subsequent visits, and their
follow-up was based on reviews of medical re-
cords. By December 2010, a total of 523 partici-
pants (7.0%) had been lost to follow-up for 2 or
more years. Dropout rates were higher in the con-
trol group (11.3%) than in the Mediterranean-
diet groups (4.9%) (Fig. S2 in the Supplementary
Appendix). As compared with participants who
remained in the trial, those who dropped out
were younger (by 1.4 years), had a higher BMI
(the weight in kilograms divided by the square of
the height in meters; by 0.4), a higher waist-to-
height ratio (by 0.01), and a lower score for ad-
herence to the Mediterranean diet (by 1.0 points
on the 14-item dietary screener) (P<0.05 for all
comparisons).
Compliance with the Dietary Intervention
Participants in the three groups reported similar
adherence to the Mediterranean diet at baseline
(Table 2, and Fig. S3 in the Supplementary Ap-
pendix) and similar food and nutrient intakes.
During follow-up, scores on the 14-item Medi-
terranean-diet screener increased for the par-
ticipants in the two Mediterranean-diet groups
(Fig. S3 in the Supplementary Appendix). There
were significant differences between these groups
and the control group in 12 of the 14 items at
3 years (Table S5 in the Supplementary Appen-

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 11

dix). Changes in objective biomarkers also indi-
cated good compliance with the dietary assign-
ments (Fig. S4 and S5 in the Supplementary
Appendix).
Participants in the two Mediterranean-diet
groups significantly increased weekly servings of
fish (by 0.3 servings) and legumes (by 0.4 serv-
ings) in comparison with those in the control
group (Table S6 in the Supplementary Appendix).
In addition, participants assigned to a Mediter-
ranean diet with extra-virgin olive oil and those
assigned to a Mediterranean diet with nuts sig-
nificantly increased their consumption of extra-
virgin olive oil (to 50 and 32 g per day, respec-
tively) and nuts (to 0.9 and 6 servings per week,
respectively). The main nutrient changes in the
Mediterranean-diet groups reflected the fat con-
tent and composition of the supplemental foods
(Tables S7 and S8 in the Supplementary Appen-
dix). No relevant diet-related adverse effects
were reported (see the Supplementary Appen-
dix). We did not find any significant difference
in changes in physical activity among the three
groups.

Table 3. Outcomes According to Study Group.*

Mediterranean Mediterranean
Diet with EVOO Diet with Nuts Control Diet
End Point (N = 2543) (N = 2454) (N = 2450) P Value†
Mediterranean Mediterranean
Diet with EVOO Diet with Nuts
vs. Control Diet vs. Control Diet
Person-yr of follow-up 11,852 10,365 9763
Primary end point‡
No. of events 96 83 109
Crude rate/1000 person-yr (95% CI) 8.1 (6.6–9.9) 8.0 (6.4–9.9) 11.2 (9.2–13.5) 0.009 0.02
Secondary end points
Stroke
No. of events 49 32 58
Crude rate/1000 person-yr (95% CI) 4.1 (3.1–5.5) 3.1 (2.1–4.4) 5.9 (4.5–7.7) 0.03 0.003
Myocardial infarction
No. of events 37 31 38
Crude rate/1000 person-yr (95% CI) 3.1 (2.2–4.3) 3.0 (2.0–4.2) 3.9 (2.8–5.3) 0.31 0.25
Death from cardiovascular causes
No. of events 26 31 30
Crude rate/1000 person-yr (95% CI) 2.2 (1.4–3.2) 3.0 (2.0–4.2) 3.1 (2.1–4.4) 0.15 0.85
Death from any cause
No. of events 118 116 114
Crude rate/1000 person-yr (95% CI) 10.0 (8.2–11.9) 11.2 (9.3–13.4) 11.7 (9.6–14.0) 0.11 0.68
Hazard ratio for each Mediterranean diet
vs. control (95% CI)
Primary end point
Unadjusted 0.70 (0.53–0.91) 0.70 (0.53–0.94) 1.00 (ref) 0.009 0.02
Multivariable-adjusted 1§ 0.69 (0.53–0.91) 0.72 (0.54–0.97) 1.00 (ref) 0.008 0.03
Multivariable-adjusted 2¶ 0.70 (0.54–0.92) 0.72 (0.54–0.96) 1.00 (ref) 0.01 0.03
Secondary end points‖
Stroke 0.67 (0.46–0.98) 0.54 (0.35–0.84) 1.00 (ref) 0.04 0.006
Myocardial infarction 0.80 (0.51–1.26) 0.74 (0.46–1.19) 1.00 (ref) 0.34 0.22
Death from cardiovascular causes 0.69 (0.41–1.16) 1.01 (0.61–1.66) 1.00 (ref) 0.17 0.98
Death from any cause 0.82 (0.64–1.07) 0.97 (0.74–1.26) 1.00 (ref) 0.15 0.82

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12 nejm readers’ choice clinical
Mediterr anean care
Dietcollection
and Cardiovascular Events

Table 3. (Continued.)

Mediterranean Mediterranean
Diet with EVOO Diet with Nuts Control Diet
End Point (N = 2543) (N = 2454) (N = 2450) P Value†
Mediterranean Mediterranean
Diet with EVOO Diet with Nuts
vs. Control Diet vs. Control Diet
Hazard ratio for Mediterranean diets combined
vs. control (95% CI)
Primary end point
Unadjusted 0.70 (0.55–0.89) 1 (ref) 0.003
Multivariable-adjusted 1§ 0.71 (0.56–0.90) 1 (ref) 0.004
Multivariable-adjusted 2¶ 0.71 (0.56–0.90) 1 (ref) 0.005
Secondary end points‖
Stroke 0.61 (0.44–0.86) 1 (ref) 0.005
Myocardial infarction 0.77 (0.52–1.15) 1 (ref) 0.20
Death from cardiovascular causes 0.83 (0.54–1.29) 1 (ref) 0.41
Death from any cause 0.89 (0.71–1.12) 1 (ref) 0.32

* CI denotes confidence interval, and ref reference.

† All P values were calculated with the use of Cox proportional-hazards models with robust variance estimators and stratification according to
recruiting center.
‡ The primary end point was a composite of myocardial infarction, stroke, and death from cardiovascular causes.
§ The primary end point was stratified according to recruiting center and adjusted for sex, age (continuous variable), family history of pre-
mature coronary heart disease (yes or no), and smoking status (never smoked, former smoker, or current smoker).
¶ The primary end point was additionally adjusted for body-mass index (continuous variable), waist-to-height ratio (continuous variable),
hypertension at baseline (yes or no), dyslipidemia at baseline (yes or no), and diabetes at baseline (yes or no).
‖ The secondary end points were stratified according to recruiting center and adjusted for sex, age (continuous variable), family history of
premature coronary heart disease (yes or no), smoking status (never smoked, former smoker, or current smoker), body-mass index (con-
tinuous variable), waist-to-height ratio (continuous variable), hypertension at baseline (yes or no), dyslipidemia at baseline (yes or no), and
diabetes at baseline (yes or no).

End Points
The median follow-up period was 4.8 years. A
total of 288 primary-outcome events occurred:
96 in the group assigned to a Mediterranean diet
with extra-virgin olive oil (3.8%), 83 in the group
assigned to a Mediterranean diet with nuts
(3.4%), and 109 in the control group (4.4%). Tak-
ing into account the small differences in the ac-
crual of person-years among the three groups,
the respective rates of the primary end point
were 8.1, 8.0, and 11.2 per 1000 person-years
(Table 3). The unadjusted hazard ratios were 0.70
(95% confidence interval [CI], 0.53 to 0.91) for a
Mediterranean diet with extra-virgin olive oil and
0.70 (95% CI, 0.53 to 0.94) for a Mediterranean
diet with nuts (Fig. 1) as compared with the con-
trol diet (P = 0.015, by the likelihood ratio test,
for the overall effect of the intervention).
The results of multivariate analyses showed a
similar protective effect of the two Mediterra-
nean diets versus the control diet with respect to
the primary end point (Table 3). Regarding com-
ponents of the primary end point, only the com-
parisons of stroke risk reached statistical signifi-
cance (Table 3, and Fig. S6 in the Supplementary
Appendix). The Kaplan–Meier curves for the
primary end point diverged soon after the trial
started, but no effect on all-cause mortality was
apparent (Fig. 1). The results of several sensitiv-
ity analyses were also consistent with the find-
ings of the primary analysis (Table S9 in the
Supplementary Appendix).
Subgroup Analyses
Reductions in disease risk in the two Mediterra-
nean-diet groups as compared with the control
group were similar across the prespecified sub-
groups (Fig. 2, and Table S10 in the Supplemen-
tary Appendix). In addition, to account for the
protocol change in October 2006 whereby the
intensity of dietary intervention in the control
group was increased, we compared hazard ratios

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 13

A Primary End Point (acute myocardial infarction, stroke, or death from cardiovascular causes)
1.0
Control diet
Med diet, EVOO: hazard ratio, 0.70 0.06

Incidence of Composite Cardiovascular

(95% CI, 0.53–0.91); P=0.009
Med diet, nuts: hazard ratio, 0.70 0.05 Med diet, nuts
0.8
(95% CI, 0.53–0.94); P=0.02
0.04

0.03
0.6 Med diet, EVOO
End Point

0.02

0.4 0.01

0.00
0 1 2 3 4 5
0.2

0.0
0 1 2 3 4 5
Years
No. at Risk
Control diet 2450 2268 2020 1583 1268 946
Med diet, EVOO 2543 2486 2320 1987 1687 1310
Med diet, nuts 2454 2343 2093 1657 1389 1031

B Total Mortality
1.0 0.07
Med diet, EVOO: hazard ratio, 0.81
(95% CI, 0.63–1.05); P=0.11 0.06 Med diet, nuts
Med diet, nuts: hazard ratio, 0.95
0.8 0.05
(95% CI, 0.73–1.23); P=0.68
0.04 Control diet Med diet, EVOO
Total Mortality

0.6 0.03

0.02
0.4 0.01

0.00
0 1 2 3 4 5
0.2

0.0
0 1 2 3 4 5
Years
No. at Risk
Control diet 2450 2268 2026 1585 1272 948
Med diet, EVOO 2543 2485 2322 1988 1690 1308
Med diet, nuts 2454 2345 2097 1662 1395 1037

Figure 1. Kaplan–Meier Estimates of the Incidence of Outcome Events in the Total Study Population.
Panel A shows the incidence of the primary end point (a composite of acute myocardial infarction, stroke, and death
from cardiovascular causes), and Panel B shows total mortality. Hazard ratios were stratified according to center
(Cox model with robust variance estimators). CI denotes confidence interval, EVOO extra-virgin olive oil, and Med
Mediterranean.

for the Mediterranean-diet groups (both groups Discussion

merged vs. the control group) before and after
this date. Adjusted hazard ratios were 0.77 (95% In this trial, an energy-unrestricted Mediterra-
CI, 0.59 to 1.00) for participants recruited before nean diet supplemented with either extra-virgin
October 2006 and 0.49 (95% CI, 0.26 to 0.92) for olive oil or nuts resulted in an absolute risk re-
those recruited thereafter (P = 0.21 for interaction). duction of approximately 3 major cardiovascular

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14 nejm readers’ choice clinical
Mediterr aneancare
Dietcollection
and Cardiovascular Events

Combined Control P Value for

Subgroup Mediterranean Diets Diet Hazard Ratio (95% CI) Interaction
no. of participants with primary end-point
event/total no. of participants
Sex 0.62
Male 107/2178 64/987 0.69 (0.51–0.94)
Female 72/2819 45/1463 0.73 (0.50–1.07)
Age 0.84
<70 yr 86/3272 47/1504 0.73 (0.52–1.05)
≥70 yr 93/1725 62/946 0.71 (0.51–0.98)
Diabetes 0.63
No 58/2572 40/1261 0.67 (0.45–1.01)
Yes 121/2425 69/1189 0.71 (0.53–0.96)
Hypertension 0.06
No 40/885 11/400 1.25 (0.64–2.45)
Yes 139/4112 98/2050 0.65 (0.50–0.84)
Dyslipidemia 0.06
No 77/1377 36/687 0.95 (0.64–1.42)
Yes 102/3620 73/1763 0.60 (0.44–0.80)
Smoking 0.75
Never 80/3037 54/1527 0.67 (0.47–0.94)
Ever 99/1960 55/923 0.75 (0.54–1.03)
Family history of premature CHD 0.97
No 144/3889 87/1890 0.72 (0.55–0.94)
Yes 35/1108 22/560 0.75 (0.43–1.29)
BMI 0.05
<25 18/399 7/164 0.69 (0.29–1.67)
25–30 88/2316 37/1085 1.04 (0.71–1.54)
>30 73/2282 65/1201 0.51 (0.37–0.71)
Waist 0.72
<Median 87/2561 48/1177 0.76 (0.53–1.08)
≥Median 92/2436 61/1273 0.67 (0.48–0.93)
Waist-to-height ratio 0.82
<Median 81/2549 47/1182 0.74 (0.52–1.06)
≥Median 98/2448 62/1268 0.68 (0.50–0.94)
Baseline score for adherence to Mediterranean diet 0.44
<9 (low) 93/2178 61/1256 0.81 (0.58–1.12)
≥9 (high) 86/2819 48/1194 0.64 (0.45–0.92)
End-point components
Stroke 81/4997 58/2450 0.61 (0.44–0.86)
Myocardial infarction 68/4997 38/2450 0.77 (0.52–1.15)
Death from cardiovascular causes 57/4997 30/2450 0.83 (0.54–1.29)
0.5 1.0 2.0

Mediterranean Diets Better Control Diet Better

Figure 2. Results of Subgroup Analyses.

Shown are adjusted hazard ratios for the primary end point within specific subgroups. Squares denote hazard ratios; horizontal lines
represent 95% confidence intervals. Hazard ratios indicate the relative risk in both intervention groups merged together (vs. the control
group) within each stratum. Hazard ratios were stratified according to recruiting center and were adjusted for sex, age (continuous vari-
able), family history of premature coronary heart disease (CHD) (yes or no), smoking (never smoked, former smoker, or current smok-
er), body-mass index (BMI) (continuous variable), waist-to-height ratio (continuous variable), hypertension at baseline (yes or no), dys-
lipidemia at baseline (yes or no), and diabetes at baseline (yes or no). Scores for adherence to the Mediterranean diet range from 0 to
14, with higher scores indicating greater adherence.

events per 1000 person-years, for a relative risk
reduction of approximately 30%, among high-
risk persons who were initially free of cardiovas-
cular disease. These results support the benefits
of the Mediterranean diet for cardiovascular risk
reduction. They are particularly relevant given the
challenges of achieving and maintaining weight
loss. The secondary prevention Lyon Diet Heart
Study also showed a large reduction in rates of
coronary heart disease events with a modified

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 The n e w e ng l a n d j o u r na l
Mediterranean diet enriched with alpha-linolenic
acid (a key constituent of walnuts). That result,
however, was based on only a few major events.4,19,20
There were small between-group differences
in some baseline characteristics in our trial, which
were not clinically meaningful but were statisti-
cally significant, and we therefore adjusted for
these variables. In fully adjusted analyses, we found
significant results for the combined cardiovas-
cular end point and for stroke, but not for myo-
cardial infarction alone. This could be due to
stronger effects on specific risk factors for stroke
but also to a lower statistical power to identify
effects on myocardial infarction. Our findings
are consistent with those of prior observational
studies of the cardiovascular protective effects
of the Mediterranean diet,2,5 olive oil,21-23 and
nuts24,25; smaller trials assessing effects on tra-
ditional cardiovascular risk factors6-9 and novel
risk factors, such as markers of oxidation, in-
flammation, and endothelial dysfunction6,8,26-28;
and studies of conditions associated with high
cardiovascular risk — namely, the metabolic
syndrome6,16,29 and diabetes.30-32 Thus, a causal
role of the Mediterranean diet in cardiovascular
prevention has high biologic plausibility. The
results of our trial might explain, in part, the
lower cardiovascular mortality in Mediterranean
countries than in northern European countries
or the United States.33
The risk of stroke was reduced significantly
in the two Mediterranean-diet groups. This is
consistent with epidemiologic studies that showed
an inverse association between the Mediterra-
nean diet2,34 or olive-oil consumption22 and in-
cident stroke.
Our results compare favorably with those of
the Women’s Health Initiative Dietary Modifica-
tion Trial, wherein a low-fat dietary approach
resulted in no cardiovascular benefit.35 Salient
components of the Mediterranean diet report-
edly associated with better survival include mod-
erate consumption of ethanol (mostly from wine),
low consumption of meat and meat products,
and high consumption of vegetables, fruits, nuts,
legumes, fish, and olive oil.36,37 Perhaps there is
a synergy among the nutrient-rich foods includ-
ed in the Mediterranean diet that fosters favor-
able changes in intermediate pathways of car-
diometabolic risk, such as blood lipids, insulin
sensitivity, resistance to oxidation, inflammation,
and vasoreactivity.38
288 n engl j med 368;14
of m e dic i n e nejm.org 15
Our study has several limitations. First, the
protocol for the control group was changed half-
way through the trial. The lower intensity of
dietary intervention for the control group during
the first few years might have caused a bias to-
ward a benefit in the two Mediterranean-diet
groups, since the participants in these two groups
received a more intensive intervention during
that time. However, we found no significant in-
teraction between the period of trial enrollment
(before vs. after the protocol change) and the
benefit in the Mediterranean-diet groups. Sec-
ond, we had losses to follow-up, predominantly
in the control group, but the participants who
dropped out had a worse cardiovascular risk pro-
file at baseline than those who remained in the
study, suggesting a bias toward a benefit in the
control group. Third, the generalizability of our
findings is limited because all the study partici-
pants lived in a Mediterranean country and were
at high cardiovascular risk; whether the results
can be generalized to persons at lower risk or to
other settings requires further research.
As with many clinical trials, the observed rates
of cardiovascular events were lower than antici-
pated, with reduced statistical power to sepa-
rately assess components of the primary end
point. However, favorable trends were seen for
both stroke and myocardial infarction. We ac-
knowledge that, even though participants in the
control group received advice to reduce fat in-
take, changes in total fat were small and the
largest differences at the end of the trial were in
the distribution of fat subtypes. The interventions
were intended to improve the overall dietary pat-
tern, but the major between-group differences
involved the supplemental items. Thus, extra-
virgin olive oil and nuts were probably respon-
sible for most of the observed benefits of the
Mediterranean diets. Differences were also ob-
served for fish and legumes but not for other
food groups. The small between-group differ-
ences in the diets during the trial are probably
due to the facts that for most trial participants
the baseline diet was similar to the trial Mediter-
ranean diet and that the control group was given
recommendations for a healthy diet, suggesting
a potentially greater benefit of the Mediterra-
nean diet as compared with Western diets.
In conclusion, in this primary prevention trial,
we observed that an energy-unrestricted Medi-
terranean diet, supplemented with extra-virgin
nejm.org april 4, 2013
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16 nejm readers’ choice clinical care collection
Mediterr anean Diet and Cardiovascular Events

olive oil or nuts, resulted in a substantial reduc-
tion in the risk of major cardiovascular events
among high-risk persons. The results support
the benefits of the Mediterranean diet for the
primary prevention of cardiovascular disease.
Supported by the official funding agency for biomedical re-
search of the Spanish government, Instituto de Salud Carlos III
(ISCIII), through grants provided to research networks specifi-
cally developed for the trial (RTIC G03/140, to Dr. Estruch; RTIC
RD 06/0045, to Dr. Martínez-González and through Centro de
Investigación Biomédica en Red de Fisiopatología de la Obesi-
dad y Nutrición [CIBERobn]), and by grants from Centro Nacio-
nal de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo
de Investigación Sanitaria–Fondo Europeo de Desarrollo Re-
gional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138,
PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and
P11/02505), Ministerio de Ciencia e Innovación (AGL-2009-
13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010,
Consejería de Salud de la Junta de Andalucía (PI0105/2007), Pub-
lic Health Division of the Department of Health of the Auto-
nomous Government of Catalonia, Generalitat Valenciana
(ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, CS2010-
AP-111, and CS2011-AP-042), and Regional Government of Na-
varra (P27/2011).
Dr. Estruch reports serving on the board of and receiving
lecture fees from the Research Foundation on Wine and Nutri-
tion (FIVIN); serving on the boards of the Beer and Health
Foundation and the European Foundation for Alcohol Research
(ERAB); receiving lecture fees from Cerveceros de España and
Sanofi-Aventis; and receiving grant support through his institu-
tion from Novartis. Dr. Ros reports serving on the board of and
receiving travel support, as well as grant support through his
institution, from the California Walnut Commission; serving on
the board of the Flora Foundation (Unilever); serving on the
board of and receiving lecture fees from Roche; serving on the
board of and receiving grant support through his institution
from Amgen; receiving consulting fees from Damm and Abbott
Laboratories; receiving consulting fees and lecture fees, as well
as grant support through his institution, from Merck; receiving
lecture fees from Danone, Pace, AstraZeneca, and Rottapharm;
receiving lecture fees and payment for the development of edu-
cational presentations, as well as grant support through his in-
stitution, from Ferrer; receiving payment for the development of
educational presentations from Recordati; and receiving grant
support through his institution from Sanofi-Aventis, Takeda,
Daiichi Sankyo, Nutrexpa, Feiraco, Unilever, and Karo Bio. Dr.
Salas-Salvadó reports serving on the board of and receiving grant
support through his institution from the International Nut and
Dried Fruit Council; receiving consulting fees from Danone;
and receiving grant support through his institution from Eroski
and Nestlé. Dr. Arós reports receiving payment for the develop-
ment of educational presentations from Menarini and AstraZeneca.
Dr. Lamuela-Raventos reports serving on the board of and re-
ceiving lecture fees from FIVIN; receiving lecture fees from
Cerveceros de España; and receiving lecture fees and travel sup-
port from PepsiCo. Dr. Serra-Majem reports serving on the
boards of the Mediterranean Diet Foundation and the Beer and
Health Foundation. Dr. Pintó reports serving on the board of
and receiving grant support through his institution from the
Residual Risk Reduction Initiative (R3i) Foundation; serving on
the board of Omegafort; serving on the board of and receiving
payment for the development of educational presentations, as
well as grant support through his institution, from Ferrer; re-
ceiving consulting fees from Abbott Laboratories; receiving lec-
ture fees, as well as grant support through his institution, from
Merck and Roche; receiving lecture fees from Danone and Esteve;
receiving payment for the development of educational presenta-
tions from Menarini; and receiving grant support through his
institution from Sanofi-Aventis, Kowa, Unilever, Boehringer
Ingelheim, and Karo Bio. No other potential conflict of interest
relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the participants in the trial for their enthusiastic
and sustained collaboration and Joan Vila from Institut Munici-
pal d’Investigació Mèdica, Barcelona, for expert assessment in
the statistical analyses.

appendix
The author’s affiliations are as follows: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (R.E.,
E.R., J.S.-S., M.-I.C., D.C., M.F., J.L., R.M.L.-R., J.B., J.V.S., J.A.M.) and the PREDIMED (Prevención con Dieta Mediterránea) Network
(RD 06/0045) (R.E., J.S.-S., F.A., E.G.-G., V.R.-G., R.M.L.-R., L.S.-M., X.P., J.B., J.V.S., J.A.M., M.A.M.-G.), Instituto de Salud Carlos
III, Madrid; the Department of Internal Medicine (R.E.) and Lipid Clinic, Department of Endocrinology and Nutrition (E.R.), Institut
d’Investigacions Biomèdiques August Pi I Sunyer, Hospital Clinic, University of Barcelona, Barcelona; Human Nutrition Department,
Hospital Universitari Sant Joan, Institut d’Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus (J.S.-S.); Cardiovascular
and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona (M.-I.C.); the Department of Preventive Medicine, Uni-
versity of Valencia, Valencia (D.C.); the Department of Cardiology, University Hospital of Alava, Vitoria (F.A.); the Department of Preven-
tive Medicine, University of Malaga, Malaga (E.G.-G.); Instituto de la Grasa, Consejo Superior de Investigaciones Cientificas, Seville
(V.R.-G.); Institute of Health Sciences (IUNICS), University of Balearic Islands, and Hospital Son Espases, Palma de Mallorca (M.F.);
the Department of Family Medicine, Primary Care Division of Seville, San Pablo Health Center, Seville (J.L.); the Department of Nutrition
and Food Science, School of Pharmacy, Xarxa de Referència en Tecnologia dels Aliments, Instituto de Investigación en Nutrición y Se-
guridad Alimentaria, University of Barcelona, Barcelona (R.M.L.-R.); the Department of Clinical Sciences, University of Las Palmas de
Gran Canaria, Las Palmas (L.S.-M.); Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de
Llobregat, Barcelona (X.P.); Primary Care Division, Catalan Institute of Health, Institut d’Investigació en Atenció Primària Jordi Gol,
Tarragona-Reus (J.B.) and Barcelona (M.A.M.); Primary Care Division, Valencia Institute of Health, Valencia (J.V.S.); and the Depart-
ments of Nutrition and Food Sciences, Physiology and Toxicology (J.A.M.) and Preventive Medicine and Public Health (M.A.M.-G.),
University of Navarra, Pamplona — all in Spain.

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Giugliano D. Prevention and control of
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Copyright © 2013 Massachusetts Medical Society.
18 nejm readers’ choice clinical care collection
Donor-Feces Infusion for Recurrent C. difficile

ORIGINAL ARTICLE

Duodenal Infusion of Donor Feces for Recurrent

Clostridium difficile
Els van Nood, M.D., Anne Vrieze, M.D., Max Nieuwdorp, M.D., Ph.D., Susana Fuentes, Ph.D.,
Erwin G. Zoetendal, Ph.D., Willem M. de Vos, Ph.D., Caroline E. Visser, M.D., Ph.D., Ed J. Kuijper, M.D., Ph.D.,
Joep F.W.M. Bartelsman, M.D., Jan G.P. Tijssen, Ph.D., Peter Speelman, M.D., Ph.D.,
Marcel G.W. Dijkgraaf, Ph.D., and Josbert J. Keller, M.D., Ph.D.

A bs t r ac t

Background
Recurrent Clostridium difficile infection is difficult to treat, and failure rates for anti- From the Departments of Internal Medi-
biotic therapy are high. We studied the effect of duodenal infusion of donor feces cine (E.N., A.V., M.N., P.S.), Microbiology
(C.E.V.), Gastroenterology (J.F.W.M.B.,
in patients with recurrent C. difficile infection. J.J.K.), and Cardiology (J.G.P.T.) and the
Clinical Research Unit (M.G.W.D.), Aca-
Methods demic Medical Center, University of Am-
sterdam, Amsterdam; the Laboratory of
We randomly assigned patients to receive one of three therapies: an initial vanco- Microbiology, Wageningen University,
mycin regimen (500 mg orally four times per day for 4 days), followed by bowel Wageningen (S.F., E.G.Z., W.M.V.); the
lavage and subsequent infusion of a solution of donor feces through a nasoduode- Department of Experimental and Medical
Microbiology, Leiden University Medical
nal tube; a standard vancomycin regimen (500 mg orally four times per day for Center, Leiden (E.J.K.); and the Department
14 days); or a standard vancomycin regimen with bowel lavage. The primary end of Gastroenterology, Hagaziekenhuis, The
point was the resolution of diarrhea associated with C. difficile infection without Hague (J.J.K.) — all in the Netherlands;
and the Department of Bacteriology and
relapse after 10 weeks. Immunology, Medical Faculty, University
of Helsinki, Helsinki (W.M.V.). Address
Results reprint requests to Dr. Keller at the Aca-
demic Medical Center, Department of
The study was stopped after an interim analysis. Of 16 patients in the infusion Gastroenterology, Meibergdreef 9, 1105
group, 13 (81%) had resolution of C. difficile–associated diarrhea after the first infu- AZ Amsterdam, the Netherlands, or at
sion. The 3 remaining patients received a second infusion with feces from a differ- keller@hagaziekenhuis.nl.

ent donor, with resolution in 2 patients. Resolution of C. difficile infection occurred This article was published on January 16,
in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) 2013, at NEJM.org.
receiving vancomycin with bowel lavage (P<0.001 for both comparisons with the N Engl J Med 2013;368:407-15.
infusion group). No significant differences in adverse events among the three study DOI: 10.1056/NEJMoa1205037
groups were observed except for mild diarrhea and abdominal cramping in the in- Copyright © 2013 Massachusetts Medical Society.

fusion group on the infusion day. After donor-feces infusion, patients showed in-
creased fecal bacterial diversity, similar to that in healthy donors, with an increase
in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in
Proteobacteria species.

Conclusions
The infusion of donor feces was significantly more effective for the treatment of
recurrent C. difficile infection than the use of vancomycin. (Funded by the Nether-
lands Organization for Health Research and Development and the Netherlands
Organization for Scientific Research; Netherlands Trial Register number, NTR1177.)

n engl j med 368;5 nejm.org january 31, 2013 407

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 The n e w e ng l a n d j o u r na l
A
ntibiotic treatment for an initial
Clostridium difficile infection typically does
not induce a durable response in approxi-
mately 15 to 26% of patients.1-3 An effective
treatment against recurrent C. difficile infection is
not available. Generally, repeated and extended
courses of vancomycin are prescribed.4 The esti-
mated efficacy of antibiotic therapy for a first
recurrence is 60%, a proportion that further de-
clines in patients with multiple recurrences.2,5-7
Mechanisms that have been proposed for recur-
rence include persistence of spores of C. difficile,
diminished antibody response to clostridium tox-
ins, and persistent disturbance with a reduced di-
versity of intestinal microbiota.8-12
Infusion of feces from healthy donors has
been reported as an effective treatment for recur-
rent C. difficile infection in more than 300 pa-
tients.13-18 However, experience with this proce-
dure is limited by a lack of randomized trials
supporting its efficacy and the unappealing na-
ture of the treatment. In this study, donor feces
were infused in patients with recurrent C. difficile
infection and compared with conventional 14-day
vancomycin treatment, with and without bowel
lavage.
Me thods
Study Design
The complete methods are included in the Sup-
plementary Appendix, which along with the re-
search protocol is available with the full text of
this article at NEJM.org.
In this open-label, randomized, controlled trial,
we compared three treatment regimens: the in-
fusion of donor feces preceded by an abbreviated
regimen of vancomycin and bowel lavage, a stan-
dard vancomycin regimen, and a standard van-
comycin regimen with bowel lavage.
The study was conducted at the Academic
Medical Center in Amsterdam. Patients who had
been admitted to referring hospitals were visited
by the study physicians, who performed the ran-
domization. All participants provided written in-
formed consent. A data and safety monitoring
board monitored the trial on an ongoing basis.
The research protocol was approved by the ethics
committee at the Academic Medical Center. The
first and last two authors vouch for the accuracy
and completeness of the reported data and for
the fidelity of the report to the study protocol.
08 n engl j med 368;5
of m e dic i n e nejm.org 19
Study Population
Included in the study were patients who were at
least 18 years of age and who had a life expectancy
of at least 3 months and a relapse of C. difficile in-
fection after at least one course of adequate antibi-
otic therapy (≥10 days of vancomycin at a dose of
≥125 mg four times per day or ≥10 days of metro-
nidazole at a dose of 500 mg three times per day).
C. difficile infection was defined as diarrhea (≥3
loose or watery stools per day for at least 2 con-
secutive days or ≥8 loose stools in 48 hours) and
a positive stool test for C. difficile toxin. Available
isolates were characterized by polymerase-chain-
reaction (PCR) ribotyping.19
Exclusion criteria were prolonged compromised
immunity because of recent chemotherapy, the
presence of human immunodeficiency virus (HIV)
infection with a CD4 count of less than 240, or
prolonged use of prednisolone at a dose of at
least 60 mg per day; pregnancy; use of antibiot-
ics other than for treatment of C. difficile infection
at baseline; admission to an intensive care unit; or
need for vasopressor medication.
Treatments
Patients received an abbreviated regimen of van-
comycin (500 mg orally four times per day for 4 or
5 days), followed by bowel lavage with 4 liters of
macrogol solution (Klean-Prep) on the last day of
antibiotic treatment and the infusion of a suspen-
sion of donor feces through a nasoduodenal tube
the next day; a standard vancomycin regimen
(500 mg orally four times per day for 14 days); or
a standard vancomycin regimen with bowel lavage
on day 4 or 5. Patients in whom recurrent C. difficile
infection developed after the first donor-feces in-
fusion were given a second infusion with feces
from a different donor. Patients in whom antibi-
otic therapy failed were offered treatment with
donor feces off protocol.
Infusion of Donor Feces
Donors (<60 years of age) were volunteers who
were initially screened using a questionnaire ad-
dressing risk factors for potentially transmissible
diseases. Donor feces were screened for parasites
(including Blastocystis hominis and Dientamoeba fra-
gilis), C. difficile, and enteropathogenic bacteria.
Blood was screened for antibodies to HIV; human
T-cell lymphotropic virus types 1 and 2; hepatitis
A, B, and C; cytomegalovirus; Epstein–Barr virus;
Treponema pallidum; Strongyloides stercoralis; and Ent-
nejm.org january 31, 2013
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20 nejm readers’ choice clinical care collection
Donor-Feces Infusion for Recurrent C. difficile
amoeba histolytica. A donor pool was created, and
screening was repeated every 4 months. Before
donation, another questionnaire was used to
screen for recent illnesses.
Feces were collected by the donor on the day
of infusion and immediately transported to the
hospital. Feces were diluted with 500 ml of ster-
ile saline (0.9%). This solution was stirred, and
the supernatant strained and poured in a sterile
bottle. Within 6 hours after collection of feces
by the donor, the solution was infused through
a nasoduodenal tube (2 to 3 minutes per 50 ml).
The tube was removed 30 minutes after the infu-
sion, and patients were monitored for 2 hours.
For patients who had been admitted at referring
hospitals, the donor-feces solution was produced
at the study center and immediately transported
and infused by a study physician.
Outcomes
The primary end point was cure without relapse
within 10 weeks after the initiation of therapy.
For patients in the infusion group who required
a second infusion of donor feces, follow-up was
extended to 10 weeks after the second infusion.
The secondary end point was cure without relapse
after 5 weeks. Cure was defined as an absence of
diarrhea or persistent diarrhea that could be ex-
plained by other causes with three consecutive
negative stool tests for C. difficile toxin. Relapse
was defined as diarrhea with a positive stool test
for C. difficile toxin. An adjudication committee
whose members were unaware of study-group
assignments decided which patients were cured.
Patients kept a stool diary and were ques-
tioned about stool frequency and consistency,
medication use, and adverse effects on days 7,
14, 21, 35, and 70 after the initiation of vanco-
mycin. Stool tests for C. difficile toxin were per-
formed in a central laboratory (Premier Toxins
A&B, Meridian Bioscience) on days 14, 21, 35,
and 70 and whenever diarrhea occurred.
Analysis of Fecal Microbiota
We analyzed the fecal microbiota for bacterial
diversity by extracting DNA from samples from
patients before and after donor-feces infusion
and from the respective donor samples.20 We
then characterized 16S ribosomal RNA gene am-
plicons using the Human Intestinal Tract Chip
(HITChip), a phylogenetic microarray, as described
previously.21 We estimated the diversity of the
n engl j med 368;5
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bacterial communities before and after donor-
feces infusion using Simpson’s Reciprocal Index of
diversity,22 on a scale ranging from 1 to 250, with
higher values indicating greater diversity.
Statistical Analysis
The objective was to determine the superiority of
donor-feces infusion, as compared with vanco-
mycin, both without and with bowel lavage. A
cure rate of 90% for donor-feces infusion13,14 and
of 60% for antibiotic therapy2,6 was assumed. Per
group, 38 patients were needed to achieve a pow-
er of 80% to detect a difference between groups
with a one-sided level of significance of 0.025. To
account for dropouts, we planned to enroll 40 pa-
tients per group. All analyses were performed on
a modified intention-to-treat basis with the ex-
clusion of one patient who required high-dose
prednisolone treatment after randomization but
before the study treatment was initiated. Differ-
ences in cure rates were assessed with Fisher’s
exact probability test. Since the trial was termi-
nated early according to the Haybittle–Peto rule
(i.e., P<0.001 for the primary end point), rate ra-
tios for the primary end point (overall cure) were
calculated with their exact 99.9% confidence in-
terval.
On the basis of Simpson’s Reciprocal Index of
diversity,22 the statistical significance of a change
in microbiota diversity was assessed with the use
of a paired-samples Student t-test. A principal
component analysis was performed on profiles
derived from the HITChip phylogenetic microar-
ray.21 Wilcoxon signed-rank tests were performed
with the application of the Benjamini–Hochberg
approach to determine microbial groups that
were significantly different in matched pairs of
fecal samples obtained from patients before and
after infusion.23
R e sult s
Patients and Termination of the Trial
From January 2008 through April 2010, a total of
43 patients were randomly assigned to receive
donor-feces infusion (17 patients), vancomycin
(13), or vancomycin and bowel lavage (13). Ini-
tially, the inclusion of 40 patients per study group
was planned. Because most patients in both con-
trol groups had a relapse, the data and safety
monitoring board performed the interim efficacy
analysis and advised termination of the trial, as
nejm.org january 31, 2013 40
 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 21

described in the Supplementary Appendix. At that
time, 43 patients were included, with one of them
subsequently excluded from further analysis (Ta-
ble 1 and Fig. 1). In 39 patients, a positive toxin
test before inclusion was confirmed by a positive
C. difficile culture. PCR ribotyping was performed
on strains obtained from 34 patients (see the
Supplementary Appendix).
Forty-one patients completed the study proto-
col. One patient in the vancomycin-only group
was discharged home from the hospital after the
initiation of vancomycin. At home, the patient
decided to discontinue all medication because of
severe heart failure and chronic obstructive pul-
monary disease and died 13 days after random-
ization, without providing data on response. In
the intention-to-treat analysis, vancomycin ther-
apy was considered to have failed in this patient.
Another patient in the infusion group required
high-dose prednisolone because of a rapid de-
crease in renal-graft function. The patient had
received a renal transplant from an unrelated do-
nor 11 months before study enrollment, and graft
dysfunction was noted immediately after ran-
domization but before the study treatment was
initiated. At that time, the nephrologist objected

Table 1. Baseline Demographic and Clinical Characteristics of the Patients.*

Donor-Feces Vancomycin and

Infusion Vancomycin Only Bowel Lavage
Characteristic (N = 16) (N = 13) (N = 13) P Value†
Age — yr 73±13 66±14 69±16 0.39
Body-mass index‡ 22±3 22±4 24±4 0.41
Female sex — no. (%) 8 (50) 7 (54) 3 (23) 0.22
Karnofsky performance status§ 50±18 50±17 56±21 0.62
Median Charlson comorbidity index (range) — score¶ 3 (0–4) 1 (0–8) 1 (0–6) 0.53
Median recurrences of CDI (range) — no. 3 (1–5) 3 (1–4) 2 (1–9) 0.69
Previous failure of tapered vancomycin therapy — no. (%) 10 (62) 8 (62) 6 (46) 0.63
Reported antibiotic use before CDI — no. (%) 16 (100) 12 (92) 13 (100) 0.62
Hospital-acquired CDI infection — no. (%) 10 (62) 6 (46) 10 (77) 0.27
Admitted to a hospital at study inclusion — no. (%) 5 (31) 4 (31) 4 (31) 1.00
Days of antibiotic use for CDI since first diagnosis — no.‖ 63±41 51±27 49±38 0.56
Use of proton-pump inhibitor — no. (%) 13 (81) 10 (77) 11 (85) 0.88
ICU admission in preceding month — no. (%) 1 (6) 0 1 (8) 1.00
Feeding tube present — no. (%) 3 (19) 2 (15) 2 (15) 0.96
Median stool frequency per 24 hr (range) — no. 5 (3–20) 5 (3–12) 5 (3–10) 0.72
Leukocyte count — per mm3**
Median 8000 8100 6500 0.39
Range 4000–15,000 4000–23,000 3000–14,000
Albumin — g/dl** 3.7±0.7 3.8±0.7 3.9±0.8 0.66
Median creatinine (range) — mg/dl** 1.3 (0.6–10.3) 1.0 (0.5–1.8) 0.9 (0.6–5.2) 0.26
Ribotype 027 in first sample — no. (%)†† 3 (23) 1 (11) 0 0.28

* Plus–minus values are means ±SD. To convert the values for creatinine to micromoles per liter, multiply by 88.4. CDI denotes Clostridium
difficile infection, and ICU intensive care unit.
† P values are for the overall comparison among the three groups.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ The Karnofsky performance status ranges from 0 to 100, with higher scores indicating improved functional status.
¶ Scores on the Charlson comorbidity index range from 0 to 6 for each of 17 indicators, with higher scores indicating greater severity of illness.
‖ Data were missing for one patient in the infusion group and one in the vancomycin-only group.
** Data were missing for one patient in the vancomycin-only group.
†† Data for ribotype 027 (a more virulent strain of C. difficile) were missing for three patients in the infusion group, four in the vancomycin-
only group, and two in the group receiving vancomycin with bowel lavage.

410 n engl j med 368;5 nejm.org january 31, 2013

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22 nejm readers’ choice clinical care collection
Donor-Feces Infusion for Recurrent C. difficile

102 Patients were assessed for eligibility

or their treating physicians contacted
the study center

49 Were excluded
2 Were pregnant
2 Were admitted to the intensive care unit
2 Had life expectancy <3 mo
3 Were immunocompromised
8 Were not able to give informed consent
1 Was allergic to vancomycin
31 Did not meet criteria of both diarrhea and
positive stool toxin for Clostridium difficile
10 Declined to participate

43 Underwent randomization

17 Were assigned to receive 13 Were assigned to receive 13 Were assigned to receive

donor-feces infusion vancomycin vancomycin and bowel lavage

1 Was excluded 1 Died

16 Completed evaluation 12 Completed evaluation 13 Completed evaluation

Figure 1. Enrollment and Outcomes.

After randomization, one patient in the infusion group required high-dose prednisolone because of a rapid decrease
in renal-graft function that was noted immediately after randomization but before the study treatment was initiated.
This patient was excluded from the analysis. One patient in the vancomycin-only group died before the first stool
sample could be tested for the presence of Clostridium difficile toxin.

to treatment with donor feces. The patient was Study Outcomes

treated with vancomycin for 45 days, had a re-
currence 41 days after cessation of vancomycin,
and was subsequently cured by donor-feces infu-
sion. This patient was excluded from the analysis
because of a clinically driven protocol deviation,
which meant that the patient’s response to treat-
ment could not be evaluated.
Donors
Of 77 candidates, 25 donors were approved (see
the Supplementary Appendix for results of donor
screening). Feces from 15 donors were used for
43 infusions in the infusion group and for pa-
tients who had a relapse after vancomycin treat-
ment. A mean (±SD) of 141±71 g of feces was in-
fused. The mean time from defecation to infusion
was 3.1±1.9 hours.
Of 16 patients in the infusion group, 13 (81%)
were cured after the first infusion of donor feces.
The 3 remaining patients received a second infu-
sion with feces from a different donor at 14, 50,
and 53 days after randomization; of these pa-
tients, 2 were subsequently cured. Overall, donor
feces cured 15 of 16 patients (94%). Resolution of
infection occurred in 4 of 13 patients (31%) in
the vancomycin-alone group and in 3 of 13 pa-
tients (23%) in the group receiving vancomycin
with bowel lavage. Donor-feces infusion was sta-
tistically superior to both vancomycin regimens
(P<0.01 for both comparisons after the first infu-
sion and P<0.001 for overall cure rates) (Fig. 2).
The overall cure rate ratio of donor-feces infusion
was 3.05 as compared with vancomycin alone
(99.9% confidence interval [CI], 1.08 to 290.05)

n engl j med 368;5 nejm.org january 31, 2013 41

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 23

Table 2. Adverse Events in 16 Patients in the Infusion

P<0.001 Group.*

P<0.001 On Day of Infusion During

Adverse Event of Donor Feces Follow-up
P=0.008
no. of events
P=0.003 Belching 3 0
100 Nausea 1 0
93.8
Vomiting 0 0
Percentage Cured without Relapse

90
81.3
80
70
60
50
40
30.8
30
23.1
20
10
0 Other adverse event
First Infusion Infusion of Donor Vancomycin Vancomycin with
of Donor Feces Feces Overall (N=13) Bowel Lavage
(N=16) (N=16) (N=13)
Figure 2. Rates of Cure without Relapse for Recurrent Clostridium difficile
Infection.
Shown are the proportions of patients who were cured by the infusion of
donor feces (first infusion and overall results), by standard vancomycin
therapy, and by standard vancomycin therapy plus bowel lavage.
and 4.05 as compared with vancomycin with
bowel lavage (99.9% CI, 1.21 to 290.12).
The median time to recurrence was 23 days
(range, 13 to 43) after the initiation of vancomy-
cin alone and 25 days (range, 18 to 70) after the
initiation of vancomycin with bowel lavage. Five
weeks after the initiation of therapy, there was a
recurrence of infection in 1 of 16 patients (6%)
in the infusion group, 8 of 13 (62%) in the van-
comycin-alone group, and 7 of 13 (54%) in the
group receiving vancomycin with bowel lavage.
Fourteen patients who were cured reported
having diarrhea during follow-up; these episodes
were short and self-limited in 10 patients. Three
patients had a preexistent defecation frequency
of at least three stools per day, a frequency that was
markedly increased during episodes with C. dif-
ficile infection and returned to normal after donor-
feces infusion. In these patients, toxin tests were
repeatedly negative, and there was no clinical
suspicion of recurrence. One patient in the van-
comycin-only group had persistent diarrhea,
with repeatedly negative toxin tests; this patient
was considered to have had a response, although
there was clinical suspicion of recurrence.
Abdominal cramps 5 0
Diarrhea 15 0
Constipation 0 3
Abdominal pain 2 (associated with 0
cramping)
Infection 0 2†
Hospital admission NA 1‡
Death 0 0
1§ 1‡
* Adverse events that were reported on the day of donor-
feces infusion and those that were reported during follow-
up are listed separately. NA denotes not applicable.
† During follow-up, one patient with recurrent urinary tract
infections had a urinary tract infection for which antibiotics
were prescribed. Another patient had fever during hemo-
dialysis for which antibiotics were prescribed; cultures
remained negative.
‡ On day 56, one patient was hospitalized for symptomatic
choledocholithiasis, for which endoscopic retrograde
cholangiopancreatography and stone extraction were per-
formed.
§ One patient with autonomic dysfunction had dizziness
combined with diarrhea after donor-feces infusion.
Eighteen patients who had a relapse after ini-
tial antibiotic treatment received off-protocol do-
nor-feces infusions; of these patients, 15 (83%)
were cured. Eleven patients were cured after one
donor-feces infusion, and 4 patients were cured
after a second infusion.
Adverse Events
A complete description of adverse events is includ-
ed in the Supplementary Appendix. Immediately
after donor-feces infusion, most patients (94%)
had diarrhea. In addition, cramping (31%) and
belching (19%) were reported (Table 2). In all pa-
tients, these symptoms resolved within 3 hours.
During follow-up, three patients who were treat-
ed with donor feces (19%) had constipation. No
other adverse events related to study treatment
were reported. The death of one patient from se-
vere heart failure and chronic obstructive pulmo-
nary disease in the vancomycin-only group was
considered to be unrelated to the study drug.

412 n engl j med 368;5 nejm.org january 31, 2013

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24 nejm readers’ choice clinical care collection
Donor-Feces Infusion for Recurrent C. difficile

Fecal Microbiota
The Simpson’s Reciprocal Index of diversity of fe- 250
cal microbiota obtained from nine patients who
were evaluated before the donor-feces infusion 200

Simpson’s Reciprocal Index

was consistently low (mean, 57±26) and increased
within 2 weeks after infusion to 179±42 (P<0.001), 150
becoming undistinguishable from the fecal mi-
crobiota diversity level of the donors (mean,
100
172±54) (Fig. 3). In eight patients for whom sam-
ples were available, the diversity of fecal micro-
biota remained undistinguishable from that of 50

the donor during follow-up.

In addition, a principal component analysis 0
Donors Patients before Patients after
was performed on the phylogenetic microarray Infusion Infusion
profiles of each sample. This unsupervised anal-
ysis showed that nearly 50% of the variation in Figure 3. Microbiota Diversity in Patients before and
the data was explained by the first two principal after Infusion of Donor Feces, as Compared with
Diversity in Healthy Donors.
components, indicating a major shift in the pa-
Microbiota diversity is expressed as Simpson’s Recip-
tients’ microbiota after donor-feces infusion to- rocal Index of diversity in fecal samples obtained from
ward that of the donors (Fig. S2 in the Supple- nine patients before and 14 days after the first infusion
mentary Appendix). of donor feces, as compared with their donors. The in-
After donor-feces infusion, we observed dex ranges from 1 to 250, with higher values indicating
quantitative changes in relevant groups of intes- more diversity. The box-and-whisker plots indicate in-
terquartile ranges (boxes), medians (dark horizontal
tinal bacteria (P<0.05) (Table S2 in the Supple- lines in the boxes), and highest and lowest values
mentary Appendix). These changes included in- (whiskers above and below the boxes).
creased numbers of Bacteroidetes species and of
clostridium clusters IV and XIVa (by a factor of
2 to 4 for both groups) and decreased numbers ing additional antibiotics to treat infections oth-
of Proteobacteria (by a factor of up to 100). er than C. difficile because it seems reasonable to
postpone donor-feces infusion until antibiotics
Discussion can be stopped, enabling colonization of the
bowel with healthy donor feces.
In this small, open-label, randomized, controlled Although our study was designed for patients
trial, we found that the infusion of donor feces is with any recurrence of C. difficile infection, only
a potential therapeutic strategy against recurrent 8 of 43 patients were included after a first re-
C. difficile infection. Our study population of lapse, reflecting the reluctance of patients and
mainly elderly patients reflects the population in physicians to choose donor-feces infusion at an
whom C. difficile infection develops in daily prac- early stage. The efficacy of antibiotic therapy de-
tice. However, we excluded three groups of pa- creases with subsequent recurrences, and it seems
tients at risk for recurrent C. difficile infection. reasonable to initiate treatment with donor-feces
Patients with prolonged immunodeficiency were infusion after the second or third relapse. It has
excluded to prevent the potential translocation of yet to be established whether other promising
infused intestinal bacteria. Infectious complica- treatment strategies, such as fidaxomycin or infu-
tions were not observed after donor infusion in sion of antibodies against clostridium toxins,3,27
our study and have not been reported in the lit- are effective against recurrent C. difficile infection.
erature.15 Also, critically ill patients who were The power calculation of our study was based
admitted to an intensive care unit (ICU) were ex- on the efficacy of vancomycin for a first recur-
cluded. However, C. difficile infection in the ICU is rence of C. difficile infection. Because most pa-
associated with high death rates,24 and anecdotal tients had several relapses before inclusion in
reports have shown promising results of donor- the study (typically, after a failure of vancomycin
feces infusion in critically ill patients.25,26 The therapy), the efficacy of vancomycin in our study
third excluded group comprised patients requir- was considerably lower than expected, which prob-

n engl j med 368;5 nejm.org january 31, 2013 41

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 25

ably contributed to the findings of a difference
between study groups. At study termination, 16
patients had been treated with donor-feces infu-
sion. The success rate of donor-feces infusion was
extended off protocol in another 18 patients who
had initially been assigned to receive antibiotic
therapy. A prolonged tapering schedule of vanco-
mycin may be prescribed for recurrent C. difficile
infection and was not incorporated into the trial
for practical reasons. This may be a limitation of
our study, although 56% of the patients were un-
successfully treated with prolonged and tapering
vancomycin schedules before inclusion.
Several questions remain unanswered. The op-
timal protocol for donor-feces infusion is un-
known. We pretreated patients with vancomycin
and bowel lavage, following a protocol that was
effective in previously published case series.15,28
Bowel lavage was incorporated to reduce the
pathogenic bowel content, facilitating coloniza-
tion of healthy donor microbiota. Whether bowel
lavage indeed contributes to the efficacy of do-
nor-feces infusion is not known.29 However, the
possibility that bowel lavage itself cures C. diffi-
cile is unlikely, since no benefit was seen in the
second control group, in whom vancomycin was
combined with bowel lavage. Furthermore, the
amount of feces required and the importance of
varying potential routes of infusion (nasoduode-
nal tube, enema, or colonoscopy) are unknown
since the literature reports many different treat-
ment protocols.15,18,30 In our study, infusion of a
relatively large amount of feces through a naso-
duodenal tube had an acceptable adverse-event
profile and was logistically manageable.
The mechanism underlying the efficacy of
donor-feces infusion is probably the reestablish-
ment of the normal microbiota as a host defense
against C. difficile.31 Changes in the gut bacterial
phyla Firmicutes and Bacteroidetes were associ-
ated with C. difficile infection.31,32 We found that
the fecal microbiota in patients with C. difficile
infection had a reduced bacterial diversity, as com-
pared with healthy persons, extending previous
observations.12 Infusion of donor feces resulted
in improvement in the microbial diversity, which
persisted over time. Also, there was an increase
in Bacteroidetes species and clostridium clusters
IV and XIVa (Firmicutes), whereas Proteobacteria
species decreased.
In conclusion, in patients with recurrent C. dif-
ficile infection, the infusion of donor feces, as
compared with vancomycin therapy, resulted in
better treatment outcomes. In particular, patients
with multiple relapses of C. difficile infection ben-
efited from this unconventional approach.
Supported by grants from the Netherlands Organization for
Health Research and Development (ZonMW, 170881001; VENI
grant, MN: 016096044) and a Spinoza Award (to Dr. de Vos)
from the Netherlands Organization for Scientific Research.
Dr. van Nood reports receiving lecture fees from Astellas;
Drs. Kuijper, Speelman, and Keller, serving on an advisory
board for and receiving consulting fees from Astellas; and Drs.
Kuijper and Keller, serving on an advisory board for and receiv-
ing consulting fees from Microbex. No other potential conflict
of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Hans Zaaijer and Tom van Gool for their contribu-
tion to the donor screening; the European Study Group of Clos-
tridium difficile for their support; Jeroen Jansen, Martijn Bauer,
Jeanin van Hooft, Hanke Wattel, Wim Meijer, Jan Veenstra, An-
nekatrien Depla, Ser Peters, Gitte van Twillert, Marcel Spanier,
Michiel van Agtmael, Reindert Vermeijden, Gerard van Asselt,
Oanh Thang, and all other participating doctors in the referring
hospitals; Paul Fockens, Jan van der Meer, Harry Buller, Zinzi
Hegeman, Rob Weijts, Isaie Reuling, Iuke Douwes Dekker, Men-
no Vergeer, Wim Nicolaas, and Vanessa Harris for their contri-
bution to the study; Philippe Puylaert and Wilma Akkermans-
van Vliet for their assistance in the microbiota analysis; and
Frank Giardiello, Johan Offerhaus, and Marcel Levi for review-
ing a previous draft of the manuscript.

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From the CRISMA (Clinical Research, Inves-
tigation, and Systems Modeling of Acute
Illness) Center, Department of Critical
Care Medicine, University of Pittsburgh
School of Medicine, Pittsburgh (D.C.A.);
and the Center for Experimental and Mo-
lecular Medicine, Division of Infectious
Diseases, and Center for Infection and
Immunity Amsterdam, Academic Medical
Center, University of Amsterdam, Am-
sterdam (T.P.). Address reprint requests
to Dr. Angus at the Department of Criti-
cal Care Medicine, University of Pitts-
burgh, 614 Scaife Hall, 3550 Terrace St.,
Pittsburgh, PA 15261, or at angusdc@
upmc.edu; or to Dr. van der Poll at the
Division of Infectious Diseases, Academ-
ic Medical Center, Meibergdreef 9, Rm.
G2-130, 1105 AZ Amsterdam, the Nether-
lands, or at t.vanderpoll@amc.uva.nl.
This article was updated on November
21, 2013, at NEJM.org.
N Engl J Med 2013;369:840-51.
DOI: 10.1056/NEJMra1208623
Copyright © 2013 Massachusetts Medical Society.
840
The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 27
review article
Critical Care Medicine
Simon R. Finfer, M.D., and Jean-Louis Vincent, M.D., Ph.D., Editors
Severe Sepsis and Septic Shock
Derek C. Angus, M.D., M.P.H., and Tom van der Poll, M.D., Ph.D.
S
epsis is one of the oldest and most elusive syndromes in medicine.
Hippocrates claimed that sepsis (σηψις)
´ was the process by which flesh rots,
swamps generate foul airs, and wounds fester.1 Galen later considered sepsis
a laudable event, necessary for wound healing.2 With the confirmation of germ
theory by Semmelweis, Pasteur, and others, sepsis was recast as a systemic infec-
tion, often described as “blood poisoning,” and assumed to be the result of the
host’s invasion by pathogenic organisms that then spread in the bloodstream.
However, with the advent of modern antibiotics, germ theory did not fully explain
the pathogenesis of sepsis: many patients with sepsis died despite successful erad-
ication of the inciting pathogen. Thus, researchers suggested that it was the host,
not the germ, that drove the pathogenesis of sepsis.3
In 1992, an international consensus panel defined sepsis as a systemic inflam-
matory response to infection, noting that sepsis could arise in response to mul-
tiple infectious causes and that septicemia was neither a necessary condition nor
a helpful term.4 Instead, the panel proposed the term “severe sepsis” to describe
instances in which sepsis is complicated by acute organ dysfunction, and they
codified “septic shock” as sepsis complicated by either hypotension that is refrac-
tory to fluid resuscitation or by hyperlactatemia. In 2003, a second consensus
panel endorsed most of these concepts, with the caveat that signs of a systemic
inflammatory response, such as tachycardia or an elevated white-cell count, occur
in many infectious and noninfectious conditions and therefore are not helpful in
distinguishing sepsis from other conditions.5 Thus, “severe sepsis” and “sepsis”
are sometimes used interchangeably to describe the syndrome of infection com-
plicated by acute organ dysfunction.
Incidence a nd C ause s
The incidence of severe sepsis depends on how acute organ dysfunction is defined
and on whether that dysfunction is attributed to an underlying infection. Organ
dysfunction is often defined by the provision of supportive therapy (e.g., mechani-
cal ventilation), and epidemiologic studies thus count the “treated incidence” rath-
er than the actual incidence. In the United States, severe sepsis is recorded in 2% of
patients admitted to the hospital. Of these patients, half are treated in the intensive
care unit (ICU), representing 10% of all ICU admissions.6,7 The number of cases in
the United States exceeds 750,000 per year7 and was recently reported to be rising.8
However, several factors — new International Classification of Diseases, 9th Revision
(ICD-9) coding rules, confusion over the distinction between septicemia and severe
sepsis, the increasing capacity to provide intensive care, and increased awareness
and surveillance — confound the interpretation of temporal trends.
Studies from other high-income countries show similar rates of sepsis in the
ICU.9 The incidence of severe sepsis outside modern ICUs, especially in parts of
n engl j med 369;9 nejm.org august 29, 2013
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28 nejm readers’ choice clinical care collection
critical care medicine
the world in which ICU care is scarce, is largely
unknown. Extrapolating from treated incidence
rates in the United States, Adhikari et al. estimated
up to 19 million cases worldwide per year.10 The
true incidence is presumably far higher.
Severe sepsis occurs as a result of both com-
munity-acquired and health care–associated in-
fections. Pneumonia is the most common cause,
accounting for about half of all cases, followed by
intraabdominal and urinary tract infections.7,8,11,12
Blood cultures are typically positive in only one
third of cases, and in up to a third of cases,
cultures from all sites are negative.7,11,13,14 Staphy-
lococcus aureus and Streptococcus pneumoniae are the
most common gram-positive isolates, whereas
Escherichia coli, klebsiella species, and Pseudomonas
aeruginosa predominate among gram-negative iso-
lates.11,14 An epidemiologic study of sepsis
showed that during the period from 1979 to
2000, gram-positive infections overtook gram-
negative infections.15 However, in a more recent
study involving 14,000 ICU patients in 75 coun-
tries, gram-negative bacteria were isolated in 62%
of patients with severe sepsis who had positive
cultures, gram-positive bacteria in 47%, and
fungi in 19%.12
Risk factors for severe sepsis are related both
to a patient’s predisposition for infection and to
the likelihood of acute organ dysfunction if in-
fection develops. There are many well-known risk
factors for the infections that most commonly
precipitate severe sepsis and septic shock, includ-
ing chronic diseases (e.g., the acquired immuno-
deficiency syndrome, chronic obstructive pul-
monary disease, and many cancers) and the use
of immunosuppressive agents.7 Among patients
with such infections, however, the risk factors
for organ dysfunction are less well studied but
probably include the causative organism and the
patient’s genetic composition, underlying health
status, and preexisting organ function, along
with the timeliness of therapeutic intervention.16
Age, sex, and race or ethnic group all influence
the incidence of severe sepsis, which is higher in
infants and elderly persons than in other age
groups, higher in males than in females, and
higher in blacks than in whites.7,17
There is considerable interest in the contribu-
tion of host genetic characteristics to the inci-
dence and outcome of sepsis, in part because of
strong evidence of inherited risk factors.18 Many
studies have focused on polymorphisms in genes
n engl j med 369;9
Back to Table of Contents
encoding proteins implicated in the pathogene-
sis of sepsis, including cytokines and other me-
diators involved in innate immunity, coagula-
tion, and fibrinolysis. However, findings are
often inconsistent, owing at least in part to the
heterogeneity of the patient populations stud-
ied.19,20 Although a recent genomewide associa-
tion study21 explored drug responsiveness in
sepsis, no such large-scale studies of susceptibil-
ity to or outcome of sepsis have been performed.
Cl inic a l Fe at ur e s
The clinical manifestations of sepsis are highly
variable, depending on the initial site of infec-
tion, the causative organism, the pattern of acute
organ dysfunction, the underlying health status
of the patient, and the interval before initiation
of treatment. The signs of both infection and or-
gan dysfunction may be subtle, and thus the
most recent international consensus guidelines
provide a long list of warning signs of incipient
sepsis (Table 1).5 Acute organ dysfunction most
commonly affects the respiratory and cardiovas-
cular systems. Respiratory compromise is classi-
cally manifested as the acute respiratory distress
syndrome (ARDS), which is defined as hypox-
emia with bilateral infiltrates of noncardiac ori-
gin.22 Cardiovascular compromise is manifested
primarily as hypotension or an elevated serum
lactate level. After adequate volume expansion,
hypotension frequently persists, requiring the
use of vasopressors, and myocardial dysfunction
may occur.23
The brain and kidneys are also often affected.
Central nervous system dysfunction is typically
manifested as obtundation or delirium. Imaging
studies generally show no focal lesions, and
findings on electroencephalography are usually
consistent with nonfocal encephalopathy. Criti-
cal illness polyneuropathy and myopathy are
also common, especially in patients with a pro-
longed ICU stay.24 Acute kidney injury is mani-
fested as decreasing urine output and an in-
creasing serum creatinine level and frequently
requires treatment with renal-replacement ther-
apy. Paralytic ileus, elevated aminotransferase
levels, altered glycemic control, thrombocytope-
nia and disseminated intravascular coagulation,
adrenal dysfunction, and the euthyroid sick syn-
drome are all common in patients with severe
sepsis.5
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Table 1. Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock.*

Sepsis (documented or suspected infection plus ≥1 of the following)†

General variables
Fever (core temperature, >38.3°C)
Hypothermia (core temperature, <36°C)
Elevated heart rate (>90 beats per min or >2 SD above the upper limit of the normal range for age)
Tachypnea
Altered mental status
Substantial edema or positive fluid balance (>20 ml/kg of body weight over a 24-hr period)
Hyperglycemia (plasma glucose, >120 mg/dl [6.7 mmol/liter]) in the absence of diabetes
Inflammatory variables
Leukocytosis (white-cell count, >12,000/mm3)
Leukopenia (white-cell count, <4000/mm3)
Normal white-cell count with >10% immature forms
Elevated plasma C-reactive protein (>2 SD above the upper limit of the normal range)
Elevated plasma procalcitonin (>2 SD above the upper limit of the normal range)
Hemodynamic variables
Arterial hypotension (systolic pressure, <90 mm Hg; mean arterial pressure, <70 mm Hg; or decrease in systolic
pressure of >40 mm Hg in adults or to >2 SD below the lower limit of the normal range for age)
Elevated mixed venous oxygen saturation (>70%)‡
Elevated cardiac index (>3.5 liters/min/square meter of body-surface area)§
Organ-dysfunction variables
Arterial hypoxemia (ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, <300)
Acute oliguria (urine output, <0.5 ml/kg/hr or 45 ml/hr for at least 2 hr)
Increase in creatinine level of >0.5 mg/dl (>44 μmol/liter)
Coagulation abnormalities (international normalized ratio, >1.5; or activated partial-thromboplastin time, >60 sec)
Paralytic ileus (absence of bowel sounds)
Thrombocytopenia (platelet count, <100,000/mm3)
Hyperbilirubinemia (plasma total bilirubin, >4 mg/dl [68 μmol/liter])
Tissue-perfusion variables
Hyperlactatemia (lactate, >1 mmol/liter)
Decreased capillary refill or mottling
Severe sepsis (sepsis plus organ dysfunction)
Septic shock (sepsis plus either hypotension [refractory to intravenous fluids] or hyperlactatemia)¶

* Data are adapted from Levy et al.5

† In children, diagnostic criteria for sepsis are signs and symptoms of inflammation plus infection with hyperthermia or
hypothermia (rectal temperature, >38.5°C or <35°C, respectively), tachycardia (may be absent with hypothermia), and at
least one of the following indications of altered organ function: altered mental status, hypoxemia, increased serum lac-
tate level, or bounding pulses.
‡ A mixed venous oxygen saturation level of more than 70% is normal in newborns and children (pediatric range, 75 to 80%).
§ A cardiac index ranging from 3.5 to 5.5 liters per minute per square meter is normal in children.
¶ Refractory hypotension is defined as either persistent hypotension or a requirement for vasopressors after the adminis-
tration of an intravenous fluid bolus.

Ou t c ome death from septic shock were often in excess of

Before the introduction of modern intensive care
with the ability to provide vital-organ support,
severe sepsis and septic shock were typically le-
thal. Even with intensive care, rates of in-hospital
80% as recently as 30 years ago.25 However, with
advances in training, better surveillance and
monitoring, and prompt initiation of therapy to
treat the underlying infection and support failing
organs, mortality is now closer to 20 to 30% in

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30 nejm readers’ choice clinical care collection
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many series.7,26 With decreasing death rates, at- four main classes — toll-like receptors, C-type
tention has focused on the trajectory of recovery lectin receptors, retinoic acid inducible gene 1–like
among survivors. Numerous studies have sug- receptors, and nucleotide-binding oligomerization
gested that patients who survive to hospital dis- domain–like receptors — have been identified,
charge after sepsis remain at increased risk for with the last group partially acting in protein
death in the following months and years. Those complexes called inflammasomes (Fig. 1).31
who survive often have impaired physical or neu- These receptors recognize structures that are
rocognitive functioning, mood disorders, and a conserved among microbial species, so-called
low quality of life.27 In most studies, determining pathogen-associated molecular patterns, result-
the causal role of sepsis in such subsequent disor- ing in the up-regulation of inflammatory gene
ders has been difficult. However, a recent analy- transcription and initiation of innate immunity.
sis of the Health and Retirement Study, involving The same receptors also sense endogenous mol-
a large, longitudinal cohort of aging Americans, ecules released from injured cells, so-called
suggested that severe sepsis significantly acceler- damage-associated molecular patterns, or alarm-
ated physical and neurocognitive decline.28 ins, such as high-mobility group protein B1, S100
proteins, and extracellular RNA, DNA, and his-
Pathoph ysiol o gy tones.32 Alarmins are also released during sterile
injury such as trauma, giving rise to the concept
Host Response that the pathogenesis of multiple organ failure in
As the concept of the host theory emerged, it was sepsis is not fundamentally different from that in
first assumed that the clinical features of sepsis noninfectious critical illness.32
were the result of overly exuberant inflamma-
tion. Later, Bone et al.29 advanced the idea that Coagulation Abnormalities
the initial inflammatory response gave way to a Severe sepsis is almost invariably associated with
subsequent “compensatory antiinflammatory re- altered coagulation, frequently leading to dis-
sponse syndrome.” However, it has become ap- seminated intravascular coagulation.33 Excess
parent that infection triggers a much more com- fibrin deposition is driven by coagulation
plex, variable, and prolonged host response, in through the action of tissue factor, a transmem-
which both proinflammatory and antiinflamma- brane glycoprotein expressed by various cell
tory mechanisms can contribute to clearance of types; by impaired anticoagulant mechanisms,
infection and tissue recovery on the one hand including the protein C system and antithrom-
and organ injury and secondary infections on the bin; and by compromised fibrin removal owing
other.30 The specific response in any patient de- to depression of the fibrinolytic system (Fig. 2).33
pends on the causative pathogen (load and viru- Protease-activated receptors (PARs) form the mo-
lence) and the host (genetic characteristics and lecular link between coagulation and inflamma-
coexisting illnesses), with differential responses tion. Among the four subtypes that have been
at local, regional, and systemic levels (Fig. 1). The identified, PAR1 in particular is implicated in
composition and direction of the host response sepsis.33 PAR1 exerts cytoprotective effects when
probably change over time in parallel with the stimulated by activated protein C or low-dose
clinical course. In general, proinflammatory reac- thrombin but exerts disruptive effects on endo-
tions (directed at eliminating invading pathogens) thelial-cell barrier function when activated by
are thought to be responsible for collateral tissue high-dose thrombin.34 The protective effect of
damage in severe sepsis, whereas antiinflamma- activated protein C in animal models of sepsis is
tory responses (important for limiting local and dependent on its capacity to activate PAR1 and
systemic tissue injury) are implicated in the en- not on its anticoagulant properties.34
hanced susceptibility to secondary infections.
Antiinflammatory Mechanisms
Innate Immunity and Immunosuppression
Knowledge of pathogen recognition has in- The immune system harbors humoral, cellular,
creased tremendously in the past decade. Patho- and neural mechanisms that attenuate the poten-
gens activate immune cells through an interac- tially harmful effects of the proinflammatory
tion with pattern-recognition receptors, of which response (Fig. 1).30 Phagocytes can switch to an

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 31

Proinflammatory response Excessive inflammation causing collateral damage (tissue injury)

Damage-associated
Pathogen factors Perpetuation of inflammation molecular patterns
Load
Virulence
Pathogen-associated
molecular patterns
Cytokines
Proteases
Reactive oxygen species Complement products Coagulation proteases
CLRs
Host–pathogen interaction

TLRs Leukocyte activation Complement activation Coagulation activation Necrotic cell death

Impaired function Inhibition of proinflammatory

Neuroendocrine regulation
of immune cells gene transcription
NLRs
Brain

Vagus Apoptosis of T, B,
RLRs nerve Celiac and dendritic cells
Endosome ganglion
Antiinflammatory cytokines
Liver,
Host cell Spleen Soluble cytokine receptors
intestine
Negative regulators
Expansion of regulatory of TLR signaling
Norepinephrine
T and myeloid Epigenetic regulation
Host factors Hypothalamic– suppressor cells
Environment pituitary– Acetylcholine
adrenal axis
Genetics
Age Inhibition of proinflammatory
Other illnesses cytokine production Impaired
Medications phagocytosis
Adrenal Catecholamines
gland Cortisol

Antiinflammatory response Immunosuppression with enhanced susceptibility to secondary infections

Figure 1. The Host Response in Severe Sepsis. COLOR FIGURE

Draft 6
The host response to sepsis is characterized by both proinflammatory responses (top of panel, in red) and antiinflammatory immunosup- 8/09/13
Author Angus
pressive responses (bottom of panel, in blue). The direction, extent, and duration of these reactions are determined by1 both host factors
Fig #
(e.g., genetic characteristics, age, coexisting illnesses, and medications) and pathogen factors (e.g., microbial Title
load and virulence). In-
flammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and pattern-
ME
recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the
DE Drazen
endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors [RLRs] and nucleotide-binding Artist
oligomerization
Knoper
domain–like receptors [NLRs]). The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell PLEASE
AUTHOR death, which
NOTE:
results in the release of damage-associated molecular patterns, so-called danger molecules that perpetuate inflammation at least in part
Figure has been redrawn and type has been reset
Please check carefully
by acting on the same pattern-recognition receptors that are triggered by pathogens. Issue date 8/29/13

antiinflammatory phenotype that promotes tis-
sue repair, and regulatory T cells and myeloid-
derived suppressor cells further reduce inflam-
mation. In addition, neural mechanisms can
inhibit inflammation.35 In the so-called neuroin-
flammatory reflex, sensory input is relayed
through the afferent vagus nerve to the brain
stem, from which the efferent vagus nerve acti-
vates the splenic nerve in the celiac plexus, re-
sulting in norepinephrine release in the spleen
and acetylcholine secretion by a subset of CD4+
T cells. The acetylcholine release targets α7 cho-
linergic receptors on macrophages, suppressing
the release of proinflammatory cytokines.36 In
animal models of sepsis,35 disruption of this
neural-based system by vagotomy increases sus-
ceptibility to endotoxin shock, whereas stimula-
tion of the efferent vagus nerve or α7 cholinergic
receptors attenuates systemic inflammation.
Patients who survive early sepsis but remain
dependent on intensive care have evidence of im-
munosuppression, in part reflected by reduced

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32 nejm readers’ choice clinical care collection
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Tissue hypoperfusion Loss of barrier function

Increased coagulation Decreased anticoagulation

Endothelial cell
↓Tissue
↑ Tissue factor pathway S1P3 S1P1
factor inhibitor ↓ TM ↓ Endothelial PAR1
Monocyte ↑ S1P3 and
protein C receptor
↓ S1P1
↓ Antithrombin ↓ Protein C
Microcirculation

↓ Activated protein C ↑ Angiopoietin 2

NETs Vasodilatation and ↑ thrombin
↓ Activated
with trapped protein C ↓ Blood pressure
platelets
↑ PAI-1 ↓Fibrinolysis ↓ Red-cell
Cell shrinkage
deformability and cell death
Neutrophil ↓ VE cadherin and
Thrombus ↓Tight junctions
Thrombosis

Capillary leak
and interstitial
edema
Loss of
Tissue hypoperfusion barrier function
Tissue

Release of Mitochondrial
mitochondrial dysfunction
↓Tissue oxygenation
contents

Organ failure

Figure 2. Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria.
Sepsis is associated with microvascular thrombosis caused by concurrent activation of coagulation (mediated by tissue factor) COLOR FIGURE and im-

pairment of anticoagulant mechanisms as a consequence of reduced activity of endogenous anticoagulant pathways Draft(mediated
6 by acti-
7/24/13
vated protein C, antithrombin, and tissue factor pathway inhibitor), plus impaired fibrinolysis owing to enhanced release
Author Angus of plasminogen
Fig # 2
activator inhibitor type 1 (PAI-1). The capacity to generate activated protein C is impaired at least in part by reduced expression of two
Title
endothelial receptors: thrombomodulin (TM) and the endothelial protein C receptor. Thrombus formation is further facilitated by neu-
trophil extracellular traps (NETs) released from dying neutrophils. Thrombus formation results in tissue hypoperfusion,
ME which is aggra-
vated by vasodilatation, hypotension, and reduced red-cell deformability. Tissue oxygenation is further impaired DEby the loss of barrier
Drazen
Artist Knoper
function of the endothelium owing to a loss of function of vascular endothelial (VE) cadherin, alterations in endothelial cell-to-cell tight
AUTHOR PLEASE NOTE:
junctions, high levels of angiopoietin 2, and a disturbed balance between sphingosine-1 phosphate receptor 1 (S1P1) Figure hasand S1P3
been redrawn within
and type has been reset
Please check carefully
the vascular wall, which is at least in part due to preferential induction of S1P3 through protease activated receptor 1 (PAR1)
Issue date 8/29/13
as a result
of a reduced ratio of activated protein C to thrombin. Oxygen use is impaired at the subcellular level because of damage to mitochondria
from oxidative stress.

expression of HLA-DR on myeloid cells.37 These
patients frequently have ongoing infectious foci,
despite antimicrobial therapy, or reactivation of
latent viral infection.38,39 Multiple studies have
documented reduced responsiveness of blood
leukocytes to pathogens in patients with sep-
sis,30 findings that were recently corroborated by
postmortem studies revealing strong functional
impairments of splenocytes obtained from pa-
tients who had died of sepsis in the ICU.37 Be-
sides the spleen, the lungs also showed evidence
of immunosuppression; both organs had en-
hanced expression of ligands for T-cell inhibi-
tory receptors on parenchymal cells.37 Enhanced
apoptosis, especially of B cells, CD4+ T cells,
and follicular dendritic cells, has been implicat-
ed in sepsis-associated immunosuppression and
death.40,41 Epigenetic regulation of gene expres-

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 Table 2. Guidelines for the Treatment of Severe Sepsis and Septic Shock from the Surviving Sepsis Campaign.*

846
Element of Care Grade†
Resuscitation
Begin goal-directed resuscitation during first 6 hr after recognition 1C
Begin initial fluid resuscitation with crystalloid and consider the addition of albumin 1B
Consider the addition of albumin when substantial amounts of crystalloid are required to maintain adequate arterial pressure 2C
Avoid hetastarch formulations 1C
Begin initial fluid challenge in patients with tissue hypoperfusion and suspected hypovolemia, to achieve ≥30 ml of crystalloids per kilogram of body weight‡ 1C
Continue fluid-challenge technique as long as there is hemodynamic improvement UG
Use norepinephrine as the first-choice vasopressor to maintain a mean arterial pressure of ≥65 mm Hg 1B
Use epinephrine when an additional agent is needed to maintain adequate blood pressure 2B
Add vasopressin (at a dose of 0.03 units/min) with weaning of norepinephrine, if tolerated UG
Avoid the use of dopamine except in carefully selected patients (e.g., patients with a low risk of arrhythmias and either known marked left ventricular systolic dys- 2C
The

function or low heart rate)

Infuse dobutamine or add it to vasopressor therapy in the presence of myocardial dysfunction (e.g., elevated cardiac filling pressures or low cardiac output) or on- 1C
going hypoperfusion despite adequate intravascular volume and mean arterial pressure
Avoid the use of intravenous hydrocortisone if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability; if hydrocortisone is used, ad- 2C
minister at a dose of 200 mg/day
Target a hemoglobin level of 7 to 9 g/dl in patients without hypoperfusion, critical coronary artery disease or myocardial ischemia, or acute hemorrhage 1B

n engl j med 369;9

Infection control
Obtain blood cultures before antibiotic therapy is administered 1C

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Perform imaging studies promptly to confirm source of infection UG
n e w e ng l a n d j o u r na l

Administer broad-spectrum antibiotic therapy within 1 hr after diagnosis of either severe sepsis or septic shock 1B/1C
of

Reassess antibiotic therapy daily for de-escalation when appropriate 1B

Perform source control with attention to risks and benefits of the chosen method within 12 hr after diagnosis 1C

august 29, 2013

Respiratory support
Use a low tidal volume and limitation of inspiratory-plateau-pressure strategy for ARDS 1A/1B
m e dic i n e

Apply a minimal amount of positive end-expiratory pressure in ARDS 1B

Administer higher rather than lower positive end-expiratory pressure for patients with sepsis-induced ARDS 2C
Use recruitment maneuvers in patients with severe refractory hypoxemia due to ARDS 2C
Use prone positioning in patients with sepsis-induced ARDS and a ratio of the partial pressure of arterial oxygen (mm Hg) to the fraction of inspired oxygen of 2C
<100, in facilities that have experience with such practice
Elevate the head of the bed in patients undergoing mechanical ventilation, unless contraindicated 1B
nejm.org

Use a conservative fluid strategy for established acute lung injury or ARDS with no evidence of tissue hypoperfusion 1C
Use weaning protocols 1A
33
34 nejm readers’ choice clinical care collection
critical care medicine

sion may also contribute to sepsis-associated

ministration of a bolus of 20 ml of crystalloids (or albumin equivalent) per kilogram of body weight during a period of 5 to 10 minutes for hypovolemia (2C); increased use of inotropes
tinuous positive end-expiratory pressure in the presence of respiratory distress and hypoxemia (2C); use of physical examination therapeutic end points, such as capillary refill (2C); ad-
† For all grades, the number indicates the strength of the recommendation (1, recommended; 2, suggested), and the letter indicates the level of evidence, from high (A) to low (D), with

and vasodilators in septic shock with low cardiac output associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or prov-
UG indicating ungraded. Recommendations that are specific to pediatric severe sepsis include therapy with face-mask oxygen, high-flow nasal cannula oxygen, or nasopharyngeal con-
immunosuppression.42
1C
2C

2C
1A
1B

2B
1B
1B

1B
Organ Dysfunction
Although the mechanisms that underlie organ
failure in sepsis have been only partially eluci-
Use a protocol-specified approach to blood glucose management, with the initiation of insulin after two consecutive blood glucose levels of >180 mg/dl (10 mmol/

Administer oral or enteral feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hr after a diagnosis
dated, impaired tissue oxygenation plays a key
role (Fig. 2). Several factors — including hypo-
tension, reduced red-cell deformability, and
microvascular thrombosis — contribute to dimin-
ished oxygen delivery in septic shock. Inflamma-
tion can cause dysfunction of the vascular endo-
thelium, accompanied by cell death and loss of
barrier integrity, giving rise to subcutaneous and
Use the equivalent of continuous venovenous hemofiltration or intermittent hemodialysis as needed for renal failure or fluid overload

body-cavity edema.43 In addition, mitochondrial

damage caused by oxidative stress and other mech-
anisms impairs cellular oxygen use.44 Moreover,
injured mitochondria release alarmins into the
* Data are adapted from Dellinger et al.23 ARDS denotes acute respiratory distress syndrome, and ICU intensive care unit.

extracellular environment, including mitochon-

drial DNA and formyl peptides, which can acti-
vate neutrophils and cause further tissue injury.45

T r e atmen t
Administer a short course of a neuromuscular blocker (<48 hr) for patients with early, severe ARDS

The Surviving Sepsis Campaign, an international

consortium of professional societies involved in
critical care, treatment of infectious diseases,
Address goals of care, including treatment plans and end-of-life planning as appropriate

‡ The guidelines recommend completing the initial fluid resuscitation within 3 hours (UG).

and emergency medicine, recently issued the third

iteration of clinical guidelines for the manage-
Administer stress-ulcer prophylaxis to prevent upper gastrointestinal bleeding

ment of severe sepsis and septic shock (Table 2).23

The most important elements of the guidelines
are organized into two “bundles” of care: an ini-
Use sedation protocols, targeting specific dose-escalation end points
Avoid neuromuscular blockers if possible in patients without ARDS

tial management bundle to be accomplished with-

in 6 hours after the patient’s presentation and a
management bundle to be accomplished in the
ICU.23 Implementation of the bundles is associ-
liter), targeting a blood glucose level of <180 mg/dl

ated with an improved outcome.46,47

Administer prophylaxis for deep-vein thrombosis

The principles of the initial management

bundle are to provide cardiorespiratory resusci-
tation and mitigate the immediate threats of
uncontrolled infection. Resuscitation requires the
of severe sepsis or septic shock

en absolute adrenal insufficiency (2C).

use of intravenous fluids and vasopressors, with

oxygen therapy and mechanical ventilation pro-
Central nervous system support

vided as necessary. The exact components re-

quired to optimize resuscitation, such as the
General supportive care

choice and amount of fluids, appropriate type

and intensity of hemodynamic monitoring, and
role of adjunctive vasoactive agents, all remain the
subject of ongoing debate and clinical trials;
many of these issues will be covered in this se-
ries.23 Nonetheless, some form of resuscitation is
considered essential, and a standardized approach

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 The n e w e ng l a n d j o u r na l
has been advocated to ensure prompt, effective
management.23 The initial management of in-
fection requires forming a probable diagnosis,
obtaining cultures, and initiating appropriate
and timely empirical antimicrobial therapy and
source control (i.e., draining pus, if appropriate).
The choice of empirical therapy depends on
the suspected site of infection, the setting in
which the infection developed (i.e., home, nurs-
ing home, or hospital), medical history, and lo-
cal microbial-susceptibility patterns. Inappropri-
ate or delayed antibiotic treatment is associated
with increased mortality.48,49 Thus, intravenous
antibiotic therapy should be started as early as
possible and should cover all likely pathogens. It
has not been determined whether combination
antimicrobial therapy produces better outcomes
than adequate single-agent antibiotic therapy in
patients with severe sepsis.50-53 Current guide-
lines recommend combination antimicrobial
therapy only for neutropenic sepsis and sepsis
caused by pseudomonas species. Empirical anti-
fungal therapy should be used only in patients at
high risk for invasive candidiasis.50
The patient should also be moved to an ap-
propriate setting, such as an ICU, for ongoing
care. After the first 6 hours, attention focuses on
monitoring and support of organ function,
avoidance of complications, and de-escalation of
care when possible. De-escalation of initial broad-
spectrum therapy may prevent the emergence of
resistant organisms, minimize the risk of drug
toxicity, and reduce costs, and evidence from
observational studies indicates that such an ap-
proach is safe.54 The only immunomodulatory
therapy that is currently advocated is a short
course of hydrocortisone (200 to 300 mg per day
for up to 7 days or until vasopressor support is
no longer required) for patients with refractory
septic shock.23 This recommendation is support-
ed by a meta-analysis,55 but the two largest stud-
ies had conflicting results,56,57 and other clinical
trials are ongoing.58,59
se a rch for ne w ther a pie s
Recent Failures
One of the great disappointments during the past
30 years has been the failure to convert advances
in our understanding of the underlying biologic
features of sepsis into effective new therapies.60
Researchers have tested both highly specific
48 n engl j med 369;9
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agents and agents exerting more pleiotropic ef-
fects. The specific agents can be divided into
those designed to interrupt the initial cytokine
cascade (e.g., antilipopolysaccharide or anti–pro-
inflammatory cytokine strategies) and those de-
signed to interfere with dysregulated coagulation
(e.g., antithrombin or activated protein C).61 The
only new agent that gained regulatory approval
was activated protein C.62 However, postapproval
concern about the safety and efficacy of activated
protein C prompted a repeat study, which did not
show a benefit and led the manufacturer, Eli Lilly,
to withdraw the drug from the market.11 All other
strategies thus far have not shown efficacy. With
the recent decision to stop further clinical devel-
opment of CytoFab, a polyclonal anti–tumor ne-
crosis factor antibody (ClinicalTrials.gov number,
NCT01145560), there are no current large-scale
trials of anticytokine strategies in the treatment
of sepsis.
Among the agents with broader immunomod-
ulatory effects, glucocorticoids have received the
most attention. Intravenous immune globulin is
also associated with a potential benefit,63 but
important questions remain, and its use is not
part of routine practice.23 Despite a large num-
ber of observational studies suggesting that the
use of statins reduces the incidence or improves
the outcome of sepsis and severe infection,64
such findings have not been confirmed in ran-
domized, controlled trials, so the use of statins
is not part of routine sepsis care.23
PROBLEMS WITH therapeutic development
Faced with these disappointing results, many ob-
servers question the current approach to the de-
velopment of sepsis drugs. Preclinical studies
commonly test drugs in young, healthy mice or
rats exposed to a septic challenge (e.g., bacteria or
bacterial toxins) with limited or no ancillary treat-
ment. In contrast, patients with sepsis are often
elderly or have serious coexisting illnesses, which
may affect the host response and increase the risk
of acute organ dysfunction. Furthermore, death in
the clinical setting often occurs despite the use of
antibiotics, resuscitation, and intensive life sup-
port, and the disease mechanisms in such cases
are probably very different from those underlying
the early deterioration that typically occurs in ani-
mal models in the absence of supportive care.
There are also large between-species genetic dif-
ferences in the inflammatory host response.65
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36 nejm readers’ choice clinical care collection
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In clinical studies, the enrollment criteria are
typically very broad, the agent is administered on
the basis of a standard formula for only a short
period, there is little information on how the agent
changes the host response and host–pathogen
interactions, and the primary end point is death
from any cause. Such a research strategy is prob-
ably overly simplistic in that it does not select pa-
tients who are most likely to benefit, cannot adjust
therapy on the basis of the evolving host response
and clinical course, and does not capture poten-
tially important effects on nonfatal outcomes.
NEW STRATEGIES
Consequently, hope is pinned on newer so-called
precision-medicine strategies with better preclin-
ical models, more targeted drug development,
and clinical trials that incorporate better patient
selection, drug delivery, and outcome measure-
ment. For example, options to enrich the pre-
clinical portfolio include the study of animals
that are more genetically diverse, are older, or
have preexisting disease. Longer experiments
with more advanced supportive care would allow
better mimicry of the later stages of sepsis and
multiorgan failure, permitting the testing of
drugs in a more realistic setting and perhaps fa-
cilitating the measurement of outcomes such as
cognitive and physical functioning. In addition,
preclinical studies could be used to screen for
potential biomarkers of a therapeutic response
for which there are human homologues.
Activated protein C mutants that lack antico-
agulant properties are examples of more target-
ed drug development and were shown to provide
protection from sepsis-induced death in animals,
without an increased risk of bleeding.66 Bio-
markers such as whole-genome expression pat-
terns in peripheral-blood leukocytes may aid in
stratifying patients into more homogeneous sub-
groups or in developing more targeted therapeu-
tic interventions.67 The insight that severe sepsis
can cause immunosuppression raises the possi-
bility of using immune-stimulatory therapy (e.g.,
interleukin-7, granulocyte–macrophage colony-
stimulating factor,68 or interferon-γ69), but ide-
ally, such therapy would be used only in patients
in whom immunosuppression is identified or
predicted. Thus, such therapies could be deployed
on the basis of laboratory measures, such as
monocyte HLA-DR expression. In addition, con-
cern about accelerated neurocognitive decline in
n engl j med 369;9
Back to Table of Contents
survivors of sepsis opens up avenues to explore
agents currently being tested in patients with
dementia and related conditions.
The designs of trials could be modified to
more easily incorporate these ideas. For exam-
ple, the considerable uncertainty at the begin-
ning of a trial with regard to the appropriate
selection of patients and drug-administration
strategy and the possibility of treatment inter-
actions may be better handled with the use of
a Bayesian design. A trial could commence with
multiple study groups that reflect the various un-
certainties to be tested but then automatically nar-
row assignments to the best-performing groups
on the basis of predefined-response adaptive
randomization rules. Such designs could be par-
ticularly helpful when testing combination ther-
apy or incorporating potential biomarkers of drug
responsiveness.
C onclusions
Severe sepsis and septic shock represent one of
the oldest and most pressing problems in medi-
cine. With advances in intensive care, increased
awareness, and dissemination of evidence-based
guidelines, clinicians have taken large strides in
reducing the risk of imminent death associated
with sepsis. However, as more patients survive
sepsis, concern mounts over the lingering se-
quelae of what was previously a lethal event.
Strategies are also needed to reach the many mil-
lions of patients with sepsis who are far from
modern intensive care. At the same time, advanc-
es in molecular biology have provided keen in-
sight into the complexity of pathogen and alarm
recognition by the human host and important
clues to a host response that has gone awry.
However, harnessing that information to provide
effective new therapies has proved to be difficult.
To further improve the outcome of patients with
sepsis through the development of new therapeu-
tic agents, newer, smarter approaches to clinical-
trial design and execution are essential.
Dr. Angus reports receiving grant support through his insti-
tution from Eisai, consulting fees from Idaho Technology, Pfizer,
Eisai, MedImmune, BioAegis, and Ferring, and fees from Eli
Lilly for serving as a member of a clinical-trial data and safety
monitoring board. Dr. van der Poll reports receiving grant sup-
port through his institution from Sirtris Pharmaceuticals and
consulting fees from Eisai. No other potential conflict of inter-
est relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
nejm.org august 29, 2013 84
 The n e w e ng l a n d j o u r na l
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Copyright © 2013 Massachusetts Medical Society.

images in clinical medicine

The Journal welcomes consideration of new submissions for Images in Clinical
Medicine. Instructions for authors and procedures for submissions can be found
on the Journal’s website at NEJM.org. At the discretion of the editor, images that
are accepted for publication may appear in the print version of the Journal,
the electronic version, or both.

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 39

clinical practice

Vitamin B12 Deficiency

Sally P. Stabler, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the author’s clinical recommendations.

A 57-year-old woman reports increasing symptoms of painful paresthesias in both From the University of Colorado School
legs for the past 18 months. Physical examination reveals impaired position sense of Medicine, Aurora. Address reprint re-
quests to Dr. Stabler at the Division of
and vibration sense. The serum vitamin B12 level is 205 pg per milliliter (151.2 pmol Hematology, University of Colorado,
per liter), which is above the lower end of the laboratory reference range. The hemato- Aurora, CO 80045, or at sally.stabler@
crit is 42%, with a mean corpuscular volume of 96 fl. The serum methylmalonic acid ucdenver.edu.

level is 3600 nmol per liter (normal level, <400), and the serum homocysteine level N Engl J Med 2013;368:149-60.
49.1 μmol per liter (normal level, <14). How should this patient be further evaluated DOI: 10.1056/NEJMcp1113996
Copyright © 2013 Massachusetts Medical Society.
and treated?

The Cl inic a l Probl em

The recognition and treatment of vitamin B12 deficiency is critical since it is a re-
versible cause of bone marrow failure and demyelinating nervous system disease.
Vitamin B12 (cobalamin) is synthesized by microorganisms and detected in trace
amounts mostly in foods of animal origin.1 Uptake in the gastrointestinal tract
depends on intrinsic factor, which is synthesized by the gastric parietal cells, and
on the “cubam receptor” in the distal ileum.2 The most frequent cause of severe
vitamin B12 deficiency is a loss of intrinsic factor due to autoimmune atrophic gas- An audio version
of this article is
tritis,3 historically called “pernicious anemia,” even though many patients present available at
with mainly neurologic manifestations.4,5 NEJM.org

Pathophysiology of Vitamin B 12 Deficiency

Vitamin B12 is a cofactor for only two enzymes: methionine synthase and l-methyl-
malonyl–coenzyme A mutase6,7 (see Fig. 1 in the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org). The interaction between folate
and B12 is responsible for the megaloblastic anemia seen in both vitamin deficien-
cies. Dyssynchrony between the maturation of cytoplasm and that of nuclei leads to
macrocytosis, immature nuclei, and hypersegmentation in granulocytes6 in the
peripheral blood (Fig. 1A). The hypercellular and dysplastic bone marrow can be
mistaken for signs of acute leukemia (Fig. 1B).10 The ineffective erythropoiesis re-
sults in intramedullary hemolysis and release of lactate dehydrogenase, features
that are similar to those of microangiopathic hemolytic anemia.8 Clinical and labo-
ratory findings of megaloblastic anemia in the peripheral blood and bone marrow
are shown in Figure 2.
Vitamin B12 is necessary for the development and initial myelination of the
central nervous system as well as for the maintenance of its normal function.
Demyelination of the cervical and thoracic dorsal and lateral columns of the spinal
cord, occasional demyelination of cranial and peripheral nerves, and demyelin-
ation of white matter in the brain5 (i.e., “combined-systems disease” or “subacute
combined degeneration”) can occur with vitamin B12 deficiency (Fig. 2). Pathologi-

n engl j med 368;2 nejm.org january 10, 2013 149

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40 nejm readers’ choice clinical care
T h ecollection
n e w e ng l a n d j o u r na l of m e dic i n e

key Clinical points

vitamin b12 deficiency

• Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating neurologic disease, or both.

• Autoimmune gastritis (pernicious anemia) is the most common cause of severe deficiency.

• Methodologic problems may compromise the sensitivity and specificity of current vitamin B12 assays.

• Measurement of methylmalonic acid, homocysteine, or both is used to confirm vitamin B12 deficiency in untreated patients;
an elevated level of methylmalonic acid is more sensitive and specific for the diagnosis.

• For patients with pernicious anemia or malabsorption, lifelong vitamin B12 therapy is indicated.

• High-dose oral vitamin B12 tablets (1000 to 2000 µg) taken daily are as effective as intramuscular monthly injections in
correcting blood and neurologic abnormalities.

cal analysis reveals a “spongy degeneration” due also commonly associated with pernicious ane-
to the loss of and swelling of myelin sheaths; mia. Whether the stomach pathogen Helicobacter
this degeneration is visible on magnetic reso- pylori plays a causative role in pernicious anemia
nance imaging.11 For unclear reasons, the sever- is unclear.19 Autoimmune gastritis may cause
ity of megaloblastic anemia is inversely corre- malabsorption of iron, with clinical iron deficien-
lated with the degree of neurologic dysfunction.4,5 cy developing early in life and eventually progress-
Less common conditions associated with vi- ing to malabsorption of vitamin B12.20 The preva-
tamin B12 deficiency include glossitis, malab- lence of pernicious anemia ranges from 50 to
sorption, infertility, and thrombosis (including 4000 cases per 100,000 persons, depending on
thrombosis at unusual sites such as cerebral ve- the diagnostic criteria.1 All age groups are af-
nous sinus thrombosis).12,13 Thrombosis has been fected, but the median age range in large series
attributed to the marked hyperhomocysteinemia is 70 to 80 years.21,22 Pernicious anemia is more
seen in severe cases of vitamin B12 deficiency. common in persons of African or European an-
Patients occasionally have hyperpigmentation, cestry (4.3% and 4.0% prevalence among older
which clears with treatment.6 adults, respectively) than in those of Asian ances-
try.1,21 Milder forms of atrophic gastritis with
Causes of Vitamin B 12 Deficiency hypochlorhydria and an inability to release di-
Table 1 and Figure 3 list causes of vitamin B12 etary protein-bound vitamin B12 affect up to 20%
deficiency and recommended management. Per- of older adults.19,23,24
nicious anemia is discussed below, since this is
the most common cause of severe vitamin B12 Dietary Deficiency in Infancy and Childhood
deficiency worldwide. The infant of a mother with vitamin B12 defi-
Dietary vitamin B12 deficiency in infants and ciency may be born with the deficiency or it may
children is also discussed because of the in- occur if he or she is exclusively breast-fed,15,16
creasing recognition of severe abnormalities in usually between 4 and 6 months of age. Typical
exclusively breast-fed infants of mothers with manifestations of vitamin B12 deficiency in chil-
vitamin B12 deficiency. dren include failure of brain development and
overall growth and development, developmental
Pernicious Anemia regression, hypotonia, feeding difficulties, leth-
Pernicious anemia1 is an autoimmune gastritis argy, tremors, hyperirritability, and coma (Fig.
resulting from the destruction of gastric parietal 2).15,16 Brain imaging may reveal atrophy and
cells and the associated lack of intrinsic factor to delayed myelination. Anemia may be present.
bind ingested vitamin B12. The immune response Vitamin B12 replacement results in rapid im-
is directed against the gastric H/K–ATPase, provement in responsiveness, and many infants
which accounts for associated achlorhydria.2,3 recover fully. However, the longer the period of
Other autoimmune disorders, especially thyroid deficiency, the more likely that there will be
disease, type 1 diabetes mellitus, and vitiligo, are permanent disabilities. Mothers of infants with

150 n engl j med 368;2 nejm.org january 10, 2013

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 clinical pr actice
vitamin B12 deficiency often have unrecognized
pernicious anemia, but alternatively, they may
have a history of gastric bypass surgery, the
short-gut syndrome, or a long-term vegetarian or
vegan diet.16 Tandem mass spectrometry, used
in neonatal screening programs in all 50 states,
may detect nutritional B12 deficiency owing to
an increase in propionyl carnitine, but direct
measurement of methylmalonic acid has higher
sensitivity.25 Other causes of B12 deficiency in
children, such as ileal resections, the Imerslund–
Gräsbeck syndrome, inflammatory bowel disease,
and pernicious anemia, are listed in Table 1.18
S t r ategie s a nd E v idence
Evaluation
Both the clinical recognition of vitamin B12 defi-
ciency and confirmation of the diagnosis by
means of testing can be difficult. An approach to
testing is shown in Table 2.
The patient’s history may include symptoms
of anemia, underlying disorders causing malab-
sorption, and neurologic symptoms. The most
common neurologic symptoms are symmetric
paresthesias or numbness and gait problems.4,5
The physical examination may reveal pallor, ede-
ma, pigmentary changes in the skin, jaundice, or
neurologic defects such as impaired vibration
sense, impaired position and cutaneous sensa-
tion, ataxia, and weakness (Fig. 2).
Bone marrow biopsy and aspiration are not
necessary for the diagnosis of megaloblastic
anemia and may be misleading in cases of severe
pancytopenia with hypercellularity, increased
erythroblasts, and even cytogenetic abnormali-
ties, confusing the diagnosis with acute leuke-
mia.8-10 Imaging of the spinal cord is not indi-
cated in patients with recognized vitamin B12
deficiency, but in cases of severe myelopathy that
are not initially recognized as the result of vita-
min B12 deficiency, there is characteristic hyper-
intensity on T2-weighted imaging, described as
an inverted V-shaped pattern in the cervical and
thoracic spinal cord.11
Vitamin B12 Assay
The first test performed to confirm the diagnosis
of vitamin B12 deficiency is generally measure-
ment of the serum vitamin B12 level. Although
an extremely low level (<100 pg per milliliter
[<73.8 pmol per liter]) is usually associated with
clinical deficiency, such low levels are infre-
n engl j med 368;2
nejm.org 41
A
B
Figure 1. Peripheral-Blood Cells and Bone Marrow
Specimen Obtained from a Patient with Vitamin B12
Deficiency.
In Panel A, a peripheral-blood smear shows oval macro-
cytes as well as fragmented, misshapen cells and an
immature megaloblastic nucleated red cell (arrow).
The variation in red-cell size and shape could lead to a
misdiagnosis of microangiopathic hemolytic anemia
instead of megaloblastic anemia.8,9 The mean corpuscu-
lar volume was in the normal range, but an extremely
high red-cell distribution width suggested macrocytosis
combined with microcytic fragmented cells. In Panel B,
a bone marrow aspirate shows megaloblastic features.
Large erythroblasts and other red-cell precursors are
characterized by an open, immature nuclear chromatin
pattern. There is dyssynchrony between the maturation
of cytoplasm and that of nuclei in later red-cell and
granulocyte precursors. A “giant” band is present. Sev-
eral red-cell precursors have dysplastic nuclei (arrows),
with nuclear fragments (arrowhead) that are compati-
ble with cellular apoptosis and resulting intramedullary
hemolysis. (Photographs courtesy of John W. Ryder,
M.D., Department of Pathology, University of Colorado
School of Medicine.)
quently observed. Both false negative and false
positive values are common (occurring in up to
50% of tests) with the use of the laboratory-
reported lower limit of the normal range as a
cutoff point for deficiency.4,24,26 The high rate of
false negative and false positive results may be
nejm.org january 10, 2013 151
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42 nejm readers’ choice clinical care
T h ecollection
n e w e ng l a n d j o u r na l of m e dic i n e

Brain
Altered mental status
Cognitive defects
“Megaloblastic madness”: depression,
Optic atrophy, anosmia, loss of taste, mania, irritability, paranoia,
delusions, lability
glossitis

Spinal cord
Myelopathy
Spongy degeneration
Abnormalities in infants and children
Developmental delay or regression,
permanent disability
Does not smile
Feeding difficulties
Hypotonia, lethargy, coma
Hyperirritability, convulsions, tremors, Paresthesias
myoclonus Loss of proprioception: vibration,
Microcephaly position, ataxic gait, limb weakness;
spasticity (hyperreflexia); positive
Choreoathetoid movements
Romberg sign; Lhermitte’s sign;
segmental cutaneous sensory level
Autonomic nervous system
Postural hypotension
Infertility Incontinence
Impotence
Peripheral nervous system
Peripheral blood Cutaneous sensory loss
Macrocytic red cells, macroovalocytes Hyporeflexia
Anisocytosis, fragmented forms Symmetric weakness
Hypersegmented neutrophils, 1% with Paresthesias
six lobes or 5% with 5 lobes
Leukopenia, possible immature white
cells Bone marrow
Thrombocytopenia Hypercellular, increased erythroid
Pancytopenia precursors
Elevated lactate dehydrogenase level Open, immature nuclear chromatin
(extremes possible) Dyssynchrony between maturation of
Elevated indirect bilirubin and cytoplasm and nuclei
aspartate aminotransferase levels Giant bands, metamyelocytes
Decreased haptoglobin level Karyorrhexis, dysplasia
Elevated levels of methylmalonic acid, Abnormal results on flow cytometry
homocysteine, or both and cytogenetic analysis

152 n engl j med 368;2 nejm.org january 10, 2013

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 clinical pr actice
Figure 2 (facing page). Clinical and Laboratory Findings
in Vitamin B12 Deficiency.
The spectrum of disease associated with vitamin B12
deficiency is wide, from asymptomatic to life-threatening
pancytopenia or myelopathy. An increase in the mean
red-cell volume or distribution width or a mean volume
that is higher than expected for the patient’s age, pre-
sumed iron status (either high or low iron levels), and
the presence of thalassemia are important determinants
of macrocytosis, rather than an absolute value above the
reference range. Cerebral symptoms are usually accom-
panied by paresthesias and signs of myelopathy or
neuropathy.5
due to the fact that only 20% of the total mea-
sured vitamin B12 is on the cellular delivery pro-
tein, transcobalamin; the remainder is bound to
haptocorrin, a protein of unknown function.27
Most laboratories now perform automated assays
of vitamin B12 on platforms used for many other
analytes. There is often poor agreement when
samples are assayed by different laboratories or
with the use of different methods.31-34 Because
intrinsic factor is used as the assay-binding pro-
tein, anti–intrinsic factor antibodies (which are
common in pernicious anemia) must be removed
chemically from the sample, which has proved to
be problematic in the automated assays.33,34 Re-
cent studies show normal values34 or falsely high
values33 of vitamin B12 in many patients with per-
nicious anemia. New assays of holotranscobala-
min (to measure the vitamin B12 saturation of
transcobalamin) provide a modest improvement
in specificity over that provided by assays of total
serum vitamin B12, but they have not been clini-
cally validated27-29 and are not yet available com-
mercially in the United States.
Given the limitations of available assays, cli-
nicians should not use a laboratory’s reported
lower limit of the normal range to rule out the
diagnosis of vitamin B12 deficiency in patients
with compatible clinical abnormalities. Clinicians
should also recognize that vitamin B12 values are
frequently low in patients without other meta-
bolic or clinical evidence of vitamin B12 deficiency
(i.e., megaloblastic anemia or myelopathy).
Measurement of Serum Methylmalonic Acid
and Total Homocysteine
Measurement of methylmalonic acid, total ho-
mocysteine, or both is useful in making the diag-
nosis of vitamin B12 deficiency in patients who
have not received treatment.4,22,24,26,33,35,36 The
levels of both methylmalonic acid and total ho-
n engl j med 368;2 nejm.org
nejm.org 43
mocysteine are markedly elevated in the vast ma-
jority (>98%) of patients with clinical B12 defi-
ciency (Fig. 4),7,22 including those who have only
neurologic manifestations of deficiency (i.e., no
anemia).4,22
Elevated levels of methylmalonic acid and total
homocysteine decrease immediately after treat-
ment, and the levels can be remeasured to docu-
ment adequate vitamin B12 replacement. Levels of
these metabolites are normal in up to 50% of
patients with low vitamin B12 levels who have no
hematologic or neurologic response to replacement
therapy, indicating that the low values are false
positive results.26 Given the limitations of vitamin
B12 assays in confirming the diagnosis of B12
deficiency,31,34 it may be prudent to measure meth-
ylmalonic acid, total homocysteine, or both in pa-
tients with compatible clinical findings or pro-
vide empirical treatment with the use of defined
end points to document a clinical response.
An elevated level of methylmalonic acid is rea-
sonably specific for vitamin B12 deficiency, and the
level always decreases with vitamin B12 thera-
py.24,36 Modest increases (to 300 to 700 nmol per
liter) occur with renal failure.36,37 However,
nearly all patients with megaloblastic anemia or
myelopathy have levels of methylmalonic acid
that are higher than 500 nmol per liter, and 86%
have levels that are higher than 1000 nmol per
liter (Fig. 3). The level of serum total homocys-
teine is less specific, since it is also elevated in
folate deficiency,22,35 classic homocystinuria, and
renal failure.
Tests to Determine the Cause of Vitamin B 12
Deficiency
If the patient consumes sufficient amounts of vi-
tamin B12 and has clinically confirmed B12 defi-
ciency, then malabsorption must be present.
Testing for pernicious anemia is described in
Table 2. A positive test for anti–intrinsic factor or
anti–parietal-cell antibodies is indicative of per-
nicious anemia; surveillance for autoimmune
thyroid disease is reasonable in patients with
positive antibody tests. Chronic atrophic gastritis
can be diagnosed on the basis of an elevated fast-
ing serum gastrin level and a low level of serum
pepsinogen I.3,19 Some experts recommend en-
doscopy to confirm gastritis and rule out gastric
carcinoid and other gastric cancers, since pa-
tients with pernicious anemia are at increased
risk for such cancers.3
The Schilling test of radioactive vitamin B12
january 10, 2013 153
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 44

154
Table 1. Causes and Treatment of Vitamin B12 Deficiency.

Cause Treatment Follow-up

Severe malabsorption
Pernicious anemia (autoimmune gastritis)
Intramuscular cyanocobalamin at a dose of 1000 µg administered Administer iron and folate replacement as needed for full hemo-
intramuscularly daily or every other day for 1 wk, then weekly globin response, especially in patients with intestinal dis-
for 4 to 8 wk, and then monthly for life, or oral cyanocobala- ease; perform surveillance for other autoimmune condi-
min at a daily dose of 1000 to 2000 µg for life* tions, especially thyroid disease in patients with pernicious
anemia; perform upper endoscopy in patients with symp-
toms of gastric cancer† or iron deficiency
nejm readers’ choice clinical care

Total or partial gastrectomy Same as for pernicious anemia Same as for pernicious anemia
Gastric bypass or other bariatric surgery Same as for pernicious anemia Same as for pernicious anemia
Ileal resection or organ reconstructive surgery Same as for pernicious anemia Same as for pernicious anemia
(ileal conduit diversion and ileocysto-
plasty)
T h ecollection

Inflammatory bowel disease, tropical sprue Same as for pernicious anemia Same as for pernicious anemia

n engl j med 368;2

Imerslund–Gräsbeck and other syndromes‡ Same as for pernicious anemia Genetic counseling to detect vitamin B12 deficiency in family

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members
Mild malabsorption

nejm.org
Protein-bound vitamin B12 malabsorption Oral cyanocobalamin at a dose of 500 to 1000 µg daily or intra- Perform tests for iron deficiency, anemia of chronic kidney dis-
muscular cyanocobalamin at a dose of 1000 µg daily or every ease, and anemia of chronic inflammation; these conditions
n e w e ng l a n d j o u r na l

other day for 1 wk, then weekly for 4 to 8 wk, and then coexist frequently in older adults, may limit the response to
of

monthly for life treatment, and may require further treatment

Mild atrophic gastritis Same as for protein-bound vitamin B12 malabsorption Same as for protein-bound vitamin B12 malabsorption

january 10, 2013

Use of metformin14 Same as for protein-bound vitamin B12 malabsorption Same as for protein-bound vitamin B12 malabsorption
Use of drugs that block stomach acid Same as for protein-bound vitamin B12 malabsorption Same as for protein-bound vitamin B12 malabsorption
m e dic i n e

Dietary deficiency
Adults
Vegan or vegetarian diet, or diet low in meat Supplements containing >2 µg of vitamin B12 or foods fortified Perform tests for iron deficiency, which is very common
and dairy products with vitamin B12
Infants
Breast-feeding in infants with vitamin B12– Intramuscular cyanocobalamin at a dose of 250 to 1000 µg daily, Confirm metabolic response in infants or refer parents to genet-
deficient mothers15,16 then weekly until patient recovers; treatment of mother to ics specialist for evaluation; provide nutritional counseling
enrich breast milk; oral supplementation with 1 to 2 µg of for mothers
vitamin B12 daily or vitamin B12–enriched formula or food
 clinical pr actice nejm.org 45

absorption is no longer available. A potential

† Experts are not in agreement about the necessity or frequency of routine upper endoscopy in patients with pernicious anemia. However, symptoms suggestive of gastric carcinoma, un-
Evaluate for vitamin B12 malabsorption; provide addiction coun-

‡ Congenital malabsorption of vitamin B12 results from mutations of the ileal cubam receptor, cubilin, or amnionless (as in the Imerslund–Gräsbeck syndrome) and from mutations in
replacement absorption test is under develop-
Confirm pernicious anemia or congenital malabsorption ment wherein the increase in vitamin B12 satura-

§ Nitrous oxide inactivates the vitamin B12–dependent enzyme methionine synthase and causes formation of vitamin B12 analogues and gradual tissue depletion of vitamin B12.
tion of holotranscobalamin is measured after
several days of oral B12 loading,39 but this re-

* Intramuscular hydroxocobalamin can be substituted for intramuscular cyanocobalamin, but document the long-term response if it is administered at 3-month intervals.
quires further study.

gastric intrinsic factor. These syndromes are usually manifested in infancy and early childhood, although studies have shown a delay in onset even into adolescence.18
Treatment of Vitamin B 12 Deficiency
The daily requirement of vitamin B12 has been set
at 2.4 μg,40,41 but higher amounts — 4 to 7 μg
per day — which are common in persons who eat
meat or take a daily multivitamin, are associated
with lower methylmalonic acid values.42 Healthy
older adults should consider taking supplemental
crystalline vitamin B12 as recommended by the
Food and Nutrition Board.41 However, most pa-
seling

tients with clinical vitamin B12 deficiency have

malabsorption and will require parenteral or high-
dose oral replacement. Adequate supplementa-
tion results in resolution of megaloblastic anemia
above and for life if underlying pernicious anemia is present
100 µg of intramuscular vitamin B12 monthly or high-dose oral

tered on the same schedule as that for pernicious anemia

Recreational or occupational abuse of nitrous oxide§ Intramuscular cyanocobalamin at a dose of 1000 µg adminis-

and resolution of or improvement in myelopathy.

vitamin B12 daily in younger children; treatment as per

Injected Vitamin B12

There are many recommended schedules for in-
explained iron deficiency, and proven gastrointestinal blood loss should prompt a full investigation.

jections of vitamin B12 (called cyanocobalamin in

the United States and hydroxocobalamin in Eu-
rope).6,23 About 10% of the injected dose (100 of
1000 μg) is retained. Patients with severe abnor-
malities should receive injections of 1000 μg at
least several times per week for 1 to 2 weeks,
adults in older children

then weekly until clear improvement is shown,

followed by monthly injections. Hematologic re-
sponse is rapid, with an increase in the reticulo-
cyte count in 1 week and correction of megalo-
blastic anemia in 6 to 8 weeks. Patients with
severe anemia and cardiac symptoms should be
treated with transfusion and diuretic agents, and
Nitrous oxide anesthesia in occult pernicious anemia17

electrolytes should be monitored. Neurologic

symptoms may worsen transiently and then sub-
Diseases similar to those causing malab-

side over weeks to months.5 The severity and du-

ration of the neurologic abnormalities before
treatment influence the eventual degree of recov-
ery.4,5 Treatment of pernicious anemia is lifelong.
In patients in whom vitamin B12 supplementa-
sorption in adults

tion is discontinued after clinical recovery, neu-

rologic symptoms recur within as short a period
as 6 months, and megaloblastic anemia recurs in
several years.6
Children

High-Dose Oral Treatment

High-dose oral treatment is effective and is increas-
ingly popular. A study performed 45 years ago

n engl j med 368;2 nejm.org january 10, 2013 155

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46 nejm readers’ choice clinical care
T h ecollection
n e w e ng l a n d j o u r na l of m e dic i n e

Figure 3. The Normal Mechanisms and Defects of Absorption of Vitamin B12 .

The vitamin B12 (Cbl) released from food protein by peptic action is bound to haptocorrin (HC) in the stomach and
travels to the duodenum, where pancreatic proteases digest the HC, releasing Cbl to bind to intrinsic factor (IF).
The IF-Cbl complex binds to a specific receptor in the distal ileum (the cubam receptor) and is internalized, eventu-
ally released from lysosomes, and transported into the blood. Both HC and transcobalamin (TC) bind Cbl in the cir-
culation, although the latter is the cellular delivery protein. Adapted from Stabler.6

156 n engl j med 368;2 nejm.org january 10, 2013

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 Table 2. Laboratory Testing in Vitamin B12 Deficiency.*

Test Sensitivity Specificity Comments

Measurement to detect deficiency
Serum vitamin B12 <200 pg/ml or labo-
ratory cutoff level
Serum vitamin B12 <350 pg/ml
Holotranscobalamin <20 to 45 pmol/
liter‡
Serum methylmalonic acid >400 nmol/
liter§
Serum or plasma total homocysteine
>21 µmol/liter
65–95% for proven clinical deficiency†; 50%
for detecting elevated level of methylma-
lonic acid
90%
Insufficient data on sensitivity for clinical de-
ficiency; 46–89% for detecting elevated
level of methylmalonic acid
98% for clinical deficiency
96% for clinical deficiency
50–60% for clinical response†; 80% for de-
tecting elevated level of methylmalonic
acid
25% for detecting elevated level of methyl-
malonic acid
Insufficient data on specificity for clinical de-
ficiency; 28–96% for detecting elevated
level of methylmalonic acid
Poor specificity for clinical response in patients Renal failure and volume depletion may in-
with modest elevation of level of methyl-
malonic acid (300–1000 nmol/liter)¶
Homocysteine level also increased in clinical
folate deficiency and renal insufficiency
Current vitamin B12 assays are especially
problematic in patients with anti–intrinsic
factor antibodies
Levels of holotranscobalamin increase in re-
nal failure; superior to measurement of
total vitamin B12 in pregnancy, when the
total level decreases
crease level of serum methylmalonic
acid, but rarely to >1000 nmol/liter

n engl j med 368;2

Test to determine cause of deficiency‖
Pernicious anemia
Anti–intrinsic factor antibodies 50% 100% Must be tested >7 days after vitamin B12 in-

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jection to prevent false positive result
Anti–parietal-cell antibodies 80% 50–100%
clinical pr actice

Atrophic body gastritis (antral sparing)**

Fasting high serum gastrin level 85%
(>100 pmol/liter)

january 10, 2013

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Low level of serum pepsinogen I 90%
(<30 µg/liter)
Endoscopy with pentagastrin-fast 100% Rarely performed
hypochlorhydria
Malabsorption of vitamin B12††
Vitamin B12 absorption test Schilling test no longer available
Increase in serum holotranscobalamin Unknown Unknown Promising preclinical data, but still experi-
level after oral loading mental

* To convert the values for vitamin B12 to picomoles per liter, multiply by 0.7378.
† Available assays are largely chemiluminescent microparticle immunoassays performed with the use of automated analyzers that in general show higher values than the radiodilution
and microbiologic assays used in past studies of clinically confirmed deficiency.4,22,24,26 Thus, these tests are likely to have lower sensitivities and specificities than the older assays.
‡ The holotranscobalamin assay has been studied widely in Europe27-30 but is not yet commercially available in the United States. The appropriate lower end of the reference range is
still under debate.33 The values for sensitivity and specificity are reviewed in Heil et al.29
§ Urinary methylmalonic acid has not been extensively studied, but values greater than 2.5 µmol per millimole of creatinine suggest deficiency.
¶ Elevated levels of methylmalonic acid fall with vitamin B12 therapy, but an associated clinical response is highly variable, depending largely on the presence of vitamin B12–related disease.
nejm.org

‖ Evidence of a causal pathologic process does not confirm coexisting B12 deficiency, since underlying gastrointestinal disease may predate the deficiency by many years.
** The relationship between atrophic body gastritis (autoimmune gastritis) and infection with Helicobacter pylori is variable. Antral sparing is a type of atrophic body gastritis in which
the cells in the antrum can produce high levels of gastrin.
47

157
†† There is malabsorption if clinically proven vitamin B12 deficiency is present in a patient who eats meat, receives multivitamin therapy, or both.
48 nejm readers’ choice clinical care
T h collection
e n e w e ng l a n d j o u r na l
300,000
Serum Methylmalonic Acid (nmol/liter)
100,000
50,000
10,000
5,000
1,000
500
100
0 10 50 100 150 200 250 300 350 400 450
Serum Total Homocysteine (µmol/liter)
Figure 4. Serum Methylmalonic Acid and Total Homocysteine Concentrations
in 491 Episodes of Vitamin B12 Deficiency.
The data shown have been combined from studies performed over a period
of 25 years.4,6,22,24,26,35,37,38 Most of the patients with clinically confirmed
vitamin B12 deficiency had documented pernicious anemia and a proven re-
sponse to vitamin B12 therapy. Open circles indicate episodes in patients
with a hematocrit lower than 38%, and solid circles indicate episodes in
those with a hematocrit of 38% or higher. Patients without anemia had
neurologic manifestations of vitamin B12 deficiency and similar values of
methylmalonic acid and total homocysteine. The axis for serum methylmalo-
nic acid is plotted on a log scale. The dashed lines indicate values that are
3 SD above the mean for healthy blood donors: 376 nmol per liter for meth-
ylmalonic acid and 21.3 µmol per liter for total homocysteine. The level of
methylmalonic acid was greater than 500 nmol per liter in 98% of the pa-
tients and greater than 1000 nmol per liter in 86%. Adapted from Stabler.7
showed that 0.5 to 4% of radioactively labeled
oral vitamin B12 can be absorbed by passive dif-
fusion in both normal controls and patients with
pernicious anemia.43 Thus, oral doses of 1000 μg
deliver 5 to 40 μg, even if taken with food.
A randomized trial that compared an oral
dose of 2000 μg daily with parenteral therapy
(seven injections of 1000 μg of cyanocobalamin
over a period of 1 month, followed by monthly
injections) in patients with pernicious anemia,
atrophic gastritis, or a history of ileal resection
showed similar reductions in the mean corpus-
cular volume and increases in the hematocrit at
4 months in both groups.38 All participants
(four in each group) with paresthesias, ataxia, or
memory loss had resolution or improved with Vitamin B12 deficiency is the major cause of hy-
treatment. However, levels of methylmalonic perhomocysteinemia in countries with folate-
acid after treatment were significantly lower fortified food, such as the United States and
158 n engl j med 368;2
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of m e dic i n e
with daily oral treatment (169 nmol per liter, vs.
265 nmol per liter with parenteral treatment)
and vitamin B12 levels were significantly higher
(1005 pg per milliliter vs. 325 pg per milliliter
[741.5 vs. 239.8 pmol per liter]). A more recent
trial with a similar design involving a proprie-
tary oral vitamin B12 preparation also revealed
significantly lower levels of methylmalonic acid
in the oral-treatment group at the 3-month follow-
up.30 In a randomized trial comparing oral with
intramuscular vitamin B12 (1000-μg doses, daily
for 10 days, then weekly for 4 weeks, and month-
ly thereafter), the two groups had similar im-
provements in hematologic abnormalities and
vitamin B12 levels at 90 days.44 Case series of
patients treated with oral vitamin B12 have
yielded variable results; elevated levels of meth-
ylmalonic acid, homocysteine, or both were re-
ported in about half of patients with malabsorp-
tion who were treated with twice-weekly oral
doses of 1000 μg,45 whereas normal homocyste-
ine levels were reported in patients treated with
1500 μg daily after gastrectomy.46 Data are lack-
ing from long-term studies to assess whether
oral treatment is effective when doses are ad-
ministered less frequently than daily. Studies
involving older adults, many of whom had
chronic atrophic gastritis, showed that 60% re-
quired large oral doses (>500 μg daily) to correct
elevated levels of methylmalonic acid.47,48
Proponents of parenteral therapy state that
compliance and monitoring are better in patients
who receive this form of therapy because they
have frequent contact with health care providers,
whereas proponents of oral therapy maintain
that compliance will be improved in patients
who receive oral therapy because of convenience,
comfort, and decreased expense. High-dose vita-
min B12 tablets (500 to 1500 μg) are available in
the United States without a prescription. Self-
administered injections are also easily taught,
economical, and in my experience, effective. Pa-
tients should be informed of the pros and cons
of oral versus parenteral therapy, and regardless
of the form of treatment, those with pernicious
anemia or malabsorption should be reminded of
the need for lifelong replacement.
A r e a s of Uncer ta in t y
nejm.org january 10, 2013
 clinical pr actice nejm.org 49

Canada. Epidemiologic studies show significant
associations between elevated homocysteine lev-
els and vascular disease and thrombosis. How-
ever, large randomized trials of combined high-
dose vitamin B therapy in patients with vascular
disease have shown no reduction in vascular
events.49 Vitamin B12 status should be evaluated
in patients with hyperhomocysteinemia before
folic acid treatment is initiated.
The potential role of mild vitamin B12 defi-
ciency in cognitive decline with aging remains
uncertain. Epidemiologic studies indicate an in-
verse association between vitamin B12 supplemen-
tation and neurodegenerative disease, but results
of randomized trials have been largely negative.50
Besides oral tablets, vitamin B is available in
sublingual preparations, oral sprays, nasal gels
or sprays, and transdermal patches. Data on the
absorption and efficacy of these alternative prep-
arations are lacking.
Guidel ine s
Nutritional guidelines for vitamin B12 intake are
published by the Food and Nutrition Board,41
and nutritional guidelines for vegetarians are
published by the American Dietetic Association.40
There are no recommendations from the Ameri-
can Society of Hematology for the diagnosis and
treatment of vitamin B12 deficiency. The Ameri-
can Academy of Neurology recommends mea-
surements of vitamin B12, methylmalonic acid,
and homocysteine in patients with symmetric
polyneuropathy.51 The American Society for Gas-
trointestinal Endoscopy recommends a single
endoscopic evaluation at the diagnosis of perni-
cious anemia.52
C onclusions
a nd R ec om mendat ions
The patient in the vignette has neurologic abnor-
malities that are consistent with vitamin B12 de-
ficiency. Since vitamin B12 levels may be above
the lower end of the laboratory reference range
even in patients with clinical deficiency, methyl-
malonic acid, total homocysteine, or both should
be measured to document vitamin B12 deficiency
before treatment is initiated; the elevated levels
in this patient confirm the diagnosis. In the ab-
sence of dietary restriction or a known cause of
malabsorption, further evaluation is warranted
— in particular, testing for pernicious anemia
(anti–intrinsic factor antibodies). Either paren-
teral vitamin B12 treatment (8 to 10 loading injec-
tions of 1000 μg each, followed by monthly
1000-μg injections), or high-dose oral vitamin
B12 treatment (1000 to 2000 μg daily) is an effec-
tive therapy. I would review both options (includ-
ing the possibility of self-injection at home) with
the patient. Effective vitamin replacement will
correct blood counts in 2 months and correct or
improve neurologic signs and symptoms within
6 months.
Dr. Stabler reports holding patents (assigned to the University
of Colorado and Competitive Technologies) on the use of homo-
cysteine, methylmalonic acid, and other metabolites in the diag-
nosis of vitamin B12 and folate deficiency, but no longer receiv-
ing royalties for these patents. No other potential conflict of
interest relevant to this article was reported.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.

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25. Sarafoglou K, Rodgers J, Hietala A,
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26. Stabler SP, Allen RH, Savage DG, Lin-
denbaum J. Clinical spectrum and diag-
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27. Nexo E, Hoffmann-Lücke E. Holo-
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28. Schrempf W, Eulitz M, Neumeister V,
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33. Yang DT, Cook RJ. Spurious eleva-
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34. Carmel R, Agrawal YP. Failures of co-
balamin assays in pernicious anemia.
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35. Stabler SP, Marcell PD, Podell ER, et
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serum of patients with cobalamin or fo-
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Invest 1988;81:466-74.
36. Stabler SP, Marcell PD, Podell ER, Al-
len RH, Lindenbaum J. Assay of methyl-
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cumulation and implications for diagno-
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38. Kuzminski AM, Del Giacco EJ, Allen
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39. Greibe E, Nexo E. Vitamin B12 ab-
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41. Institute of Medicine Food and Nutri-
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45. Bor MV, Cetin M, Aytaç S, Altay C,
Ueland PM, Nexo E. Long term biweekly
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ited vitamin B12 deficiency. Haematolog-
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46. Kim HI, Hyung WJ, Song KJ, Choi SH,
Kim CB, Noh SH. Oral vitamin B12 re-
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Beresford SA, Allen RH, Stabler SP. Re-
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older adults. J Am Geriatr Soc 2002;50:
1789-95.
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Copyright © 2013 Massachusetts Medical Society.
 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 51

clinical practice

Infective Endocarditis
Bruno Hoen, M.D., Ph.D., and Xavier Duval, M.D., Ph.D.

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors’ clinical recommendations.

A 55-year-old man with a history of mitral regurgitation seeks care after an episode of From Service de Maladies Infectieuses et
Tropicales, Centre Hospitalier Régional
transient weakness in his right arm and speech difficulties. He underwent dental
Universitaire, and Unité Mixte de Recher-
scaling 1 month earlier. He notes recent intermittent fevers and weight loss. On cardiac che 6249 Chrono-environnement, Centre
examination, his regurgitation murmur appears to be unchanged. A transthoracic National de la Recherche Scientifique,
Université de Franche-Comté, Besançon
echocardiogram shows a mobile, 12-mm mitral-valve vegetation and grade 2 (mild)
(B.H.); Association pour l’Etude et la
regurgitation. Magnetic resonance imaging of the brain reveals recent ischemic le- Prévention de l’Endocardite Infectieuse,
sions. How should the patient be further evaluated and treated? Paris (B.H., X.D.); and INSERM Centre
d’Investigation Clinique 007, Assistance
Publique–Hôpitaux de Paris, Hôpital
THE CL INIC A L PROBL EM Universitaire Bichat, and INSERM Unité
738, Université Paris Diderot, Paris 7,
Unité de Formation et de Recherche de
Infective endocarditis has an estimated annual incidence of 3 to 9 cases per 100,000
Médecine–Bichat, Bichat (X.D.) — all in
persons in industrialized countries.1-7 The male:female case ratio is more than 2:1. France. Address reprint requests to Dr.
The highest rates are observed among patients with prosthetic valves, intracardiac Hoen at Service de Maladies Infectieuses
et Tropicales, CHRU de Besançon, 25030
devices, unrepaired cyanotic congenital heart diseases, or a history of infective endo-
Besançon CEDEX, France, or at bruno
carditis, although 50% of cases of infective endocarditis develop in patients with no .hoen@univ-fcomte.fr.
known history of valve disease. Other risk factors include chronic rheumatic heart
Drs. Hoen and Duval contributed equally
disease (which now accounts for <10% of cases in industrialized countries), age-
to this article.
related degenerative valvular lesions,1,2,5 hemodialysis, and coexisting conditions
such as diabetes, human immunodeficiency virus infection, and intravenous drug This article was updated on June 27,
2013, at NEJM.org.
use. More than one third of the cases of infective endocarditis in the United States
in recent years were reported to be health care–associated (nosocomial or non- N Engl J Med 2013;368:1425-33.
DOI: 10.1056/NEJMcp1206782
nosocomial).8 The clustering of several of these predisposing factors with age probably
Copyright © 2013 Massachusetts Medical Society.
explains the increased incidence of infective endocarditis among persons 65 years
of age or older (Fig. 1).7

MICROBIOLOGY
Streptococci and staphylococci account for 80% of cases of infective endocarditis, with
proportions varying according to valve (native vs. prosthetic), source of infection, An audio version
patient age, and coexisting conditions. Staphylococci are now the most frequently of this article is
identified microorganisms in several types of infective endocarditis (Fig. 1; and available at
NEJM.org
Table 1 in the Supplementary Appendix, available with the full text of this article at
NEJM.org),2,7,9 which results from the increased proportion of health care–associated
cases of infective endocarditis. In parallel, the incidence of cases attributable to oral
streptococci has decreased in industrialized countries.2
Cases of infective endocarditis in which a blood culture is negative (10% of cases)
may reflect one of two situations: infective endocarditis in patients exposed to
antibiotic agents before the diagnosis of infective endocarditis or infective endocar-
ditis caused by fastidious microorganisms. In the latter case, serologic testing, valve
or blood polymerase-chain-reaction (PCR) assay, and highly specialized microbio-
logic techniques lead to the identification of the pathogen in 60% of cases,10 with
the most frequent microorganisms being bartonella species, brucella species,

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52 nejm readers’ choice clinical care
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n e w e ng l a n d j o u r na l of m e dic i n e

key Clinical points

infective endocarditis
• Staphylococci and streptococci account for 80% of cases of infective endocarditis, with staphylococci currently the most
common pathogens.
• Cerebral complications are the most frequent and most severe extracardiac complications. Vegetations that are large, mo-
bile, or in the mitral position and infective endocarditis due to Staphylococcus aureus are associated with an increased risk of
symptomatic embolism.
• Identifying the causative microorganism is central to diagnosis and appropriate treatment; two or three blood cultures
should routinely be drawn before antibiotic therapy is initiated.
• When infective endocarditis is suspected, echocardiography should be performed as soon as possible.
• Indications for surgery include heart failure, uncontrolled infection, and prevention of embolic events.
• Treatment should involve a multidisciplinary team with expertise in cardiology, cardiac surgery, and infectious disease.
• Indications for antibiotic prophylaxis have been restricted to invasive dental procedures in patients with a prosthetic valve,
a history of infective endocarditis, or unrepaired cyanotic congenital heart disease.

Coxiella burnetii (the agent causing Q fever), bacte- more than one group. Table 1 in the Supplemen-
ria in the HACEK group (haemophilus species, tary Appendix shows the distribution of cases
Aggregatibacter [formerly Actinobacillus] actinomy- among these categories and the corresponding
cetemcomitans, Cardiobacterium hominis, Eikenella cor- microorganisms.
rodens, and Kingella kingae), and Tropheryma whip-
plei.6,10,11 OUTCOMES
In contemporary population-based studies of in-
PATHOGENESIS fective endocarditis in industrialized countries, in-
Normal valvular endothelium is naturally resistant hospital mortality ranges from 15 to 22%,5,7 and
to colonization by bacteria. In the conventional 5-year mortality is approximately 40%.14 How-
model of native-valve infectious endocarditis, in- ever, rates vary widely across subgroups of pa-
fection results from the colonization of damaged tients. For instance, in-hospital mortality is less
valvular endothelium by circulating bacteria with than 10% among patients with right-sided lesions
specific adherence properties. Endothelial dam- or oral streptococcal, left-sided, native-valve le-
age may result from so-called jet lesions due to sions, whereas it is 40% or more among patients
turbulent blood flow or may be provoked by elec- with prosthetic-valve infective endocarditis due
trodes or catheters or by repeated intravenous in- to Staphylococcus aureus. In a multivariate analysis
jections of solid particles in intravenous-drug users. assessing risk factors for death among patients
Chronic inflammation, as in chronic rheumatic with infective endocarditis, independent predic-
heart disease and degenerative valvular lesions,12 tors included higher age, S. aureus infection, heart
may also promote infective endocarditis. How- failure, cerebrovascular and embolic events, and
ever, the conventional model may not accurately health care–associated infective endocarditis.5,7
explain the pathogenesis of infective endocardi-
tis due to intracellular microorganisms, such as S T R ATEGIE S A ND E V IDENCE
C. burnetii, bartonella species, or T. whippelii, in which
the exposure and immune response of the host may PRESENTATION AND DIAGNOSIS
play a prominent role.13 The diagnosis of infective endocarditis is generally
based on clinical, microbiologic, and echocar-
CLASSIFICATION diographic findings. The Duke criteria (Table 1)
Whereas infective endocarditis was previously clas- have sensitivity and specificity of more than 80%
sified according to its mode of presentation (acute, and are the reference criteria for diagnosis.15
subacute, or chronic), it is now categorized accord- However, they should not replace clinical judg-
ing to underlying cardiac conditions, location, ment for diagnosis in the individual patient, es-
the presence of intracardiac devices, or the mode pecially in the first stage of care.
of acquisition. These classifications overlap, with Fever is common, occurring in 80% of cases.6,7
some cases of infective endocarditis belonging to In large, contemporary case series, recognition of

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 clinical pr actice nejm.org 53

Incidence per 100,000 Population
11
10
9
8 No microorganisms
7 Enterococci
6 Group D streptococci
5 Oral and pyogenic
streptococci
4 Coagulase-negative
3 staphylococci
2 Staphylococcus aureus
1 Other or mixed
microorganisms
0
24

29

34

39

44

49

54

59

64

69

74

79

84

89

94

l
Al
≥9
–

–
20

25

30

35

40

45

50

55

60

65

70

75

80

85

90
Age (yr)

Figure 1. Incidence of Definite Infective Endocarditis, According to Age and Microorganism.

Streptococci and staphylococci account for 80% of cases of infective endocarditis, with proportions varying according
to valve (native vs. prosthetic), source of infection, patient age, and coexisting conditions. The clustering of various
predisposing factors with age probably explains the higher incidence of infective endocarditis in persons 65 years
of age or older. Adapted from Selton-Suty et al.7

a new murmur and worsening of a known murmur Mycotic aneurysms result from septic arterial
are reported in 48% and 20% of cases, respectively. embolism to the intraluminal space or vasa vaso-
Other signs are less common: hematuria in 25% rum and spread of infection through the vessel
of cases, splenomegaly in 11%, splinter hemor- wall. These aneurysms were reported in 5% of
rhages in 8%, Janeway’s lesions in 5%, Roth’s cases in older case series,24 but they are now
spots in 5%, and conjunctival hemorrhage in 5%. detected more frequently because of the wider use
Sepsis, meningitis, unexplained heart failure, sep- of imaging. Magnetic resonance angiography is
tic pulmonary emboli, stroke, acute peripheral the best confirmation test.25
arterial occlusion, and renal failure may also be
presenting manifestations.16 Elevated inflamma- MICROBIOLOGIC DIAGNOSIS
tory markers (erythrocyte sedimentation rate and Identifying the causative microorganism is cen-
C-reactive protein level) are observed in two thirds tral to making the diagnosis of infective endocar-
of cases, and leukocytosis and anemia in about ditis and guiding antimicrobial treatment. Blood
half the cases.6,17 cultures should be performed routinely before the
Cerebral complications are the most severe ex- administration of antibiotics. When three sets of
tracardiac complications of infective endocarditis, blood cultures are performed, the pathogen is
as well as the most frequent (occurring in 15 to identified in about 90% of cases. Serologic tests
20% of patients).18,19 They include ischemic and for bartonella, C. burnetii, and brucella should be
hemorrhagic stroke (preceding the diagnosis of performed in patients with negative blood cultures
infective endocarditis in 60% of patients20,21), who have risk factors for these infections. If the
transient ischemic attack, silent cerebral embolism, causative pathogen has not been identified by
mycotic aneurysm, brain abscess, and meningitis. means of blood cultures and the patient requires
Specific characteristics of vegetations (those that valve surgery, gene amplification in cardiac-valve
are large, mobile, and located in the mitral valve)21 specimens, as well as immunostaining tech-
and S. aureus infection21,22 have been associated niques, if available, may yield a microbiologic
with an increased risk of symptomatic embolic diagnosis.10,26,27
events. Systematic magnetic resonance imaging
(MRI) of the brain may reveal cerebral abnormali- DIAGNOSIS OF VALVULAR LESIONS
ties in up to 80% of patients, including embolic Transthoracic echocardiography is performed first
events (mostly asymptomatic) in 50%.23 and is better than transesophageal echocardiog-

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54 nejm readers’ choice clinical care
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n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Duke Criteria for the Diagnosis of Infective Endocarditis.*

Definite diagnosis
Pathological criteria: microorganisms identified by culture or histologic examination of a vegetation, a vegetation that has
embolized, or an intracardiac abscess specimen; or active endocarditis confirmed by histologic examina-
tion of vegetation or intracardiac abscess
Clinical criteria: two major, one major and three minor, or five minor criteria
Major clinical criteria
Blood culture positive for infective endocarditis
Microorganisms typically associated with infective endocarditis identified from two separate blood cultures:
viridans streptococci, Streptococcus bovis, bacteria in the HACEK group, or Staphylococcus aureus; or
community-acquired enterococci in the absence of a primary focus
Microorganisms consistent with infective endocarditis identified from persistently positive blood cultures:
at least two positive cultures of blood samples drawn >12 hr apart, or positive results of all of three or a
majority of four or more separate blood cultures (with first and last samples drawn at least 1 hr apart)
Single positive blood culture for Coxiella burnetii or IgG antibody titer for Q fever phase 1 antigen >1:800
Evidence of endocardial involvement
Echocardiogram positive for infective endocarditis: pendulum-like intracardiac mass on valve or supporting
structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative ana-
tomical explanation; abscess; or new partial dehiscence of prosthetic valve†
New valvular regurgitation (worsening or changing of preexisting murmur not a sufficient criterion)
Minor clinical criteria
Predisposition to infective endocarditis, such as a predisposing heart condition, or intravenous drug use
Fever, defined as a temperature >38°C
Vascular phenomena, such as major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial
hemorrhage, conjunctival hemorrhage, and Janeway’s lesions
Immunologic phenomena, such as glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor
Microbiologic evidence: positive blood culture but with no major clinical criterion met or serologic evidence of
active infection with an organism consistent with infective endocarditis
Possible diagnosis
Clinical criteria (see above): one major criterion and one minor criterion or three minor criteria
Rejected diagnosis
Firmly established alternative diagnosis; resolution of infective endocarditis–like syndrome with antibiotic therapy for
≤4 days; no pathological evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy
for ≤4 days; or criteria for possible infective endocarditis not met

* Adapted from Li et al.15 HACEK denotes haemophilus species, Aggregatibacter (formerly Actinobacillus) actinomycetem-
comitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.
† Transesophageal echocardiography is recommended in patients with prosthetic valves and possible infective endocarditis
according to clinical criteria or infective endocarditis complicated by paravalvular abscess; transthoracic echocardiography
is recommended as the first test in other patients.

raphy for detecting abscesses in the anterior aortic
valve in a patient with a prosthetic valve and for
assessing the hemodynamic consequences of val-
vular dysfunction. Transesophageal echocardiog-
raphy has higher sensitivity and specificity overall
and is recommended when the results of trans-
thoracic echocardiography are negative and there
is a high clinical suspicion, poor imaging quality,
and the presence of prosthetic valves or an intra-
cardiac device, as well as in cases in which the
transthoracic echocardiographic findings are sug-
gestive of infective endocarditis but not definitive.
Combined transthoracic and transesophageal
echocardiography shows vegetations (Fig. 2) in
90% of cases, valve regurgitation in 60%, para-
valvular abscess in 20%,6,7 and infrequently, de-
hiscence of the prosthesis, pseudoaneurysms, and
fistulas. In cases with initially negative findings
on echocardiography, repeat examination should
be performed if infective endocarditis continues
to be suspected. Repeat transthoracic or trans-
esophageal echocardiography is recommended if
a new complication is suspected and when ther-
apy has been completed.

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 clinical pr actice
TREATMENT
The treatment of patients with suspected or con-
firmed infective endocarditis should be provided
by a multidisciplinary team with expertise in car-
diology, cardiac surgery, and infectious disease.28
Successful treatment is dependent on eradication
of the causative agent, which requires prolonged
bactericidal antibiotic treatment. Surgery may con-
tribute to this goal by removing infected material
and draining abscesses.
Antibiotic Treatment
Guidelines for appropriate antibiotic treatment of
infective endocarditis are published by profession-
al societies and updated regularly.29-31 Table 2 in
the Supplementary Appendix is adapted from the
European Society of Cardiology guidelines and
reviews antibiotic regimens recommended be-
fore an organism is identified and for most com-
mon causative bacteria.30
For native-valve infective endocarditis due to
common microorganisms, the duration of anti-
biotic treatment ranges from 2 weeks (for un-
complicated infective endocarditis due to fully
penicillin-susceptible streptococci treated with a
beta-lactam antibiotic combined with an amino-
glycoside) to 6 weeks (for enterococcal infective
endocarditis). For infective endocarditis involving
a prosthetic valve, the duration of antibiotic thera-
py is usually 6 weeks, and regimens are basi-
cally the same as those for native-valve infective
endocarditis, with the notable exception of staphy-
lococcal prosthetic-valve infective endocarditis,
for which the regimen should include both rif-
ampin, whenever the strain is susceptible to this
antibiotic, and gentamicin.
When valve replacement is performed during
antibiotic treatment of native-valve infective endo-
carditis, the duration of antibiotic therapy should
remain the same as the duration recommended
for native-valve infective endocarditis and should
not be switched to that recommended for pros-
thetic-valve infective endocarditis. In both na-
tive-valve and prosthetic-valve infective endocar-
ditis, the duration of treatment should be
calculated from the first day of appropriate anti-
biotic therapy, not from the day of surgery. After
surgery, a new full course of treatment should be
started only if valve cultures are positive.32
Among aminoglycosides, only gentamicin has
been fully evaluated for the treatment of infec-
tive endocarditis and should be used when the
disease is caused by gram-positive cocci. Clinical
n engl j med 368;15
nejm.org 55
LA
LV
Figure 2. Transesophageal Echocardiogram Showing
a Large Vegetation on a Native Mitral Valve.
A large vegetation (white arrow) can be seen near the
mitral valve (black arrow). LA denotes left atrium, and
LV left ventricle.
trials have shown that a 14-day course of genta-
micin, given once daily instead of twice daily, in
combination with ceftriaxone is effective for the
treatment of uncomplicated cases of streptococcal
infective endocarditis involving a native valve.33,34
Combination therapy with a beta-lactam antibi-
otic and an aminoglycoside should be used for
prosthetic-valve infective endocarditis (Table 2 in
the Supplementary Appendix).
In cases of enterococcal infective endocarditis,
whenever the strain does not exhibit high-level
resistance to gentamicin, that drug should be used
in combination with an antibiotic agent that is
active against the bacterial cell wall. Gentamicin
is generally given for the full 6-week course of
antibiotic treatment; however, in an observational
study, the cure rate of enterococcal infective endo-
carditis was as high as 81%, with a median dura-
tion of aminoglycoside administration of 15 days.
This suggests that shorter courses of aminogly-
cosides (2 to 3 weeks), which minimize the risk
of renal toxicity, may be effective.35 The question
of whether gentamicin should be administered
in divided daily doses continues to be debated;
clinical data are lacking, and experimental data
are conflicting. The combination of ampicillin
(at a dose of 12 g per 24 hours) with ceftriaxone
(at a dose of 2 g twice daily) may be effective in
infective endocarditis due to Enterococcus faecalis,
regardless of whether the strain is highly resis-
tant to gentamicin36 or not highly resistant.37
Gentamicin is no longer recommended for
staphylococcal infective endocarditis involving a
native valve, because there is no documented
clinical benefit and there is a risk of nephrotox-
nejm.org april 11, 2013 1429
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56 nejm readers’ choice clinical care
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n e w e ng l a n d j o u r na l
icity.38 In cases involving a prosthetic valve, how-
ever, a regimen that includes gentamicin for the
first 2 weeks is recommended, especially in cases
of methicillin-resistant S. aureus (MRSA) infection,
to mitigate the risk of selection of rifampin-
resistant escape mutants.
Daptomycin (at a dose of 6 mg per kilogram
of body weight per day, given once daily) was
approved by the Food and Drug Administration
for adults with S. aureus bacteremia and right-
sided infective endocarditis, on the basis of a
randomized trial showing its noninferiority to
standard therapy (vancomycin or an antistaphy-
lococcal penicillin).39 Observational studies have
also shown the efficacy of daptomycin in pa-
tients with left-sided infective endocarditis40
and in patients with infective endocarditis in-
volving an implanted intracardiac device (with
daptomycin used at a dose of 8 to 10 mg per
kilogram per day).41 Daptomycin has been recom-
mended as an alternative to vancomycin for the
treatment of adults with infective endocarditis
due to MRSA.42
Surgical Treatment
The rate of early valve replacement or repair (i.e.,
surgery performed during the course of antibi-
otic treatment for infective endocarditis) has in-
creased over the past three decades to approxi-
mately 50%.6,7 The main indications for early
valve surgery are heart failure, uncontrolled in-
fection, and prevention of embolic events (Table
2).30 Observational studies assessing associations
between the timing of surgery and outcomes
have yielded inconsistent results.14
In a recent randomized trial involving 76 pa-
tients with severe left-sided infective endocardi-
tis and a large vegetation but no indications for
emergency surgery at the time of randomization,
the incidence of the composite end point of in-
hospital death or embolic events within the first
6 weeks after randomization was significantly
lower among patients assigned to surgery within
48 hours after randomization than among those
assigned to usual care (3% vs. 23%); the benefit
was driven by the reduction in embolic events.43
However, it is unclear whether these results should
be generalized to support the routine use of early
valve surgery, because the patients enrolled in this
study were young (mean age, 47 years), with a low
frequency of coexisting conditions and very low Prophylaxis
mortality (<5%).
After a cerebral embolic event, most patients indications for antibiotic prophylaxis against infec-
1430 n engl j med 368;15
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of m e dic i n e
still have an indication for valve surgery. The
decision to proceed with surgery must take into
account the risk of further embolism and the
risks associated with surgery. The incidence of
stroke among patients receiving appropriate an-
timicrobial therapy decreases from 4.8 cases per
1000 patient-days in the first week of therapy to
1.7 per 1000 patient-days in the second week, with
further decreases thereafter.20 A history of em-
bolic stroke or transient ischemic attack is not in
itself a contraindication to surgery. Postoperative
neurologic deterioration is infrequent after a silent
cerebral embolism or a transient ischemic attack.
After an ischemic stroke, the risk associated with
surgery depends on the neurologic condition of
the patient19; generally, surgery is performed if
the patient does not have severe neurologic dam-
age, as long as cerebral hemorrhage has been
ruled out by means of cerebral imaging.30
Anticoagulant and Antiplatelet Therapies
Observational data have suggested an increased
risk of death from cerebral hemorrhage, with no
reduction in the risk of embolic events, in pa-
tients with prosthetic-valve infective endocarditis
due to S. aureus who were receiving treatment with
oral anticoagulant agents.44 European Society of
Cardiology guidelines currently recommend that
in patients already receiving oral anticoagulant
therapy in whom infective endocarditis develops
and is complicated by ischemic and nonhemor-
rhagic stroke, the oral anticoagulant agent be
replaced with heparin for 2 weeks; however, the
guidelines acknowledge the low level of evidence
supporting this recommendation.30
Antiplatelet agents are not recommended for
patients with infective endocarditis. In a double-
blind, placebo-controlled trial, patients with in-
fective endocarditis who were randomly assigned
to receive aspirin at a dose of 325 mg per day for
4 weeks had no significant decrease in the inci-
dence of embolic events and had a nonsignifi-
cant increase in the rate of cerebral bleeding
episodes.45 Observational studies have yielded
conflicting findings with respect to the associa-
tions of aspirin use before infective endocarditis
with risks of death and embolic events.46-49 In
the absence of bleeding, aspirin taken for other
indications may not need to be discontinued.
In the past decade, on the basis of expert opinion,
nejm.org april 11, 2013
 clinical pr actice nejm.org 57

Table 2. Indications for and Timing of Surgery in Patients with Left-Sided, Native-Valve Infective Endocarditis.*

Indication Timing of Surgery†

Heart failure
Aortic or mitral-valve infective endocarditis with severe acute regurgitation or obstruction caus- Emergency
ing refractory pulmonary edema or cardiogenic shock
Aortic or mitral-valve infective endocarditis with fistula into a cardiac chamber or pericardium Emergency
causing refractory pulmonary edema or cardiogenic shock
Aortic or mitral-valve infective endocarditis with severe acute regurgitation or obstruction and Urgent
persistent heart failure or signs of poor hemodynamic tolerance (early mitral-valve closure or
pulmonary hypertension)
Aortic or mitral-valve infective endocarditis with severe regurgitation and heart failure easily con- Elective
trolled with medical treatment
Uncontrolled infection
Locally uncontrolled infection (abscess, false aneurysm, fistula, enlarging vegetation, or dehis- Urgent
cence of prosthetic valve)
Persistent fever and positive blood cultures for >5–7 days Urgent
Infection caused by fungi or multidrug-resistant organisms, such as Pseudomonas aeruginosa Elective
and other gram-negative bacilli
Prevention of embolism
Aortic or mitral-valve infective endocarditis with large vegetations (>10 mm in length) after one Urgent
or more embolic episodes, despite appropriate antibiotic therapy, especially during the first
2 weeks of therapy
Aortic or mitral-valve infective endocarditis with large vegetations (>10 mm) and other predictors Urgent
of complicated course (heart failure, persistent infection, or abscess)
Isolated, very large vegetations (>15 mm); surgery may be preferred if a procedure preserving Urgent
the native valve is feasible

* Adapted from Habib et al.30

† Emergency surgery was defined as surgery performed within 24 hours after the condition was identified, urgent surgery
as that performed within a few days after the condition was identified, and elective surgery as that performed after at
least 1 or 2 weeks of antibiotic therapy.

tive endocarditis have been restricted to patients rifampin was reported to be effective for S. aureus
who have a prosthetic valve, a history of infective infective endocarditis in a study of intravenous-
endocarditis, or unrepaired cyanotic congenital drug users,54 oral therapy cannot currently be rec-
heart disease and who are planning to undergo an ommended for infective endocarditis.
invasive dental procedure; the recommended regi- Despite the recent randomized trial suggesting
mens are summarized in Table 3 in the Supple- a benefit of early surgery,43 the appropriate tim-
mentary Appendix.30,50 In the United Kingdom, ing of surgery remains controversial. When sur-
antibiotic prophylaxis against infective endocarditis
gery is performed within the first week of anti-
is no longer recommended in any circumstances.51 biotic treatment, there may be increased risks of
To date, reports indicate no appreciable increase inrelapse and prosthetic-valve dysfunction.55
the incidence of infective endocarditis due to viri- The usefulness of systematic brain imaging and
dans group streptococci since the guidelines were the preferred treatment of patients with infective
revised to recommend a restricted use of antibi- endocarditis and cerebral mycotic aneurysms are
otic prophylaxis.52,53 Good oral, dental, and skin also uncertain. Because unruptured aneurysms
hygiene are recommended to reduce risks. may resolve with antibiotic therapy alone,24 such
patients should receive antibiotics, with serial an-
A R E A S OF UNCER TA IN T Y giography performed to document the resolution
of the aneurysm. Endovascular treatment should
The appropriate duration of antibiotic therapy, es- be pursued only if the aneurysm is very large
pecially aminoglycosides, remains uncertain. Al- (e.g., >10 mm) or if it is not resolving or is en-
though a combination of oral ciprofloxacin and larging despite treatment with antibiotics.25

n engl j med 368;15 nejm.org april 11, 2013 1431

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58 nejm readers’ choice clinical care
T h ecollection
n e w e ng l a n d j o u r na l of m e dic i n e

GUIDEL INE S valve vegetation seen on the echocardiogram are

Guidelines addressing the prophylaxis and man-
agement of infective endocarditis have been pub-
lished by professional societies in the United States
and Europe.29-31 The recommendations presented
here are largely consistent with these guidelines.
C ONCLUSIONS
A ND R EC OM MENDAT IONS
The patient in the vignette has evidence of native
mitral-valve infective endocarditis complicated by
cerebral emboli. Antibiotic treatment should be
started immediately after two to three blood cul-
tures have been drawn. Pending culture results, an
aminopenicillin with beta-lactam inhibitor (either
ampicillin with sulbactam or amoxicillin with
clavulanate potassium)29,30 should be given in
combination with gentamicin. The recent cere-
bral embolic events and the large, mobile mitral-
indications for urgent mitral-valve surgery, in the
absence of contraindications. If blood cultures are
still negative at the time of surgery, a sample of
valve tissue should be obtained for culture, and a
broad-range PCR assay should be performed to
help identify the causative microorganism, with
adaptation of the antibiotic regimen to the iden-
tified microorganism. The patient should be coun-
seled concerning the prevention of recurrent in-
fective endocarditis (oral and overall hygiene and
appropriate use of antibiotic prophylaxis, given that
he will now have both a history of infective endo-
carditis and a prosthetic valve).
Dr. Duval reports receiving grant support through his institu-
tion from Pfizer and travel expenses from Roche. No other po-
tential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. L. Kritharides and Dr. R.W. Sy for sharing data
from the Australian population-based study on infective endo-
carditis.

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Copyright © 2013Massachusetts Medical Society.
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60 nejm readers’ choice
The n clinical
e w e ng l a n d care
j o u rcollection
na l o f m e dic i n e

clinical practice

Caren G. Solomon, M.D., M.P.H., Editor

Herpes Zoster
Jeffrey I. Cohen, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the author’s clinical recommendations.

A 65-year-old man presents with a rash of 2 days’ duration over the right forehead From the Medical Virology Section, Lab-
with vesicles and pustules, a few lesions on the right side and tip of the nose, and oratory of Infectious Diseases, National
Institutes of Health, Bethesda, MD. Ad-
slight blurring of vision in the right eye. The rash was preceded by tingling in the area dress reprint requests to Dr. Cohen at the
and is now associated with aching pain. How should this patient be evaluated and Laboratory of Infectious Diseases, Nation-
treated? al Institutes of Health, Bldg. 50, Rm. 6134,
50 South Dr., MSC1807, Bethesda, MD
20892-1807, or at jcohen@niaid.nih.gov.
The Cl inic a l Probl em N Engl J Med 2013;369:255-63.
DOI: 10.1056/NEJMcp1302674
Primary infection with varicella–zoster virus (VZV) results in chickenpox, charac- Copyright © 2013 Massachusetts Medical Society.
terized by viremia with a diffuse rash and seeding of multiple sensory ganglia,
where the virus establishes lifelong latency. Herpes zoster is caused by reactivation
of latent VZV in cranial-nerve or dorsal-root ganglia, with spread of the virus along
the sensory nerve to the dermatome. There are more than 1 million cases of herpes
zoster in the United States each year, with an annual rate of 3 to 4 cases per 1000
persons. Studies suggest that the incidence of herpes zoster is increasing.1 Unvac-
cinated persons who live to 85 years of age have a 50% risk of herpes zoster. Up to
3% of patients with the disease require hospitalization.
The major risk factor for herpes zoster is increasing age. With increasing time
after varicella infection, there is a reduction in the level of T-cell immunity to VZV,2 An audio version
of this article is
which, unlike levels of virus-specific antibodies, correlates with protection against available at
herpes zoster. The risk is higher for women than for men, for whites than for blacks, NEJM.org
and for persons with a family history of herpes zoster than for those without such
a background.3 Chickenpox that occurs in utero or early in infancy, at a time when
the cellular immune system is not fully mature, is associated with herpes zoster in
childhood. Immunocompromised persons with impaired T-cell immunity, includ-
ing recipients of organ or hematopoietic stem-cell transplants, those receiving im-
munosuppressive therapy, and those with lymphoma, leukemia, or human immu-
nodeficiency virus (HIV) infection, are at increased risk for herpes zoster and for
severe disease.
Postherpetic neuralgia, or pain persisting after the rash has resolved (often de-
fined specifically as pain persisting for 90 days or more after the onset of the rash),
is a feared complication of herpes zoster. The pain may persist for many months or
even years; it may be severe and interfere with sleep and activities of daily living,
resulting in anorexia, weight loss, fatigue, depression, withdrawal from social ac-
tivities and employment, and loss of independent living. Depending on age and the
definition used, postherpetic neuralgia develops in 10 to 50% of persons with
herpes zoster. The risk increases with age (particularly after 50 years of age) and
is also increased among persons with severe pain at the onset of herpes zoster or
with a severe rash and a large number of lesions.
Various neurologic complications have been reported to occur with herpes zos-

n engl j med 369;3 nejm.org july 18, 2013 255

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 61

key Clinical points

herpes zoster
• In the absence of the herpes zoster vaccine, persons who live to 85 years of age have a 50% risk of her-
pes zoster.
• The persons most likely to benefit from antiviral therapy for herpes zoster are those who have or are at
risk for complications of herpes zoster, including immunocompromised persons, those 50 years of age
or older, and those with severe pain or severe rash.
• Antiviral agents hasten the resolution of herpes zoster lesions and decrease the severity of acute pain
but have not been shown to reduce the risk of postherpetic neuralgia.
• Valacyclovir or famciclovir is preferable to acyclovir because of ease of dosing and higher levels of anti-
viral drug activity.
• Patients with herpes zoster and new visual symptoms should be evaluated by an ophthalmologist to
determine whether eye-specific therapy is needed.
• The herpes zoster vaccine is recommended by the Advisory Committee on Immunization Practices for
persons 60 years of age or older and is used in those with or without a history of herpes zoster.

ter, including Bell’s palsy, the Ramsay Hunt syn- Depending on the location and severity, this pro-
drome, transverse myelitis, transient ischemic dromal pain may lead to misdiagnosis and costly
attacks, and stroke.4 In addition, ophthalmologic testing. The rash begins as macules and papules,
complications of herpes zoster occurring in the which evolve into vesicles and then pustules (Fig.
V1 distribution of the trigeminal nerve can include 1B). New lesions appear over a period of 3 to 5 days,
keratitis, scleritis, uveitis, and acute retinal ne- often with filling in of the dermatome despite
crosis (Table 1). Immunocompromised persons antiviral treatment. The rash usually dries with
can have additional complications, including dis- crusting in 7 to 10 days. Some persons have pain
seminated skin disease, acute or progressive outer in the absence of a rash, termed zoster sine herpete,
retinal necrosis, chronic herpes zoster with verru- which is difficult to diagnose and may lead to
cous skin lesions, and development of acyclovir- numerous unnecessary tests or procedures. Im-
resistant VZV. In these patients, the disease can munocompromised patients may have dissemi-
nated rashes with viremia and new lesions occur-
involve multiple organs (e.g., lung, liver, brain, and
gastrointestinal tract), and patients may present ring for up to 2 weeks. The characteristics of
with hepatitis or pancreatitis several days before pain associated with herpes zoster vary. Patients
the rash appears.5 may have paresthesias (e.g., burning and tingling),
dysesthesia (altered or painful sensitivity to touch),
S t r ategie s a nd E v idence allodynia (pain associated with nonpainful stim-
uli), or hyperesthesia (exaggerated or prolonged
Symptoms response to pain). Pruritus is also commonly as-
The rash of herpes zoster is dermatomal and does sociated with herpes zoster.
not cross the midline, a feature that is consistent
with reactivation from a single dorsal-root or Diagnosis
cranial-nerve ganglion. The thoracic, trigeminal Most cases of herpes zoster can be diagnosed
(Fig. 1A), lumbar, and cervical dermatomes are clinically, although atypical rashes may require a
the most frequent sites of rash, although any area direct immunofluorescence assay for VZV antigen
of the skin can be involved. In nonimmunocom- or a polymerase-chain-reaction (PCR) assay for
promised persons, a few scattered lesions outside VZV DNA in cells from the base of lesions after
the affected dermatome are not unexpected. The they are unroofed. In a study comparing PCR
rash is often preceded by tingling, itching, or pain with other diagnostic methods, the sensitivity and
(or a combination of these) for 2 to 3 days, and specificity of PCR for detecting VZV DNA were
these symptoms can be continuous or episodic. 95% and 100%, respectively, whereas the values

56 n engl j med 369;3 nejm.org july 18, 2013

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62 nejm readers’ choice clinical care collectionclinical pr actice

Table 1. Selected Complications of Herpes Zoster in Nonimmunocompromised Persons.*

Complication Manifestations Site of VZV Reactivation

Aseptic meningitis
Bacterial superinfection
Bell’s palsy
Eye involvement (herpes zoster
ophthalmicus)
Hearing impairment
Motor neuropathy
Postherpetic neuralgia
Ramsay Hunt syndrome
Transverse myelitis
Vasculopathy (encephalitis)
Headache, meningismus Cranial nerve V
Streptococcus, staphylococcus cellulitis Any sensory ganglia
Unilateral facial paralysis Cranial nerve VII
Keratitis, episcleritis, iritis, conjunctivi- Cranial nerve II, III, or V (ophthalmic
tis, uveitis, acute retinal necrosis, [V1] branch)
optic neuritis, acute glaucoma
Deafness Cranial nerve VIII
Weakness, diaphragmatic paralysis, Any sensory ganglia
neurogenic bladder
Pain persisting after the rash has resolved Any sensory ganglia
Ear pain and vesicles in the canal, Cranial nerve VII geniculate ganglia,
numbness of anterior tongue, with spread to cranial nerve VIII
facial paralysis
Paraparesis, sensory loss, sphincter Vertebral ganglia
impairment
Vasculitis of cerebral arteries, confu- Cranial nerve V
sion, seizures, TIAs, stroke

* TIA denotes transient ischemic attack, and VZV varicella–zoster virus.

for immunofluorescence testing for VZV antigen Other persons might also benefit from antiviral
were 82% and 76%.6 The condition that is most therapy, although they have a lower risk of com-
commonly mistaken for herpes zoster is herpes plications from herpes zoster. Three guanosine
analogues — acyclovir, valacyclovir, and famci-
simplex virus infection, which can recur in a der-
matomal distribution; accordingly, when patients clovir — have been approved by the Food and
present with “recurrent zoster” or atypical lesions
Drug Administration (FDA) for the treatment of
or are immunocompromised with disseminated herpes zoster (Table 3). The oral bioavailability
skin lesions, specific testing for both VZV and and levels of antiviral drug activity in the blood
herpes simplex virus is often useful. VZV has been
are higher and more consistent in patients receiv-
detected in the saliva of persons with herpes zos-
ing thrice-daily valacyclovir or famciclovir than
ter,7 although such testing does not currently in those receiving acyclovir five times daily. This
have a demonstrated role in clinical practice. is important because VZV is less sensitive than
A PCR assay of the cerebrospinal fluid (CSF) herpes simplex virus to acyclovir, valacyclovir, and
has been used for the diagnosis of central nervous
famciclovir.
system (CNS) vasculopathy; evidence of an increase These antiviral agents hasten the resolution
in the ratio of the anti-VZV antibody level in the
of lesions, reduce the formation of new lesions,
CSF to that in the blood is more sensitive.4 A PCR
reduce viral shedding, and decrease the severity
assay of the blood may be helpful for the diag- of acute pain (Table 3). For example, in the largest
nosis of visceral herpes zoster in immunocom- randomized, double-blind trial of acyclovir for
promised persons who present with hepatitis or herpes zoster, oral acyclovir given within 47 hours
pancreatitis in the absence of a rash.5 A PCR as-after the onset of rash shortened the mean time
say for VZV in the blood or CSF has been used forto the last day of new-lesion formation, the loss
the diagnosis of zoster sine herpete. of vesicles, and full crusting by 0.5 days, 1.8 days,
and 2.2 days, respectively, as compared with
Treatment and Prevention placebo.10 In another large trial, acyclovir re-
Antiviral Therapy duced the duration of viral shedding by 0.8 days
Antiviral therapy is recommended for herpes zos- as compared with placebo.11 In a meta-analysis of
ter in certain nonimmunocompromised patients several randomized, controlled trials, antiviral
and all immunocompromised patients (Table 2). agents did not significantly reduce the incidence

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 The n e w e ng l a n d j o u r na l
A Table 2. Indications for Antiviral Treatment in Patients
B zoster are present, treatment should be initiated
Figure 1. Clinical Features of Herpes Zoster.
Panel A shows herpes zoster in the ophthalmic (V1)
branch of the trigeminal ganglia. Photograph courtesy
of Michael Oxman, M.D. Panel B shows vesicles and
pustules in a patient with herpes zoster. These are
representative photographs and are not from the case
presented.
of postherpetic neuralgia,20 and they are not ap-
proved for the prevention of the condition by the
FDA. In some studies, treatment with either va-
lacyclovir or famciclovir has been shown to be
superior to treatment with acyclovir for reducing
pain associated with herpes zoster.14,15 Valacy-
clovir is similar to famciclovir in terms of effi-
cacy in reducing acute pain and accelerating
healing.21 As compared with acyclovir, valacyclo-
vir and famciclovir require fewer daily doses but
are more expensive.
In controlled trials, treatment has been initi-
58 n engl j med 369;3
of m e dic i n e nejm.org 63
with Herpes Zoster.*
Age ≥50 yr
Moderate or severe pain
Severe rash
Involvement of the face or eye
Other complications of herpes zoster
Immunocompromised state
* Although antiviral agents may benefit other patients with
herpes zoster, they are primarily recommended by experts
for patients with these indications who either have com-
plications or are at increased risk for complications from
herpes zoster.8,9
ated within 72 hours after the onset of the rash,
and it is recommended that treatment start as
early as possible within this interval. However,
many experts recommend that if new skin lesions
are still appearing or complications of herpes
even if the rash began more than 3 days earlier.
Treatment is usually given for 7 days in the ab-
sence of complications of herpes zoster. Intrave-
nous acyclovir is recommended for immunocom-
promised persons who require hospitalization and
for persons with severe neurologic complications.
Foscarnet is used for immunocompromised pa-
tients with acyclovir-resistant VZV.
Glucocorticoids
The use of glucocorticoids with antiviral therapy
for uncomplicated herpes zoster remains contro-
versial. Randomized, controlled trials have shown
benefits of a tapering course of predisone22 or
prednisolone,12 including a reduction in acute
pain,12,22 improved performance of activities of
daily living,22 accelerated early healing,12 and in
one study22 but not another,12 a reduction in the
time to complete healing. The addition of gluco-
corticoids to antiviral therapy has not been shown
to reduce the incidence of postherpetic neuralgia.
Owing to their immunosuppressive properties,
glucocorticoids should not be administered for
herpes zoster without concomitant antiviral ther-
apy. Glucocorticoids should be avoided in patients
with hypertension, diabetes mellitus, peptic ulcer
disease, or osteoporosis; particular caution is war-
ranted in the case of elderly patients, who are at
increased risk for serious adverse events. Predni-
sone is used for the treatment of certain CNS com-
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64 nejm readers’ choice clinical care collection
clinical pr actice

Table 3. Antiviral Therapy for Herpes Zoster.

Medication Dose Effects Observed in Controlled Trials Side Effects

Nonimmunocompromised persons
Acyclovir (e.g., Zovirax)
Famciclovir (e.g., Famvir)
Valacyclovir (e.g., Valtrex)
Brivudin (e.g., Zostex,
Helpin)*
Immunocompromised persons
requiring hospitalization or persons
with severe neurologic complications
Acyclovir (e.g., Zovirax)
Foscarnet (e.g., Foscavir) for
acyclovir-resistant VZV†
800 mg orally five times daily Reduced time to last new-lesion formation,
for 7–10 days
500 mg orally three times
daily for 7 days
1 g orally three times daily
for 7 days
125 mg orally once daily
for 7 days
10 mg/kg intravenously
every 8 hr for 7–10 days
40 mg/kg intravenously
every 8 hr until lesions
are healed
Malaise
loss of vesicles, full crusting, cessation
of viral shedding, reduced severity of
acute pain10-12
Reduced time to last new-lesion formation, Headache, nausea
loss of vesicles, full crusting, cessation
of viral shedding, cessation of pain13,14
Reduced time to last new-lesion formation, Headache, nausea
loss of vesicles, full crusting, cessation
of pain15,16
Reduced time to last new-lesion formation, Headache, nausea; contraindi-
full crusting, cessation of pain17 cated in persons receiving
fluorouracil or other fluoro-
pyrimidines
Reduced time to last new-lesion formation, Renal insufficiency
full crusting, cessation of viral shedding,
cessation of pain, reduced cutaneous
dissemination, reduced visceral herpes
zoster18,19
Not reported Renal insufficiency, hypokale-
mia, hypocalcemia, hypo-
magnesemia, hypophospha-
temia, nausea, diarrhea,
vomiting, anemia, granulocy-
topenia, headache

* Brivudin is not available in the United States and has not been approved by the Food and Drug Administration (FDA).
† Foscarnet is not approved for this use by the FDA.

plications of herpes zoster, such as vasculopathy or shown to be effective in randomized, controlled

Bell’s palsy in nonimmunocompromised patients. clinical trials for acute pain associated with her-
pes zoster, they have been used when opioids were
Acute Pain Associated with Herpes Zoster insufficient for pain.
Several medications have been used for the treat-
ment of acute pain associated with herpes zoster Eye Disease Associated with Herpes Zoster
(Table 4). Nonsteroidal antiinflammatory drugs Patients with herpes zoster in the V1 distribution
or acetaminophen can be administered in patients of the trigeminal nerve (including lesions on the
with mild pain. Opioids, such as oxycodone, are forehead and the upper eyelid) and either lesions
used for more severe pain associated with herpes on the tip or side of the nose or new visual symp-
zoster. Opioids were more effective than gabapen- toms should be evaluated by an ophthalmologist.
tin for herpes zoster–related pain in a random- Other treatment may be needed in addition to
ized, placebo-controlled trial.23 In one controlled antiviral therapy, including mydriatic eyedrops to
trial24 but not another,23 gabapentin reduced pain dilate the pupil and reduce the risk of scarring
associated with herpes zoster. Lidocaine patches (synechiae); topical glucocorticoids for keratitis,
reduced pain associated with herpes zoster in a episcleritis, or iritis; medications to reduce intra-
placebo-controlled trial; they should be applied ocular pressure for the treatment of glaucoma;
to intact skin only, not to the area of the rash.25 and intravitreal antiviral therapy for immuno-
Although tricyclic antidepressants have not been compromised patients with retinal necrosis.

n engl j med 369;3 nejm.org july 18, 2013 259

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 Table 4. Medications Commonly Used for Treatment of Acute Pain Associated with Herpes Zoster.*

Medication Dose Dose Adjustment Maximum Dose Side Effects

Opioid and nonopioid analgesics
Oxycodone 5 mg every 4 hr as needed Increase by 5 mg four times daily every None specified, but should not exceed Drowsiness, dizziness, con-
2 days as tolerated 120 mg daily except in consultation stipation, nausea, vom-
with a pain specialist iting
Tramadol 50 mg once or twice daily Increase by 50–100 mg daily in divided 400 mg daily; 300 mg daily if patient is Drowsiness, dizziness, con-
The

doses every 2 days as tolerated >75 years of age stipation, nausea, vom-
iting
Glucocorticoids†
Prednisone 60 mg daily for 7 days, then decrease None 60 mg daily Gastrointestinal distress,
to 30 mg daily for 7 days, then de- nausea, vomiting, mood
crease to 15 mg daily for 7 days changes, edema, glu-
cose intolerance, in-

n engl j med 369;3

creased blood pressure
Anticonvulsants
Gabapentin 300 mg at bedtime or 100–300 mg Increase by 100–300 mg three times 3600 mg daily Drowsiness, dizziness, atax-

nejm.org
three times daily daily every 2 days as tolerated ia, peripheral edema
n e w e ng l a n d j o u r na l

Pregabalin 75 mg at bedtime or 75 mg twice daily Increase by 75 mg twice daily every 600 mg daily Drowsiness, dizziness, atax-
of

3 days as tolerated ia, peripheral edema

Tricyclic antidepressants

july 18, 2013

Nortriptyline 25 mg at bedtime Increase by 25 mg daily every 2–3 days 150 mg daily Drowsiness, dry mouth,
as tolerated blurred vision, weight
m e dic i n e

gain, urinary retention

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Topical therapy
Lidocaine patch (5%) One patch, applied to intact skin only, None One patch for up to 12 hr per day Local irritation; if systemic,
for up to 12 hr per day absorption can cause
drowsiness, dizziness

* This table provides examples and is not meant to be comprehensive. Modified from Dworkin et al.8 by permission of Oxford University Press.
† The use of glucocorticoids is controversial because they are often associated with adverse events in older patients.
nejm.org
65
66 nejm readers’ choice clinical care collectionclinical pr actice

Postherpetic Neuralgia ter (at a mean of 3.6 years before vaccination) and
Pain associated with postherpetic neuralgia is among those with no history of the disease.38
often challenging to treat. A detailed discussion The optimal timing of vaccination after an
of the management of postherpetic neuralgia is episode of herpes zoster is uncertain. Because the
beyond the scope of this article. In brief, medica- risk of recurrent herpes zoster after a recent epi-
tions shown in randomized trials to reduce pain sode of the disease is relatively low39 and because
associated with postherpetic neuralgia include the cellular immune response to VZV during the
topical lidocaine,26 anticonvulsant agents (e.g., first 3 years after vaccination is similar to that after
gabapentin27 and pregabalin28), opioids,29 tricyclic an episode of herpes zoster,40 one might delay
antidepressants (e.g., nortriptyline30), and capsa- vaccination for 3 years in immunocompetent
icin.31 Combination therapy, such as gabapentin persons with a recent history of herpes zoster,
and nortriptyline32 or an opiate and gabapentin,33 provided that the diagnosis of herpes zoster has
have been more effective for postherpetic neural- been well documented by a health care provider.
gia than single-agent therapy but also confer a The vaccine is contraindicated in persons with
greater risk of side effects. Even with treatment, hematologic cancers whose disease is not in re-
many patients do not have adequate relief of pain, mission or who have received cytotoxic chemo-
and for such patients, referral to a pain specialist therapy within 3 months, in persons with T-cell
can be helpful. immunodeficiency (e.g., HIV infection with a CD4
cell count of ≤200 per cubic millimeter or <15%
Prevention of Herpes Zoster of total lymphocytes), and in those receiving
A live attenuated herpes zoster vaccine is recom- high-dose immunosuppressive therapy (e.g.,
mended by the Advisory Committee on Immuni- ≥20 mg of prednisone daily for ≥2 weeks or
zation Practices for persons 60 years of age or anti–tumor necrosis factor therapy).
older to prevent herpes zoster and its complica-
tions, including postherpetic neuralgia.9,34 On the Infection Control
basis of the results of a recent clinical trial, the Although herpes zoster is less contagious than
vaccine is now approved by the FDA to prevent varicella, patients with herpes zoster can trans-
herpes zoster in persons 50 years of age or old- mit VZV to susceptible persons, in whom vari-
er.35 The efficacy of the vaccine in preventing cella may develop. For nonimmunocompromised
herpes zoster is 70% for persons 50 to 59 years of persons with dermatomal herpes zoster, contact
age, 64% for persons 60 to 69 years of age, and precautions should be used, and lesions should
38% for persons 70 years of age or older.34-36 be covered if possible.41 Despite these measures,
However, vaccine efficacy in preventing posther- viral transmission has occasionally been reported
petic neuralgia is 66% for persons 60 to 69 years in such patients.42 For persons with disseminat-
of age and is undiminished at 67% for persons ed lesions and for immunocompromised persons
70 years of age or older.34,36 Although the effec- with herpes zoster, airborne and contact precau-
tiveness of the vaccine to prevent herpes zoster is tions are required until all lesions have crusted.
reduced in persons 70 years of age or older, the
increased risk of severe disease and the persisting A r e a s of Uncer ta in t y
efficacy of the vaccine in preventing postherpetic
neuralgia in these older persons strongly favor Improved therapies are needed for pain associ-
vaccinating them. A follow-up study showed that ated with herpes zoster and postherpetic neural-
the reduction in the risk of herpes zoster remained gia and to prevent the development of postherpetic
significant for at least 5 years after vaccination, neuralgia. In addition, studies are needed to deter-
though the effectiveness declined over time.37 In mine which patients are at highest risk for posther-
vaccinated (as compared with unvaccinated) per- petic neuralgia so that more aggressive therapy
sons in whom herpes zoster developed, pain was can be given. There is uncertainty regarding the
significantly shorter in duration and less severe.34 safety and effectiveness of the vaccine in persons
The vaccine can be given to persons with a his- with immunocompromising conditions that are
tory of herpes zoster. In a recent study, rates of currently considered contraindications to vacci-
adverse events associated with vaccination were nation, the duration of immunity induced by the
similar among persons who had had herpes zos- vaccine, and the need for booster doses.

n engl j med 369;3 nejm.org july 18, 2013 26

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 67

Guidel ine s rash. Valacyclovir or famciclovir is preferred over

Recommendations have been developed for the
management of herpes zoster by a group of ex-
perts8 and for the prevention of herpes zoster by
the Advisory Committee on Immunization Prac-
tices.9 The present review is generally concordant
with these recommendations.
C onclusions a nd
R ec om mendat ions
Whereas herpes zoster is often mild in healthy
young persons, older persons are at increased
risk for pain and complications, including
postherpetic neuralgia, ocular disease, motor
neuropathy, and CNS disease. In the vast major-
ity of cases, the diagnosis can be made clinically.
Antiviral therapy is most beneficial for persons
who have complications of herpes zoster or who
are at increased risk for complications, such as
older persons and immunocompromised per-
sons, and should be initiated as soon as possible,
generally within 72 hours after the onset of the
acyclovir owing to the reduced frequency of dos-
ing and higher levels of antiviral drug activity.
The patient described in the vignette should re-
ceive oral antiviral therapy, medication for pain
(e.g., an opioid, with the addition of gabapentin
if needed), and prompt referral to an ophthal-
mologist. He should also be advised to avoid con-
tact with persons who have not had varicella or
have not received the varicella vaccine until his
lesions have completely crusted. I would recom-
mend herpes zoster vaccination to reduce the
risk of recurrence, but in an immunocompetent
patient such as this one, I would defer vaccina-
tion for approximately 3 years, since the current
episode of herpes zoster should boost his cellular
immune response to VZV for that period of time.
The views expressed here are those of the author and not
necessarily those of the U.S. government.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
I thank Drs. Adriana Marques and Michael Oxman for their
comments on an earlier version of the manuscript.

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Clin Infect Dis 2012;55:1320-8.
38. Morrison VA, Oxman MN, Levin MJ,
et al. Safety of zoster vaccine in elderly
adults following documented herpes zos-
ter. J Infect Dis 2013 May 31 (Epub ahead
of print).
39. Tseng HF, Chi M, Smith N, Marcy SM,
Sy LS, Jacobsen SJ. Herpes zoster vaccine
and the incidence of recurrent herpes zos-
ter in an immunocompetent elderly popu-
lation. J Infect Dis 2012;206:190-6.
40. Weinberg A, Zhang JH, Oxman MN,
et al. Varicella-zoster virus-specific im-
mune responses to herpes zoster in el-
derly participants in a trial of a clinically
effective zoster vaccine. J Infect Dis
2009;200:1068-77.
41. Siegel JD, Rhinehart E, Jackson M,
Chiarello L. 2007 Guideline for isolation
precautions: preventing transmission of
infectious agents in health care settings.
Am J Infect Control 2007;35:Suppl 2:S65-
S164.
42. Lopez AS, Burnett-Hartman A, Nam-
biar R, et al. Transmission of a newly
characterized strain of varicella-zoster vi-
rus from a patient with herpes zoster in a
long-term-care facility, West Virginia,
2004. J Infect Dis 2008;197:646-53.
Copyright © 2013 Massachusetts Medical Society.

images in clinical medicine

The Journal welcomes consideration of new submissions for Images in Clinical
Medicine. Instructions for authors and procedures for submissions can be found
on the Journal’s website at NEJM.org. At the discretion of the editor, images that
are accepted for publication may appear in the print version of the Journal,
the electronic version, or both.

n engl j med 369;3 nejm.org july 18, 2013 26

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 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 69

clinical practice
Caren G. Solomon, M.D., M.P.H., Editor

Carotid Stenosis
James C. Grotta, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the author’s clinical recommendations.

A 53-year-old woman who smoked and had hypertension had brief numbness of the
right side of her body. Six months later, aphasia and right hemiparesis suddenly devel-
oped, and they resolved after 48 hours. Computed tomographic angiography (CTA)
showed left internal-carotid-artery stenosis of 70% just distal to the bifurcation. Mag-
netic resonance imaging (MRI) confirmed a left frontotemporal infarct without hem-
orrhagic transformation or cerebral edema. Cardiac evaluation was normal. What is
the appropriate management of this patient’s carotid stenosis?

The Cl inic a l Probl em

Carotid artery disease causes approximately 10 to 20% of strokes, and appropriate From the University of Texas Medical
intervention is important for secondary and possibly primary stroke prevention. School at Houston. Address reprint re-
quests to Dr. Grotta at the Department of
The degree of carotid stenosis is the strongest determinant of stroke risk. Neurology, University of Texas Medical
School at Houston, 6431 Fannin St., 7.044,
Atherosclerosis Houston, TX 77030, or at james.c.grotta@
uth.tmc.edu.
Atherosclerosis, the most common disease affecting the carotid artery, occurs most
frequently at its bifurcation (Fig. 1A and 1B). Atherosclerotic plaques cause symp- N Engl J Med 2013;369:1143-50.
DOI: 10.1056/NEJMcp1214999
toms most often through distal embolism to branches of the retinal or cerebral Copyright © 2013 Massachusetts Medical Society.
arteries; hemodynamically significant luminal stenosis may also result in critical
reduction of perfusion.
Most emboli result from activation of platelets on the plaque surface; less fre-
quently, they result from cholesterol particles. An “unstable plaque” with rupture
of the cap may cause emboli.1 Emboli in retinal arterioles lead to transient mon- An audio version
ocular blindness (amaurosis fugax).2 Emboli in the cerebral circulation most often of this article is
available at
lodge in the middle cerebral-artery branches, but they can also end up in anterior
NEJM.org
or posterior cerebral-artery branches, depending on the anatomy of the circle of
Willis. If patients who have had a stroke attributed to carotid disease are ques-
tioned closely, at least 50% report symptoms preceding the stroke that are consis-
tent with a transient ischemic attack (TIA).3 Stroke syndromes related to carotid
disease involve some combination of motor or sensory symptoms (involving the
contralateral face, arm, or leg) or speech, language, or visual symptoms.
Reduction of flow due to high-grade stenosis causes symptoms referable to
brain regions at the border zones between the anterior, middle, and posterior cere-
bral arteries, where perfusion pressure is the lowest and most vulnerable to further
reduction by proximal stenosis.4 Such lesions often cause repetitive TIAs that are
brief (<1 minute), sometimes with limb shaking, as compared with embolic TIAs,
which tend to be longer (5 to 30 minutes).5 Border-zone (“watershed”) infarcts can
be distinguished from embolic infarcts on brain imaging (see Fig. S1a and S1b in the
Supplementary Appendix, available with the full text of this article at NEJM.org).

n engl j med 369;12 nejm.org september 19, 2013 1143

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70 nejm readers’ choice clinical care
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n e w e ng l a n d j o u r na l of m e dic i n e

key Clinical points

CAROTID STENOSIS
• Carotid artery disease is a common cause of stroke and should be assessed by means of one of
several readily available noninvasive tests in all patients who have had a transient ischemic attack
(TIA) or stroke in the carotid-artery distribution.

• Control of smoking, hypertension, and hyperlipidemia and the use of an antiplatelet agent are in-
dicated to reduce the risk of stroke among persons with carotid artery disease.

• In patients with an ischemic stroke or a TIA in the carotid-artery distribution, carotid endarterectomy
should be considered within 2 weeks if there is stenosis of more than 70% of the diameter of the ipsi-
lateral carotid artery (measured according to the method used in the North American Symptomatic
Carotid Endarterectomy Trial) due to atherosclerosis. There is less benefit in patients with stenosis of 50
to 69% and in asymptomatic patients, and there is no benefit in patients with stenosis of less than 50%.

• Carotid stenting is an alternative to carotid endarterectomy, particularly in patients at high surgical

risk and in younger patients (<70 years of age).

The prognosis for patients with carotid disease is
most closely linked to the degree of stenosis, with
a 2-mm residual luminal diameter or a 60 to 70%
reduction in diameter associated with a marked
increase in the risk of stroke.6 Plaque ulcerations
are common, but they do not strongly correlate
with subsequent ipsilateral ischemic stroke.7
Whereas total occlusion of the carotid in some
patients results in a devastating stroke, it can be
asymptomatic in patients with adequate collateral
flow to the intracranial arteries.8 The contralateral
carotid provides collateral flow through the an-
terior communicating artery (Fig. S2 in the Sup-
plementary Appendix). Consequently, contralat-
eral carotid stenosis or occlusion is an important
determinant of risk that should be considered in
planning treatment. Carotid siphon atherosclero-
sis can also cause TIAs and strokes.9
Dissection and Fibromuscular Dysplasia
Dissection of the carotid artery is a common
cause of stroke in patients younger than 45 years
of age, and it is frequently detected by means of
noninvasive vascular imaging.10,11 Carotid dissec-
tion usually occurs about 2 cm distal to the bifur-
cation (Fig. S3a in the Supplementary Appendix),
and it may be related to trauma to the artery by
the transverse processes of the C2 and C3 verte-
brae or the styloid process. Dissection, which can
occur spontaneously, is due to a hematoma in the
tunica media that ruptures through the intima and
compromises the arterial lumen. If the dissection
extends toward the adventitia, a dissecting aneu-
rysm (often erroneously called a pseudoaneurysm)
can develop, but these aneurysms rarely bleed un-
less the dissection extends intracranially. Consid-
erable ipsilateral neck, facial, or head pain occurs
in more than 60% of dissections, and if such pain
is present after trauma or in association with a TIA
or stroke, dissection should be suspected. Horner’s
syndrome may also be present as a result of in-
jured sympathetic nerves in the arterial wall, and
lower cranial nerves may be compressed. Genetic
collagen abnormalities such as the Ehlers–Danlos
syndrome (type IV) should be considered in pa-
tients with spontaneous dissection.
Fibromuscular dysplasia is twice as common in
women as in men,11 and it is marked by fibrotic
thickening of the arterial wall, most often the me-
dia (Fig. S3b in the Supplementary Appendix).
Fibromuscular dysplasia is associated with intra-
cranial aneurysms and carotid dissection. Both
dissection and fibromuscular dysplasia can cause
strokes due to embolization or hemodynamically
significant narrowing of the luminal diameter.
Other, less common arterial diseases are be-
yond the scope of this review. Coiling, looping,
and kinking of the extracranial carotids are com-
mon but rarely of pathologic significance.12
S t r ategie s a nd E v idence
Diagnosis
A carotid bruit may signal the presence of clini-
cally significant internal carotid artery disease; this
finding is present in 70 to 89% of patients with a

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 clinical pr actice nejm.org 71

Figure 1. Atherosclerosis at the Bifurcation of the Ca- A

rotid Artery in the Patient in the Case Vignette.
Panel A shows a cerebral arteriogram indicating ste-
notic plaque (arrow) before stenting. Panel B shows a
three-dimensional reconstruction of the angiogram.
Panel C shows calculation of the percentage of steno-
sis with the use of the North American Symptomatic
Carotid Endarterectomy Trial criteria. The minimal di-
ameter (X3) is 0.89 mm, and the distal diameter (X2)
is 3.30 mm. The percentage of stenosis is calculated as
[1 − (X3 ÷ X2)] × 100, which in this case is 73%. Imag-
es courtesy of Peng Chen, M.D.

2-mm luminal narrowing. However, a bruit is a

nonspecific finding, since it is heard in 5% of pa-
tients who are 45 to 80 years of age in the absence
of clinically significant internal carotid disease.13
The various tests for evaluating carotid disease B
are listed in Table 1. The most common screening
test is duplex Doppler ultrasonography (Fig. 2).
Ultrasonography is highly accurate in identifying
calcification of carotid-artery plaque and intra-
plaque hemorrhage and measuring the degree of
stenosis,14 and it is indicated in patients who have
had ischemic symptoms in the carotid-artery dis-
tribution or who have a carotid bruit and would
be candidates for intervention. A peak systolic ve-
locity in excess of 200 cm per second usually in-
dicates stenosis of 50% or more.15
CTA (Fig. 3) and magnetic resonance angiog-
raphy (MRA) are widely used to evaluate the ca-
rotid artery.16,17 Carotid Doppler ultrasonography
with either CTA or MRA may be sufficient for
making clinical decisions about the management
of carotid disease. However, in some cases, ce- C
rebral angiography may be necessary to provide
additional anatomical detail18 (Fig. 1A and 1B).
The most important information gained from
each of these tests is the percentage of stenosis.
The measurement method used in the North
American Symptomatic Carotid Endarterectomy
Trial (NASCET)19 is used most widely (Fig. 1C).
The diameter of the smallest residual lumen is
compared with the diameter of the normal artery
distal to the carotid bifurcation, according to the
following formula: the percentage of stenosis =
[1 − (minimal diameter ÷ distal diameter)] × 100.
Imaging also identifies the location of the bifur-
cation in relation to the angle of the jaw, the
extent of plaque, distal arterial tortuosity or ste-
nosis, and the status of contralateral carotid and

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72 nejm readers’ choice clinical care
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n e w e ng l a n d j o u r na l
Table 1. Tests to Detect Carotid Stenosis.
Test Feasibility
Ultrasonography Widely available, rapidly
performed
Magnetic resonance Requires patient to be
angiography immobile for duration
of test; not feasible in
patients with metallic
implants or in severely
obese patients
Computed tomographic Widely available, rapidly
angiography performed
Catheter angiography Requires angiography team
collateral flow, and it can usually be used to dis-
tinguish atherosclerosis from other conditions
(Fig. S3a and S3b in the Supplementary Appendix).
Other techniques to assess carotid atheroscle-
rosis have been described; these include high-reso-
lution MRI of the arterial wall to examine the
morphologic characteristics of the plaque,1 ultra-
sonographic assessment of the carotid intima–
media thickness,20 detection of microemboli by
means of ultrasonography,21 and imaging of ad-
hesion molecules on the surface of the plaque or
inflamed area.22 However, data are lacking to de-
termine the role of these techniques, if any, in
clinical practice.
Medical Management
Aggressive treatment of modifiable risk factors
for carotid atherosclerosis — especially hyperten-
sion and hyperlipidemia — and cessation of smok-
ing are central to stroke prevention. Measures to
reduce stroke risk have been reviewed in a previ-
ous Clinical Practice article23 and in guidelines for
primary and secondary stroke prevention.24,25
Some aspects of risk-factor management par-
ticular to patients with severe carotid-artery ste-
nosis warrant mention. In patients with hyper-
tension, treatment goals must take into account
the risk of reduced cerebral perfusion with overly
aggressive treatment, pending correction of steno-
sis. Treated patients should be followed carefully
for clinical deterioration, and relative hypotension
should be immediately corrected. Furthermore,
special attention to blood-pressure control is re-
1146 n engl j med 369;12
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of m e dic i n e
Accuracy Risks
Detects bifurcation only None
Cannot discriminate Gadolinium usually not needed;
subtotal from total when used, it carries risk of
occlusion nephrogenic systemic fibrosis;
gadolinium contraindicated in
patients with renal insufficiency
Provides good resolution Iodinated contrast material carries
of entire vascular tree risk of nephrotoxic effects;
computed tomographic angi-
ography should be avoided in
patients with renal insufficiency
Excellent 0.5–1.0% Risk of stroke, myocar-
dial infarction, arterial injury,
retroperitoneal bleeding
quired to avoid hypoperfusion during carotid
endarterectomy or stenting and the hyperperfu-
sion syndrome immediately afterward.26
Statin drugs are effective for both primary and
secondary stroke prevention, and they may lead
to stabilization and even regression of intima–
media thickness of the carotid-artery wall.27
Antiplatelet drugs logically would be of par-
ticular benefit in patients with carotid plaques
that cause platelet activation. Patients undergoing
carotid endarterectomy have a reduced risk of
perioperative stroke if they receive aspirin preop-
eratively.28 For long-term secondary prevention
of stroke, current guidelines recommend aspirin,
clopidogrel, or the combination of aspirin and
dipyridamole.24 The combination of aspirin and
clopidogrel is not recommended because of an
increased risk of bleeding, but data from studies
of coronary stenting suggest that this combina-
tion should be routinely used for a short period
(e.g., 1 to 3 months) after carotid-artery stenting.29
Current guidelines suggest that anticoagula-
tion therapy with heparin followed by warfarin
can be used for 3 to 6 months in patients with
acute extracranial dissection.24 Newer oral anti-
coagulants have not been studied in these patients.
Patients with extensive trauma, intracranial dis-
section, or dissection that is discovered weeks after
it occurred probably should not receive anticoagu-
lation therapy. Treatment with antiplatelet agents
is a reasonable alternative; a study comparing
warfarin with aspirin in patients with a carotid
dissection is ongoing.30 Patients with fibromus-
nejm.org september 19, 2013
 clinical pr actice
cular dysplasia usually receive aspirin for stroke
prevention.
Carotid Endarterectomy
Symptomatic Carotid Stenosis
In several randomized trials involving patients who
had a TIA or stroke associated with ipsilateral
carotid stenosis (symptomatic stenosis), carotid
endarterectomy reduced the subsequent risk of
stroke.31-34 In the NASCET,31,32 among patients
with stenosis of 70% or more, the 2-year risk of
ipsilateral stroke was 9% in the group of patients
randomly assigned to carotid endarterectomy (plus
medical therapy) versus 26% in the group assigned
to medical therapy alone (P<0.001). The 5-year risks
were 15.7% in the endarterectomy group versus
22.2% in the medical-therapy group (P = 0.04)
among patients with stenosis of 50 to 69%. There
was no benefit of carotid endarterectomy in pa-
tients with stenosis of less than 50%. Among all
patients who were randomly assigned to carotid
endarterectomy, perioperative strokes occurred
in 5.5% (nondisabling in 3.7% and disabling in
1.8%), death in 1.1%, and wound hematoma in
5.5%. The European Carotid Surgery Trial,33 an-
other randomized trial comparing carotid endar-
terectomy plus medical management with medical
management alone, yielded similar results, with a
significant benefit of surgery in patients with
stenosis of at least 70%.
A meta-analysis of the major trials of carotid
endarterectomy showed that the benefit from this
procedure was greatest when it was performed
within 2 weeks after a TIA or stroke, rather than
later.35
Asymptomatic Carotid Stenosis
Carotid stenosis that is not associated with ipsi-
lateral symptoms (asymptomatic stenosis) is typ-
ically detected on screening ultrasonographic ex-
amination or as part of the investigation of a
symptomatic contralateral artery. The most ap-
propriate management of asymptomatic stenosis
is less clear than that for symptomatic disease,
despite several randomized trials addressing this
question.36-41 The Asymptomatic Carotid Athero-
sclerosis Surgery study,39 which involved patients
with stenosis of more than 60% who were random-
ly assigned to carotid endarterectomy with medical
management or medical management alone, was
discontinued after a mean follow-up of 2.7 years.
The combined risk of perioperative stroke or death
n engl j med 369;12
nejm.org 73
Figure 2. Duplex Ultrasonography of the Carotid Artery
Showing Severe Carotid Stenosis.
On the left, the arrowheads outline the internal carotid
artery. The plaque is visible in the lumen. On the right,
the spectral Doppler waveform shows elevated peak
systolic and end diastolic velocities (486 and 164 cm
per second, respectively) that are consistent with ste-
nosis of more than 70%. The ultrasonographic device
(CX50, Philips Healthcare) had a linear 3-to-12-MHz
transducer. Images courtesy of Andrew Barreto, M.D.
was 1.5%. The risk of ipsilateral stroke projected
over 5 years was 5.1% with carotid endarterecto-
my versus 11.0% without carotid endarterectomy
(P = 0.004). A similar study in Europe, the Asymp-
tomatic Carotid Surgery Trial,40 showed a similar
projected reduction in the risk of stroke with ca-
rotid endarterectomy but a higher rate of periop-
erative stroke or death (3.1%). In both studies,
the absolute risk reduction for stroke associated
with carotid endarterectomy was only 1 percent-
age point per year; this finding indicates that a
substantial benefit is likely only in patients with
a prolonged life expectancy. The absolute risk re-
duction was 11.0 percentage points among men
but only 2.8 percentage points among women. In
post hoc analyses, besides female sex, factors as-
sociated with increased surgical risk included a
long plaque dimension and contralateral carotid
stenosis or occlusion.41 Surgical expertise and
surgical technique are critically important for
minimizing the risk of perioperative complica-
tions and realizing the small benefit of carotid
endarterectomy. Since these trials were carried
out more than two decades ago, before the use of
statins and other aggressive approaches to the
management of risk factors, it is possible that a
benefit of carotid endarterectomy in asymptom-
atic patients would no longer be observed if both
groups received current medical treatment.
Carotid Stenting
Carotid-artery angioplasty with stenting has
emerged as an alternative to carotid endarterec-
tomy in patients at high risk for complications
nejm.org september 19, 2013 1147
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74 nejm readers’ choice clinical care
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n e w e ng l a n d j o u r na l
A
B better outcome after carotid stenting, whereas
Figure 3. Computed Tomographic (CT) Arteriography
in the Patient in the Case Vignette.
In Panel A, a CT arteriogram shows left carotid-artery
stenosis (arrow). In Panel B, embolic occlusion (arrow)
of the left middle cerebral-artery branch is shown.
from endarterectomy such as contralateral occlu-
sion or severe coronary artery disease. The Stent-
ing and Angioplasty with Protection in Patients
at High Risk for Endarterectomy study42 showed
that stenting (with an emboli-protection device)
was not inferior to endarterectomy with respect
to the rate of a composite outcome of stroke,
myocardial infarction, or death at 30 days (4.8%
vs. 9.8%) and the rate of ipsilateral stroke or
death between 31 days and 1 year. Other trials,
however, were discontinued because of high
rates of periprocedural neurologic events with
1148 n engl j med 369;12
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of m e dic i n e
carotid stenting.43-46 More recently, the Carotid
Revascularization Endarterectomy versus Stenting
Trial (CREST)47 and the International Carotid
Stenting Study (ICSS)48 have provided additional
informative results. In CREST, symptomatic and
asymptomatic patients with stenosis of 50% on
angiography or 70% or more on ultrasonography
or CTA were randomly assigned to the study
treatments; this study required training of inter-
ventionists and used distal protection devices.
CREST showed no significant difference between
the stenting and endarterectomy groups overall
in the rates of a composite outcome that included
major periprocedural complications (stroke, myo-
cardial infarction, or death) and ipsilateral stroke
over a 4-year follow-up period (7.2% vs. 6.8%).
Whereas the presence or absence of symptoms
did not significantly affect the findings, there was
a significant interaction of treatment with age: pa-
tients younger than 70 years of age had a slightly
older patients benefited more from carotid end-
arterectomy. The endarterectomy group, as com-
pared with the stenting group, had a higher fre-
quency of periprocedural myocardial infarction
(2.3% vs. 1.1%) but a lower frequency of peripro-
cedural stroke (2.3% vs. 4.1%). At 2 years of fol-
low-up, the rate of carotid restenosis (a predictor
of subsequent stroke) was relatively low (approxi-
mately 6%) in both groups.49 Among patients in
the ICSS, only short-term follow-up has been re-
ported, but for those randomly assigned to ca-
rotid stenting there was a significantly increased
risk of stroke, death, or myocardial infarction at
120 days. In both studies, medical management
was at the discretion of the treating physician.
In aggregate, the available data provide sup-
port for carotid endarterectomy or carotid stent-
ing in most patients with symptomatic stenosis of
more than 70% (number needed to treat to pre-
vent one stroke at 24 months, 6),31 in selected
patients with symptomatic stenosis of 50 to 69%
(number needed to treat to prevent one stroke
at 5 years, 15),32 and in a selected subgroup of
asymptomatic patients with a low risk of peri-
procedural complications (e.g., no clinically sig-
nificant cardiopulmonary or other coexisting
conditions and an age younger than 70 years)
(number needed to treat to prevent one stroke at
5 years, 17).39 Carotid endarterectomy is currently
considered the preferable intervention in most
patients, although selected patients (e.g., those
nejm.org september 19, 2013
 clinical pr actice nejm.org 75

younger than 70 years of age with favorable ana-

tomical features or symptomatic patients with C onclusions a nd
R ec om mendat ions
severe stenosis who have coexisting conditions
conferring a high surgical risk) may benefit more The patient described in the vignette had a TIA,
from carotid stenting. and 6 months later she had a stroke due to em-
bolization from a stenotic atherosclerotic plaque
A r e a s of Uncer ta in t y in the left internal carotid artery. She is at high
risk for subsequent stroke, and the carotid steno-
The benefits of carotid endarterectomy or carotid sis should be treated. On the basis of a meta-anal-
stenting in addition to current medical therapy, ysis of randomized trials and current guidelines,
as compared with current medical therapy alone, I would recommend treatment within 2 weeks after
are uncertain in patients with asymptomatic ca- her stroke.29,35,50 Either carotid endarterectomy
rotid stenosis, especially women. The most ap- or stenting is an option for management. Where-
propriate timing and choice of carotid interven- as carotid endarterectomy is preferred in many
tion after stroke also remain uncertain, as do the cases, given this patient’s relatively young age as
timing and choice of procedure in patients with well as her recent stroke, which increases the
carotid stenosis who require other major surgery, risks associated with surgery and general anes-
especially coronary-artery bypass grafting. It is thesia, I would consider her to be a good candi-
not known whether improvements in techniques date for carotid stenting as long as the lesion
of carotid stenting will result in reduced rates of could be treated with this approach. Advice and
complications. Data are lacking on the benefits treatment are needed to help her quit smoking.
and risks of carotid stenting in patients with dis- Her hypertension should be well controlled; she
section or fibromuscular dysplasia; these patients should receive statin therapy. Although the most
are at high risk for complications from interven- appropriate duration of combined therapy with
tion, and dissections often heal with medical man- aspirin and clopidogrel after stent placement re-
agement.11 The most appropriate duration of dual mains unclear, I would provide treatment with
antiplatelet therapy after carotid stenting is also aspirin and clopidogrel for 1 month and then as-
uncertain. pirin indefinitely.

Dr. Grotta reports receiving consulting fees from Merck, Hae-

Guidel ine s
Guidelines for the treatment of patients with ca-
rotid stenosis have been published previous-
ly.24,25,29,50 The recommendations in this article
are generally consistent with these guidelines.
monetics, Genentech, Janssen, Pfizer, Lundbeck, and Ferrer;
lecture fees from IPG and Vindico; a grant to his institution
from Haemonetics; and royalties from patents regarding a
method for treating cerebral ischemia. No other potential con-
flict of interest relevant to this article was reported.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.

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39. Executive Committee for the Asymp-
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40. Halliday A, Mansfield A, Marro J, et
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1996;27:2216-24.
42. Yadav JS, Wholey MH, Kuntz RE, et
al. Protected carotid-artery stenting ver-
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N Engl J Med 2004;351:1493-501.
43. CAVATAS Investigators. Endovascular
versus surgical treatment in patients with
carotid stenosis in the Carotid and Verte-
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(CAVATAS): a randomised trial. Lancet
2001;357:1729-37.
44. CaRESS Steering Committee. Carotid
Revascularization Using Endarterectomy
or Stenting Systems (CaRESS) phase I
clinical trial: 1-year results. J Vasc Surg
2005;42:213-9.
45. Ringleb PA, Allenberg J, Brückmann
H, et al. 30 Day results from the SPACE
trial of stent-protected angioplasty versus
carotid endarterectomy in symptomatic
patients: a randomised non-inferiority
trial. Lancet 2006;368:1239-47. [Erratum,
Lancet 2006;368:1238.]
46. Mas J-L, Chatellier G, Beyssen B, et al.
Endarterectomy versus stenting in pa-
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stenosis. N Engl J Med 2006;355:1660-71.
47. Brott TG, Hobson RW II, Howard G,
et al. Stenting versus endarterectomy for
treatment of carotid-artery stenosis. N Engl
J Med 2010;363:11-23. [Errata, N Engl J Med
2010;363:198, 498.]
48. Ederle J, Dobson J, Featherstone RL,
et al. Carotid artery stenting compared
with endarterectomy in patients with
symptomatic carotid stenosis (Interna-
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Lancet 2010;375:985-97. [Erratum, Lancet
2010;376:90.]
49. Lal BK, Beach KW, Roubin GS, et al.
Restenosis after carotid artery stenting
and endarterectomy: a secondary analysis
of CREST, a randomised controlled trial.
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50. Brott TG, Halperin JL, Abbara S, et al.
2011 ASA/ACCF/AHA/AANN/AANS/ACR/
ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS
guideline on the management of patients
with extracranial carotid and vertebral
artery disease: executive summary. Cath-
eter Cardiovasc Interv 2013;81(1):E76-
E123.
Copyright © 2013 Massachusetts Medical Society.

From the Department of Medicine, Brig­
ham and Women’s Hospital, and Har­
vard Medical School — both in Boston.
Address reprint requests to Dr. Miller at
the Department of Internal Medicine,
Brigham and Women’s Hospital, 75 Fran­
cis St., Boston, MA 02115, or at almiller@
partners.org.
N Engl J Med 2013;369:966-72.
DOI: 10.1056/NEJMcps1300093
Copyright © 2013 Massachusetts Medical Society.
An Interactive
Medical Case
related to this
Clinical Problem-
Solving article
is available at
NEJM.org
966
The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 77
clinical problem-solving
Caren G. Solomon, M.D., M.P.H., Editor
A Patient with Syncope
Michelle C. Fox, M.D., Neal Lakdawala, M.D., Amy Leigh Miller, M.D., Ph.D.,
and Joseph Loscalzo, M.D., Ph.D.
In this Journal feature, information about a real patient is presented in stages (boldface type)
to an expert clinician, who responds to the information, sharing his or her reasoning with
the reader (regular type). The authors’ commentary follows.
A 35-year-old man presented to the emergency department after having an episode of
syncope while playing soccer. Loss of consciousness lasted only seconds and was pre-
ceded by a brief period of light-headedness. When he regained consciousness, he had
no nausea, diaphoresis, chest pain, or dyspnea. He was not injured and had no bowel
or bladder incontinence. Witnesses reported no tonic–clonic movements. The patient
had no history of fainting or light-headedness.
In the evaluation of syncope, the history of the episode is critical; particular atten-
tion should be paid to any symptoms that occurred before loss of consciousness,
the context within which syncope occurred, and any consequences (e.g., injury or
postictal confusion). Neurally mediated, or vasovagal, syncope is typically associ-
ated with a prodrome of nausea, diaphoresis, and tunnel vision. In the absence of
a prodrome, a diagnosis of cardiac syncope is more likely, although the presence
of a prodrome does not rule out cardiac syncope. Cardiac syncope is generally
related to inadequate cardiac output, which may be a consequence of an outflow-
tract obstruction, tachycardia, or bradycardia. The occurrence of an injury with
syncope is also suggestive of — though not specific for — cardiac syncope. How-
ever, the absence of injury does not rule out cardiac syncope.
Vasovagal syncope is often situational, occurring in association with specific
activities (e.g., coughing or micturition) or with pain, and it generally occurs when
the patient is standing. It is atypical for vasovagal syncope to occur when a person
is seated or reclining and even more atypical during exercise, which further sup-
ports a diagnosis of cardiac syncope in this patient. The patient’s normal mental
status on recovery of consciousness and the absence of bowel or bladder inconti-
nence argue against seizure. The patient did not have tonic–clonic jerks, but their
presence is in any case not specific for seizure as the underlying cause. A more
detailed history should be obtained to identify any risk factors for cardiac disease,
including a family history of heart disease or sudden death.
The patient did not take medications, did not use tobacco or illicit drugs, and drank
alcohol only occasionally. He was born in Mexico, immigrated to the United States as
a teenager, and lived with his wife in western Massachusetts, where he worked as a
dairy farmer. He did not recall any major childhood illnesses. His maternal grand-
mother and a maternal uncle had both died suddenly at 65 years of age without known
antecedent cardiovascular disease. He had five siblings and three children, all of
whom were well.
The fact that the patient took no medications eliminates one point of concern,
since some medications, particularly beta-blockers, calcium-channel blockers, anti-
hypertensive agents, and QT-prolonging medications, can cause syncope. The ab-
n engl j med 369;10 nejm.org september 5, 2013
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78 nejm readers’ choice clinical care collection
clinical problem-solving
sence of risk factors for coronary disease argues
against myocardial ischemia, and a seemingly
healthy childhood lowers the index of suspicion
for undiagnosed congenital heart disease. Al-
though the patient had two relatives who died
suddenly, neither death occurred at a young age.
At initial presentation, the patient had normal vi-
tal signs, and the physical examination was un-
remarkable. An electrocardiogram (ECG) was
normal. Echocardiography showed a structurally
normal heart. The patient was discharged with an
event monitor, and 2 weeks later he had an episode
of monomorphic wide-complex tachycardia, with
a heart rate of almost 300 beats per minute, while
playing soccer. At the time, he noted mild dyspnea
and neck discomfort but reported no chest pain,
palpitations, or light-headedness. He was admit-
ted for further evaluation and management of his
condition.
Monomorphic wide-complex tachycardias include
supraventricular tachycardia with aberrant con-
duction, supraventricular tachycardia with pre-
excitation, and ventricular tachycardia. Although
ventricular tachycardia is the most common cause
of wide-complex tachycardia, in a young healthy
patient, supraventricular tachycardias remain a
distinct possibility. In general, however, patients
should be presumed to have ventricular tachy-
cardia until proved otherwise. A history of coro-
nary artery disease increases the likelihood of
ventricular tachycardia, whereas structural cardiac
abnormalities can be associated with an increased
likelihood of preexcitation, ventricular tachycar-
dia, or both. Accordingly, evaluation for both
ischemia and structural heart disease is warrant-
ed in patients presenting with wide-complex
tachycardia.
In a patient with sustained, hemodynamically
stable wide-complex tachycardia, physical find-
ings suggestive of atrioventricular dissociation
can be diagnostic. In most cases, however, the
diagnosis is made on the basis of ECG or inva-
sive testing. A finding of atrioventricular disso-
ciation on ECG is diagnostic of ventricular
tachycardia; other features, such as the QRS
axis, width, and morphologic characteristics, are
informative but not definitive. Unfortunately,
recordings obtained by means of ambulatory
monitoring rarely provide diagnostic informa-
tion. In such cases, programmed stimulation (an
electrophysiological study) can often induce the
n engl j med 369;10
Back to Table of Contents
tachycardia, allowing for definitive diagnosis
and appropriate treatment.
This patient’s clinical course underscores the
risk of discharging a patient with possible car-
diac syncope with a plan for ambulatory moni-
toring. The intensity of the initial evaluation of
syncope depends on clinical risk stratification.
In a patient presenting with exercise-associated
syncope, an exercise stress test should be per-
formed as part of the initial evaluation; in this
patient, a stress test might have reproduced the
arrhythmia in a controlled environment.
The results of coronary angiography were normal.
An invasive electrophysiological study showed a
ventricular tachycardia originating from an endo-
cardial, inferolateral focus in the left ventricle; an
endocardial voltage map did not reveal significant
scarring. After radiofrequency endocardial abla-
tion, ventricular tachycardia could no longer be
induced.
In assessing monomorphic ventricular tachycar-
dia, the first consideration is the presence or ab-
sence of structural heart disease. In this young,
healthy patient whose echocardiogram showed a
structurally normal heart, the leading diagnosis
is idiopathic ventricular tachycardia, which fre-
quently occurs with exercise or emotional stress
and is most often explained by an automatic
focus, although reentrant circuits involving the
Purkinje fibers can also produce idiopathic ven-
tricular tachycardia. It tends to be paroxysmal
and spontaneously terminating and is often as-
sociated with premature ventricular beats from
the same automatic focus. Syncope is not typical
of idiopathic ventricular tachycardia but can be
associated with it. Although the most common
site of origin is the right ventricular outflow
tract, resulting in a pattern of left bundle-branch
block with an inferior axis, inferolateral idio-
pathic ventricular tachycardias can be observed.
There are no findings suggestive of a more
sinister cause of arrhythmia, such as multiple
ventricular tachycardia involving different cir-
cuits (which would suggest processes such as
sarcoidosis), an electroanatomical map sugges-
tive of marked scarring (which would be mani-
fested as reduced voltage level), or concomitant
conduction abnormalities.
Given that the patient spent his childhood in
Mexico, Chagas’ disease is an important consid-
eration. In Chagas’ disease, conduction abnor-
nejm.org september 5, 2013 96
 The n e w e ng l a n d j o u r na l of m e dic i n e nejm.org 79

malities (right bundle-branch block or left ante- suppression of ventricular arrhythmias depends
rior hemiblock, high-grade atrioventricular in part on the proposed mechanism of ventricu-
nodal block, sinus-node dysfunction, or a com- lar tachycardia. Beta-blockers may prevent exer-
bination of these conduction abnormalities) of- cise-induced ventricular tachycardia by suppress-
ten precede other abnormalities. In the absence ing reentry, reducing automaticity, or reducing
of conduction abnormalities, idiopathic ventric- myocardial oxygen demand. Some idiopathic left
ular tachycardia remains the most likely diagno- ventricular tachycardias are exquisitely sensitive
sis, but it must be considered a diagnosis of ex- to verapamil; these “verapamil-sensitive ventric-
clusion. Cardiac magnetic resonance imaging ular tachycardias” are typically induced by exer-
(MRI), which has greater sensitivity for detect- cise and in classic cases are characterized by a
ing subtle abnormalities than echocardiography, pattern of right bundle-branch block with a su-
should be considered to rule out structural heart perior axis. Antiarrhythmic agents (e.g., amio-
disease. Although ischemia is associated with darone or sotalol) may be considered, since they
polymorphic ventricular tachycardia and ven- can both reduce the burden of the arrhythmia
tricular fibrillation rather than monomorphic and slow its rate. Some patients are reluctant to
ventricular arrhythmias, given its high preva- undergo long-term treatment with medication.
lence and the ready availability of treatments, In considering treatment options, the risks asso-
ischemia should be ruled out in patients with ciated with the medications and with ICD place-
new ventricular arrhythmias. As in this case, ment must be discussed, the latter including
cardiac catheterization is often performed in inappropriate shocks and post-traumatic stress
patients with wide-complex tachycardia, since it disorder.
can be used to rule out obstructive coronary ar-
tery disease or anomalies. A year later, during sexual intercourse, the pa-
tient had an episode of monomorphic ventricular
A cardiac MRI scan showed no abnormalities oth- tachycardia, which was terminated by a single
er than the lesions created by radiofrequency abla- shock from his ICD.
tion. On follow-up exercise stress testing, the pa-
tient achieved 17.8 metabolic equivalents; he had Given the recurrence of ventricular arrhythmias,
frequent premature ventricular contractions with another catheter ablation should be strongly
the same morphologic features as his ventricular considered. Although antiarrhythmic therapy
tachycardia, but there was no sustained arrhyth- could be contemplated, catheter ablation is pref-
mia. Given continued ectopy, which was consis- erable as the next therapeutic intervention, given
tent with his clinical arrhythmia, and given the the patient’s young age. A repeat echocardio-
hemodynamically significant nature of that ar- gram should be obtained to reassess the patient
rhythmia, the decision was made to place an im- for structural heart disease, since the recurrent
plantable cardioverter–defibrillator (ICD) before arrhythmia raises the question of whether the
discharge. initial diagnosis of idiopathic ventricular tachy-
cardia was incorrect or (although much less
Whereas ICDs are clearly indicated for the sec- likely) whether a different, unrelated arrhythmia
ondary prevention of cardiac events related to may have developed. Unfortunately, the presence
structural heart disease, idiopathic ventricular of an ICD precludes repeat cardiac MRI, but volt-
tachycardia is rarely an indication for ICD place- age mapping in the electrophysiology laboratory
ment, since these arrhythmias are generally can be very informative with respect to the bur-
nonlethal and can in most cases be eliminated den of scarring.
by means of catheter ablation. However, alterna-
tive approaches to the management of care On admission, the patient was afebrile, with a
should be considered when there is concern that heart rate of 92 beats per minute, blood pressure
the arrhythmia will recur after an initial attempt of 125/66 mm Hg, and oxygen saturation of 99%
at ablation; options include a second attempt at while he was breathing ambient air. Notable find-
ablation, particularly if there is a substantial ec- ings on physical examination included a nondis-
topic burden, or long-term pharmacologic ther- placed precordial impulse and a widely split sec-
apy. The choice of pharmacologic agent for the ond heart sound without a murmur or a gallop. An

68 n engl j med 369;10 nejm.org september 5, 2013

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80 nejm readers’ choice clinical care collection
clinical problem-solving
I aVR
II aVL
III aVF
V1
II
V5
Figure 1. Electrocardiogram Obtained on Admission, Showing Right Bundle-Branch Block and Right-Axis Deviation.
ECG revealed a new right bundle-branch block
(Fig. 1). An echocardiogram showed normal left
ventricular size and thickness, with minimally re-
duced systolic function (ejection fraction, approx-
imately 50 to 55%); it was otherwise normal. An
electrophysiological study showed a large endo-
cardial and epicardial scar in the lateral wall of the
left ventricle that was consistent with myocardial
fibrosis (Fig. 2). After endocardial and epicardial
ablation along the scar, ventricular tachycardia
was no longer inducible.
The development of a new structural abnormal-
ity, a clinically significant scar, suggests a pro-
gressive cardiomyopathy. Although ventricular
tachycardia can lead to a transient depression in
global systolic function, the abnormalities ob-
served on electroanatomical mapping cannot be
attributed to the arrhythmia or to the earlier
ablation. In the absence of coronary heart dis-
ease, these findings are suggestive of certain
cardiomyopathies, including cardiac sarcoidosis,
giant-cell myocarditis, genetic cardiomyopa-
thies, and Chagas’ disease.
The cause of Chagas’ disease is the protozoal
parasite Trypanosoma cruzi, which is endemic in
Central and South America. Infection with T. cruzi
should be suspected in persons who have emi-
grated from these areas, including this patient, Combined 18F-fluorodeoxyglucose (FDG) PET-CT
who was born in Mexico. Although acute infec- did not show FDG avidity but did reveal a trans-
n engl j med 369;10 nejm.org
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V1 V4
V2 V5
V3 V6
tion often goes unrecognized, chronic disease
will develop in up to 30% of patients with acute
infection. A hallmark of chronic disease is car-
diomyopathy. Conduction abnormalities, such as
the right bundle-branch block observed in this
patient, are characteristic of Chagas’ disease, and
involvement of the posterolateral wall of the left
ventricle is very common.
Cardiac sarcoidosis can also cause conduc-
tion abnormalities and ventricular arrhythmias,
but it is typically a patchy process that is less
likely than Chagas’ disease to produce a single
large region of fibrosis. Nonetheless, sarcoidosis
must be considered in patients with unexplained,
recurrent ventricular arrhythmias. When sarcoid-
osis is a possibility, cardiac MRI (which is con-
traindicated in this patient because of his ICD)
or combined positron-emission tomography and
computed tomography (PET-CT) should be per-
formed. Other, less likely possibilities include
giant-cell myocarditis, an autoimmune disease
that results in severe heart failure and refractory
ventricular arrhythmias characterized by a much
more accelerated course than that observed in
this patient, and genetic cardiomyopathies, in-
cluding those caused by mutations in the lamin
A (LMNA) and desmosomal genes.
september 5, 2013 96
 The n e w e ng l a n d j o u r na l
Figure 2. Electroanatomical Map Showing the Endocardial
Surface of the Patient’s Heart.
The representation of the heart in the lower right corner
shows the orientation. Normal voltage on the endocar­
dial map is indicated by pink; the voltage is increasing­
ly abnormal as the color changes from blue to green to
red. The map reveals a significant scar in the lateral wall
of the left ventricle. Red and white spheres indicate
points of ablation, and gray spheres indicate a dense
scar where pacing could not capture the local tissue.
mural perfusion defect extending from the basal
to the midlateral wall, suggesting the formation of
an aneurysm (Fig. 3). Tests for T. cruzi with both an
immunofluorescence assay and an enzyme-linked
immunosorbent assay (ELISA) were positive. The
patient was referred to an infectious-disease spe-
cialist for the initiation of antiparasitic therapy
and was treated with a 60-day course of benznida-
zole. At follow-up 9 months later, he remained
symptom-free.
C om men ta r y
Approximately 10 million people worldwide are
infected with T. cruzi, the parasite responsible for
Chagas’ disease,1 which is endemic in rural
parts of Latin America.1,2 Although historically
Chagas’ disease has been rare in developed
countries, its prevalence is expected to increase
in the United States and other developed coun-
tries as more people emigrate from regions
where the disease is endemic.2
Chronic Chagas’ disease, the hallmarks of
which are cardiomyopathy, megaesophagus, and
70 n engl j med 369;10
of m e dic i n e nejm.org 81
megacolon, occurs in 10 to 30% of infected per-
sons, usually manifested 10 to 30 years after
initial infection.2 Cardiac manifestations pre-
dominate; gastrointestinal manifestations are
much less common and are usually restricted to
patients in the southern part of South America.3
The mechanism of cardiac damage in Chagas’
disease remains elusive. Inciting factors may
represent a response to the persistence of T. cruzi
within the myocardium or an autoimmune pro-
cess triggered by its presence.1 No matter what
the cause, ongoing inflammation results in pro-
gressive cardiac dysfunction.
In Chagas’ disease, arrhythmia and conduc-
tion abnormalities (particularly right bundle-
branch block, left anterior hemifascicular block,
and ventricular tachycardia) typically precede
overt myocardial dysfunction, apical aneurysm,
and the progressive biventricular systolic dys-
function that culminates in heart failure.2,4 Pa-
tients with advanced disease may die from heart
failure, whereas those with earlier stages of car-
diac involvement may die from sudden arrhyth-
mia. This pattern of conduction disease and ar-
rhythmia accompanying or preceding structural
heart disease is not unique to Chagas’ disease; it
may also be seen in persons with ischemic, in-
flammatory, genetic, or infiltrative diseases.5
The diagnosis of Chagas’ disease is generally
based on serologic testing for IgG antibodies to
T. cruzi antigens in a patient with supportive
clinical findings. No one of the available assays
(ELISA, immunofluorescence assay, and hemag-
glutination assay) has adequate sensitivity and
specificity for the diagnosis. Two tests, in which
different antigens or techniques are used, are
required to make the diagnosis; when the results
are discordant, additional testing must be per-
formed.3 Potential causes of the clinical mani-
festations other than Chagas’ disease should
also be ruled out with appropriate testing (e.g.,
18F-FDG PET-CT would be used to rule out sar-
coidosis).
The best management strategy for chronic
Chagas’ cardiac disease remains uncertain. Most
management guidelines for Chagas’ cardiomy-
opathy are extrapolated from data on ischemic
and nonischemic dilated cardiomyopathy.6 Ow-
ing to the resource-poor nature of the regions in
which Chagas’ disease is endemic, primary data
are limited to retrospective studies and small
registries. Whereas sustained ventricular tachy-
nejm.org september 5, 2013
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82 nejm readers’ choice clinical care collection
clinical problem-solving
Figure 3. Images Obtained on 18F-Fluorodeoxyglucose Positron-Emission Tomography and CT, Showing
a Transmural Perfusion Defect in the Patient’s Heart.
The arrows point to the perfusion defect in the basal to midlateral left myocardial wall.
cardia is an accepted indication for ICD im-
plantation,7 the annual mortality rate is high
among patients with Chagas’ disease who have
an ICD,8 and there is uncertainty regarding the
efficacy of an ICD as compared with amioda-
rone (the preferred antiarrhythmic medication
for patients with Chagas’ cardiomyopathy).6,9
In patients with Chagas’ disease who have sus-
tained ventricular tachycardia, the occurrence
of syncope does not appear to portend a poor
prognosis,10 but moderate or severe ventricular
systolic dysfunction does portend a poor prog-
nosis for patients with unsustained or sus-
tained ventricular tachycardia11; the relatively
preserved ejection fraction in this patient is
reassuring. Cardiac transplantation has been
successfully performed in a few patients with
Chagas’ disease.
Antitrypanosomal medications are now being
used in the management of Chagas’ disease.
Observational data indicate that their use is as-
sociated with a reduced likelihood of progres-
sion of cardiomyopathy, although gastrointesti-
nal problems may not resolve.1,3,12 Benznidazole
and nifurtimox have established antitrypano-
somal efficacy; neither agent is widely available
in the United States.3,13,14 Benznidazole generally
n engl j med 369;10 nejm.org
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has fewer side effects than nifurtimox and is
recommended as first-line treatment.3,12 Adults
younger than 50 years of age who have acute or
chronic infection without end-stage cardiac dis-
ease should generally be treated with antitrypano-
somal medications.3 An ongoing blinded, ran-
domized trial of benznidazole (ClinicalTrials.gov
number, NCT00123916) should further clarify
the role of antitrypanosomal medications in
patients with chronic Chagas’ infection and car-
diac involvement.15 Anticoagulation is not indi-
cated in the absence of intracavitary thrombus.6
Whereas idiopathic ventricular tachycardia
was the most likely diagnosis at the time of this
patient’s initial presentation, the clinical fea-
tures of recurrent arrhythmia and the patient’s
region of origin argued for a more complicated
process. It is essential in such cases to perform
a reassessment for the presence of structural
heart disease, which can evolve over time. This
case underscores the importance of such a reas-
sessment and of the consideration of diseases
endemic to a patient’s region of origin.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. James Maguire for expert clinical insights.
september 5, 2013 97
 clinical problem-solving nejm.org 83

References
1. Control of Chagas’ disease: second
report of the WHO Expert Committee.
Geneva: World Health Organization, 2002.
2. Rassi A Jr, Rassi A, Marin-Neto JA.
Chagas disease. Lancet 2010;375:1388-402.
3. Gayraud M, Guillevin L, le Toumelin P,
et al. Long-term follow-up of polyarteritis
nodosa, microscopic polyangiitis, and
Churg-Strauss syndrome: analysis of four
prospective trials including 278 patients.
Arthritis Rheum 2001;44:666-75.
4. Rassi A Jr, Rassi A, Little WC. Chagas’
heart disease. Clin Cardiol 2000;23:883-9.
5. Lakdawala NK, Givertz MM. Dilated
cardiomyopathy with conduction disease
and arrhythmia. Circulation 2010;122:527-
34.
6. Andrade JP, Marin Neto JA, Paola AA,
et al. I Latin American guidelines for the
diagnosis and treatment of Chagas’ heart
disease: executive summary. Arq Bras
Cardiol 2011;96:434-42.
7. Muratore CA, Batista Sa LA, Chiale
PA, et al. Implantable cardioverter defi-
brillators and Chagas’ disease: results of
the ICD Registry Latin America. Europace
2009;11:164-8.
8. Cardinalli-Neto A, Bestetti RB, Cor-
deiro JA, Rodrigues VC. Predictors of all-
cause mortality for patients with chronic
Chagas’ heart disease receiving implant-
able cardioverter defibrillator therapy.
J Cardiovasc Electrophysiol 2007;18:1236-
40.
9. Rassi A Jr. Implantable cardioverter-
defibrillators in patients with Chagas
heart disease: misperceptions, many ques-
tions and the urgent need for a random-
ized clinical trial. J Cardiovasc Electro-
physiol 2007;18:1241-3.
10. Leite LR, Fenelon G, Paes AT, de Paola
AA. The impact of syncope during clinical
presentation of sustained ventricular
tachycardia on total and cardiac mortality
in patients with chronic Chagasic heart
disease. Arq Bras Cardiol 2001;77:439-52.
11. Sarabanda AV, Marin-Neto JA. Predic-
tors of mortality in patients with Chagas’
cardiomyopathy and ventricular tachycar-
dia not treated with implantable cardio-
verter-defibrillators. Pacing Clin Electro-
physiol 2011;34:54-62.
12. Bern C, Montgomery SP, Herwaldt BL,
et al. Evaluation and treatment of Chagas
disease in the United States: a systematic
review. JAMA 2007;298:2171-81.
13. Viotti R, Vigliano C, Lococo B, et al.
Long-term cardiac outcomes of treating
chronic Chagas disease with benznida-
zole versus no treatment: a nonrandom-
ized trial. Ann Intern Med 2006;144:724-
34.
14. Viotti R, Vigliano C, Lococo B, et al.
Side effects of benznidazole as treatment
in chronic Chagas disease: fears and re-
alities. Expert Rev Anti Infect Ther 2009;
7:157-63.
15. Marin-Neto JA, Rassi A Jr, Avezum A Jr,
et al. The BENEFIT trial: testing the hy-
pothesis that trypanocidal therapy is ben-
eficial for patients with chronic Chagas
heart disease. Mem Inst Oswaldo Cruz
2009;104:Suppl 1:319-24. [Erratum, Mem
Inst Oswaldo Cruz 2009;104:937.]
Copyright © 2013 Massachusetts Medical Society.

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72 n engl j med 369;10 nejm.org september 5, 2013

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84 nejm readers’ choice clinical care collection
T h e n e w e ng l a n d j o u r na l
From the Department of Medicine, Univer-
sity of California, Irvine, Orange (K.K.-Z.);
and the Departments of Radiology (R.N.U.)
and Pathology (K.B.L.), Massachusetts
General Hospital, and the Departments
of Radiology (R.N.U.) and Pathology
(K.B.L.), Harvard Medical School — both
in Boston.
N Engl J Med 2013;369:374-82.
DOI: 10.1056/NEJMcpc1208154
Copyright © 2013 Massachusetts Medical Society.
374
of m e dic i n e
case records of the massachusetts general hospital
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
Case 23-2013: A 54-Year-Old Woman with
Abdominal Pain, Vomiting, and Confusion
Kamyar Kalantar-Zadeh, M.D., M.P.H., Ph.D., Raul N. Uppot, M.D.,
and Kent B. Lewandrowski, M.D.
Pr e sen tat ion of C a se
Dr. Sara R. Schoenfeld (Medicine): A 54-year-old woman was admitted to this hospital
because of abdominal pain, vomiting, and confusion.
The patient was in her usual health until approximately 3 days before admission,
when she reportedly began to feel unwell, with weakness, chills, and skin that was
abnormally warm to the touch. She self-administered aspirin, without improvement.
During the next 2 days, her oral intake decreased. Approximately 22 hours before
presentation, vomiting occurred. Nine hours before presentation, she began to
travel home to Italy from the eastern United States. During the next 2 hours, increas-
ing abdominal pain occurred, associated with vomiting and shortness of breath, and
she took additional aspirin for pain. Approximately 2 hours before presentation,
while the patient was in flight, abdominal pain markedly worsened, vomiting in-
creased, and she became confused and unresponsive. The flight was diverted to
Boston. On examination by emergency medical services personnel, she was non-
verbal and was moaning continuously. The blood pressure was 120/70 mm Hg, the
pulse 52 beats per minute, and the respiratory rate 26 breaths per minute. The
capillary blood glucose level was 116 mg per deciliter (6.4 mmol per liter). She was
brought to the emergency department at this hospital by ambulance.
The patient’s history was obtained from her husband through an interpreter.
She had non–insulin-dependent (type 2) diabetes mellitus, hypertension, nephro-
lithiasis, and chronic kidney disease. Medications included enalapril, metformin,
glimepiride, nimesulide, imipramine, aspirin, and ibuprofen. She had no known
allergies. She was married and had children. She lived in Italy and did not speak
English. She had vacationed in North America for 10 days, traveling to urban areas.
She did not smoke, drink alcohol, or use illicit drugs, and there was no history of
unusual ingestions.
On examination, the patient was incoherent and appeared agitated and uncom-
fortable, with frequent groaning. She was oriented to person only and opened her
eyes to command. The blood pressure was 120/70 mm Hg, the pulse 52 beats per
minute, the temperature 36.7°C, the respiratory rate 18 breaths per minute, and the
oxygen saturation 95% while she was breathing ambient air. The pupils were 3 mm
n engl j med 369;4 nejm.org july 25, 2013
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 case records of the massachuset ts gener al hospital
in diameter and minimally reactive to light; the
oral mucous membranes were dry, and the neck
was supple. The abdomen was soft, without
distention, rebound tenderness, or guarding.
The skin was cool. The remainder of the gen-
eral examination was normal. The neurologic
examination was limited because of the pa-
tient’s inability to follow commands; she with-
drew all extremities to pain, and cranial nerves
and strength appeared normal. Normal saline
was rapidly infused, and dextrose, insulin, on-
dansetron, and morphine sulfate were adminis-
tered intravenously. An electrocardiogram re-
vealed atrial fibrillation at a rate of 115 beats
per minute and a QRS duration of 94 msec,
with a tremulous baseline possibly obscuring
ST-segment depression in the inferior leads.
Blood levels of calcium, triglycerides, glycated
hemoglobin, and haptoglobin were normal, as
were the results of liver-function tests; other
test results are shown in Table 1. Placement
of an indwelling urinary catheter was followed
by placement of intravascular catheters in the
right external jugular vein and the femoral
artery.
Within 2 hours after the patient’s arrival in the
emergency department, tachypnea and increas-
ing somnolence developed; results of venous
oximetry are shown in Table 1. The trachea was
intubated after the administration of etomidate
and rocuronium, and 100% oxygen was admin-
istered and bicarbonate was infused. A chest
radiograph showed no evidence of pneumonia or
pleural effusion. There were ill-defined calcifica-
tions in the soft tissue of the left breast.
Approximately 3 hours after the patient’s ar-
rival, the rectal temperature decreased to 31.7°C
and the blood pressure to 84/43 mm Hg. Norepi-
nephrine bitartrate and bicarbonate were admin-
istered; fluids were warmed before infusion, and
a blanket warmer was placed. Dark-brown gas-
tric secretions that were positive for occult blood
were aspirated through an orogastric tube; the
gastric pH was 5.7.
Dr. Raul N. Uppot: Computed tomography (CT)
of the abdomen and pelvis without the adminis-
tration of intravenous or oral contrast material
(Fig. 1) revealed pancreatic edema, peripancreatic
fat stranding, a small amount of perihepatic and
pericholecystic fluid without biliary ductal dila-
tation, some thickened walls in several loops of
n engl j med 369;4
nejm.org 85
small bowel, and an atrophic left kidney contain-
ing a nonobstructing calculus. CT of the chest
revealed dependent atelectasis, with no focal
consolidation, masses, or effusions, and calci-
fications of the left breast. CT of the brain was
normal.
Dr. Schoenfeld: Cefepime, vancomycin, and met-
ronidazole were administered intravenously. Af-
ter laboratory results were known, sodium poly-
styrene sulfonate was given orally. Toxicologic
screening of the blood and urine was negative.
The patient was admitted to the cardiac inten-
sive care unit (ICU). Vasopressin, propofol, and
calcium were added, and additional bicarbonate
and glucose were administered. Eight hours after
her presentation, continuous venovenous hemo-
filtration with bicarbonate solution was begun.
Cultures of the blood and urine were obtained.
Fourteen hours after presentation, the urine so-
dium level was 136 mmol per liter, and the urine
creatinine level was 0.25 mg per milliliter. Echo-
cardiography revealed normal global cardiac func-
tion, without pericardial effusion.
Dr. Uppot: Ultrasonography of the abdomen re-
vealed small-volume ascites, nonspecific thicken-
ing of the gallbladder wall, and an atrophic left
kidney; there was increased renal parenchymal
echogenicity of both kidneys (Fig. 2).
Dr. Schoenfeld: During the first 17 hours, the
patient had oliguria, with approximately 125 ml
of urine excreted. Additional laboratory tests are
shown in Table 1.
A diagnostic test was performed.
Differ en t i a l Di agnosis
Dr. Kamyar Kalantar-Zadeh: The patient was an
acutely ill 54-year-old woman with a medical his-
tory of type 2 diabetes, hypertension, kidney
stones, and chronic kidney disease of unknown
severity. She presented to the emergency depart-
ment with deteriorating mental state, respiratory
distress, and worsening gastrointestinal symp-
toms. Laboratory evaluation showed a profound
leukocytosis with a left shift (increased levels of
immature neutrophil forms circulating in the pe-
ripheral blood), an increase in pancreatic enzyme
levels, severe metabolic acidosis with a markedly
elevated serum lactate level, profound hyperphos-
phatemia, and oliguric kidney failure. Although
it would be helpful to have a urinalysis, it was not
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86 nejm readers’ choice clinical care
T h collection
e n e w e ng l a n d j o u r na l of m e dic i n e

performed in the first 24 to 48 hours because of
worsening oliguria, the need for other more ur-
gent tests, and other priorities.
My initial differential diagnoses include severe
lactic acidosis, probably resulting from sepsis, car-
diogenic shock, or nonhypoxic causes (e.g., med-
ications and cancer); concurrent acute pancreatitis;
and concomitant acute kidney injury, probably su-
perimposed on preexisting chronic kidney disease,
which could be a result of sepsis, the cardiorenal
syndrome, rhabdomyolysis with hyperphosphate-
mia, or other causes (Table 2).

Table 1. Laboratory Data.*

Reference Range, 17 Hr after

Variable Adults† On Admission Presentation
Hematocrit (%) 36.0–46.0 (women) 44.4 30.0
Hemoglobin (g/dl) 12.0–16.0 (women) 13.4 10.1
White-cell count (per mm3) 4500–11,000 34,800 32,100
Differential count (%)
Neutrophils 40–70 79
Band forms 0–10 2
Lymphocytes 22–44 10
Monocytes 4–11 5
Eosinophils 0–8 1
Myelocytes 0 2
Metamyelocytes 0 1
Platelet count (per mm3) 150,000–400,000 >483,000, with 179,000
platelet clumps
Erythrocyte count (per mm3) 4,000,000–5,200,000 4,340,000 3,330,000
3)
Mean corpuscular volume (μm 80–100 103 90
Mean corpuscular hemoglobin concentration (g/dl) 31.0–37.0 30.1 33.6
Smear description Toxic granulations and in-
creased burr cells pres-
ent; 3+ hypochromasia;
1+ macrocytes
Activated partial-thromboplastin time (sec) 21.0–33.0 36.2 26.4
Prothrombin time (sec) 11.0–13.7 15.7 14.3
International normalized ratio for prothrombin time 1.3 1.2
Sodium (mmol/liter) 135–145 146 140
Potassium (mmol/liter) 3.4–4.8 6.3 (not hemolyzed) 3.5
Chloride (mmol/liter) 100–108 83 88
Carbon dioxide (mmol/liter) 23.0–31.9 <2.0 16.0
Urea nitrogen (mg/dl) 8–25 94 58
Creatinine (mg/dl) 0.60–1.50 7.88 3.94
Glucose (mg/dl) 70–110 168 316
Glycated hemoglobin (%) 3.80–6.40 5.70
Protein (g/dl)
Total 6.0–8.3 6.7 4.2
Albumin 3.3–5.0 4.6 2.9
Globulin 2.3–4.1 2.1 1.3
Calcium (mg/dl) 8.5–10.5 9.5 6.6 (7.5 hr after
presentation)

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 case records of the massachuset ts gener al hospital nejm.org 87

Table 1. (Continued.)

Reference Range, 17 Hr after

Variable Adults† On Admission Presentation
Phosphorus (mg/dl) 2.6–4.5 19.3
Magnesium (mmol/liter) 0.7–1.0 1.1
Lactate dehydrogenase (U/liter) 110–210 515
Lipase (U/liter) 13–60 595 88
Amylase (U/liter) 3–100 386 276
Lactate (mmol/liter) 0.5–2.2 20.3 13.7
Troponin T (ng/ml) <0.03 0.03
Creatine kinase (U/liter) 40–150 656
Osmolality (mOsm/kg of water) 280–296 354 (11 hr after
presentation)
Blood gases
Fraction of inspired oxygen 0.21 (ambient air) 0.40
Source Venous Unspecified
pH 7.30–7.40 (venous); 6.62 7.38
7.32–7.45 (unspec-
ified)
Partial pressure of carbon dioxide (mm Hg) 38–50 (venous); 35–50 18 27
(unspecified)
Partial pressure of oxygen (mm Hg) 35–50 (venous); 40–90 73 156
(unspecified)
Base excess (mmol/liter) −35.1 −8.6

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter,
multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to milli-
moles per liter, multiply by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for
magnesium to milligrams per deciliter, divide by 0.4114. To convert the values for lactate to milligrams per deciliter, divide by 0.1110.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They
may therefore not be appropriate for all patients.

Acid–base disorders
Some of the patient’s test results are markedly
abnormal. These include a profoundly low blood
pH (6.62), a markedly low serum bicarbonate level
(<2 mmol per liter; target range, 23 to 25), and
a low partial pressure of carbon dioxide (Pco2)
(18 mm Hg). Given the severely acidemic pH,
which is unusual even for a venous blood sample,1
we should first confirm that this blood-gas analysis
is correct. The concentration of hydrogen ions in
the patient’s blood is calculated (with the modi-
fied Henderson’s equation2) to be 216 nmol per
liter, which corresponds to a blood pH between
6.6 and 6.7 and confirms the accuracy of the re- Figure 1. Abdominal Imaging.
ported blood-gas data and suggests that she had A CT scan of the abdomen and pelvis, without intrave-
nous or oral contrast material, reveals pancreatic ede-
an exceptionally severe metabolic acidosis.
ma and peripancreatic fat stranding and fluid (arrows),
The patient had a markedly elevated anion gap features consistent with acute pancreatitis. No pseudo-
of 61 mmol per liter (reference range, 8 to 12), in- cyst or gallstones were visualized.
dicating that she had a profound anion-gap meta-

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88 nejm readers’ choice clinical care
T h ecollection
n e w e ng l a n d j o u r na l
A
B
Figure 2. Renal Imaging.
An ultrasonographic study of the abdomen shows an
atrophic left kidney (Panel A) and increased renal pa-
renchymal echogenicity of both kidneys (Panels A
and B), features suggestive of chronic renal disease.
bolic acidosis. Conditions causing this degree of
acidosis include lactic acidosis, aspirin overdose,
methanol or ethylene glycol toxicity, diabetic keto-
acidosis, and uremia. Lactic acidosis in this pa-
tient was corroborated by a markedly elevated
serum lactate level (>20 mmol per liter); other
causes of metabolic acidosis could not be sub-
stantiated by the test results.
Estimating this patient’s osmolal gap is an-
other way to refine the differential diagnosis. She
had a mildly elevated osmolal gap (the difference
between the measured and calculated serum
osmolality) of 18 mOsm per kilogram of water
(reference range, 5 to 15). A slightly elevated or
borderline high osmolal gap is usually caused by
either lactic acidosis or ketoacidosis; methanol
or ethylene glycol ingestion often leads to a more
378 n engl j med 369;4
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of m e dic i n e
profound rise in the osmolal gap, making such
ingestion a less likely diagnosis in this case.
Furthermore, the patient’s anion gap is ap-
proximately 50 mmol per liter above the normal
level, and the serum bicarbonate level is ap-
proximately 20 mmol per liter below the normal
level (i.e., the deviation from normal of the an-
ion gap is more than two times as high as the
deviation from normal of the bicarbonate level).
This suggests that she could have a concomitant
metabolic alkalosis, probably because of repeated
vomiting and loss of hydrochloric acid. Never-
theless, the patient’s profound hyperphosphate-
mia may have contributed to the disproportion-
ately high anion gap.3
Respiratory acid–base disorders
Does this patient have a concurrent respiratory
acid–base disorder? We would expect that for
each 10 mmol per liter decrease from normal in
the bicarbonate level, a compensatory decrease
in the Pco2 of at least 12 mm Hg would ensue.4
Since the patient’s serum bicarbonate level was
22 mmol per liter lower than the target level of
24 mmol per liter, the expected drop in the Pco2
should have been approximately 26 mm Hg. In-
deed, despite her acute illness and altered mental
state, she was capable of lowering the Pco2 by
22 mm Hg (from a normal value of 40 mm Hg to
18 mm Hg), probably by breathing deeply and in-
creasing her respiratory rate in an attempt to
compensate for the marked decrease in the serum
bicarbonate level. Her remarkable and effective
compensatory hyperventilation, classically known
as Kussmaul respiration, is often perceived by cli-
nicians as “respiratory distress.”5 In addition, the
chest radiograph obtained on the patient’s arrival
in the emergency department was normal, pro-
viding further support that she probably had no
respiratory disease. Her need for intubation and
mechanical ventilation was probably the result of
her worsening mental state, which could have
been aggravated by the administration of mor-
phine in association with renal insufficiency.6
severe Acidemia
Many, if not all, features of this patient’s presen-
tation can be explained by profound acidemia
(Fig. 3). Altered mental status, including lethargy,
stupor, and even coma, can be a direct consequence
of acidosis.7 Acidemia may lead to increased vaso-
dilatation and warm skin, which the patient had
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 case records of the massachuset ts gener al hospital nejm.org 89

Table 2. Differential Diagnoses.

Diagnosis
Sepsis (e.g., pyelonephritis and Leukocytosis, lactic acidosis (type A),
intraabdominal infection,
such as emphysematous
pyelonephritis)
Cardiogenic shock (e.g., acute
coronary syndrome)
Metformin-associated lactic
acidosis
Cancer (e.g., lymphoma and
leukemia)
Overdose of salicylates (e.g.,
acetylsalicylic acid)
Intoxication with ethylene gly-
col, methanol, or paralde-
hyde
Mesenteric ischemia
Rhabdomyolysis
Diabetic ketoacidosis
Acute pancreatitis
Acute kidney injury, super-
imposed on chronic
kidney disease
Findings More Consistent with Diagnosis Findings Less Consistent with Diagnosis
Initial normal blood pressure, no identifi-
hypothermia, altered mental state able source of infection
Lactic acidosis (type A), arrhythmias, pre- Initial normal blood pressure, normal tropo-
existing vascular calcification, pulmo- nin level, normal echocardiogram, hypo-
nary edema thermia, profound leukocytosis
Metformin therapy, lactic acidosis (type Profound leukocytosis, prominent gastro-
B), profound acidemia, altered mental intestinal symptoms
state, preexisting renal insufficiency
Hyperphosphatemia (possible tumor lysis Prominent gastrointestinal symptoms, no
syndrome), leukocytosis (with leuke- other identifiable clues to malignant
moid reaction), lactic acidosis (type B), conditions
kidney failure
History of aspirin intake, anion-gap No respiratory alkalosis, too-severe lactic
acidosis, hyperventilation acidosis, no initial respiratory alkalosis,
negative toxicologic screening
Anion-gap acidosis, altered mental state, Negative toxicologic screening, too-small
worsening kidney function osmolal gap, too-severe lactate acidosis
Severe gastrointestinal symptoms, leuko- Upper gastrointestinal bleeding, non-
cytosis, hypothermia, lactic acidosis supporting imaging studies
(type A), altered mental state
Hyperphosphatemia, large anion gap, Profound leukocytosis, no other support-
increased creatine kinase level ing clues
History of diabetes, abdominal pain, Normal glucose level, normal glycated
anion-gap acidosis hemoglobin, high lactate level (too
high for diabetic ketoacidosis)
Gastrointestinal symptoms, elevated A pattern of abdominal pain not typical
amylase and lipase levels, evidence for pancreatitis
on imaging studies
History of chronic kidney disease, history of Normal hemoglobin level
nephrolithiasis with atrophic left kidney,
type 2 diabetes, history of intake of an
angiotensin-converting–enzyme inhibi-
tor and nonsteroidal antiinflammatory
drugs, hyperkalemia, hyperphosphate-
mia, low urinary creatinine level

reported during the 3 days before hospitalization.
However, by the time the patient arrived at the
emergency department, the acidosis had dramat-
ically worsened and had most likely led to her
paradoxical hypothermia, which is a known com-
plication of profound acidosis.7 She also had some
of the cardiovascular consequences of acidosis,
including cardiac failure and catecholamine re-
lease, which led to arrhythmia and respiratory
compromise. Her atrial fibrillation could be a di-
rect complication of acute acidemia.
Although we need to rule out cardiogenic or
septic shock, which could explain the acute kid-
ney injury, severe acidosis could lead to a decline
in the glomerular filtration rate (GFR).7 Given
the patient’s reported medical history of chronic
kidney disease, probably caused by diabetic or
tubulointerstitial nephropathy or hypertensive
nephrosclerosis and the administration of an an-
giotensin-converting–enzyme (ACE) inhibitor and
nonsteroidal antiinflammatory drugs (NSAIDs),
she was probably susceptible to the development
of superimposed acute kidney injury from any of
these events.8 Her gastrointestinal manifestations
were impressive and most likely were due to a
concurrent acute pancreatitis. Nevertheless, we
should note again that acidemia could cause
gastric atony, nausea, vomiting, and abdominal

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90 nejm readers’ choice clinical care collection
T h e n e w e ng l a n d j o u r na l of m e dic i n e

Central Nervous System Cardiovascular

Weakness Reduced left ventricular contractility
Altered sensorium Decreased cardiac output
Lethargy Increased catecholamine release
Stupor and coma
Arrhythmias
Respiratory
Hypotension
Increased respiratory rate
Increased tidal volume
Respiratory alkalosis Endocrine
Decreased venous compliance Insulin resistance
Pulmonary edema Increased calcium release from bone
Increased protein catabolism
Gastrointestinal
Gastric atony Renal
Nausea and vomiting Decreased GFR
Abdominal pain (tubuloglomerular feedback)
Decreased hepatic blood flow Increased urinary calcium excretion
Hyperkalemia
Skin Hyperphosphatemia
Increased peripheral vasodilatation
Blood
Warm skin Leukocytosis with left shift
(warm shock)

Hypothermia

Figure 3. Clinical Manifestations of Acidemia.

COLOR FIGURE

GFR denotes glomerular filtration rate.

Draft 5 6/26/13
Author Kalantar-Zadeh
Fig # 3
Title

pain. Finally, the remarkable leukocytosis with a
left shift can also be explained by severe acido-
sis9; however, an infectious disease is a more
likely explanation, as are malignant conditions
such as leukemia and lymphoma.
Anion-gap metabolic acidosis
What could explain anion-gap metabolic acidosis
with an elevated serum lactate level in this patient?
One possible cause of a classic (type A) lactic aci-
dosis is impaired tissue perfusion that typically
happens in patients with septic or cardiogenic
shock or during cardiopulmonary arrest. However,
another likely cause of anion-gap metabolic aci-
dosis in this patient is nonhypoxic (type B) lactic
acidosis. Impaired lactate metabolism can occur
in association with the administration of certain
medications (e.g., metformin, salicylate, isoniazid,
and zidovudine) or in association with certain
cancers (e.g., lymphoma and leukemia), among
other reasons.10 This patient had been taking met-
formin, which, like other biguanides (e.g., phen-
formin and buformin), can lead to the increased
generation and accumulation of lactate by re-
ME
ducing gluconeogenesis DE and glycogenolysis,
Harris in-
hibiting oxygen consumption,Artist Knoper and impairing
mitochondrial function inFigurethe has beenliver
AUTHOR PLEASE NOTE:
redrawn andand other
type has been reset
Please check carefully
organs.11 In fact, phenformin
Issue dateand buformin were
7/25/13
removed from the market because they are as-
sociated with an unacceptably high risk of lactic
acidosis.12
This patient had a high risk of metformin ac-
cumulation, given her history of chronic kidney
disease, and this is corroborated by seemingly
normalized glucose and glycated hemoglobin
levels, which probably resulted from the progres-
sion of renal insufficiency.13,14 The profound aci-
demia with a massive decrease in the serum bi-
carbonate level and a markedly elevated serum
lactate level is consistent with other reports of
metformin-associated acidosis.11,15 A case series
comparing metformin-associated acidosis with
other types of lactic acidosis, such as those as-
sociated with postcardiac arrest, septic shock,
cardiogenic shock, mesenteric ischemia, and
hemorrhagic shock, described only metformin
as being associated with a mean blood pH below
7.0, as in this patient.16 Survival rates associated

380 n engl j med 369;4 nejm.org july 25, 2013

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 case records of the massachuset ts gener al hospital
with the toxic effects of metformin are generally
better, despite a more severe acidemia, than the
rates associated with other causes of lactic aci-
dosis.16 Therefore, I expect and certainly hope that
this patient survived, especially since she under-
went continuous venovenous hemodiafiltration
therapy for oliguric renal failure, which could also
effectively lower the metformin level despite its
large volume of distribution.11,17 Not many labo-
ratories can measure metformin levels rapidly; if
such testing is available, it is usually performed as
a late confirmatory test.17
In my experience and on the basis of the data
reviewed in the literature,16,17 metformin overdose
or accumulation as the cause of lactic acidosis is
highly likely in any patient who has most or all
of the following five criteria even if the metformin
level is not known: a history of metformin ad-
ministration (e.g., in a patient with type 2 diabe-
tes), a markedly elevated lactate level (>15 mmol
per liter) and a large anion gap (>20 mmol per li-
ter), severe acidemia (pH <7.1), a very low serum
bicarbonate level (<10 mmol per liter), and a his-
tory of renal insufficiency (estimated GFR, <45 ml
per minute per 1.73 m2 of body-surface area; or
serum creatinine level, >2.0 mg per deciliter [>177
μmol per liter]).
This patient has all these features. The acute
pancreatitis also could have been caused by met-
formin accumulation.12,18 Therefore, I expect that
the diagnostic test in this case was a high met-
formin level or maybe a novel surrogate of the
metformin level that I am not aware of.
Dr. Eric S. Rosenberg (Pathology): Dr. Schoenfeld,
what was your initial impression when you evalu-
ated this patient?
Dr. Schoenfeld: Our initial impression was that
the renal failure was due to a combination of
factors, including poor oral intake and multiple
nephrotoxic agents, including an ACE inhibitor
and NSAIDs. We believed that the lactic acidosis
was probably a result of metformin accumulation
in association with the renal failure. Given the
CT findings of peripancreatic fat stranding and
pancreatic edema, we wondered whether the
initial insult may have been pancreatitis, which
led to the abdominal pain, nausea, and reduced
oral intake. However, we could not be certain
that pancreatitis was the primary insult; alterna-
tively, the abdominal pain and pancreatitis could
have been a result of severe acidemia and the
toxic effects of metformin.
n engl j med 369;4
nejm.org 91
Cl inic a l Di agnosis
Lactic acidosis caused by the toxic effects of met-
formin.
DR . K A M Y A R K A L A N TA R-Z A DEH ’ S
DI AGNOSIS
Type B lactic acidosis caused by metformin ac-
cumulation.
Pathol o gic a l Discussion
Dr. Kent B. Lewandrowski: The patient’s plasma
metformin level was 23 μg per milliliter (refer-
ence range, 1 to 2), which explains her presenta-
tion. The clinical thinking at the time was that
her exposure to multiple nephrotoxic drugs, in-
cluding aspirin, ibuprofen, and enalapril, result-
ed in acute kidney injury. Metformin is excreted
unmetabolized in the urine. Therefore, the pa-
tient’s impaired renal function resulted in the ac-
cumulation of metformin in the plasma, causing
lactic acidosis. In patients who have toxic effects
of metformin, the mechanism of lactic acidosis is
multifactorial, including enhanced conversion of
glucose to lactate in the small intestine and in-
hibition of gluconeogenesis by lactate, pyruvate,
and alanine. As in this patient, the toxic effects
of metformin typically present with nausea and
abdominal pain,19 and the mortality rate is high,
approaching 50%. The diagnosis requires a high
index of suspicion and a consideration of clinical
and laboratory findings and the patient’s medica-
tion history. Measurement of a metformin level
will firmly establish the diagnosis; however, this
approach is usually impractical because few hospi-
tals offer this test in-house and obtaining results
from a reference laboratory may take several days.
Dr. Schoenfeld: The patient was admitted to the
cardiac ICU, and continuous venovenous hemo-
filtration was continued. Within the first 24 hours
after admission, her mental status improved dra-
matically. She was extubated 1 day after admis-
sion. Within the next 48 hours, her metabolic
abnormalities started to normalize and she be-
gan to make copious amounts of urine. At that
point, continuous venovenous hemofiltration was
discontinued and she was weaned off vasopressin.
Out of concern for infection, she had been started
on broad-spectrum antibiotics at the time of ad-
mission, but after 48 hours, cultures of blood and
nejm.org july 25, 2013 381
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92  nejm readers’ choice clinical
casecare collection
records of the massachuset ts gener al hospital

urine remained negative and the antibiotics were Fina l Di agnosis

discontinued. She was transferred to the general
medical unit, where her hypertension was man- Toxic effects of metformin.
aged with a calcium-channel blocker. Her renal This case was presented as part of the Harvard Medical School
function completely normalized. She was dis- postgraduate course Internal Medicine: Comprehensive Review
and Update, directed by Ravi I. Thadhani, M.D., M.P.H., Sekar
charged from the hospital 1 week after admis- Kathiresan, M.D., and Dennis Ausiello, M.D.
sion, and she returned home to Italy. We received Dr. Uppot reports receiving payment for reviewing testimony
notification from her primary care doctor 1 week for a legal case involving renal biopsy. No other potential conflict
of interest relevant to this article was reported.
later that she was doing well and had resumed Disclosure forms provided by the authors are available with
her normal daily activities. the full text of this article at NEJM.org.

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