Correspondence
scenario in favor of the STAN technology, there
was still no difference in the primary outcome
or the operative-delivery rate. We stand by our
study.
Michael A. Belfort, M.D., Ph.D.
Baylor College of Medicine
Houston, TX
belfort@​­bcm​.­edu
George R. Saade, M.D.
University of Texas Medical Branch
Galveston, TX
Elizabeth A. Thom, Ph.D.
George Washington University Biostatistics Center
Washington, DC
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
Electrolyte and Acid–Base Disturbances in Diabetes Mellitus
To the Editor: Palmer and Clegg (Aug. 6 issue)1
provide a comprehensive review of electrolyte
disturbances in patients with diabetes. To ex-
plain the presence of hyperkalemia in patients
with type 4 renal tubular acidosis, the authors
adopt the classic explanation of potassium reten-
tion due to defective potassium secretion; this
defective secretion has been confirmed in exper-
iments.
To directly test the hypothesis of potassium
retention as the explanation for hyperkalemia,
my colleagues and I measured total-body potas-
sium in a cohort of patients with type 4 renal
tubular acidosis and found that, if anything,
total-body potassium was low in these patients.2
Our result is not consistent with renal potassium
retention as the major cause of hyperkalemia,
and it points to a more generalized problem with
potassium transport in all cells as a more likely
explanation that suggests that efforts to augment
potassium secretion may actually be deleterious if
total-body potassium is already low.
Mark L. Graber, M.D.
RTI International
Durham, NC
graber​.­mark@​­gmail​.­com
No potential conflict of interest relevant to this letter was re-
ported.
1. Palmer BF, Clegg DJ. Electrolyte and acid–base disturbances
in patients with diabetes mellitus. N Engl J Med 2015;​373:​548-
59.
n engl j med 373;25 nejm.org  December 17, 2015
The New England Journal of Medicine
Downloaded from nejm.org at LATROBE UNIVERSITY on December 18, 2015. For personal use only. No other uses without permission.
Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1. Westgate J, Harris M, Curnow JS, Greene KR. Plymouth ran-
domized trial of cardiotocogram only versus ST waveform plus
cardiotocogram for intrapartum monitoring in 2400 cases. Am
J Obstet Gynecol 1993;​169:​1151-60.
2. Amer-Wåhlin I, Hellsten C, Norén H, et al. Cardiotocogra-
phy only versus cardiotocography plus ST analysis of fetal elec-
trocardiogram for intrapartum fetal monitoring: a Swedish ran-
domised controlled trial. Lancet 2001;​358:​534-8.
3. Ojala K, Vääräsmäki M, Mäkikallio K, Valkama M, Tekay A.
A comparison of intrapartum automated fetal electrocardiogra-
phy and conventional cardiotocography — a randomised con-
trolled study. BJOG 2006;​113:​419-23.
4. Westerhuis ME, Visser GH, Moons KG, et al. Cardiotocogra-
phy plus ST analysis of fetal electrocardiogram compared with
cardiotocography only for intrapartum monitoring: a random-
ized controlled trial. Obstet Gynecol 2010;​115:​1173-80.
5. FIGO Subcommittee on Standards in Perinatal Medicine.
Guidelines for the use of fetal monitoring. Int J Gynaecol Obstet
1987;​25:​159-67.
DOI: 10.1056/NEJMc1513251
2. Graber ML, Shreeve WW, Ma R-M, Richards J, Pierson RN Jr.
Hyperkalemia in advanced diabetes: potassium retention or cell
transport adaptation? A case control study with body composi-
tion analysis. Int J Body Compos Res 2004;​2:​93-8.
DOI: 10.1056/NEJMc1511638
To the Editor: Palmer and Clegg summarize
the major issues regarding electrolyte and acid–
base disturbances in patients with diabetes mel-
litus. Recent studies show that sodium–glucose
cotransporter type 2 (SGLT2) inhibitors may also
lead to ketoacidosis. The Food and Drug Admin-
istration (FDA) recently released a warning re-
garding the risk of ketoacidosis associated with
SGLT2 inhibitors.1,2 From March 2013 through
June 2014, the FDA Adverse Event Reporting Sys-
tem database identified 20 episodes of acidosis
associated with SGLT2 inhibitors; these episodes
were reported as ketoacidosis, diabetic ketoaci-
dosis, or ketosis.1 All the patients required emer-
gency department visits or were hospitalized.
Most cases of ketoacidosis associated with SGLT2
inhibitors occurred in patients with type 2 diabe-
tes who had mildly elevated blood glucose con-
centrations, whereas diabetic ketoacidosis was
most common in patients with type 1 diabetes
who had considerably elevated blood glucose
concentrations.
It is important to be aware of this potentially
serious complication of SGLT2 inhibitors and
consider discontinuing these agents in patients
who have metabolic acidosis. In addition, it is
2481
 The n e w e ng l a n d j o u r na l of m e dic i n e

important that all cases of ketoacidosis involving Martijn C.G.J. Brouwers, Ph.D.

SGLT2 inhibitors be reported to the MedWatch Maastricht University Medical Center
Maastricht, the Netherlands
program of the FDA. martijn​.­brouwers@​­maastrichtuniversity​.­nl
Angela M. Righi, Pharm.D. No potential conflict of interest relevant to this letter was re-
Michael J. Peeters, Pharm.D. ported.

University of Toledo Medical Center 1. Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical
Toledo, OH features, diagnosis and management of maternally inherited
angela​.­righi@​­utoledo​.­edu diabetes and deafness (MIDD) associated with the 3243A>G mito-
chondrial point mutation. Diabet Med 2008;​25:​383-99.
Bryan Dotson, Pharm.D. 2. Madiraju AK, Erion DM, Rahimi Y, et al. Metformin sup-
Harper University Hospital presses gluconeogenesis by inhibiting mitochondrial glycero-
Detroit, MI phosphate dehydrogenase. Nature 2014;​510:​542-6.
3. Brouwers MC, Ham JC, Wisse E, et al. Elevated lactate levels
No potential conflict of interest relevant to this letter was re-
in patients with poorly regulated type 1 diabetes and glycogenic
ported.
hepatopathy: a new feature of Mauriac syndrome. Diabetes Care
2015;​38:​e11-2.
1. FDA drug safety communication: FDA warns that SGLT2 in-
hibitors for diabetes may result in a serious condition of too DOI: 10.1056/NEJMc1511638
much acid in the blood. May 15, 2015 (http://www​ .fda​
.gov/​
Drugs/​DrugSafety/​ucm446845​.htm).
2. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predis-
pose to ketoacidosis. J Clin Endocrinol Metab 2015;​100:​2849-52. To the Editor: A simpler and potentially more
reliable clinical approach to determine whether
DOI: 10.1056/NEJMc1511638
the lower sodium concentration is purely dilu-
tional after hyperglycemia-induced osmotic fluid
To the Editor: In their article, Palmer and Clegg shifts involves the estimation of the effective os-
rightfully mention ketoacidosis and metformin molality (or tonicity), in milliosmoles per kilo-
use as potential causes of lactic acidosis in pa- gram, calculated as (2 × [Na+]) + ([glucose] ÷ 18),
tients with diabetes. However, physicians may where Na+ denotes sodium (measured in milli-
encounter other diabetes-related causes of hyper- moles per liter) and glucose is measured in mil-
lactatemia. ligrams per deciliter.1 In patients with euvolemic
First, maternally inherited diabetes and deaf- hyperglycemia, the smaller contribution of a
ness and the syndrome of mitochondrial en- lower sodium concentration to the osmolality is
cephalomyopathy, lactic acidosis, and strokelike offset by an increased contribution to the osmo-
episodes are overlapping mitochondrial syn- lality by the elevated glucose concentration. An
dromes, both of which are caused by the effective osmolality that deviates from the nor-
m.3243A→G mutation. It is estimated that ap- mal range indicates an abnormal hydration sta-
proximately 1% of all patients with diabetes have tus. Patients with dehydration have an elevated
this mutation.1 Metformin may aggravate hyper- effective osmolality reflecting the free-water
lactatemia in these patients, since it also affects deficit, whereas patients with excess free water
intracellular redox potential.2 Indeed, the plasma would have a lower-than-normal effective osmo-
lactate level was substantially elevated (to 7.8 mmol lality and could be expected to have persistent
per liter) and subsequently decreased (but did hyponatremia, even after correction of the hyper-
not normalize) after discontinuation of metfor- glycemia.
min in one of my patients who had maternally Sumit Mohan, M.D., M.P.H.
inherited diabetes and deafness. Columbia University Medical Center
Second, my colleagues and I recently observed New York, NY
elevated plasma lactate levels (up to 10 mmol per sm2206@​­cumc​.­columbia​.­edu
liter) in young adult patients with poorly con- No potential conflict of interest relevant to this letter was re-
ported.
trolled type 1 diabetes and glycogenic hepa-
topathy. Additional analyses suggested that the 1. Gennari FJ. Serum osmolality: uses and limitations. N Engl
hyperlactatemia was caused by an acquired mito- J Med 1984;​310:​102-5.
chondrial defect, most likely because of poor DOI: 10.1056/NEJMc1511638
glucose control, since plasma lactate levels re-
turned to normal levels after strict glucose The authors reply: Graber cites studies involv-
regulation.3 ing patients with advanced diabetes that suggest

2482 n engl j med 373;25 nejm.org  December 17, 2015

The New England Journal of Medicine

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 Correspondence

that hyperkalemia caused by impaired renal ex- contrast, the osmotic diuretic effect can worsen
cretion is not reflective of increased body stores renal function and cause hyperkalemia, particu-
but may occur with decreased total-body potas- larly when administered to patients with hypo-
sium content. A poor correlation exists between volemia who are receiving blockers of the renin–
the plasma potassium concentration and total- angiotensin–aldosterone system.
body potassium content.1 Techniques that in- We agree with Brouwers that lactic acidosis
clude skeletal-muscle biopsies indicate that body that is not easily explainable in a patient with
stores of potassium are either normal or reduced diabetes mellitus may occur. Such cases should
in patients with chronic kidney disease.2 These prompt consideration of more unusual causes.
contradictory results may be reconciled by con- Mohan argues that calculation of effective
sidering the clinical setting. For example, a true osmolality is potentially a more reliable approach
potassium deficit, correctable by potassium sup- to estimate changes in the sodium concentra-
plements, occurs during the course of advancing tion after normalization of plasma glucose con-
renal failure when it is accompanied by vomiting, centrations. This equation may provide a rapid
high-dose diuretic therapy, and low potassium initial clue as to the patient’s hydration status.
intake. Abnormalities of membrane transport However, like other correction factors, the equa-
occur in renal failure, impairing the ability to tion lacks precision because it does not account
maintain a normal intracellular potassium con- for the 4 to 5 liters of intracellular water in tissues
tent. Stores that are decreased because of this where glucose uptake is not insulin-dependent
mechanism are not correctable with the use of and the effects of volume status on the transfer
potassium supplements. Total-body potassium of fluid from the intracellular into the extracel-
deficits that are refractory to supplements also lular space. These issues are discussed more
occur with decreased muscle mass in patients in fully in the Supplementary Appendix, available
whom the cellular potassium concentration is with the full text of our article at NEJM.org.
normal. These various types of low reserves fre- Biff F. Palmer, M.D.
quently coexist, making any generalized conclu- University of Texas Southwestern Medical Center
sion regarding body stores difficult. Dallas, TX
A thorough investigation of precipitating biff​.­palmer@​­utsouthwestern​.­edu
events is of critical importance in the manage- Deborah J. Clegg, Ph.D
ment of hyperglycemic crises. In this regard, Cedars–Sinai Medical Center
Righi et al. call attention to recent reports link- Beverly Hills, CA
ing the use of SGLT2 inhibitors to the onset of Since publication of their article, the authors report no fur-
ther potential conflict of interest.
diabetic ketoacidosis. Inhibition of glucose–­
sodium cotransport by these drugs increases 1. van Ypersele de Strihou C. Potassium homeostasis in renal
both the flow and delivery of sodium to the failure. Kidney Int 1977;​11:​491-504.
2. Palmer BF. Potassium metabolism in chronic kidney dis-
distal nephron, yet renal potassium wasting and ease. In:​Kimmel P, Rosenberg M, eds. Chronic renal disease.
hypokalemia have not been major side effects. New York:​Elsevier, 2015:​381-90.
Decreased aldosterone levels due to inhibition of 3. Thomson SC, Rieg T, Miracle C, et al. Acute and chronic ef-
fects of SGLT2 blockade on glomerular and tubular function in
renin release through tubuloglomerular feed- the early diabetic rat. Am J Physiol Regul Integr Comp Physiol
back, the use of renin–angiotensin system block- 2012;​302:​R75-R83.
ers, or both probably account for this effect.3 In DOI: 10.1056/NEJMc1511638

Examination of the Retina

To the Editor: As students of medicine, we
found the video “Examination of the Retina”1
and accompanying text to be helpful to our
­understanding of this basic clinical examination.
However, we wonder about the indications to
perform a dilated-eye examination that were pre-
sented. In particular, we raise concerns regard-
ing the recommendation that clinical suspicion
during direct funduscopy warrants an ophthal-
mic referral for a dilated-eye examination. Screen-
ing retinal examinations with a dilated pupil can
be safely performed in primary care.

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