Albumin replacement in patients with

severe sepsis or septic shock

Fang, Haoshu,
Department of Pathophysiology

Caironi P1, Tognoni G, Masson S, et al.

N Engl J Med. 2014 Apr 10;370(15):1412-21.
Background = clinical problem
• Albumin is the main protein responsible for plasma
colloid osmotic pressure
• Previous studies have suggested the potential
advantages of albumin administration in patients with
severe sepsis, its efficacy has not been fully
established.

Treatment with 20% Albumin could

Increase survival rate of patients
What is sepsis?
 Definition of SIRS and Sepsis
SIRS: Systemic Inflammatory Response Syndrome
= Two or more of the following symptoms :
• Body Temperature > 38 °C or < 36 °C
• Heart rate > 90 bpm
• Respiratory rate >20 breaths/min or PaCO2 < 32 mm Hg
• White blood cell count >12,000/mm3 or <4000/mm3

Sepsis:
= the systemic response to infection.
The manifestations of sepsis are the same as those defined for SIRS

Per-Olof Nyström. J of Antimicrobial Chemotherapy, 1998 Avery B. Nathens, et al. Word J.Surg. 1996
 Relationship between
infection, sepsis and SIRS
Other

Bacteremia

Trauma
Fungemia

Infection
Parasi-
temia
Sepsis SIRS

Viremia
Burns
Other

Pancrea-
titis

Avery B. Nathens et al. World J Surg, 1996

Sepsis is a health problem

Mortality of sepsis ranging from 18% - 50%!!!

http://www.dsxtherapeutics.com/
Sepsis is a health problem in surgical ICU

Sepsis/liver failure after PH

Patient
Author
condition absolute numbers (%)

Healthy
Sepsis
4/4500 0.2%
Living related liver
Trotter, Liver transplantation, 2006
donors Sepsis/liver failure
8/4500 0.4%

Tumor patients
Benign/malignant
Sepsis 39/1083 3.6% Jamagin, Annals of Surgery, 2002
(40% minor PH)
Tumor patients
Children
Sepsis 6/ 54 11.0% Malek, Surgery, 2010
(malignant)

Adult Sepsis
84/ 705 11.9% Farid, Annals of Surgery, 2010
(colorectal PH = partial hepatectomy
metastasis) Sepsis + MOF 96/ 705 13.6% Farid, Annals of Surgery, 2010
 Cause of sepsis
• Infection
• Bacterial translocation
• Overt inflammatory response
•
 Bacterial translocation & human sepsis
Normal Barrier Function Impaired Barrier Function
Balanced
Bacterial
Intestinal
Overgrowth
Flora
INSUL
T
Normal Normal Disturbed Intestinal
Immunologic Intestinal Immunologic Hypo-
System Motility System motility

Bacterial translocation Bacterial Translocation

is a phenomenon in which bacteria or
its products cross the intestinal barrier.

Human sepsis

Balzan, S. J. Gastroentero. Hepato, 2007

Pathogenesis of SIRS and sepsis
Why sepsis is dangerous

Infection

Decrease of cardiac output Increase of vasodilatation

Systemic Hypotension

Organ hypoperfusion

Organ dysfunction

death
Harmful molecular mechanisms in sepsis

75584-Daniel Rittirsch et al, nature review, 2008

Development of sepsis
SIRS->Sepsis->Severe Sepsis+MOF->Death

Riedemann, Nat Med 2003

Inflammatory response depends on
health status of patient

SIRS Sepsis Severe sepsis Death

Hotchkiss, N Engl J Med 2003

Death of immune cells

Hotchkiss, N Engl J Med 2003

 Potential therapies for sepsis
• Activated protein C
• Intensive insulin therapy for hyperglycemia
• Volume resuscitation
• Corticosteroids
• Albumin replacement!!!
Why the albumin concentration
decreases during sepsis?
 Impaired liver function => decreased
production of albumin
 Alteration of microcirculation => leakage of
albumin and other proteins to the tissue

Decrease of plasma osmotic pressure

Insufficient
Circulatory
volume !!!!
Design of the clinical trial
 Design
• Albumin Italian outcome sepsis (ALBIOS)
study
• Investigator initiated, multicenter, open-
lable, randomized, controlled trial
= 100 intensive cere units in Italy
 Groups:
Control:
=>Crystalloid solution
Experiment:
=>20% Albumin + Crystalloid solution
 Readout
• 28 days mortality or discharge from ICU
• 90 days mortality
• Nr of patients with organ dysfunction, and
the degree of dysfunction and the length of
stay in the ICU or hospital
Results
Figure S1. Randomization,
Stratification, and Follow-up of Study
Patients. Six patients were excluded after
the end of the study as they had been
already and previously randomized in the
trial. Two patients withdrew consent for
the use of their data after the end of the
study. Due to the high number of
participating centers (100 ICUs), and the
potential heterogeneity between their
organizational structures, no data on
Basic information of the patients
Baseline characteristics were similar between groups, except for a slight imbalance
In the number of patients with organ dysfunction and values of central venous oxygen
saturation

Fluid
balance
Metabolic
acidosis
The primary site of infection, the type of identified microorganism, and the proportion
Of patients receiving antibiotics were similar in two groups
Fluid therapy and treatment effects:
The albumin group receive the 20%
Albumin, and less crystalloid solution.
The total daily amount was similar between
Two groups.
Serum albumin level was significantly
higher in the albumin group.
The patients in albumin group had a significantly lower heart rate and higher
Mean arterial pressure
 The patients in albumin group had a significantly lower heart rate and higher
Mean arterial pressure

Figure S2. Mean Arterial and Central Venous Pressure through Day 7 Albumin denotes the
Albumin group (receiving albumin and crystalloids), while Crystalloids the Crystalloid group (receiving
crystalloids alone). Data are expressed as median value and interquartile range. P values are for between-
group comparisons performed by using 2-factor analysis of variance for repeated measurements to test
time and group effects.
Daily net fluid balances were lower in the albumin group
The main cumulative net fluid balance was
Also significantly lower in the albumin group
28 and 90 days survival rate were similar
in two groups
Similar survival rate was observed in two groups
No significant difference was observed
in the prespecified subgroups
Adjustment for baseline covariates did
not significantly modify these results
 Discussion
• The main results provide evidence
regarding both the efficacy and the safety
of the use of human albumin during severe
sepsis.
• The albumin treatment during the first 28
days maintained a serum albumin level of
30 g/L.
• Treatment of albumin is safe, but dose not
provide a survival advantage.
 Discussion
• The hypothesis was supported by the
significant hemodynamic advantages
– = decreased HR and incread AP
– Reduce the severity of organ dysfunction
 Discussion - limitations
• They included the use of albumin solutions
with a greater concentration (20% vs. 4%).
• The observed mortality at 28 days was
lower than originally expected, thereby
increasing the likelihood that the study
was underpowered.
• Only approximately one third of the
patients were enrolled during the early
phase of severe sepsis.
 Conclusion
• In patients with severe sepsis, albumin
replacement in addition to crystalloids, as
compared with crystalloids alone, did not
improve the rate of survival at 28 and 90
days.
What we have learned?
 Clinical trial
• Clinical Trials are conducted to allow safety and efficacy data to be co
llected for health interventions (e.g., drugs,
diagnostics, devices, therapy protocols). These trials can take place on
ly after satisfactory information has been gathered on
the quality of the nonclinical safety, and Health Authority/Ethics Co
mmittee approval is granted in the
country where the trial is taking place
 Basis of clinical trial
1. The drug must be free from any extraneous accidental quality.
2. It must be used on a simple, not a composite, disease.
3.the drug must be tested with two contrary types of diseases, because sometimes a drug cures
one disease by essential qualities and another by its accidental one
4.The quality of the drug must correspond to the strength of the disease. For example, there are s
ome drugs whose
heat is less than the coldness of certain diseases, so that they would have no effect on them.
5.The time of action must be observed, so that essence and accident are not confused.
6.The effect of the drug must be seen to occur constantly or in many cases, for if this did not hap
pen, it was an accidental effect.
7.The experimentation must be done with the human body, for testing a drug on a lion or a horse
might not prove anything about its effect on man.
 Types of clinical trial I
• Observational study: the investigators observe the subje-
cts and measure their outcomes. The researchers do
not actively manage the experiment.

• Interventional study: the investigators give the research

subjects a particular medicine or other intervention.
intervention
Usually, they compare the treated subjects to subjects
who receive no treatment or standard treatment.
Then theresearchers measure how the subjects' health changes
 Types of clinical trial II
• Prevention trials: look for better ways to prevent disease in people who have never had the dis
ease or to prevent disease from returning. These approaches may include medicines, vitamins,
vaccines, minerals, or lifestyle changes.
• Screening trials: test the best way to detect certain diseases or health conditions.
• Diagnostic trials: conducted to find better tests or procedures for diagnosing a particular diseas
e or condition.
• Treatment trials: test experimental treatments, new combinations of drugs, or new approaches
to surgery or radiation therapy.
• Quality of life trials:explore ways to improve comfort and the quality of life for individuals wi
th a chronic illness
• Compassionate use trials or expanded access: provide partially tested, unapproved therapeutic
s prior to a number of patients that have no other realistic options. Usually, this involves a dise
ase for which no effectivetherapy exists, or a patient that has already attempted and failed all o
ther standard treatments and whose health isso poor that he does not qualify for participation i
n randomized clinical trials. Usually, case by case approval mustbe granted by both the FDA a
nd the pharmaceutical company for such exceptions
 Task
• Design a clinical trial related to your topic

– Use the example of the paper