ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12616001505493

Ethics application status

Approved

Date submitted

13/10/2016

Date registered

31/10/2016

Date last updated

17/02/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

Mass balance of albumin in sepsis

Scientific title

An observational pilot study of albumin kinetics as assessed by mass balance in patients with severe sepsis/septic shock

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1188-1309

Trial acronym

Albumin 6B

Linked study record

Health condition

Health condition(s) or problem(s) studied:

severe sepsis / septic shock

Condition category

Condition code

Infection

Other infectious diseases

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

Patients with severe sepsis/septic shock, admitted to the ICU, will be studied during 24 hrs. Blood will be sampled repeatedly (at arrival to ICU, at 1, 2, 4, 8-12 and 24 hrs after the first sample) for assessment of albumin, markers of endothelial injury and markers of inflammation. Samples will also be taken from any patient excretions and from intravenously infused blood products. Baseline plasma volume will be calculated by anthropometry. The sum of all blood samples will not exceed 20 ml.

Intervention code [1]

Diagnosis / Prognosis

Comparator / control treatment

Not applicable

Control group

Uncontrolled

Outcomes

Primary outcome [1]

cumulative albumin shift, i.e. loss of albumin from the blood not explained by bleeding or other external losses. By repeated measurements of blood hemoglobin and plasma albumin, combined with meticulous assessment of gained and lost albumin and hemoglobin, it is possible to compare losses of albumin with losses of hemoglobin. In a previous study in surgical patients, albumin was lost to a higher amount, i.e. the cumulative albumin shift, presumably to the extracellular space.

Timepoint [1]

24 hrs after ICU admission (compared to baseline at ICU admission, when the cumulative albumin shift per definition is zero)

Secondary outcome [1]

Plasma albumin by nephelometry

Timepoint [1]

At admission to ICU, after approximately 1, 2, 4, 8-12, and 24 hrs

Secondary outcome [2]

Time course of markers of endothelial injury (such as heparan sulphate, syndecan 1, hyalorone) measured by ELISA in plasma samples

Timepoint [2]

At ICU admission, and after approximately 2, 4, 8-12 and 24 hrs

Secondary outcome [3]

Time course of markers of inflammation (such as IL6, IL8, IL10) measured by ELISA in plasma samples

Timepoint [3]

At ICU admission, and after approximately 2, 4, 8-12 and 24 hrs

Secondary outcome [4]

Plasma volume dilution, by repeated measures of B-Hb and P-alb and gains and losses of fluids

Timepoint [4]

At ICU admission, and after approximately 1, 2, 4, 8-12, and 24 hrs

Secondary outcome [5]

Body weight by scale

Timepoint [5]

At ICU admission and after approximately 24 hrs

Secondary outcome [6]

Fluid balance by keeping track of gains and losses. Infused fluid volumes are registered in the ICU electronic data record (both intravenous and enteral, all fluids given by pumps), urine is sampled continuously and registered hourly in the same electronic system. Other fluid losses such as bleeding or gastric retensions) are recorded at demand or at least every 8 hrs in the electronic patient record.

Timepoint [6]

At ICU admission and after approximately 24 hrs

Secondary outcome [7]

Composite hypothesis generating correlations between albumin kinetic parameters, markers of inflammation and endothelial injury, and indices of volume status. Albumin kinetic parameters (P-alb, plasma dilution, cumulative albumin shift) are assessed by P-alb, B-Hb and assessment of gains and losses of albumin and hemoglobin. Markers of inflammation and endothelial injury by ELISA of plasma samples. Volume status is assessed by gain and losses of fluids and by scale, respectively.

Timepoint [7]

At ICU admission and at approximately 24 hrs.

Secondary outcome [8]

Rate of fluid administration, by the ICU computerized record system

Timepoint [8]

Continuously during the the first day after ICU admission.

Eligibility

Key inclusion criteria

Patients admitted to ICU for severe sepsis/septic shock

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Absence of written informed consent
Death or transport to another hospital

Study design

Purpose

Screening

Duration

Cross-sectional

Selection

Defined population

Timing

Prospective

Statistical methods / analysis

Normality of data will be assessed by Sharpio-Wilk’s test of normality and parametric or non-parametric analysis applied accordingly. The primary endpoint will be evaluated by t-test or Wilcoxon, as appropriate. Likewise correlations will be reported as Pearson’s correlation coefficient r or Spearman's rank correlation rs.
Demographic preoperative data such as age, height, weight, BMI, gender, routine lab, history of weight loss, diagnoses, and current medications will be presented as numbers, averages and standard deviation, or as median range as applicable.
In a previous study in patients undergoing major abdominal surgery at Karolinska University Hospital Huddinge the cumulative loss of albumin at the end of surgery was 24 +/- 17 g that was not explained by bleeding. The situation in septic ICU patients has not previously been described by mass balance of albumin to our knowledge. The Transcapillary escape rate of albumin is elevated, but if this is accompanied by a decreased return of lymph to the blood is not known. Because large body weight gain and an increased capillary leakage have been demonstrated by other techniques, it seems likely that albumin is accumulated outside the blood. If, by the present routine, the same amount is lost during the first 24 hrs as during major surgery, i.e. 24 +/- 17 g albumin, this corresponds to a effect size of 1.4 (difference divided by standard deviation). Then only n=8 patients are necessary to reach a statistical power of 90%. Because ICU patients are likely to have a larger variation, we aim at 10 evaluable patients. Furthermore, in the absence of a true baseline, it is important to take the first blood sample at the earliest possible instant.
Under "recruitment" (step 7) we specify the total number of patients to 20. Death, transfer to other hospitals or extreme outliers are possible, and we aim at 10 fully evaluable patients.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

20/02/2017

Actual

Date of last participant enrolment

Anticipated

30/03/2018

Actual

Date of last data collection

Anticipated

31/03/2018

Actual

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

Sweden

State/province [1]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Supported by grants provided by the Stockholm County Council (ALF project), grant #20160054

Address [1]

Stockholm County Council
Box 22550
SE-104 22 Stockholm

Country [1]

Sweden

Primary sponsor type

Individual

Name

Ake Norberg

Address

Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm

Country

Sweden

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Regional Ethical Board in Stockholm

Ethics committee address [1]

Regionala etikprovningsnamnden i Stockholm
FE 289
SE-171 77 STOCKHOLM

Ethics committee country [1]

Sweden

Date submitted for ethics approval [1]

24/10/2016

Approval date [1]

16/11/2016

Ethics approval number [1]

Summary

Brief summary

Septic shock is a leading cause of hospital mortality. Manifest circulatory instability characterizes septic shock, and intravenous infusion of fluids is a cornerstone in the treatment, to maintain blood pressure and blood flow to vital organs. However, the fluid will to some part leak into the interstitial space causing edema, and the size of this weight gain is correlated to mortality and morbidity. 
Plasma albumin (P-alb) is a negative phase reactant. The effect of albumin is reported to be no more harmful than that of normal saline, but the volume sparing effect of albumin is small in ICU patients. An increased rate of leakage of albumin from the vascular system in septic patients has been demonstrated, but the return of proteins and fluid by the lymphatic system is impossible to measure directly. However, the combined effect of leakage and return can be assessed by albumin mass balance. Thus, the relationship between the negative phase reactant plasma albumin and the amount of albumin accumulating outside the blood vessels can be estimated and increase our knowledge of our present fluid treatment effects.  
We have previously demonstrated albumin leakage from the blood stream in major abdominal surgery by albumin mass balance describing the relationship between albumin within and outside the vascular system perioperatively. We want to apply the same technique to septic ICU patients.
In this observational study we investigate patients with severe sepsis/septic shock. We will collect blood samples during the first 24 hrs in ICU and quantify cumulative albumin shift, i.e. the amount of albumin accumulating supposedly in the extracellular space. We will also characterize markers of endothelial injury (components of the glycocalyx), markers of inflammations (interleukins) and indices of volume status (fluid balance, weight gain, rate of infusions). Finally all these indices will be correlated to albumin kinetic parameters to generate hypothesis for future studies.
The overall aim of our research program is to define the role of albumin in modern fluid therapy. This study is an important step to understand the effects of our present fluid strategy on the vasculature, and to generate new hypotheses on the mechanisms. Future studies will depend on these results.

Trial website

Trial related presentations / publications

Public notes

Attachments [1]

/AnzctrAttachments/371651-Beslut EPN 161116.pdf (Ethics approval)

Contacts

Principal investigator

Name

Dr Ake Norberg

Address

Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC)
and
Department of Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm

Country

Sweden

Phone

+46 73 966 11 52

Fax

+46 8 779 54 24

ake.norberg@ki.se

Contact person for public queries

Name

Ake Norberg

Address

Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC)and
Department of Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm

Country

Sweden

Phone

+46 73 966 11 52

Fax

+46 8 779 54 24

ake.norberg@ki.se

Contact person for scientific queries

Name

Ake Norberg

Address

Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC)and
Department of Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm

Country

Sweden

Phone

+46 73 966 11 52

Fax

+46 8 779 54 24

ake.norberg@ki.se

No information has been provided regarding IPD availability

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No Supporting Document Provided

Results publications and other study-related documents

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