Albumin Mass Balance in Liver Transplantation

Albumin Mass Balance in Liver Transplantation, an Open Prospective Cohort Study

This clinical observational cohort study assess the loss of albumin from blood circulation during and after liver transplantation by mass balance of albumin. The overall assumption of this method is that if albumin is more diluted than hemoglobin, it must have left the plasma, presumably into the interstitial space. Predictors of albumin leakage will be assessed, including biomarkers of inflammation and of endothelial damage and dysfunction. The sub cohorts children and patients with complications, defined as prolonged postoperative treatment in the intensive care unit, respectively, will be focused in separate publications.

Study Overview

• Status: Unknown
• Conditions: Fluid Overload; Liver Transplant; Complications
• Intervention / Treatment: Other: General anesthesia and surgery (liver transplantation)

Detailed Description

Background Capillary leakage has been recognized to be associated with surgery and inflammation [Fleck 1985]. In liver transplantation considerable amounts of exogenous albumin is administered to support circulatory stability and a post operative plasma albumin concentration of 25 g/L to facilitate interpretation of immuno suppressive drug concentrations. However, the long term effects of exogenous albumin is not well characterized in the literature, and extravasation might promote edema formation and impair wound healing. In previous studies we have demonstrated the ability of the albumin mass balance method to identify leakage of albumin in major abdominal surgery [Norberg 2016].

In a pilot study in patients undergoing liver transplantation (n=11) we found a net leakage of albumin from plasma of 37 ± 17 g at end of surgery and 48 ± 33 g at postoperative day 3.

The primary aim of the new study is to find if this net leakage is still there at postoperative day 7. We are also looking into predictors of positive albumin shift from plasma including markers of inflammation and endothelial injury or dysfunction. Focus will also be put on the subgroup of children during and after liver transplantation. Finally a subgroup of patients in need of prolonged ICU stay after liver transplantation will be investigated to see the prolonged effects of our present routines, and these patients ability to synthetize albumin.

All patients undergoing liver transplantation at Karolinska University Hospital are eligible.

Recruitment will be made in advance as soon as patients are put on the transplant waiting list. In adults, at the day of surgery, blood samples will be taken repeatedly for estimation of plasma albumin. In all patients we will keep track of any gains or losses of albumin or hemoglobin in suction bottles, drains, exogenous blood products, exogenous albumin etc. This sampling will proceed during the study period that will end at hospital discharge or not later than post-operative day 21. Adult patients that are still in the ICU on postoperative day 3 will be subjected to a measurement of albumin synthesis rate by the flooding method [Ballmer 1993]. All subjects, even children, will have blood sampled for ELISAs of markers of inflammation and endothelial injury or dysfunction.

Total study specific blood sampling will be limited to 100 mL in adults and 6 mL in children.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

Study Locations

• Sweden
  • Huddinge, Sweden, 14186
    • Recruiting
    • Karolinska University Hospital, Huddinge
    • Contact: Åke Norberg, MD PhD; Phone Number: +46739661152; Email: ake.norberg@sll.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All patients undergoing liver transplantation at our unit (approximately 85 patients per year) will be asked to participate.

Description

Inclusion Criteria:

All patients undergoing liver transplantation are eligible

Exclusion Criteria:

No consent Unability to understand the study information (language or consciousness)

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adults, uncomplicated; Adults undergoing liver transplantation. Mass balance of albumin will be undertaken by sampling of albumin in plasma and in all fluids that is infused or lost from the body to keep track of albumin and hemoglobin changes until postoperative day 7. B-Hb is taken routinely and not study specific samples. Plasma for ELISAs is taken at 2-3 time points.	Other: General anesthesia and surgery (liver transplantation); The effects of general anesthesia and surgery under the hospital routine of albumin administration during and after liver transplantation is studied with the mass balance of albumin method.
Adults, complicated; Adults undergoing liver transplantation. Mass balance of albumin will be undertaken by sampling of albumin in plasma and in all fluids that is infused or lost from the body to keep track of albumin and hemoglobin changes until hospital discharge or postoperative day 21. B-Hb is taken routinely and not study specific samples. Plasma for ELISAs is taken at 2-3 time points. A infusion of deuterium labeled phenylalanine will be given in the ICU at 1-3 occasions to determine the synthesis rate of albumin.	Other: General anesthesia and surgery (liver transplantation); The effects of general anesthesia and surgery under the hospital routine of albumin administration during and after liver transplantation is studied with the mass balance of albumin method.
Children; Children undergoing liver transplantation. Mass balance of albumin will be undertaken by sampling of albumin in in all fluids that is infused or lost from the body to keep track of albumin and hemoglobin changes until postoperative day 7. P-albumin and B-Hb is only taken routinely and not study specific samples. Plasma for ELISAs is taken at 2-3 time points.	Other: General anesthesia and surgery (liver transplantation); The effects of general anesthesia and surgery under the hospital routine of albumin administration during and after liver transplantation is studied with the mass balance of albumin method.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative perioperative shift of albumin	By mass balance of albumin (i.e keeping track of all gains and losses of albumin and compare these to hemoglobin) it is possible to estimate the loss of albumin from plasma that is not explained by losses in bleeding or drains.	Post-operative day 7 after liver transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predictors of cumulative perioperative shift of albumin	anthropometric and laboratory values including markers of inflammation and endothelial injury or dysfunction will be analyzed by regression analysis to cumulative perioperative shift of albumin	from pre-operative risk assessment until post-operative day 7
Predictors of prolonged need for ICU stay	anthropometric and laboratory values including markers of inflammation and endothelial injury or dysfunction will be analyzed by regression analysis to Patients in need or not in need of prolonged ICU treatment	from pre-operative risk assessment until post-operative day 21
Albumin synthesis rate	By deuterium labeled phenylalanine it is possible to assess albumin synthesis rate by the "flooding technique"	postoperative days 3-21 after liver transplantation
Cumulative perioperative shift of albumin in children	By mass balance of albumin (i.e keeping track of all gains and losses of albumin and compare these to hemoglobin) it is possible to estimate the loss of albumin from plasma that is not explained by losses in bleeding or drains.	during and after liver transplantation until postoperative day 21

Collaborators and Investigators

• Sponsor: Ake Norberg
• Investigators: Principal Investigator: Åke Norberg, Ass Prof, Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge

Publications and helpful links

General Publications

• Fleck A, Raines G, Hawker F, Trotter J, Wallace PI, Ledingham IM, Calman KC. Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury. Lancet. 1985 Apr 6;1(8432):781-4. doi: 10.1016/s0140-6736(85)91447-3.
• Norberg A, Rooyackers O, Segersvard R, Wernerman J. Leakage of albumin in major abdominal surgery. Crit Care. 2016 Apr 26;20(1):113. doi: 10.1186/s13054-016-1283-8.
• Ballmer PE, McNurlan MA, Milne E, Heys SD, Buchan V, Calder AG, Garlick PJ. Measurement of albumin synthesis in humans: a new approach employing stable isotopes. Am J Physiol. 1990 Dec;259(6 Pt 1):E797-803. doi: 10.1152/ajpendo.1990.259.6.E797.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2018
• Primary Completion (Anticipated): February 28, 2021
• Study Completion (Anticipated): June 30, 2021

Study Registration Dates

• First Submitted: February 15, 2018
• First Submitted That Met QC Criteria: February 15, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Actual): September 3, 2020
• Last Update Submitted That Met QC Criteria: September 2, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics
• Other Study ID Numbers: K2017-4774; 4-3344/2017 (Other Identifier: Karolinska Institutet)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No