Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000749303
Ethics application status
Approved
Date submitted
4/05/2017
Date registered
22/05/2017
Date last updated
11/02/2022
Date data sharing statement initially provided
27/03/2019
Date results information initially provided
5/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Fibrinogen and albumin synthesis rates in major upper abdominal surgery
Scientific title
The temporal pattern of fibrinogen and albumin synthesis rates perioperatively in major liver surgery
Secondary ID [1] 291757 0
Nil known
Universal Trial Number (UTN)
U1111-1195-8745
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver disease 302983 0
Condition category
Condition code
Oral and Gastrointestinal 302447 302447 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Surgery 302680 302680 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Brief name: Flooding dose technique with stable isotope (D5-phenylalanine) for measuring de novo synthesis of fibrinogen and albumin.

We will study patients undergoing liver resections of variable size , i.e. hemihepatectomy and extended hemihepatectomy (n=9).
Incorporation of D5-phenylalanine into fibrinogen and albumin will analysed by gas chromatography – mass spectrometry.

Patients will be investigated 3 times in the postabsorptive state (not less than 6 h after a warm meal, and not less than 4 h after coffee or tea, tap water is allowed without restriction). Postoperatively iv crystalloid solutions may be administered. If 5% dextrose is given, it should be paused not less that 2h before measurement. The measurements will be preoperatively, not less than 2 days but not more than 5 days before the measurement on postoperative day 1. A 3rd measurement will then be performed on postoperative day 3-5.
All procedures in conjunction with anesthesia, surgery and postoperative care will be in accord with the local routines at Karolinska University Hospital Huddinge, and at the discretion of the attending anesthesiologist and/or surgeon. At the preoperative measurement two venous accesses will be inserted. At the postoperative measurements existing vascular accesses will be utilized. The routine blood sampling for preoperative and postoperative surveillance will be adjusted time-wise to occur simultaneously with the measurements.
Measurement procedures will be identical except for the isotopic enrichment of D5-phenylalanine. D5-phenylalanine will be administered intravenous during 10 minutes of a 2% phenylalanine solution (45mg/kg, 5, 10 and 30 MPE [mols percent excess]) on the 3 measurement occasions. Thereafter venous blood samples will be obtained just before and at 5, 10, 15, 30, 50, 60, 70 and 90 minutes after the start of the tracer phenylalanine infusion. The samples, collected into citrate vials and kept on ice and thereafter centrifuged at 2,500 r/minute at 4oC and the plasma fraction will thereafter be stored at -80oC pending analysis. All the measurement will be performed by specific trained research nurses and a PhD-student.
For the calculation of the fractional synthesis rates the enrichment of D5-phenylalanine in the free phenylalanine pool in plasma and in circulating albumin and fibrinogen will be measured.
For the free plasma enrichment, proteins are precipitated with sulfosalicylic acid and the supernatant was cleaned using ion exchange resin. For the enrichment measurement in albumin and fibrinogen, these two proteins are isolated from plasma samples. Albumin is isolated by ethanol extraction from trichloroacetic acid precipitated proteins. Albumin is then hydrolyzed using 6M HCL (110oC for 24 hours). Fibrinogen is isolated by several times dissolving in sodium citrate and precipitation with L-ammonium sulphate. Finally fibrinogen is precipitated using perchloric acid and hydrolyzed using 6M HCL (110oC for 24 hours). Following hydrolyzation, the enrichment of phenylalanine from both proteins is analyzed after conversion of phenylalanine to phenylethylamine using tyrosine decarboxylase and extraction with diethylether. Enrichments of D5, phenylalanine in the proteins are estimated from the measurements of mass ratios of m+5/m+2, of phenylethylamine by gas chromatography – mass spectrometry (Agilent 5975C, Agilent, Kista, Sweden) and comparison with standard curve of known phenylalanine enrichments. Fractional synthesis rates will be calculated by dividing the increment of the enrichment in the protein by the area under the curve for the precursor enrichment in plasma.
Intervention code [1] 297870 0
Diagnosis / Prognosis
Comparator / control treatment
Brief name: Flooding dose technique with stable isotope (D5-phenylalanine) for measuring de novo synthesis of fibrinogen and albumin.

We will study a control group including patients undergoing distal pancreas resection (n=6)..
Control group participants will undergo identical assessments as described for liver resections.
Control group
Active

Outcomes
Primary outcome [1] 301859 0
Change in fibrinogen absolute synthesis rate assessed by isotopic techniques linked with detection by mass spectrometry.
Timepoint [1] 301859 0
Baseline(preoperatively), postoperative day 1 , postoperative day 3-5
Secondary outcome [1] 334133 0
Change in albumin absolute synthesis rate assessed by isotopic techniques linked with detection by mass spectrometry.
Timepoint [1] 334133 0
Baseline(preoperatively), postoperative day 1, postoperative day 3-5
Secondary outcome [2] 334135 0
To explore if the absolute and fractional synthesis rates of fibrinogen and albumin, assessed by isotopic techniques linked with detection by mass spectrometry., correlate following hemihepatectomy and extended hemihepatectomy
Timepoint [2] 334135 0
Baseline(preoperatively), postoperative day 1, postoperative day 3-5

Eligibility
Key inclusion criteria
Patients with indications and admited for elective major hepatic surgery or distal pancreatic resections
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. No consent
2. A surgical procedure that deviates from the standard hemihepatecomy, extended hemihepatectomy, or the standard Whipple´s procedure.
3. Any condition that the investigator find to be in potential conflict with the 3 standard procedures intended to be studied.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
In the 2 study groups there should be 6 (pancreatic surgery) and 9 (hemihepatectomy) fully evaluable subjects, which enables us to detect a difference in the primary outcome variable, corresponding to 1.5 standard deviation. The size of the samples was based on a power analysis (2 sided test) that assumed a difference of 1,5 standard deviation between the two groups, normal distribution and alpha <.05 for direct comparisons.
Groups will be compared with Student’s t-test.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
29/05/2017
Actual
18/09/2017
Date of last participant enrolment
Anticipated
28/02/2020
Actual
16/05/2019
Date of last data collection
Anticipated
31/03/2020
Actual
3/06/2019
Sample size
Target
15
Accrual to date
Final
15
Recruitment outside Australia
Country [1] 8839 0
Sweden
State/province [1] 8839 0

Funding & Sponsors
Funding source category [1] 296257 0
Government body
Name [1] 296257 0
Swedish Medical Research Council
Country [1] 296257 0
Sweden
Primary sponsor type
University
Name
Karolinska Institutet
Address
Solnavagen 1, Solna
171 77, Stockholm,
Country
Sweden
Secondary sponsor category [1] 295173 0
Hospital
Name [1] 295173 0
Karolinska University Hospital
Address [1] 295173 0
Halsovagen 13, Huddinge
141 57, Stockholm
Country [1] 295173 0
Sweden

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297494 0
Regional Ethical Review Board in Stockholm
Ethics committee address [1] 297494 0
RE 289
171 77 Stockholm
Ethics committee country [1] 297494 0
Sweden
Date submitted for ethics approval [1] 297494 0
21/12/2016
Approval date [1] 297494 0
20/02/2017
Ethics approval number [1] 297494 0
2016/2558-31/1

Summary
Brief summary
Postoperative liver insufficiency, which occurs after extended liver surgery, is directly proportional with the resection size and there is a direct relationship between the degree of liver failure and mortality. Presently there is insufficient data to have a complete view over the functional status of the remaining liver following major liver resections.
In a previous study we found a drop in plasma fibrinogen concentration on the first postoperative day following hepatic surgery. Thereafter, the concentration returns to preoperative level on the 4th postoperative day in patients undergoing extended hepatectomy, while patients undergoing hemihepatectomy exhibit an overshoot in plasma concentration at the same time point.
Fibrinogen is a positive acute phase reactant, meaning that after trauma and/or infection there is an increase in plasma concentration of fibrinogen. Changes in fibrinogen plasma concentration are attributable to changes in de novo synthesis, changes in elimination, and redistribution. Combinations of these three principal actions may occur.
In the immediate postoperative phase, the drop in plasma concentration may be attributable to consumption, redistribution, and a decrease in synthesis rate, perhaps in combination. Later on in the postoperative period the increase in plasma concentration may be attributable to redistribution and/or to increased de novo synthesis rates. In liver surgery the size of resection, leaving liver remnants of variable size may also be a factor determining the alterations in plasma fibrinogen concentration.
Our hypothesis is that the changes of fibrinogen plasma concentration may, at least to some extent, be attributable to changes in the hepatic synthesis rate of fibrinogen.
Therefore we plan to study fibrinogen synthesis rate in patients undergoing liver resections of variable sizes and as controls in patients undergoing pancreatic resections with intact liver size.
In a longitudinal protocol the patients will be studied 3 times; preoperatively, and on postoperative day 1 and day 3-5. In parallel to fibrinogen synthesis rate, quantitative synthesis rate of another liver export protein, albumin, will also be determined.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74214 0
Dr Gabriel Dumitrescu
Address 74214 0
Department of Perioperative Medicine and Intensive Care , K32, Karolinska University Hospital, Halsovagen 13, Huddinge, SE-14186 Stockholm
Country 74214 0
Sweden
Phone 74214 0
+46762562639
Fax 74214 0
Email 74214 0
[email protected]
Contact person for public queries
Name 74215 0
Dr Gabriel Dumitrescu
Address 74215 0
Department of Perioperative Medicine and Intensive Care , K32, Karolinska University Hospital, ,Halsovagen 13, Huddinge, SE-14186 Stockholm
Country 74215 0
Sweden
Phone 74215 0
+46762562639
Fax 74215 0
Email 74215 0
[email protected]
Contact person for scientific queries
Name 74216 0
Dr Gabriel Dumitrescu
Address 74216 0
Department of Perioperative Medicine and Intensive Care , K32, Karolinska University Hospital,,Halsovagen 13, Huddinge, SE-14186 Stockholm
Country 74216 0
Sweden
Phone 74216 0
+46762562639
Fax 74216 0
Email 74216 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Unclear what data can be shared legally according to the new GDPR regulations


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Other filesNo preprint date: December 11th, 2020/ DOI: https://d... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseFibrinogen and albumin synthesis rates in major upper abdominal surgery.2022https://dx.doi.org/10.1371/journal.pone.0276775
N.B. These documents automatically identified may not have been verified by the study sponsor.