Human albumin for intradialytic hypotension in haemodialysis patients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to examine the benefits and harms of human albumin versus saline or non‐protein colloids for the treatment of intradialytic hypotension in haemodialysis patients.
Background
Intradialytic hypotension (IDH) occurs in 20% to 55% of haemodialysis sessions, and is more frequent among patients on long‐term haemodialysis. IDH can result from excessive, or an excessive rate of ultrafiltration. Other contributing factors include left ventricular dysfunction, reduced cardiac output due to drugs or co‐morbid conditions, autoimmune disorders, or reduced vascular tone. Components of the dialysis procedure ‐ including the effects of low calcium and low sodium in dialysates or bio‐incompatible dialyser membranes ‐ may also be contributors to IDH (Emeli 1999; Knoll 2004; van der Sande 1999; Van der Sande 2000).
Symptomatic IDH is generally defined as a decrease in systolic blood pressure (BP) of at least 10 mm Hg or systolic BP less than 100 mm Hg, with symptoms such as cramps, nausea, vomiting, and dizziness. IDH may affect health‐related quality of life, the administration of intravenous fluids in addition to increased medical and nursing care. It may cause early termination of dialysis, resulting in inadequate fluid removal and reduced efficacy of dialysis therapy. More serious complications such as cardiac or cerebral ischaemia may also develop (Emeli 1999; Knoll 2004; van der Sande 1999; Van der Sande 2000).
IDH is managed pre‐emptively or acutely. Pre‐emptive strategies include using higher concentrations of sodium, calcium and bicarbonate in the dialysate solution. The temperature of the dialysate can also be lowered to increase myocardial contractility and peripheral vasoconstriction, the ultrafiltration rate can be closely regulated, or the time on dialysis or cardiovascular tolerance can be increased with sequential ultrafiltration. Pharmaceutical interventions include withholding antihypertensive medications before each treatment, administration of alpha‐adrenergic agonists, mannitol or sertraline (Irwin 2003).
IDH is managed acutely by volume expansion through the intravenous administration of fluids. Fluids most commonly used for managing IDH include normal saline, hypertonic saline, dextran, pentastarch, albumin and mannitol (Irwin 2003).
Albumin is a human blood protein extracted from plasma. It is reconstituted with water to reflect normal blood osmolality and used clinically to replace lost plasma volume. As a protein, it carries the risk of allergic reactions including anaphylaxis. As a human blood product, it carries the risk of viral disease transmission (e.g. hepatitis A, parvovirus) and prion disease transmission (e.g. Creutzfeldt‐Jacob disease). In 2005/2006, albumin costs approximately CA$66/25 g. In a pilot study of albumin use in British Columbia (Canada), use of albumin for intradialytic hypotension accounted for approximately 19% of total in‐hospital albumin use (Fan 2005).
Recent controversies have surrounded the use of albumin in specific indications. A 1998 Cochrane review, "Human albumin solution for resuscitation and volume expansion in critically ill patients" (Alderson 1998), examined the safety of fluid resuscitation in patients with hypovolaemia, burns and hypoproteinaemia comparing albumin to no albumin to crystalloid. The original review included 30 randomised controlled trials (RCTs) and 1419 patients and found an increase in mortality with the use of albumin (risk ratio (RR) 1.68, 95% confidence interval (CI) 1.26 to 2.23). However the updated review (Albumin Review 2004) included the SAFE trial (n = 6997) (SAFE Study 2004), which received 91% of the weight and found the RR of death for albumin administration was not significantly different from crystalloids (RR 1.01, 95% CI 0.92 to 1.10).
Clinical alternatives to albumin infusion include crystalloids and non‐protein colloids. Crystalloid solutions are fluids that contain a combination of water and electrolytes that approximate plasma osmolality. These include isotonic solutions such as normal (serum osmotic) saline and Ringer's lactate, and hypertonic solutions including 1.8%, 3%, 5%, 7.5%, and 10% sodium chloride solutions. Crystalloids are much cheaper than albumin, with normal saline costing CA$1/litre. Colloid solutions include larger complex molecules formulated to reflect normal serum osmotic pressure. Non‐protein, synthetic colloids include dextrans, gelatin‐based products and complex starches such as pentastarch. The cost of the synthetic non‐protein colloid, pentastarch, for example, was CA$84/litre in 2005/2006.
Objectives
The objective of this review is to examine the benefits and harms of human albumin versus saline or non‐protein colloids for the treatment of intradialytic hypotension in haemodialysis patients.
Methods
Criteria for considering studies for this review
Types of studies
All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods). Randomised cross‐over studies will also be included.
Types of participants
Inclusion criteria
Adult patients undergoing long‐term haemodialysis and experiencing episodes of symptomatic intradialytic hypotension defined as a decrease in systolic BP of at least 10 mm Hg or systolic BP less than 100 mm Hg, with symptoms such as cramps, nausea, vomiting, and dizziness.
Exclusion criteria
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Patients on peritoneal dialysis
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Children
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Patients having acute kidney failure or undergoing continuous renal replacement therapy
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Patients treated with haemofiltration or haemodiafiltration
Types of interventions
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Albumin versus normal saline
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Albumin versus hypertonic saline
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Albumin versus non‐protein colloids
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Albumin versus both saline and non‐protein colloids
Studies that include non‐fluid interventions will not be included.
Types of outcome measures
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Mortality (All‐cause mortality reported at end of follow‐up or longer duration)
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Non‐fatal serious adverse events (such as anaphylaxis)
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Treatment failure: defined as not reaching target ultrafiltration goal (target ultrafiltration is determined by the nephrologist and defined as the difference between the pre‐dialysis weight and the dry weight)
Surrogate outcome measures
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Per cent target ultrafiltration achieved (% target ultrafiltration = actual ultrafiltration volume/target ultrafiltration volume)
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Percentage of patients in whom systolic BP increased by at least 10 mm Hg or systolic BP was greater than 100 mm Hg
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post‐dialysis systolic BP (mm Hg)
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post‐dialysis diastolic BP (mm Hg)
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Volume of fluid used
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Time to restore BP
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Nursing time to treat episode
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Recurrent episodes of hypotension
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Other interventions to treat hypotension
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Ultrafiltration goal decreased
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Volume of additional fluids given
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Volume of additional saline used
Search methods for identification of studies
1). The Cochrane Renal Groups specialised register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, (most recent) will be searched using the following terms:‐
#1 MeSH descriptor Albumins, this term only
#2 MeSH descriptor Serum Albumin, this term only
#3 albumin*:ti,ab,kw
#4 MeSH descriptor Fluid Therapy, this term only
#5 (#1 OR #2 OR #3 OR #4)
#6 MeSH descriptor Hypotension, this term only
#7 hypotens*:ti,ab,kw
#8 low next blood next pressure:ti,ab,kw
#9 (#6 OR #7 OR #8)
#10 MeSH descriptor Renal Dialysis, this term only
#11 MeSH descriptor Hemofiltration explode all trees
#12 (haemodialysis or hemodialysis):ti,ab,kw
#13 (haemofiltration or hemofiltration):ti,ab,kw
#14 (haemodiafiltration or hemodiafiltration):ti,ab,kw
#15 dialysis:ti,ab,kw
#16 intradialytic:ti,ab,kw
#17 (#10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16)
#18 (#5 AND #9 AND #17)
CENTRAL and the Renal Groups specialised register contain the handsearched results of conference proceedings from general and speciality meetings. This is an ongoing activity across the Cochrane Collaboration and is both retrospective and prospective (Master List 2007). Therefore we will not specifically search conference proceedings. Please refer to The Cochrane Renal Review Group's Module in The Cochrane Library for the most up‐to‐date list of conference proceedings.
2). MEDLINE (1966 to most recent) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of RCTs (Dickersin 1994) with a specific search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.
1. Albumins/
2. Serum Albumin/
3. albumin$.tw.
4. Fluid Therapy/
5. or/1‐4
6. Hypotension/
7. hypotens$.tw.
8. low blood pressure.tw.
9. or/6‐8
10. Renal Dialysis/
11. exp Hemofiltration/
12. (haemodialysis or hemodialysis).tw.
13. (haemofiltration or hemofiltration).tw.
14. (haemodiafiltration or hemodiafiltration).tw.
15. dialysis.tw.
16. intradialytic.tw.
17. or/10‐16
18. and/5,9,17
3). EMBASE (1980 to most recent) using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of RCTs (Lefebvre 1996) together with a specific search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.
1. Albumin/
2. Human Albumin/
3. Human Serum Albumin/
4. Serum Albumin/
5. Recombinant Human Serum Albumin/
6. albumin$.tw.
7. or/1‐6
8. Hypotension/
9. hypotens$.tw.
10. low blood pressure.tw.
11. or/8‐10
12. Hemodialysis/
13. Hemofiltration/
14. Hemodiafiltration/
15. dialysis.tw.
16. (haemodialysis or hemodialysis).tw.
17. (haemofiltration or hemofiltration).tw.
18. (haemodiafiltration or hemodiafiltration).tw.
19. intradialytic.tw.
20. or/12‐19
21. and/7,11,20
4). Reference lists of nephrology textbooks, review articles and relevant trials.
5). Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials.
Data collection and analysis
Included and excluded studies
The review will be undertaken by four authors PF, VM, KB, DP. The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by (PF) and (VM), who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. Authors (PF) and (VM) will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. Data extraction will be carried out independently by the same authors using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one trial exists, reports will be grouped together and the most recent or most complete data set will be used. Any discrepancy between published versions will be highlighted. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved in consultation with (KB).
Study quality
The quality of studies to be included will be assessed independently by (PF) and (VM) without blinding to authorship or journal using the checklist developed for the Cochrane Renal Group. Discrepancies will be resolved by discussion with KB. The quality items to be assessed are allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention‐to‐treat analysis and completeness of follow‐up.
Quality checklist
Allocation concealment
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Adequate (A): Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
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Unclear (B): Randomisation stated but no information on method used is available
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Inadequate (C): Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group
Blinding
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Blinding of investigators: Yes/No/not stated
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Blinding of participants: Yes/No/not stated
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Blinding of outcome assessor: Yes/No/not stated
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Blinding of data analysis: Yes/No/not stated
The above are considered not blinded if the treatment group can be identified in > 20% of participants because of the side effects of treatment.
Intention‐to‐treat
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Yes: Specifically reported by authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment.
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Yes: Not stated but confirmed on study assessment
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No: Not reported and lack of intention‐to‐treat analysis confirmed on study assessment (patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation)
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No: Stated but not confirmed upon study assessment
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Not stated
Completeness of follow‐up
Per cent of participants excluded or lost to follow‐up.
Statistical assessment
For dichotomous outcomes (death, treatment failure, non serious adverse events, recurrent hypotension, systolic blood pressure increased by at least 10 mm Hg or systolic BP greater than 100 mm Hg, other interventions to treat hypotension, additional fluids given) results will be expressed as RR with 95% CI. Data will be pooled using the random effects model but the fixed effect model will also be analysed to ensure robustness of the model chosen and susceptibility to outliers.
Where continuous scales of measurement are used to assess the effects of treatment (% target ultrafiltration achieved, post‐dialysis systolic BP (mm Hg), post‐dialysis diastolic BP (mm Hg), volume of fluid used, time to restore BP, nursing time to treat episode, ultrafiltration goal decreased, volume of additional saline used), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. Heterogeneity will be analysed using a chi squared test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003).
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to age and renal pathology. Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy. Conference proceedings, abstracts and poster presentations often do not provide sufficient details to determine the validity/quality of the study or its findings. The latter requires analysis of how the trial was conducted and how the results were analysed. That is, without publication, safety and efficacy claims may not be replicable or refutable. We shall carry out subgroup analyses based on publication type (full text versus abstract only). Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference (RD) with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent. Funnel plots will be used to assess for publication bias.
