Serious adverse events associated with the use of starch-containing intravenous fluids for volume expansion: an updated systematic review and meta-analysis
Ryan Zarychanski, Ahmed Abou-Setta, Alexis Turgeon, Brett Houston, Lauralyn McIntrye, Dean Fergusson
Ryan Zarychanski, Ahmed Abou-Setta, Alexis Turgeon, Brett Houston, Lauralyn McIntrye, Dean Fergusson. Serious adverse events associated with the use of starch-containing intravenous fluids for volume expansion: an updated systematic review and meta-analysis.
Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42012002348
In critically ill patients (e.g., burns, trauma, sepsis, postoperative, etc.) requiring volume resuscitation, what is the comparative efficacy for preventing serious adverse events (e.g., acute renal failure, mortality) from the use of HES solutions compared with other resuscitation fluids?
We will perform an updated search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from 2008 to present for relevant citations of published trials using individualized search strategies prepared for each database. Our original published search strategy was amended to take account of new search strategies including the Cochrane Highly Sensitive Search Strategy (HSSS) for searching MEDLINE. A forward search will be performed in Scopus and ISI Web of Science to identify additional relevant citations. Finally, in order to identify ongoing or planned trials of starch-based solutions, the World Health Organization’s International Clinical Trials Registry Platform will be searched.
Randomized controlled trials; quasi-randomized, cross-over and cluster randomized will be excluded as well as observational study designs
Condition or domain being studied
In the management of critically ill patients, fluid resuscitation is paramount to the prevention of serious adverse events, including irreversible organ failure and death. Multiple resuscitation fluid options are available for use in this patient population. They are broadly categorized as crystalloids (true solutions that can pass through a semi-permeable membrane) and colloids (quasi-suspension where fine particles of one substance are spread evenly throughout another). Considerable research and debate exists regarding the relative superiority of either solution with numerous trials and systematic reviews attempting to provide an evidence-based answer. Until today, no solution has emerged to be superior, partially due to conflicting results from trials, the large range of commercially-available solutions, and inadequately powered studies.
Hydroxyethyl starch (HES) is a synthetic colloid that is derived from partially hydrolyzed and variably hydroxyethylated plant starch. HES compounds are differentiated by their degree of substitution (amount of hydroxyethylation) and the pattern of substitution especially at the second and sixth carbon positions. These properties affect the individual pharmacokinetic characteristics of each compound.
The use of synthetic starch solutions have increased in clinical practice despite the higher costs of these products compared with crystalloid solutions and a lack of conclusive evidence demonstrating clinical superiority. Due in part to the gap in the literature on the comparative safety and effectiveness of HES with other resuscitation fluids, HES now appears in several resuscitation guidelines, including the US Hospital Consortium Guidelines. Adverse events known to be associated with HES include coagulopathy, and allergic reactions including anaphylaxis. Long-lasting pruritis has also recently been recognized to occur following continued use of these products.
Adverse renal effects have been reported with all widely used HES preparations. The overall magnitude of renal dysfunction and the clinical impact associated with adverse renal outcomes due to starch administration have been investigated by numerous clinical trials and systematic reviews.
Critically ill patients (at least 18 years old) requiring acute volume replacement (e.g., resuscitation, but not maintenance fluid); not undergoing acute normovolemic hemodilution, elective pre-operative volume loading, or elective surgical procedures (e.g. cardiac surgery)
HES solutions (any type, composition).
Crystalloid solutions, albumin, dextran, or gelatin, but not whole blood, or packed RBCs
Acute care setting
(1) Incidence of mortality. (2) Incidence of patients with renal injury (defined according to RIFLE categories of GFR and urine output and the use of renal replacement therapy). It should be noted that the actual measurement of this outcome will be somewhat dictated by what is reported in the individual trials, therefore we will also be extracting data on the individual components (serum creatinine, percentage decrease in GFR, urine output, and presence of anuria).
(3) Incidence of patients with renal recovery to either 10% of baseline function or independence of renal replacement therapy. (4) Intensive care unit and in-patient hospital lengths of stay. (5) Duration of mechanical ventilation. (6) Incidence of patients with major or minor haemorrhage. (7) Incidence of patients requiring, and frequency of, red cell transfusion. (8) Incidence of patients with allergic reactions.
Data extraction, (selection and coding)
Data will be extracted by using a standardized form and entered into a Microsoft Excel database (Microsoft Corp., Redmond, WA). The form will be pilot tested on a sample of studies. Data from study reports will be extracted by two reviewers (AMAS and BLH) independently, with disagreements resolved through consensus. The following data will be extracted from each study: author identification, year of publication, language of publication, source of study funding, study design, methodological quality criteria (see below), study population (including study inclusion and exclusion criteria), patient characteristics (Age, sex, admission diagnosis, APACHE II score or other severity of illness score, baseline creatinine, intervention (drugs utilized, dose, route of administration) and its comparator, and results reported for the outcomes of interest.
Risk of bias (quality) assessment
The internal validity of RCTs will be assessed by using the Cochrane Collaboration Risk of Bias tool. This tool consists of six domains (sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and “other” sources of bias) and a categorization of the overall risk of bias. Each separate domain is rated “yes,” “unclear,” or “no.” The overall assessment is based on the responses to individual domains. If one or more individual domains are assessed as having a high risk of bias, the overall score will be rated as having a high risk of bias. The overall risk of bias will be considered low only if all components are rated as having a low risk of bias. The risk of bias for all other studies will be rated as unclear. In addition, information on the source of funding will be collected for each study. Information regarding methodological quality will be used to guide sensitivity analyses and explore sources of heterogeneity.
Strategy for data synthesis
The data from included studies will be analyzed using RevMan (version 5.1). A formal meta-analysis will be conducted if the data are sufficiently statistically and clinically homogeneous. Pooled continuous data will be expressed as a weighted mean difference (WMD), or standardized mean difference (SMD) where multiple scales are used to measure the same outcome, with 95% confidence intervals (CI). Pooled dichotomous data will be presented as an odds ratio (OR), or for rare outcomes using the Peto-OR. Statistical heterogeneity of the data will be explored and quantified, using the I-squared test, with 95% uncertainty intervals (uCI). If significant heterogeneity is suspected, further analysis including subgroup analysis will be conducted. Publication bias will be assessed by viewing the overlap of the study confidence intervals, using funnel plot techniques, and Begg’s rank test and Egger’s regression test, as appropriate given the known limitations of these methods.
Analysis of subgroups or subsets
The following a priori subgroup and sensitivity analyses are proposed. Such analyses will depend on the number of studies included and the availability of appropriate outcomes and covariates. Methodological: Country - North American vs. non-North American; Sponsor - Industry Funded vs. non-industry funded; Quality - Low risk of bias vs. unclear/ high risk of bias; Source - Published vs. Grey literature/ abstracts/ conf. proceedings. Clinical: Specific type of HES - eg. 200/0.5 vs. 130/0.4; Type of comparator - albumin, dextran, crystalloid, etc; Patient population - sepsis, trauma, etc; Dose - cuts off to be determined; Duration of study protocol - as per included studies.
Contact details for further information
Knowledge Synthesis Pillar, George & Fay Yee Centre for Healthcare Innovation
Department of Internal Medicine, Section of Critical Care
Department of Haematology and Medical Oncology, CancerCare Manitoba
University of Manitoba/Winnipeg Regional Health Authority
Dr Ryan Zarychanski, University of Manitoba Dr Ahmed Abou-Setta, University of Manitoba Dr Alexis Turgeon, Université Laval Ms Brett Houston, University of Manitoba Dr Lauralyn McIntrye, Ottawa Hospital Research Institute Dr Dean Fergusson, Ottawa Hospital Research Institute
Details of any existing review of the same topic by the same authors
Zarychanski R, Turgeon AF, Fergusson D, et al. Renal outcomes and mortality following hydroxyethyl starch resuscitation of critically ill patients: systematic review and meta-analysis of randomized trials. Open Medicine. 2009;3(4):E196–209.
Anticipated or actual start date
06 March 2012
Anticipated completion date
03 July 2012
No funding was specifically obtained for this systematic review. Ryan Zarychanski receives salary support from the Canadian Institute of Health Research (CIHR). Alexis Turgeon receives salary support from the Fonds de la Recherche du Québec – Santé (FRQ-S).
Conflicts of interest
This is an update of a published systematic review by the same authors. Lauralyn McIntyre is an author of primary research on this topic.
Subject index terms status
Subject indexing assigned by CRD
Subject index terms
Critical Illness; Drug Toxicity; Fluid Therapy; Hetastarch; Humans; Resuscitation
Stage of review
Completed and published
Date of registration in PROSPERO
01 May 2012
Date of publication of this revision
21 February 2013
Details of final report/publication(s)
Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of Hydroxyethyl Starch Administration With Mortality and Acute Kidney Injury in Critically Ill Patients Requiring Volume Resuscitation: A Systematic Review and Meta-analysis. JAMA. 2013;309(7):678-688. doi:10.1001/jama.2013.430. http://jama.jamanetwork.com/article.aspx?articleid=1653505
Stage of review at time of this submission
Piloting of the study selection process
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
PROSPERO This information has been provided by the named contact for this review. CRD has accepted this information in good faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record, any associated files or external websites.