Hydroxyethyl starch versus saline for resuscitation of patients in intensive care: long-term outcomes and cost-effectiveness analysis of a cohort from CHEST

doi:10.1016/S2213-2600(16)30120-5

The Lancet Respiratory Medicine

Volume 4, Issue 10, October 2016, Pages 818-825

https://doi.org/10.1016/S2213-2600(16)30120-5 Get rights and content

Summary

Background

Hydroxyethyl starch for fluid resuscitation in critically ill patients is not associated with improved short-term patient-centred outcomes compared with crystalloid fluid solutions. However, its effect on longer term health economic outcomes has not been reported.

Methods

We did a prespecified cost-effectiveness analysis of a cohort of patients from New South Wales enrolled in the Crystalloid versus Hydroxyethyl Starch Trial (CHEST), who were randomised to treatment with either 6% hydroxyethyl starch with a molecular weight of 130 kD and a molar substitution ratio of 0·4 or 0·9% sodium chloride (saline) for fluid resuscitation. Clinical outcomes were mortality and life-years gained at 6 months and 24 months, health-related quality of life at 6 months, and quality-adjusted life-years gained at 6 months. Health economic outcomes were hospital and intensive-care unit (ICU) resource use and costs at 24 months and cost-effectiveness, which we defined as the probability of reaching a willingness-to-pay threshold of less than A$50 000 per quality-adjusted life-year gained at 6 months and $100 000 per life-year gained at 24 months. CHEST is registered with ClinicalTrials.gov, number NCT00935168.

Findings

3537 (51%) of 7000 patients were enrolled into CHEST from New South Wales, of whom 3450 (98%) were included in our cost-effectiveness analysis. Mortality at both 6 months and 24 months did not differ between the hydroxyethyl starch and saline groups (6 months: 397/1684 [24%] vs 382/1706 [22%]; relative risk [RR] 1·05, 95% CI 0·93–1·19; p=0·41; 24 months: 586/1687 [35%] vs 594/1708 [35%]; RR 1·00, 95% CI 0·91–1·10; p=0·89). The mean number of life-years gained at 6 months and 24 months was similar between the hydroxyethyl starch and saline groups (6 months: 0·41 days [SD 0·18] vs 0·41 days [0·17]; p=0·25; 24 months: 1·46 years [SD 0·80] vs 1·47 years [0·79]; p=0·72). At 6 months, the mean health-related quality of life score was 0·67 (SD 0·34) with hydroxyethyl starch versus 0·69 (0·35) with saline (p=0·33). The mean number of quality-adjusted life-years gained did not differ between the hydroxyethyl starch and saline groups at 6 months (0·26 days [SD 0·18] vs 0·26 days [0·18]; p=0·33). Total hospital costs (including ICU costs) at 24 months were similar between the hydroxyethyl starch and saline groups (A$62 196 [55 935] vs $62 617 [56 452]; p=0·83). The probability that hydroxyethyl starch was cost effective was 11% at 6 months and 29% at 24 months.

Interpretation

Although longer term clinical outcomes did not differ between patients resuscitated with hydroxyethyl starch or saline in the ICU, from a health-care payer's perspective, the probability that hydroxyethyl starch is cost effective in these patients is low.

Funding

Division of Critical Care and Trauma, George Institute for Global Health.

Introduction

Fluid resuscitation is a fundamental intervention in the care of critically ill patients, and the choice of fluid remains contentious.1, 2 Hydroxyethyl starch preparations were used widely for resuscitation in patients admitted to emergency departments and intensive-care units (ICUs), and for individuals undergoing major surgery.³ Although hydroxyethyl starch preparations have been used for more than 40 years, concerns about their safety—particularly the development of acute kidney injury⁴ and increased risk of death⁵—have been confirmed in clinical trials.6, 7, 8

Although data from 2011 suggest that hydroxyethyl starch is roughly six times more expensive than an equivalent volume of 0·9% sodium chloride (saline), specifically, A$15 per 500 mL versus $2·5 per 500 mL,⁹ this difference must be considered within the overall context of treating patients in the ICU, where average costs are estimated to exceed $4000 per day.¹⁰ Survivors of critical illness carry an increased burden of disease that can persist beyond the index ICU admission and that is associated independently with increased health costs.¹¹ An accurate assessment of the health economic effect of interventions used during the acute admission period—eg, resuscitation fluids—should include longer term outcomes and indices of resource use.

The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) is a randomised controlled trial to compare resuscitation of patients in the ICU with hydroxyethyl starch or saline. No difference in 90-day mortality was noted between groups, but a significant increase in use of renal replacement therapy was reported in patients who received hydroxyethyl starch.⁸ We did a cost-effectiveness analysis of CHEST to ascertain longer term (over 24 months) clinical and economic outcomes from the perspective of the Australian health-care payer. Our analysis was a prespecified component of CHEST.¹²

Research in context

Evidence before this study

The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) was an investigator-initiated, randomised-controlled trial that compared resuscitation with 6% hydroxyethyl starch (130/0·4) with 0·9% sodium chloride (saline) in 7000 eligible patients in the intensive-care unit (ICU). The primary outcome (90-day mortality) did not differ between hydroxyethyl starch and saline groups (relative risk [RR] 1·06, 95% CI 0·96–1·18; p=0·26). However, hydroxyethyl starch was associated with a significant increase in use of renal replacement therapy (RR 1·21, 95% CI 1·00–1·45; p=0·04). In subsequent meta-analyses comparing hydroxyethyl starch with other fluid therapies (n=9857), an escalation in use of renal replacement therapy with hydroxyethyl starch was noted (RR 1·31, 95% CI 1·16–1·49; p<0·001). Despite a significant increase in 90-day mortality associated with hydroxyethyl starch in a Scandinavian study, mortality at 22 months did not differ among 798 patients in the ICU with severe sepsis resuscitated with either 6% hydroxyethyl starch (130/0·42) or Ringer's acetate.

Added value of this study

Our cost-effectiveness analysis is a preplanned extended analysis of CHEST. We reported mortality data at 24 months in a nested cohort of more than 3500 heterogeneous patients in the ICU, thereby providing new information about longer term outcomes in this population. Moreover, our analysis provides new information about the quality of life of survivors and cost-effectiveness metrics from an Australian health-care payer's perspective.

Implications of all the available evidence

Current evidence does not support the use of hydroxyethyl starch as a resuscitation fluid in critically ill patients because of adverse effects on patient-centred outcomes. Within this context, an assessment of longer term outcomes and associated health economic metrics is important, since there is increasing recognition that survivors of critical illness are left with substantive burden of disease and a trajectory of increased mortality beyond the 90-day interval. Although our cost-effectiveness analysis has relevance to the Australian health-care system and countries with similar universal-access public health systems, our findings are important for global health considerations, particularly in resource-limited countries where hydroxyethyl starch continues to be used.

Section snippets

Study population

CHEST (NCT00935168; ACTRN 12609000245291) is an investigator-initiated, prospective, multicentre, parallel-group, blinded, randomised controlled trial into which 7000 eligible patients from 32 ICUs in Australia and New Zealand were enrolled between December, 2009, and January, 2012.⁸ Eligible patients were randomly assigned to receive either 6% hydroxyethyl starch with a molecular weight of 130 kD and a molar substitution ratio of 0·4 or 0·9% sodium chloride (saline) for all episodes of

Results

Of 7000 patients enrolled into CHEST, 3537 (51%) were eligible for inclusion in the cost-effectiveness analysis; 1761 were assigned hydroxyethyl starch and 1776 received saline (figure 1). Linkage data and consent were obtained for 3450 (98%) patients, 1719 in the hydroxyethyl starch group and 1731 in the saline group. Mortality data at 24 months were available for 1687 (98%) of 1719 patients in the hydroxyethyl starch group and 1708 (99%) of 1731 in the saline group. Data for health-related

Discussion

In this extended analysis of CHEST, no differences were recorded in 6-month and 24-month mortality or in quality of life between patients who received hydroxyethyl starch or saline for fluid resuscitation in the ICU. Total hospital costs were also similar 2 years after randomisation. The probability of hydroxyethyl starch being cost effective compared with saline—with respect to quality-adjusted life-years gained or life-years gained—was low.

In previous studies of fluid resuscitation in the ICU,

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ArticlesHydroxyethyl starch versus saline for resuscitation of patients in intensive care: long-term outcomes and cost-effectiveness analysis of a cohort from CHEST

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study population

Results

Discussion

Crit Care Resusc

Crit Care Clin

Value Health

Lancet

Resuscitation fluids

N Engl J Med

Fluid resuscitation in acute medicine: what is the current situation?

J Intern Med

Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units

Crit Care

Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Cochrane Database Syst Rev

Colloids versus crystalloids for fluid resuscitation in critically ill patients

Cochrane Database Syst Rev

Intensive insulin therapy and pentastarch resuscitation in severe sepsis

N Engl J Med

Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis

N Engl J Med

Hydroxyethyl starch or saline for fluid resuscitation in intensive care

N Engl J Med

Schedule of pharmaceutical benefits

Costs of care standards 2009/10

Long-term survival and dialysis dependency following acute kidney injury in intensive care: extended follow-up of a randomized controlled trial

PLoS Med

Articles
Hydroxyethyl starch versus saline for resuscitation of patients in intensive care: long-term outcomes and cost-effectiveness analysis of a cohort from CHEST