Crystalloids vs. colloids: KO at the twelfth round?

Expanded abstract Citation Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012, 367:1901-1911. Background The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. Methods We randomly assigned 7,000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kDa and a molar substitution ratio of 0.4 (130/0.4, Voluven; Fresenius Kabi AG, Bad Homburg vor der Höhe, Germany) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal replacement therapy. Objective We conducted a large-scale randomized controlled trial to evaluate the safety and efficacy of 6% HES (130/0.4) in 0.9% saline as compared with 0.9% saline alone for fluid resuscitation in a heterogeneous population of adult patients in the ICU. Design The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) was an investigator-initiated, multicenter, prospective, blinded, parallel-group, randomized controlled trial. Setting The study was set at 32 hospitals in Australia and New Zealand. Subjects The subjects were adult patients (>18 years) who were admitted to the ICU and who required intravenous fluid above maintenance requirements determined by the treating clinician and supported by at least one objective physiological criterion. Patients were excluded if they received more than 1 L of 6% HES within 24 hours of screening or had one of the following: dialysis-dependent or impending dialysis renal failure, computed tomography evidence of non-traumatic intracranial hemorrhage (ICH) or severe traumatic ICH, creatinine of more than 3.9 mg/dL or urine output of less than 10 mL/hour for 12 hours, sodium of more than 160 meq/L, or chloride of more than 130 meq/L. Also excluded were females of childbearing age (unless proven not to be pregnant) and patients who had post-cardiac surgery status, liver transplant, or burns and those whose death was judged to be imminent or whose underlying disease process indicated a life expectancy of less than 90 days. Intervention If fluid was deemed necessary by the treating clinician by the parameters described above, the patient received 'study' fluid with identical packaging and appearance. The fluid was either 6% HES (130/0.4) in saline (Voluven) or 0.9% saline. Outcomes The primary outcome was death within 90 days. Secondary outcomes were acute kidney injury (AKI) and failure and treatment with renal replacement therapy. Results A total of 597 (18.0%) of 3,315 patients in the HES group and 566 (17.0%) of 3,336 in the saline group died (relative risk (RR) in the HES group 1.06, 95% confidence interval (CI) 0.96 to 1.18; P = 0.26). There was no significant difference in mortality in six predefined subgroups. AKI - defined by RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria - occurred in few patients receiving HES (34.6%) compared with saline (38%) (RR 0.91, 95% CI 0.85 to 0.97). However, renal replacement therapy was used in 235 (7.0%) of 3,352 patients in the HES group and 196 (5.8%) of 3,375 in the saline group (RR 1.21, 95% CI 1.00 to 1.45; P = 0.04). HES was significantly associated with more adverse events (5.3% versus 2.8%; P <0.001). Conclusions In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with6% HES (130/0.4) or saline. However, despite a lower overall rate of AKI, more patients who received resuscitation with HES were given renal replacement therapy. (The study was supported by the National Health and Medical Research Council of Australia; the Ministry of Health, New South Wales Government, Australia; and Fresenius Kabi; and by a Practitioner Fellowship from the National Health and Medical Research Council of Australia (to Drs Myburgh and Bellomo), by a Principal Research Fellowship from the National Health and Medical Research Council of Australia (to Dr Cass), and by a Practitioner Fellowship from the Medical Research Foundation of the Royal Perth Hospital (to Dr Webb); CHEST ClinicalTrials.gov number NCT00935168.)


Background
Th e safety and effi cacy of hydroxyethyl starch (HES) for fl uid resuscitation have not been fully evaluated, and adverse eff ects of HES on survival and renal function have been reported.

Methods
We randomly assigned 7,000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kDa and a molar substitution ratio of 0.4 (130/0.4, Voluven; Fresenius Kabi AG, Bad Homburg vor der Höhe, Germany) i n 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fl uid resuscitation until ICU discharge, death, or 90 days after randomization. Th e primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal replacement therapy. Objective: We conducted a large-scale randomized controlled trial to evaluate the safety and effi cacy of 6% HES (130/0.4) in 0.9% saline as compared with 0.9% saline alone for fl uid resuscitation in a heterogeneous population of adult patients in the ICU. Design: Th e Crystalloid versus Hydroxyethyl Starch Trial (CHEST) was an investigator-initiated, multicenter, prospective, blinded, parallel-group, randomized controlled trial.
Setting: Th e study was set at 32 hospitals in Australia and New Zealand. Subjects: Th e subjects were adult patients (>18 years) who were admitted to the ICU and who required intravenous fl uid above maintenance requirements determined by the treating clinician and supported by at least one objective physiological criterion. Patients were excluded if they received more than 1 L of 6% HES within 24 hours of screening or had one of the following: dialysis-dependent or impending dialysis renal failure, computed tomography evidence of non-traumatic intracranial hemorrhage (ICH) or severe traumatic ICH, creatinine of more than 3.9 mg/dL or urine output of less than 10 mL/hour for 12 hours, sodium of more than 160 meq/L, or chloride of more than 130 meq/L. Also excluded were females of childbearing age (unless proven not to be pregnant) and patients who had post-cardiac surgery status, liver transplant, or burns and those whose death was judged to be imminent or whose underlying disease process indicated a life expectancy of less than 90 days. Intervention: If fl uid was deemed necessary by the treating clinician by the parameters described above, the patient received 'study' fl uid with identical packaging and appearance. Th e fl uid was either 6% HES (130/0.4) in saline (Voluven) or 0.9% saline. Outcomes: Th e primary outcome was death within 90 days. Secondary outcomes were acute kidney injury (AKI) and failure and treatment with renal replacement therapy.

Conclusions
In patients in the ICU, there was no signifi cant diff erence in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, despite a lower overall rate of AKI, more patients who received resus citation with HES were given renal replacement therapy.

Commentary
Th e colloid-crystalloid debate has lingered for decades, resulting in the overall conclusion that composition of fl uids for resuscitation does not infl uence morbidity or mortality in the general intensive care unit (ICU) population and that the only diff erence involves cost [1]. Even with the advent of 'safer' hydroxyethyl starches (HESs) [2,3], a mortality benefi t remains elusive. However, human studies [4,5] suggest that fl uid therapies may not be as innocuous as once thought and that they may cause renal injury and perhaps aff ect mortality in specifi c subgroups.
Th e fi rst adequately powered, randomized, blinded study drawing attention to these potential diff erential eff ects was the Saline versus Albumin Fluid Evaluation (SAFE) study. Th is study found no diff erences in mortality in the general ICU population but did fi nd trends toward increased survival in patients with sepsis and increased mortality in patients with traumatic brain injury [6], suggesting that these diff erential eff ects do exist and that they may be determined by the population studied. More recently, the VISEP (Effi cacy of Volume Substitution and Insulin Th erapy in Severe Sepsis) trial [7] addressed the safety and effi cacy of HES versus lactated ringer's solution in patients with severe sepsis and septic shock. Th ese investigators demonstrated that HES increases risk of acute kidney injury (AKI) and renal replacement therapy. Similarly, a meta-analysis that included the VISEP trial showed an increased risk of AKI in the general population and an increased risk of AKI and use of renal replacement therapy in patients with sepsis. However, the VISEP trial used high doses of hyperoncotic HES and may not be relevant to usual practice. Finally, a meta-analysis by Perel and colleagues [8], which included both SAFE and VISEP trials, failed to show diff erences in mortality in hospitalized patients but recommended that future trials focus on specifi c subgroups. Taken together, these data suggested that fl uid composition may be important, at least in certain subgroups of critically ill patients, especially in patients with sepsis. Th e Scandinavian 6S trial attempted to answer this question by randomly assigning patients with severe sepsis to receive HES in a ringer's acetate solution compared with carrier solution alone. Th e 6S trial found a higher risk of 90-day mortality (relative risk = 1.17, P = 0.03) and greater use of renal replacement therapy with HES as compared with those receiving ringer's acetate [9]. However, whether the increased mortality and morbidity risk were present in a more heterogeneous ICU population was still unknown. Whether other forms of HES carry a similar risk is also unclear from the 6S trial. Th e Crystalloid versus Hydroxyethyl Starch Trial (CHEST) sought to answer these questions.
CHEST was a well-conducted, blinded, randomized trial that used a patient-centered outcome such as 90-day mortality as the primary aim and that was adequately powered to fi nd diff erences between groups using the intention-to-treat principle. Th e authors were cautious to ensure that the intervention fl uids of the two arms of the study had the expected composition by performing independent and random biochemical analyses. In addition, the study targeted a more general ICU patient population, as compared to other recent clinical trials evaluating crystalloids versus colloids, such as 6S. Importantly, the CHEST was designed to allow for a diff erence in fl uid volumes between each arm, whereas 6S proscribed equal volumes. Limitations to this study include the following: (a) predefi ned criteria for the initiation of renal replacement therapy were absent, (b) the observed death rate was lower than the predicted death rate, and this may lead to diffi culties in detecting mortality diff erences, (c) the patients who were less sick (than 6S trial) and elective surgical patients were included, and (d) the time to resolution of the objective parameter (heart rate, blood pressure, respiratory varia tion of systolic or mean arterial blood pressure, central venous pressure, capillary refi ll, and urine output) used to support a diagnosis of hypovolemia was not compared between the groups.
Th e CHEST found no diff erence in 90-day mortality between patients receiving 6% HES (130/0.4) and those receiving 0.9% saline. Interestingly, the use of renal replacement therapy was greater in patients receiving HES, even though by RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria the saline group had more AKI. Post hoc analysis suggested that increases in creatinine were more pronounced in the HES group, perhaps prompting the small but signifi cant increased use of renal replacement therapy. Shaw and Kellum [10] (2013) theorize that this paradox may be explained by a reduction in glomerular fi ltration rate by HES despite better early urine output due to more eff ective volume expansion with the colloid. Furthermore, clinicians may be trading short-term improvements in hemodynamics and urine fl ow for long-term renal toxicity [10]. Whether some patients would benefi t from better resuscitation effi ciency (that is, achieving resus ci tation goals faster with less fl uid) even at the expense of some renal toxicity cannot be addressed by this or the 6S trial. Finally, the CHEST enrolled patients an average of 11 hours after ICU admission, and most 6S patients were already resuscitated prior to study entry. Th us, these aspects of the colloid-crystalloid debate rage on. It will be important to see the one-year outcome follow-up data yet to be published. In the meantime, the existing data confi rm a renal toxicity signal from HES not only in patients with sepsis but also in the general ICU population.

Recommendations
Given this evidence of renal toxicity and in spite of the uncertainty of the eff ect on resuscitation effi ciency, we believe that HES should be avoided in patients with severe sepsis as well as in other critically ill patients at high risk of AKI. Th ere is no doubt that the colloidcrystalloid debate has been informed by these two trials. However, the remaining uncertainty on aspects such as resuscitation effi ciency and timing of intervention just might gather enough rumble for a thirteenth round.