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PubMed ID: 21178763
Ann Surg. 2010 Dec 20.[Epub]
Authors: Bulger EM, May S, Kerby JD, Emerson S, Stiell IG, Schreiber MA, Brasel KJ, Tisherman SA, Coimbra R, Rizoli S, Minei JP, Hata JS, Sopko G, Evans DC, Hoyt DB; for the ROC investigators.
Abstract:OBJECTIVE: To determine whether out-of-hospital administration of hypertonic fluids would improve survival after severe injury with hemorrhagic shock. BACKGROUND: Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion, with a smaller volume, and modulation of the inflammatory response, to reduce subsequent organ injury. METHODS: Multicenter, randomized, blinded clinical trial, May 2006 to August 2008, 114 emergency medical services agencies in North America within the Resuscitation Outcomes Consortium. Inclusion criteria: injured patients, age ≥ 15 years with hypovolemic shock (systolic blood pressure ≤ 70 mm Hg or systolic blood pressure 71-90 mm Hg with heart rate ≥ 108 beats per minute). Initial resuscitation fluid, 250 mL of either 7.5% saline per 6% dextran 70 (hypertonic saline/dextran, HSD), 7.5% saline (hypertonic saline, HS), or 0.9% saline (normal saline, NS) administered by out-of-hospital providers. Primary outcome was 28-day survival. On the recommendation of the data and safety monitoring board, the study was stopped early (23% of proposed sample size) for futility and potential safety concern. RESULTS: A total of 853 treated patients were enrolled, among whom 62% were with blunt trauma, 38% with penetrating. There was no difference in 28-day survival-HSD: 74.5% (0.1; 95% confidence interval [CI], -7.5 to 7.8); HS: 73.0% (-1.4; 95% CI, -8.7-6.0); and NS: 74.4%, P = 0.91. There was a higher mortality for the postrandomization subgroup of patients who did not receive blood transfusions in the first 24 hours, who received hypertonic fluids compared to NS [28-day mortality-HSD: 10% (5.2; 95% CI, 0.4-10.1); HS: 12.2% (7.4; 95% CI, 2.5-12.2); and NS: 4.8%, P < 0.01]. CONCLUSION: Among injured patients with hypovolemic shock, initial resuscitation fluid treatment with either HS or HSD compared with NS, did not result in superior 28-day survival. However, interpretation of these findings is limited by the early stopping of the trial. Clinical Trial Registration: ClinicalTrials.gov, NCT00316017].
Notes & Commentary:
This randomised controlled trial should be the final nail in the coffin for hypertonic saline in the resuscitation of haemorrhagic shock. The study was conducted by the Resuscitation Outcomes Consortium - a multicentre clinical trial network of trauma centres and their affiliated emergency medical services. The study was designed to enrol 3726 patients, but was stopped for futility and the possibility of harm in terms of increased mortality in the hypertonic saline sybgroups.
Overall there was no difference in 28-day mortality or any of the reported outcomes. Mortality was 25.6% for the NS group versus 27% for HS and 25.5% for HSD:
The reason for early stopping of the trial is rather tenous. Stopping a trial for "futility" lays a trial open to the vagaries of randomness and assumes that what happened in the enrolled patients was fully representative of the final study cohort. The trial was also stopped because of concern s about possibly increased mortality in a group of patients who did not receive blood transfusions. This was an observation made on a sub-group of patients that had not been identifed a priori and had not reached statistical significance. This is also a post-randomisation variable that has clear potential for interaction with the study intervention. Much of the paper is given over to the post-hoc analysis of this subgroup and presents lots of conjecture but few real conclusions.
The authors also state that the 'The DSMB [data and safety monitoring board] also noted that the setting of an exception to informed consent study warranted an abundance of caution'. Personally I think this a lousy statement that does a disservice to those subjects who did participate in the trial and is contrary to the fundamental ethics of clinical trials. Emergency consent procedures have been developed around the world to allow the study of acute diseases. Clinical trials should be designed and conducted optimally within these structures. It is not appropriate to skew robust clinical trial methodolgy and the interpretation of clinical trial data because of the ethical setting - in fact it is borderline unethical to do so (IMHO).
Anyway - fundamentally the trial is negative and it is unlikely that a large treatment effect was missed due to the early termination. There is no clinical advantage to the resuscitation of haemorrhagic shock with hypertonic saline. Whether this has any bearing on the role of HS versus mannitol in the setting of traumatic brain injury with or without hypovolaemia is unclear.