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Random snippets and thoughts - hopefully mostly trauma related!

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(RSS) Trauma Research Blog

Selected new & juicy research papers, with editorial comment.

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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:

HS Kaplan-Meier 

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. 

PubMed ID: 7935634
N Engl J Med. 1994 Oct 27;331(17):1105-9
Authors: Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL

Abstract:

BACKGROUND. Fluid resuscitation may be detrimental when given before bleeding is controlled in patients with trauma. The purpose of this study was to determine the effects of delaying fluid resuscitation until the time of operative intervention in hypotensive patients with penetrating injuries to the torso. METHODS. We conducted a prospective trial comparing immediate and delayed fluid resuscitation in 598 adults with penetrating torso injuries who presented with a pre-hospital systolic blood pressure of < or = 90 mm Hg. The study setting was a city with a single centralized system of pre-hospital emergency care and a single receiving facility for patients with major trauma. Patients assigned to the immediate-resuscitation group received standard fluid resuscitation before they reached the hospital and in the trauma center, and those assigned to the delayed-resuscitation group received intravenous cannulation but no fluid resuscitation until they reached the operating room. RESULTS. Among the 289 patients who received delayed fluid resuscitation, 203 (70 percent) survived and were discharged from the hospital, as compared with 193 of the 309 patients (62 percent) who received immediate fluid resuscitation (P = 0.04). The mean estimated intraoperative blood loss was similar in the two groups. Among the 238 patients in the delayed-resuscitation group who survived to the postoperative period, 55 (23 percent) had one or more complications (adult respiratory distress syndrome, sepsis syndrome, acute renal failure, coagulopathy, wound infection, and pneumonia), as compared with 69 of the 227 patients (30 percent) in the immediate-resuscitation group (P = 0.08). The duration of hospitalization was shorter in the delayed-resuscitation group. CONCLUSIONS. For hypotensive patients with penetrating torso injuries, delay of aggressive fluid resuscitation until operative intervention improves the outcome.

Notes & Commentary:

Spent a surprisingly enjoyable journal club discussing this paper today.  It was in the running for most important trauma paper of all time at one point.  It's certainly perhaps the trauma paper that has generated the most controversy.  The study's been criticised on many fronts but it's often overlooked how extraordinarily difficult it is to conduct a study like this.  It marked the beginning of a sea-change in the way patients were resuscitated. The whole paper needs to be read and digested to fully appreciate the implications of the results. 

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