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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: 21112053
Injury. 2010 Nov 25. [Epub ahead of print]
Authors: Floccard B, Rugeri L, Faure A, Denis MS, Boyle EM, Peguet O, Levrat A, Guillaume C, Marcotte G, Vulliez A, Hautin E, David JS, Négrier C, Allaouchiche B.

Abstract:

PURPOSE: Amongst trauma patients, early coagulopathy is common on hospital admission. No studies have evaluated the initial coagulation status in the pre-hospital setting. We hypothesise that the coagulopathic process begins at the time of trauma. We studied the on-scene and on hospital arrival coagulation profile of trauma patients.

METHODS: Prospective, observational study investigating the on-scene coagulation profile and its time course. We studied 45 patients at the scene of the accident, before fluid administration, and on hospital admission and classified their coagulopathy using the International Society on Thrombosis and Haemostasis score during a 2-month period. Prothrombin time, activated partial thromboplastin time, fibrinogen concentration, factors II, V and VII activity, fibrin degradation products, antithrombin and protein C activities, platelet counts and base deficit were measured.

RESULTS: The median injury severity score was 25 (13-35). On-scene, coagulation status was abnormal in 56% of patients. Protein C activities were decreased in the trauma-associated coagulopathy group (p=.02). Drops in protein C activities were associated with changes in activated partial thromboplastin time, prothrombin time, fibrinogen concentration, factor V and antithrombin activities. Only factor V levels decreased significantly with the severity of the trauma. On hospital admission, coagulation status was abnormal in 60% of patients. The on-scene coagulopathy was spontaneously normalised only in 2 patients whereas others had the same or a poorer coagulopathy status. All parameters of coagulation were significantly abnormal comparing to the on-scene phase. Decreases in protein C activities were related to the coagulation status (p<.0001) and changes in other coagulation parameters. Patients with base deficit ≤-6mmol/L had changes in antithrombin, factor V and protein C activities but no significant coagulopathy.

CONCLUSION: Coagulopathy occurs very early after injury, before fluid administration, at the site of accident. Coagulation and fibrinolytic systems are activated early. The incidence of coagulopathy is high and its severity is related to the injury and not to hypoperfusion.

Notes & Commentary:

Acute Traumatic Coagulopathy (ATC) has been described as present in 10-25% of trauma patients on arrival in the emergency department.  This is the first on-scene study of ATC and identifies a very high incidence of 56% when measured in 45 patients. These were patients managed by SAMU and a more severely injured group of patients (average ISS 25) but this remains a very high incidence.   UNfortunately the authors use a DIC score to define ATC.  ATC is not a DIC-type coagulopathy and ATC was not included in the development of the ISTH DIC score.  Nevertheless ATC clearly develops very soon after injury (25 minutes on average in this study) as shown by a fall in Protein C and Factor V levels as we have previously shown (PMID:18212647).   This study adds to the evidence that ATC is endogenous as this was before significant dilution or other iatrogenic interntion.  The speed at which dysfunction of coagulation and inflammation develops continues to surprise and challenge pre-existing conceptions of the pathophysiology of trauma.

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PubMed ID: 19628092
Surgery. 2009 Aug;146(2):325-33.
Authors: Alam HB, Shuja F, Butt MU, Duggan M, Li Y, Zacharias N, Fukudome EY, Liu B, Demoya M, Velmahos GC.

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BACKGROUND: We have demonstrated previously that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival in lethal models of hemorrhagic shock. This study investigated whether VPA treatment would improve survival in a clinically relevant large animal model of poly-trauma/hemorrhagic shock, and whether the protective effects are executed through the Akt survival pathway. METHODS: Yorkshire swine were subjected to a poly-trauma protocol including: (1) Pre-hospital phase- Femur fracture, 60% hemorrhage, 30 min of shock (mean arterial pressure [MAP]: 25-30 mmHg), and infusion of 154mM NaCl (3 x shed blood); (2) Early hospital phase A Grade V liver injury (simulating rupture of a previously contained hematoma) followed by liver packing; (3) Treatment/monitoring phase randomization to 3 treatment groups (n = 6-8/group): no treatment (control), fresh whole blood (FWB), and intravenous VPA (400 mg/kg, given during the pre-hospital phase). Animals were monitored for 4 h, with survival being the primary endpoint. Liver tissue was subjected to Western blot analysis. RESULTS: FWB (n = 6) and VPA treatments (n = 7) significantly increased survival (100% and 86%, respectively) compared to control group (n = 8) (25%). The protocol produced significant anemia (Hb<6 g/dL) and lactic acidosis (lactate 3-5 mmol/L). Acidosis improved after blood transfusion and worsened in the other two groups. VPA treatment increased phospho-Akt (activated), phospho-GSK-3beta (Glycogen synthase kinase 3beta), beta-catenin and Bcl-2 (B-cell leukemia/lymphoma 2) protein levels compared to control group (P = .01, .01, .03, and .02, respectively). There was no significant difference in the level of these proteins between the control and FWB groups. CONCLUSION: Treatment with VPA without blood transfusion improves early survival in a highly lethal poly-trauma and hemorrhagic shock model. The survival advantage is due not to improvement in resuscitation but to better tolerance of shock by the cells, in part due to the preservation of the Akt survival pathway.

Notes & Commentary:

Sodium valproate protects cells from ischaemic damage in this haemorrhagic shock model.  There are a number of potential therapeutics options for both ischaemia protection and ischaemia rescue ready for translational trials now.

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