The hypothesis that hypertonic fluid has a dual physiological role, increasing circulatory volume while administering minimal volumes and muting the pro-inflammatory response to injury and illness, may be appealing, but is it superior to isotonic fluids in practice? This is the question posed by Blanchard et al., in this systematic review and meta-analysis of prehospital treatment of hypotensive trauma patients.
Prehospital treatment of critically injured or ill patients with intravascular volume depletion is imperative for positive patient outcomes and could impact chance of survival. For this reason, paramedics commonly administer boluses of isotonic or near isotonic fluid to maintain a target systolic blood pressure (SBP). However, it is still unknown what the optimal fluid management strategy is for these patients.
An alternative to isotonic fluid is hypertonic saline – it has been hypothesised that hypertonic saline exerts a dual physiological role of increasing circulatory volume with minimal volumes of fluid while muting the pro-inflammatory response to injury and illness (Bulger, 2011; Rossaint et al., 2016). This has led to a further hypothesis that in hypotensive states, hypertonic saline may be superior to isotonic fluids in altering the causal pathway of low blood pressure, which leads to tissue injury, organ failure and eventually death (Bulger, 2011; Cotton et al., 2009; Dubick & Wade, 2013; Bunn et al., 2009; Perel & Ker, 2013).
What makes hypertonic saline therapy particularly appealing when comparing treatment options is the potential to allow infusion of lower fluid volumes. This is in line with the principles of damage control resuscitation where fluid volume is guided by clinical endpoints as opposed to fixed doses (Feinman et al., 2014; Briggs & Askari, 2016).
Despite promising animal and pre-clinical data, two meta-analysis studies of pre- and in-hospital clinical data didn’t reach a definitive conclusion on the impact of hypertonic saline. They found a relative risk of mortality at hospital discharge for traumatically injured patients of 0.84 (95% CI 0.69, 1.04) and 0.96 (95% CI 0.82, 1.14) respectively (Bunn et al., 2009; Wang et al., 2014).
In the hope of answering this hypothesis, and to support evidence-based prehospital clinical guideline development, Blanchard et al., asked “in patients presenting with hypotension in the prehospital setting, does the administration of hypertonic saline, compared to isotonic fluid, change survival to hospital discharge?”. The study also assessed the following secondary outcomes: longer-term survival, vital signs, fluid/blood requirements, Multiple Organ Dysfunction Score (MODS), length of hospital stay, disability and neurological outcome scales, and adverse events.
Searches of four electronic databases (Medline, Embase, CINAHL, and CENTRAL) yielded 1350 studies, of those, 5 studies were selected for inclusion based on a strict search criteria and elimination of manuscripts with duplicated data. Collectively these 5 studies comprised 1162 trauma patients, all administered either 250ml 7.5% hypertonic saline (except one study that used 300 ml) or a control fluid (isotonic or near isotonic fluid) of the same volume as a prehospital intervention. All studies also include a form of co-intervention as part of ‘routine care’, including colloids in two studies.
From the pooled data the authors found there was no significant difference in overall survival to hospital discharge between the intervention and control groups (RR 1.02; 95% CI 0.95, 1.10) (figure 1).
A number of reasons may have affected the overall survival to hospital discharge in these studies and the meta-analysis. Firstly, variation in reported injuries may affect how successful treatment is; Vasser et al., reported that the hypertonic saline arm had a higher injury severity score, a higher proportion of severe injuries to one or more body regions, and more severe injury to the brain and chest compared to the control group. This would put patients in this group at a disadvantage as their chance of survival is already lower than those with less severe injuries.
This is in addition to patients being recruited to these studies on a broad spectrum from life-threatening to non-life-threatening injuries. In the middle of this spectrum are patients with life-threatening injuries that have the potential to benefit from an effective intervention. Therefore, it’s likely that the key population is a much smaller sample, diluting the treatment effect.
It has also been hypothesised that receiving isotonic saline either before or after hypertonic saline may negate the beneficial effects of hypertonicity (Dubick & Wade, 2013). All the studies used in this meta-analysis permitted the use of isotonic fluid before and/or after administration of hypertonic saline, potentially limiting its effect.
The uniform volume of hypertonic saline administered has also been criticised as it may be too low in comparison to the weight-adjusted doses used in animal studies (Dubick & Wade, 2013). The original animal studies reported a 4 ml/kg hypertonic saline dose, however, variation in participants’ weight would result in administration of different doses. For instance, an 80 kg patient would have received a 3 ml/kg dose while a 50 kg patient would have received a 5 ml/kg dose.
The majority of the studies didn’t report statistically significant differences in secondary outcomes. This is with the exception of two studies; Bulger et al. reported a statistically significant increase in 28-day mortality when patients were stratified by the post-randomisation variable of blood transfusion in the first 24 hours after injury. The increase in mortality rate in the treatment group resulting in the study being stopped early due to safety concerns. However, there is some uncertainty over how relevant the significant increase was, and other authors have suggested it may have been caused by limitations within the study (Dubick & Wade, 2013; Holcroft, 2011; De Junce et al., 2015).
The other study to report a statistically significant secondary outcome was Vassar et al., who reported a greater mean change in systolic blood pressure in the hypertonic saline treatment group in comparison to the Lactated Ringer’s solution (34 mmHg ± 46 vs. 11 mmHg ± 49, p<0.03).
In summary, based on the available data, hypertonic saline cannot be recommended for use in prehospital clinical practice for the management of hypotensive patients. As there is a level of discordance between the pre-clinical and clinical trials, further investigation is required particularly focusing on patients most likely to benefit from hypertonic saline in addition to weight-based doses.
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Bunn FR IG, Tasker R, Trivedi D. Hypertonic versus near isotonic crystalloid for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2009;4.
Cooper DJ, Myles PS, McDermott FT, Murray LJ, Laidlaw J, Cooper G, et al. Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: a randomized controlled trial. JAMA. 2004;291(11):1350–7.
Cotton BA, Jerome R, Collier BR, Khetarpal S, Holevar M, Tucker B, et al. Guidelines for prehospital fluid resuscitation in the injured patient. J Trauma. 2009;67(2):389–402.
Del Junco DJ, Bulger EM, Fox EE, Holcomb JB, Brasel KJ, Hoyt DB, et al. Collider bias in trauma comparative effectiveness research: the stratification blues for systematic reviews. Injury. 2015;46(5):775–80.
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Duran S, Klotz P, Dubick MA, Wade CE, R. O. C. Investigators. Collider bias in trauma comparative effectiveness research: the stratification blues for systematic reviews. Injury. 2015;46(5):775–80.
Feinman M, Cotton BA, Haut ER. Optimal fluid resuscitation in trauma: type, timing, and total. Curr Opin Crit Care. 2014;20(4):366–72.
Holcroft JW. The hypertonic saline trial: a possible downside to the gold standard of double blinding. Ann Surg. 2011;253(3):442–3.
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Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.
Vassar MJ, Fischer RP, O’Brien PE, Bachulis BL, Chambers JA, Hoyt DB, Holcroft JW. A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride. The effect of added dextran 70. The multicenter Group for the Study of hypertonic saline in trauma patients. Arch Surg. 1993;128(9):1003–11.
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