This meta-analysis of 1162 hypotensive prehospital patients from five studies comparing prehospital administration of 7.5% hypertonic saline compared to isotonic fluid in hypotensive patients did not demonstrate a statistically significant change in survival to hospital discharge. There were no consistent significant differences in secondary outcomes.

These findings align with two previous systematic reviews and meta-analyses of hypertonic saline administration to trauma patients, although these reviews included studies in both the prehospital and hospital setting.

The results of our systematic review suggest that there is no evidence of benefit to the prehospital application of hypertonic saline for hypotensive injured patients. It is important, however, to consider how the included patients and the fluids may have contributed to these findings.

Patients presenting to EMS may be categorized broadly on a spectrum from life-threatening injury to non-life threatening injury. The former patients may die regardless of EMS interventions, where the latter patients may survive regardless of EMS interventions. In the middle of this spectrum are patients with life-threatening injuries amenable to appropriate EMS therapy. It is these patients that have the potential to benefit from an effective intervention, but may be a small number within the larger population of EMS patients. Identifying these patients in the very narrow assessment time that is afforded to paramedics is difficult. Indeed this was the challenge outlined by Brasel and colleagues (2008) when designing the ROC trial reported by Bulger et al. [21, 26]. They changed the inclusion from a broad approach of patients presenting with a SBP less than or equal to 90 mmHg, to a SBP less than or equal to 70 mmHg, or a patient with a SBP less than or equal to 90 mmHg and a heart rate greater than or equal to 108 beats per minute. The rationale for this change was to identify a population that was more likely to receive greater than 10 units of packed red blood cells in the first 24 h (i.e., not “mildly injured” patients), based on a previous study in 2008 [26, 29]. All studies included in this review, except Bulger et al. used a broad systolic blood pressure categorization [21]. This may mean that the group of patients that would potentially benefit from hypertonic saline are much smaller than the reported sample sizes, resulting in a bias of the effect estimate towards null. Finally, it is unclear what impact the administration of hypertonic saline might have in hypotensive patients with traumatic brain injury [30, 31].

The fluid that the patient received, as part of the study or as part of routine care, either before or after enrolment in the study is important. It has been postulated that receiving isotonic fluid either before or after hypertonic saline may negate the beneficial effects of hypertonicity [6]. All studies included in this review permitted the use of isotonic fluid before and/or after administration of the study fluid. It is unknown what magnitude of effect this may have had on outcome, but if isotonic fluids negate the effect of hypertonicity, then this would decrease the potential effect of hypertonic saline and move the effect estimate towards null. In addition, the volume of hypertonic saline provided to intervention groups was between 250 ml (4 out of 5 studies) and 300 ml. This dose has also been criticized as it may be too low compared to the weight adjusted dose used in previous animal studies [6]. While 4 ml/kg has been reported as the hypertonic saline dose used in the original animal studies, in the included studies an 80 kg (175 lb) patient would have received an approximately 3 ml/kg dose and a 50 kg (110 lb) patient a 5 ml/kg dose. Conducting a subgroup analysis based on patient weight was not possible given the available data [6, 32]. Since the majority of patients in these trials were male (range 66% to 85%), it is possible that many participants were systematically under dosed hypertonic saline compared to the original animal studies. This would also contribute towards decreasing the potential effect of hypertonic saline and move the effect estimate towards null.

It must be noted that the Bulger et al. trial was stopped early due to futility in the presence of a possible safety concern [21]. The authors suggest that the “mortality” effect in patients that received blood transfusion in the first 24 h post injury may be caused by a shift to earlier mortality in those patients receiving hypertonic saline, although this could not be statistically demonstrated. They further suggest that this shift to earlier mortality may occur because of increased bleeding in the hypertonic saline group, and possibly a change in physician behaviour that delayed the administration of transfusions [21]. Other authors have disputed that increased bleeding is a plausible explanation based on the reported hemoglobin levels, and have suggested that it was indeed a failure on the part of the first-receiver physician to recognize a shock state in the face of non-shock level systolic blood pressure and cutaneous hyperemia that occur with the use of hypertonic saline [6, 32]. Other authors have postulated that it is the creation of subgroups using a post-randomization variable (number of blood transfusions) that has introduced a “collider bias” in the study analysis [33]. The authors suggest that the “increased mortality” in the hypertonic saline /no transfusion group is a systematic bias rather than a clinical phenomenon [33].

Limitations

The homogenous nature of the intervention allowed for pooling of results, but other concentrations of hypertonic saline (e.g., 3%, 5%, etc.) [34], doses, or weight-based dosing regimens were not assessed. It is possible that a single 250 ml dose of 7.5% hypertonic saline may not be sufficient to evaluate the clinical effectiveness of hypertonic saline.

No trials except Cooper et al. (2004) reached planned sample size [23]. However, some authors have also criticized the Cooper et al. study for being underpowered [1]. All trials had low power to exclude clinically important differences, especially for secondary outcomes. The 95% confidence interval of the pooled estimate spanned a potential reduction in survival of 5% to an increase in survival of 10%. While not excessively wide, this estimate would have been more precise had studies reached their planned sample sizes and includes effects that could be clinically important.

Every effort was made to conduct thorough searches of major research databases, and be inclusive in the title and abstract review, however it is still possible that trials were missed. This is especially true for newer studies that may not have been published, or only recently published in full text and not yet indexed. Hand searching of conferences was not performed. Finally, all studies included injured patients located in civilian EMS settings, and did not include patients with other causes of hypotension or military far-forward, tactical or wilderness EMS settings where the theoretical benefits of hypertonic saline may be more readily demonstrated.