Saturday, August 9, 2014

Hypertonic Saline: Worth its salt?

Prepared by Michael. C Berrier, NRP, FP-C, C-NPT, AAS
Edited/Reviewed by: David Thomson, MS, MD, MPA, FACEP, CMTE

 There are a lot of trendy, sexy things in the world of FOAMed these days, but with that it’s important not to forget the things we see and do a lot that may not get much attention because they haven’t changed that much.

 I recently put together a lit review for our service of medical treatments for intracranial hypertension. We are a medium sized program in North Carolina that operates three rotor wing aircraft and five ground MICUs, and we transport quite a few adults and pediatrics with head injuries, intracranial hemorrhage and other causes of intracranial hypertension. Each aircraft and truck is stocked with mannitol, and I wanted to explore if it was possible, favorable and maybe even necessary that we add hypertonic saline to our formulary as well. To make that choice, it is important to consider the science, the evidence and the safety of our options.

 The science: Blunt injury or other insult induce edema of brain parenchyma due to either neuronal damage, vascular injury or changes in capillary permeability, allowing the effective third spacing of fluid into the tissue. Hyperosmolar agents like mannitol and hypertonic saline can reduce ICH by shifting water from the intracellular and extracellular spaces into the vascular space to reduce intracranial volume and subsequently ICP. Mannitol is rapidly excreted by the kidneys, thus causing profound diuresis. Hypertonic saline resists this osmotic shift and remains in the vascular space longer causing an increase in circulating volume (Mannitol IV (Mannitol injection) Drug Information, 2014) (Sodium Chloride injection, solution, 2014).

The evidence: Hyperosmolar agents have been used in the treatment of ICH for nearly a century, with mannitol being the de facto “gold standard” for much of that time (Marko, 2012), though no clear reason was found in the literature for that distinction, and there is no shortage of literature. A PubMed search for “mannitol + hypertonic saline + brain” yields 249 results, with 72% of those being published since 2000. For this review, we chose a meta-analysis of randomized human clinical trials and one animal trial that directly compared the effects of mannitol vs hypertonic saline in the management of ICH. We also chose one retrospective clinical trial that reviewed the safety of hypertonic saline administration to pediatric patients during critical care transport.

 The meta-analysis comprised five total clinical trials that enrolled 112 total patients who experienced one or more incidents of ICH resulting from several different traumatic or medical insults. A total of 184 episodes of ICH were treated randomly with either mannitol or HTS. Mannitol was effective in controlling elevated ICP 78% of the time, whereas HTS was successful 93% of the time. The data suggests also that treatment with HTS resulted in greater mean reduction of ICP and a longer duration of action. The reviewers concede that the small number and size of eligible studies somewhat limits their value, but the findings suggest hypertonic saline may be superior to mannitol (Ko, 2011).

The animal trial induced a brain lesion in rats using liquid nitrogen to simulate a TBI. The rats were monitored for ICH using a subdural catheter and then randomized to receive either normal saline, mannitol or HTS at time of maximal ICP increase (60 minutes). HTS reduced ICP by a greater margin (53.9%) than mannitol (35%) and also lasted longer (500 minutes vs 120 minutes.) The group treated with mannitol also returned to and overshot the original baseline ICP increase by 10%-25% during the same time period. This experiment is particularly useful for our purpose because it was specifically designed to use awake, non-anesthetized animals. The authors posit that most animal studies were performed under general anesthesia which may not be applicable under all conditions. Likewise, a vast majority of patients in transport are not under general anesthesia, usually only receiving an induction as part of RSI and intubation and thus may be more physiologically similar to the animals in this study. More importantly, the authors seek to explain the reasons behind the lesser effect, shorter duration and potential for rebound increases in ICP associated with mannitol administration in injured brains vs the almost equal effect seen in the uninjured control group. One theory suggested that cerebral sequestration and rapid renal excretion of mannitol (usually within three hours) may lead to a reverse osmotic shift and the reported rebound phenomenon. The study also addresses the important issue of hypovolemia and resultant cerebral hypoperfusion in the TBI patient, which may be precipitated or worsened by mannitol but has not been demonstrated with HTS (Hanley).

 Finally, one retrospective study evaluated the safety of HTS administration to pediatric patients during critical care transport. Two important ideas to come from this study were 1) no complications related to HTS administration were reported in any of the 101 children enrolled in the study, and 2) 96% of the administrations were via peripheral intravenous lines. Many interfacility transport patients do not have central venous access and virtually no patients referred by EMS from a scene have central venous access, so the ease, safety and effectiveness of HTS administration peripherally is paramount to its usefulness in the CCT environment (Luu, 2011).

Standard of Care: NCOEMS paramedic protocols make no mention of pharmacologic management of ICH, but rather only list treatments for associated blood pressure derangements. The North Carolina Medical Board Approved Medications for Credentialed EMS Personnel is an appendix document to the treatment protocols that lists all medications approved for NC EMS providers by credential. Mannitol is listed an approved medication for EMT-P administration but it is not referenced in any protocol or on the simplified drug list. The same is true of hypertonic saline, only being referenced implicitly under “Crystalloid Solutions” (EMS Patient Care Treatment protocols for NC EMS systems., 2014).

 Guidelines for the Management of Severe Traumatic Brain Injury, 3rd Edition, published by the Brain Trauma Foundation (10), state that mannitol is effective in the management of traumatic intracranial hypertension, though they stop short of making a Level I recommendation for the use of mannitol. BTF makes no recommendation about the use of hypertonic saline. It is noteworthy that these guidelines were published in 2007, while many of the trials comparing HTS and mannitol were published after that (Guidelines for the managment of severe traumatic brain injury, 2014). The Joint Theater Trauma System Clinical Practice Guideline, Management of Patients with Severe Head Trauma from the US military (current as of 2012) outlines stepwise treatment for these patients, including management of increased intracranial pressure. The guideline states:
“Patients with moderate head injury who deteriorate and those with severe head injury should receive 250ml bolus of 3% saline and then infusion of 3% saline at 50-100ml/hr for resuscitation en route to the Level III center. If further deterioration occurs or if the patient shows signs of herniation (pupillary dilation, hypertension and bradycardia, progression to decerebrate posturing) consider using Mannitol 1g/kg bolus IV, followed by 0.25g/kg rapid IV push q4hrs. Note: Do not use Mannitol in hypotensive or under-resuscitated casualties (Managment of patients with severe head trauma, 2012).”

 Clinical Considerations: Both Mannitol and 3% Saline can be given safely via peripheral IV. Any greater concentration of HTS requires administration via central venous access (Mannitol IV (Mannitol injection) Drug Information, 2014) (Mannitol injection, USP., 2014) (Sodium Chloride injection, solution, 2014). Both agents can be safely infused via intraosseous access for emergent bolus administration, though long term infusions of hypertonic solutions may cause tissue and bone necrosis, and therefore one manufacturer of IO equipment recommends only a single dose be administered this way (Intraosseous(IO) Vascular Access and the EZ-IO Frequently asked questions, 2014).

 Both mannitol and HTS are stored best at room temperature, and both can endure brief exposures to heat up to 40° C without significant impact. At colder temperatures, mannitol may crystalize in the vial and require warming prior to administration to dissolve the crystals. For this reason, an inline filter is required for mannitol bolus administration. HTS does not crystalize at room temperature and thus does not require a filter (Mannitol injection, USP., 2014) (Sodium Chloride injection, solution, 2014).

 Our service, like many I’ve talked to, stores our mannitol in the IV fluid warmer to minimize the likelihood of crystallization.

The Verdict: Most of the evidence directly comparing hypertonic saline and mannitol is inconclusive just because the studies are rather small and underpowered. However, the literature seems clear enough that HTS is as viable an option as mannitol, even if not definitively better. Saline is easier to use, lacking the necessity of filters and stringent climate control, though there have been recent shortages which may limit availability. Bottom line, hypertonic saline has likely earned a place in the decision tree of intracranial hypertension treatment, and therefor earned a spot in your bag.

 EMS Patient Care Treatment protocols for NC EMS systems. (2014, January 1). Retrieved from

 Guidelines for the managment of severe traumatic brain injury. (2014, July 14). Retrieved from

 Hanley, D. (n.d.). Comparison between hypertonic saline and mannitol in the reduction fo elevated intracranial pressure in rodent model of acute cerebral injury. Journal of neurosurgical anesthesiology, 334-344.

 Intraosseous(IO) Vascular Access and the EZ-IO Frequently asked questions. (2014, july 25). Retrieved from

Ko, N. (n.d.). Hypertonic saline vs mannitol for the treatment of elevated intracranial pressure. Critical Care Medicine, 554-559.

 Luu, J. (n.d.). Three percent saline administration during pediatric critical care transport. Pediatric Emergency Care, 1113-1117.

Managment of patients with severe head trauma. (2012). Joint Theater trauma system clinical practice guidelines. United States.

 Mannitol injection, USP. (2014, July 2014). Retrieved from

Mannitol IV (Mannitol injection) Drug Information. (2014, July 14). Retrieved from Marko, N. (2012).

Hypertonic saline, not mannitol, should be considered gold-standard medical therapy for intracranial hypertension. Critical Care, 113-116.

Sodium Chloride injection, solution. (2014, july 25). Retrieved from

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