The Role of Hypertonic Saline in the Management of Acute Traumatic Spinal Cord Injury: A Narrative Review of the Literature

Abstract

Traumatic spinal cord injury (TSCI) is a prevalent condition associated with high morbidity and mortality. The pathophysiology of TSCI involves primary injury from the traumatic insult itself and secondary injury (SI) from maladaptive biological processes that serve to aggravate the original insult, such as edema and inflammation, which exacerbate the primary injury and prevent healing and recovery. Research is currently underway to derive therapies to reduce SI-mediated damage. Hypertonic saline (HTS) has emerged as one such therapy. We conducted a literature search for animal and human studies investigating the role of HTS in TSCI on PubMed. Murine studies have shown it to possess antiedema, anti-inflammatory, and vasodilatory properties, which aid in reducing SI and thus improving functional outcomes. Combining HTS with other drugs such as procoagulants, methylprednisolone, and nitroprusside has also been shown to possess greater therapeutic benefit in rodent models of TSCI compared with single therapy with HTS. No human studies have been done till now to assess the benefits of HTS in improving human TSCI outcomes. Future research must focus on determining specific dosing and frequency regimens for HTS in human TSCI patients and on elucidating the extent of benefit it provides to them in improving their outcomes.

 

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Keywords

hypertonic - traumatic - spine - injury - outcome

Introduction

Traumatic spinal cord injury (TSCI) is a common and prevalent condition: the United States alone sees 40 incident cases per year per 1 million of its population and between 250,000 and 300,000 prevalent cases of TSCI, costing its health care industry $9.7 billion annually.[1] It is associated with high morbidity and mortality owing to the lack of regenerative potential of the central nervous system.[2] The mortality from TSCI has declined over the years due to advancements in intensive care and rehabilitation techniques; however, the morbidity from the condition continues to remain high as patients live longer without experiencing complete alleviation of their deficits.[3]

TSCI involves a complex pathophysiology comprising primary injury orchestrated by the traumatic insult itself followed by a cascade of reactive processes constituting the secondary injury (SI), which amplifies the damage caused by the primary injury.[4] There is growing evidence to suggest that these SI processes not only exacerbate the extent of the original injury but also hamper healing mechanisms from restoring tissue integrity, resulting in protracted and unrelenting illness.[5] This understanding has sparked research into developing therapies to limit SI mechanisms.[6] One of the therapies under research for this purpose is hypertonic saline (HTS). In this narrative review of the literature, we attempt to briefly review the SI mechanisms of spinal cord injury and relate them to the mechanism of action and pharmacologic properties of HTS, highlighting its merits and limitations in treating TSCI and suggesting avenues of focus for future research.

 

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Materials and Methods

A search string was developed using the terms “spinal cord injury,” “hypertonic saline,” and “HTS” to search for animal and human studies assessing the role of HTS in TSCI over the PubMed database. Eight studies in total were found to meet the criteria for our review; their authors, titles, study samples, and salient findings are summarized in [Table 1]. [Fig. 1] gives an overview of the literature review and study selection processes.

Fig. 1 Flowchart summarizing the literature review and study selection processes.

Table 1 Authors, titles, study samples, and salient findings of included studies

Authors	Title	Study sample	Salient findings
Boutonnet et al[5]	Combinatorial therapy with two procoagulants and one osmotic agent reduces the extent of the lesion in the acute phase of spinal cord injury in the rat	77 male Wistar rats	Triple therapy with tranexamic acid (TXA), fibrinogen, and HTS lead to a greater reduction of intraparenchymal hemorrhage and greater preservation of histologic neural integrity compared with dual and single therapy with the same drugs and NS
Young et al[11]	Preservation of postcompression spinal cord function by infusion of hypertonic saline	20 Sprague-Dawley rats	HTS-treated rats exhibited greater spinal cord blood flow for the first 30 minutes postinjury compared with NS-treated rats and controls. This was associated with greater preservation of spinal cord function in the HTS-treated group, as measured by somatosensory evoked potentials (SSEPs)
Sumas et al[12]	Tonicity of resuscitative fluids influences outcome after spinal cord injury	23 female Sprague-Dawley rats	HTS-treated rats exhibited greater recovery of limb movement and bladder function than those treated with Ringer's lactate (RL) or controls. Histologic integrity was also more preserved in the HTS-treated group compared with others
Levene et al[9]	A murine model of hypertonic saline as a treatment for acute spinal cord injury: effects on autonomic outcome	41 female C57Bl/6 mice	HTS-treated rats saw greater bladder function recovery and lesser inflammatory infiltrate in their spinal cord compared with NS-treated ones. HTS administration at 24 hours was associated with the best outcomes
Spera et al[8]	Effect of hypertonic saline on leukocyte activity after spinal cord injury	15 Sprague-Dawley rats	Leukocyte adherence to spinal cord microvascular walls was significantly lower in HTS-treated rats compared with controls
Spera et al[17]	The effects of hypertonic saline on spinal cord blood flow following compression injury	25 Sprague-Dawley rats	HTS administration at 5 minutes postinjury significantly increased spinal cord blood flow (SCBF) compared with administration at 15 and 60 minutes. HTS-treated animals maintained SSEPs till 4 hours postinjury while untreated animals lost them at 3 hours. Topical nitroprusside used in combination with HTS increased SCBF in injured rats but not in the uninjured ones
Legos et al[13]	Coadministration of methylprednisolone with hypertonic saline solution improves overall neurological function and survival rates in a chronic model of spinal cord injury	29 female Sprague-Dawley rats	Rats treated with a combination of methylprednisolone and HTS exhibited better functional outcomes up to 28 days postinjury compared with those treated with HTS alone, NS, and a combination of methylprednisolone and NS
Nout et al[10]	Hypertonic saline attenuates cord swelling and edema in experimental spinal cord injury: a study utilizing magnetic resonance imaging	12 female Long-Evans Hooded rats	HTS-treated rats had lower spinal cord volumes compared with NS-treated rats at all time points. T1 hypointensity and T2 hyperintensity were significantly lower in HTS-treated rats compared with NS-treated ones at 7 and 8 hours postinjury, signifying greater edema reduction in the HTS-treated rats

Abbreviations: HTS, hypertonic saline; NS, normal saline.

 

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Review of the Literature

Mechanism of Action of Hypertonic Saline in Limiting Secondary Injury

SI in TSCI causes hemorrhage within the spinal cord parenchyma.[7] It also disrupts the blood–spinal cord barrier, allowing the leakage of water, molecular contents of plasma, and inflammatory cells into the spinal cord parenchyma.[5] The inflammatory cells mediate localized inflammation while the edema and hemorrhage produce a mass effect, restricting blood flow to the injured area.[7] [8] The ensuing ischemia encourages the formation of free radicals, reactive oxygen species, and other mediators of inflammation, further amplifying the initial inflammatory reaction and thus beginning a vicious cycle that culminates in loss of neural integrity and function at the site of injury.[9] These destructive mechanisms damage the neural cell membranes to cause intracellular ionic imbalances that produce excitotoxicity-mediated neural cell death.[4]

HTS is an osmotically active agent that possesses an osmolality higher than that of plasma and intracellular fluid. This attribute allows it to draw fluid out of the site of spinal cord injury to reduce the local edema and accompanying tamponade it creates, improving blood flow to the injured cord.[1] The antiedema properties of HTS were studied by Nout et al in their study on Long-Evans Hooded rats in whom they induced spinal cord injury and observed the injury progression via magnetic resonance imaging (MRI).[10] Nout et al found T1 hypointensity and T2 hyperintensity at the site of injury to be lower in rats infused with HTS compared with controls, suggesting HTS has antiedema properties in spinal cord injury.[10] HTS also has the potential to reduce endothelial cell swelling and vascular resistance in the microvasculature associated with the site of injury.[11] Young et al hypothesized this might be the reason why the Sprague-Dawley rats used as models of TSCI in their study exhibited increased spinal blood flow for the first 30 minutes after the start of HTS infusion compared with other groups who received normal saline (NS) or no fluid resuscitation.[11] The reduction in endothelial cell swelling and microvascular dilatation improves blood flow and mitigates ischemia-mediated SI.[11]

It has also been suggested in the literature that HTS increases blood flow to the spinal cord by acting as a volume expander.[9] [12] This, however, does not seem to be a primary mechanism by which HTS acts since a study on Sprague-Dawley rat models of TSCI by Legos et al showed that coadministration of methylprednisolone with HTS had superior neurological outcomes compared with those of methylprednisolone with NS, suggesting that HTS acted through mechanisms other than volume expansion to mitigate SI in the rat models in this study since volume expansion also occurred in the NS-treated rats.[13] However, it is also known that lower volumes of HTS are needed for resuscitation compared with other, less tonic resuscitation fluids such as NS and Ringer's lactate.[14] This could be because the hypertonic nature of HTS drives osmotic homeostasis toward the conservation of water to keep the plasma osmolality from rising too high. The HTS-treated rats in the study of Legos et al might have experienced a more robust circulatory volume expansion compared with NS-treated rats based on this principle, suggesting volume expansion too plays a key role in the mechanism by which HTS acts to prevent SI. Empirical evidence would be needed to understand this relationship further.

HTS has also been shown to harbor anti-inflammatory properties. Spera et al investigated the effects of HTS on leukocyte adhesion to the microvasculature after induced spinal cord injury in Sprague-Dawley rats.[8] They found that bolus administration of HTS 5 minutes after injury significantly reduced leukocyte adhesion to the microvascular walls until 2 hours postinjury.[8] Leukocyte adhesion is an elementary stage in leukocyte recruitment in acute inflammation and so a decrease in leukocyte adhesion would directly translate to a decrease in leukocyte infiltration into tissues, thus dampening inflammation-mediated damage at the site of injury.[8] [15] Spera et al also proposed that HTS directly attenuates leukocyte activation through its osmotic action, preventing leukocytes from swelling.[8] They formulated their hypothesis based on findings from an in vitro study by Rosengren et al who concluded that neutrophils must undergo osmotic swelling before they can responsively migrate toward chemotactic signals.[16] The efficacy of HTS in reducing leukocyte recruitment was also corroborated by Levene et al in their study of HTS administered 3 and 24 hours postinjury induction in rodent models of TSCI: the authors commented on the histologic appearance of the injured cord in rodents treated with HTS as having a less pronounced inflammatory infiltrate compared with those treated with NS, a difference they also found to increase with time, suggesting that HTS had inhibited the inflammatory cascade that continued to amplify in the NS-treated group.[9]

HTS has also been suggested in the literature to possess cell-membrane stabilizing potential, as it restores resting membrane potential in aberrantly excited neurons, reduces influx and accumulation of calcium within neurons, and so reduces excitotoxicity-mediated SI.[1] There is a paucity of medical evidence to support this notion, so studies are warranted to investigate this mechanism further.

 

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Timing and Frequency of HTS Administration

The time postinjury and the frequency at which HTS was administered in the studies included in this review are summarized in [Table 2].

Table 2 Summary of the time postinjury and frequency at which HTS was administered in the studies included

Authors	Timing of initiation of HTS administration postinjury	Frequency of administration of HTS
Boutonnet et al[5]	5 min	Single infusion over 20 minutes
Young et al[11]	1 min	Single bolus infused over 1 minute
Sumas et al[12]	1 min	Single bolus (infusion time not mentioned)
Levene et al[9]	Either 3 h or 24 h	Single bolus (infusion time not mentioned)
Spera et al[8]	5 min	Single bolus (infusion time not mentioned)
Spera et al[17]	5, 15, or 60 min	Single bolus (infusion time not mentioned)
Legos et al[13]	1 min	Single bolus (infusion time not mentioned)
Nout et al[10]	30 min	8 boluses, 1 every 1 hour (infusion time not mentioned)

Abbreviation: HTS, hypertonic saline.

The first observation of significance is that all studies except for Nout et al administered HTS as a one-time bolus. The findings of these studies are thus attributable to bolus administration only. Nout et al administered serial boluses at an hourly rate and found that within the HTS-treated group, there was a temporal decline in MRI edema signals as time postinjury increased.[10] In fact, the difference in MRI signal strength between HTS-treated and NS-treated rats reached statistical significance at 7 and 8 hours postinjury, suggesting the serial boluses might have had a cumulative effect that manifested late in the study observation period.[10] However, the overall dose of HTS administered must also be taken into regard when speculating these findings. Six of the 8 studies included in this review administered HTS of a concentration of 7.5% at a dose of 5 mL/kg. Nout et al, however, administered HTS at a concentration of 5% at a dose of 1.4 mL/kg.[10] This might be the reason why statistically significant differences were achieved later in the study observation period when the cumulative dose of HTS reached therapeutic levels. The other study that differed from the general dosing protocol used was that of Boutonnet et al who administered HTS at a concentration of 7.5% at a dose of 2 mL/kg.[5] The current literature is insufficient to ascertain whether bolus administration or continuous infusion provides better outcomes and neither does it offer enough evidence to decide appropriate dosages.

Second, all studies except for that of Levene et al began HTS administration just a few minutes after injury induction. Practically, intravenous pharmacologic intervention cannot be executed so soon in humans, especially in the emergent setting, as is mostly the case with TSCI patients. The study of Levene et al is the only one to administer HTS 3 or 24 hours postinjury.[9] They found that delayed administration at 24 hours postinjury was associated with greater bladder function recovery and greater reduction in inflammatory cell infiltration into the injured spinal cord compared with administration at 3 hours postinjury.[9] An obverse observation is presented by Spera et al who found that rats treated with HTS at 5 minutes postinjury exhibited greater spinal cord blood flow (SCBF) compared with those treated at 15 and 60 minutes.[17] The study, however, did not comment on whether this difference in SCBF correlated with greater improvement in neurologic function in the group treated at 5 minutes compared with others.[17] The literature does not offer enough information regarding the optimal time of treatment, and more work must be done to ascertain the best window within which HTS can be administered to enable the best outcomes.

 

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Drugs Used in Combination with HTS

Boutonnet et al tested the efficacy of a triple-therapy regimen consisting of tranexamic acid, fibrinogen, and HTS, in male Wistar rat models of TSCI.[5] They found that rats treated with triple therapy exhibited significantly lesser intraparenchymal hemorrhage compared with rats treated with dual therapies, monotherapies, or NS and had significantly greater preserved neural tissue at 24 hours postinjury.[5] The authors attribute the success of the triple therapy to its ability to control both local hemorrhage and edema as two separate mechanisms of SI.[5]

Spera et al tested topical nitroprusside in combination with HTS in Sprague-Dawley rat models of TSCI to see their combined effects on SCBF.[17] They found that while topical nitroprusside alone failed to actuate any significant rise in SCBF in injured rats, when used in combination with HTS, injured rats saw a 74% increase in their SCBF.[17] In uninjured rats, an obverse observation was made: uninjured rats saw a 31% increase in SCBF following nitroprusside administration but no rise when nitroprusside was used in combination with HTS.[17] The authors speculate that the differing effects of nitroprusside and HTS have to do with their differing efficacies in healthy and pathologic tissue, while nitroprusside exerted its greatest effects in healthy tissue, HTS did so in pathologic tissue.[17] The study does not provide a comparison of increase in SCBF between rats treated with a combination of nitroprusside and HTS and those treated with HTS alone so a synergistic relationship between the two cannot be entirely excluded. It is important to note that in this study, nitroprusside was administered before HTS administration, so further research into a possible permissive effect of nitroprusside on HTS would be of value. Nonetheless, Spera et al do maintain that their study shows secondary vascular resistance and resulting decreased SCBF to be significant mechanisms of SI following TSCI since rats treated with HTS in their study had higher SCBF and maintained somatosensory evoked potentials for 4 hours postinjury, while untreated rats lost them 3 hours postinjury, suggesting better neurological outcomes in the treated rats.[17]

Legos et al investigated the efficacy of the combination of methylprednisolone and HTS in female Sprague-Dawley rats and found that rats treated with this combination had significantly better neurologic outcomes (measured by the Basso-Beattie-Bresnahan scoring method of locomotor function of injured rats) to those treated with a combination of methylprednisolone and NS, and to those treated with NS and HTS alone.[13] Rats treated with this combination exhibited a 100% survival rate at 28 days postinjury compared with those treated with the combination of methylprednisolone and NS, who had a survival rate of 37.5% at the same time point.[13] Rats treated with methylprednisolone and HTS also regained bladder reflexes at a median of 2 days postinjury, while the NS-treated group regained it at a median of 7 days, and the group treated with a combination of methylprednisolone and NS regained it at a median of 8.5 days postinjury.[13] The authors speculated the improved outcomes seen in the methylprednisolone and HTS-treated group may be attributable to their synergistic role in that HTS acted as a vasodilator to reduce local vascular resistance to increase the passage of methylprednisolone to the injured spinal cord or that HTS, having anti-inflammatory action itself, augmented the anti-inflammatory action of methylprednisolone to produce a more robust inhibition of inflammation-mediated SI.[13] They associated the increased survival rate seen with the methylprednisolone and HTS combination to the ability of HTS to restore function in suppressed T cells.[13] This immune-protective function of HTS might have prevented the side effects of methylprednisolone related to immunosuppression and secondary infections, thus improving long-term survival.[13] Without a formal investigation done by the authors on the deceased rats to determine whether they died due to methylprednisolone-associated side effects, these reasons must be conservatively accepted and corroborated with further study.

 

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Avenues for Future Research

To our knowledge, the eight rodent studies summarized in this narrative review represent the most impactful works done to assess the role of HTS in TSCI management. There has been, thus far, no study done to assess the same in humans. Our review shows an obvious therapeutic benefit of HTS in TSCI in rodents as a means of blunting the SI mechanisms that ensue after the primary traumatic insult to the spinal cord. However, there still remains an uncertainty in the literature regarding dosing and frequency of HTS administration. Studies must now be conducted to focus on answering these questions to facilitate the development of specific protocols in this regard. Given the already widespread use of HTS as a hyperosmolar agent in neurosurgical practice, we suggest research into repurposing HTS to be used in human patients with TSCI as a means to mitigate the evolution of the original injury due to maladaptive biological responses.[18] We believe human studies would be of greater value in establishing whether the benefits of HTS seen in rodent TSCI models extend to humans, and in coming to a consensus about which dosing and frequency regimens provide the greatest therapeutic efficacy in human TSCI patients. Most importantly, it must be seen whether the therapeutic benefits of HTS in TSCI seen in its administration within a few minutes in rodents prevail when it is administered several hours after injury in humans to determine the practicality of including it in the management of human TSCI, given the delay between injury onset and presentation to a hospital, which is all the more accentuated in the developing world.

 

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Conclusion

HTS works by various mechanisms, including the reduction of edema, inhibition of inflammation, reduction in local microvascular resistance, and reduction in excitotoxicity-mediated neurological damage to reduce the impact of SI on the injured spinal cord in rats. The combination of HTS with procoagulants, methylprednisolone, and nitroprusside demonstrated increased therapeutic benefit compared with when HTS was used alone in rodent TSCI models. Human studies are needed to determine whether these benefits extend to humans and to establish appropriate treatment regimens in the process.

 

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Conflict of Interest

None declared.

Authors' Contributions

S.F.N. developed the search string, conducted the literature search, screened the relevant articles, and wrote the final manuscript. A.H. and T.T. were responsible for extracting data and relevant information from the selected articles and also contributed to writing the final manuscript. L.E.C. and A.R. proofread the manuscript to ensure both factual accuracy and linguistic correctness. A.A.K. conceived the research question and provided critical revisions to the final manuscript.

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Publication History

Article published online:
19 May 2025