The Use of Hypertonic Saline to Reduce the Intracranial Pressure

Inhaltsverzeichnis

Overview

Literature Review

Efficacy of HTS

Comparing Efficacy of Hyperosmolar Therapies: Mannitol and HTS

Osmolarity Measurement

Responsiveness to Treatment with HTS

Conclusion

References

Overview

In retrospect, the paradigm of evidence-based practice seems to underpin the quality of care as measured by improved patient outcomes. In neurotrauma care, evidence-based interventions have led to a significant decrease of morbidity and mortality resulting from traumatic brain injury (TBI). According to epidemiological data, TBI is reported to be the leading cause of mortality and morbidity, affecting over 10 million people in the global population, annually[[1]]. This is attributable to complications associated with intracranial operations such as elevated intracranial pressure (ICP) and brain edema [[2]]. Consequently, appropriate therapeutic interventions are required to reduce brain tissue damage and cerebral perfusion. In practice, hyperosmolar agents are used to ameliorate intracranial hypertension and brain edema. Of great interest in the treatment of intracranial hypertension is the increasing use of evidence-based guidelines that require the use of mannitol and hypertonic saline (HTS) as first-line treatment agents. However, recent meta-analyses suggest that HTS exhibit more efficacy in reducing ICP than the other hyperosmolar agents, despite the scarcity of evidence within the literature [[3]]. Therefore, this paper comprises of a critical review of literature on the use of HTS to reduce the intracranial pressure.

Literature Review

Over the past decades, an immense scientific inquiry on therapeutic interventions for TBI has been ongoing. However, the principal focus of most studies has been to determine the superiority of various therapeutic agents which are used for the treatment of intracranial hypertension. As such, literature can be grouped into four main categories based on efficacy, drug pharmacokinetics and patient’s responsiveness to treatment with the drugs.

Efficacy of HTS

In order to investigate the efficacy of HTS, an array of studies has been carried out using diverse research designs and study populations. For instance, animal models have been tested to determine the effect of HTS. An outstanding example of such studies is the Sousa et al [ [4] ] study that sought to evaluate the effect of 3% HTS on intracranial hypertension. The rationale for this study was based on evidence from previous studies that showed 3% HTS solution was particularly effective. As such, investigators evaluated the maintained effect of this hyperosmolar agent in an experimental model of ICP. To achieve the objective of this study, investigators created a porcine model of reversible intracranial hypertension which involved the manipulation of a balloon catheter placed in the brain parenchyma. They used three groups of experimental animals; A, B and C, in which group B was used as the intervention group. The intervention involved infusion with 3% HTS followed by an evaluation of ICP after 60 minutes. According to the findings of this study, serum sodium levels within each group did not show any significant reduction (p=0.09). Consequently, there were no significant reductions of ICP in all the 3 groups. Therefore, investigators concluded that 3% HTS does not reduce ICP under the influence of a pump.

In another study which was carried out by Colton et al. [[5]] to investigate pressure times time dose (PTD) of ICP in severe TBI, HTS was found to reduce PTD. The rationale for this study was based on previous studies which suggested PTD to be an important aspect to consider in predicting the outcome of TBI treatment. To achieve their study’s objective, investigators in this study measured the effect of the common therapies on the dose and duration of intracranial hypertension. Participants in this study were ICP patients admitted in urban tertiary care facilities between 2008 and 2010. According to the results of this study, varying dosage of HTS produced different effects on PTD. For instance, a low dose of less than 250 ml of 3% HTS reduced PTD by 38% and 37% in the first and second hour, respectively. Additionally, this dose produced PTI decrease of 38% and 39% within the same duration. On the other hand, a high dose of 3% HTS decreased PTD by 40% and 63% after 1 and 2 hours, respectively. It was also noted that this dose reduced the time with ICP by 36% and 50% in the first and second hours, respectively. In contrast, all the other medications, notably barbiturates, Fentanyl, mannitol, and propofol failed to decrease PTD. As such, investigators concluded that HTS reduces PTD, as well as decreasing PTI burden, and its effect remains significant within 2 hours after the administration of the dose. These findings were consistent with those of a previous study that was carried out by the same investigators to evaluate ICP response after therapeutic treatment of TBI with different therapies. In this study, Colton et al. [[6]] found out that HTS therapy resulted in the largest decrease of ICP compared to Fentanyl, mannitol, propofol, and barbiturates.

Finally, findings of the recent landmark study by Shein et al. [1] that investigated the effectiveness of pharmacologic therapies for intracranial hypertension among TBI patients suggest HTS to be the most effective of all therapies. The objective of this study was to demonstrate the effects of commonly used medications for ICP in TBI patients, with the principal focus being assessing their efficacy. In this prospective study, acute cerebral hemodynamic changes associated with mannitol, 35 HTS and pentobarbital were recorded through the monitoring of cerebral perfusion and ICP every 5 seconds. The study population comprised of children with severe TBI (Glasgow Coma Scale score ≤ 8) who were admitted in a tertiary care children’s hospital. Overall, 16 children who were recruited to participate in this study received an average of 12 doses of per patient. Therefore, a total of 196 doses of mannitol, HTS, pentobarbital, and Fentanyl were administered to the participants, and the generated data was analyzed to evaluate the medications’ cerebral hemodynamic effects. According to the findings of this study, there was a significant decrease of ICP after the administration of all medications. However, controlled administration of multiple medications indicated that only HTS and pentobarbital resulted in decreased ICP. Fentanyl decreased cerebral perfusion pressure, but this increased significantly after the administration of HTS. In fact, Fentanyl resulted into frequent treatment failures. In contrast, HTS exhibited two-fold faster resolution of ICP compared to pentobarbital and Fentanyl. In addition, HTS was found to produce the most favorable cerebral hemodynamic effects. Based on these outcomes, it was concluded that HTS should be considered as the first-line agent for intracranial hypertension treatment.

Comparing Efficacy of Hyperosmolar Therapies: Mannitol and HTS

Over the past decade, evidence-based approaches have focused on the use of hyperosmolar agents, notably mannitol and HTS for the treatment of intracranial hypertension in TBI patients. However, there is no sufficient evidence on therapeutic threshold and effective dose of these agents. As such, intensive research has focused on investigating the superiority of these hyperosmolar agents on the basis of efficacy and treatment outcome [[7]].

In one retrospective study that was carried out by Mangat et al. [[8]] who investigated the effectiveness of HTS versus mannitol in reducing ICP burden after TBI found compelling evidence. The objective of this study was to determine the most effective hyperosmolar agent with an increased outcome and decreased mortality rates associated with ICP after severe TBI. This study involved 477 and 35 participants who received mannitol only and HTS only after severe TBI, respectively. Investigators measured primary outcome based on daily and cumulative ICP burden. According to the results of this study, the mean daily ICP burden (1.3 hours/day [mannitol] vs 0.3 hours/day [HTS]; p=0.001) was reported. On the other hand, the mean cumulative ICP burden (36.5% [mannitol] vs 15.52% [HTS]; p=0.003) was reported. This indicates that daily and cumulative ICP burdens were significantly reduced in the HTS group. Consequently, the HTS group recorded a lower number of ICU days compared to the mannitol group. Therefore, investigators in this study concluded that bolus therapy of HTS is more effective than mannitol in reducing daily and cumulative ICP burden after severe TBI.

Similar findings were obtained by Jagannatha et al. [[9]] who investigated the effectiveness both mannitol and HTS based on their outcomes in severe TBI. This was a controlled randomized prospective study that comprised of 38 patients with severe TBI. Investigators administered equiosmolar boluses of 3% HTS to 18 subjects, and 20% mannitol to 20 subjects, followed a 6-days’ monitoring of ICP. According to the results of this study, there was no significant progressive increase in ICP in the HTS group (p=0.1); whereas a progressive increase was noted in the mannitol group (p=0.01). Moreover, in-hospital mortality was significantly lower in the HTS group compared to the mannitol group. Therefore, it was concluded that HTS exhibits intracranial physiologic benefits over mannitol although these benefits are not evident on long-term basis.

Finally, Roumeliotis et al. [[10]] investigated hyperosmolar therapy in children with TBI to determine therapeutic threshold and dose of mannitol and HTS. The objective of this study was to examine the effect of hyperosmolar therapy on cerebral perfusion pressure and ICP. In this study, 70% of the 64 patients received 3% HTS; whereas the rest received 20% mannitol. Both groups failed to show any significant change in cerebral perfusion pressure post bolus. Similarly, both mannitol and HTS recorded non-significant decrease in ICP of p=0.055 and 0.096, respectively. As a result, investigators concluded that dose and therapeutic threshold for hyperosmolar therapy vary without clear indications and efficiency; thus, creating the need for further controlled trials.

Osmolarity Measurement

From a quantitative perspective, it is apparent that measurement and calculation of serum osmolarity during hyperosmolar therapy exhibits some discrepancies. To address this challenge, Li et al. [[11]] sought to determine a biochemical approach to reconcile the disagreement. For the two experimental agents, serum osmolarity, blood urea nitrogen, serum potassium and sodium concentration, and blood glucose were measured followed by an agreement analysis using Bland and Altman’s limits of agreement. Based on the findings of this study, measured and calculated serum osmolarity for the HTS group showed a better agreement compared to mannitol. As such, it was concluded that calculated serum osmolarity serve as surrogate for osmolarity measurement, only if HTS is used to treat TBI.

Responsiveness to Treatment with HTS

Patients’ responsiveness to HTS therapy has also been evaluated. For instance, Colton et al. investigated the initial patient response to HTS therapy and assessed its neurological outcome. In this study, 36 patients were recruited who received HTS. Monitoring for ICP was done and recorded at 1 and 2 hours after the dose administration. Results of this study showed that patients who had good outcomes had a significantly larger sustained ICP decrease in 2 hours after the intervention, compared to those who had poor outcomes. This suggested that treatment responsiveness to HTS therapy determines neurological outcomes.

Conclusion

In a brief conclusion, it is apparent that HTS exhibits beneficial advantages compared to the other medications used for the treatment of intracranial hypertension in patients with severe TBI. Foremost, this therapy is associated with a higher efficacy compared to mannitol. Second, HTS is associated with improved treatment outcomes, and this translates to reduced mortality rates. Finally, it exhibits a relative agreement between measured and calculated osmolarity measurements; thus, calculated serum osmolarity can be used as surrogate osmolarity measurement. Therefore, this evidence suggests that HTS should be used as first-line drug for the treatment of intracranial hypertension after severe TBI.

References

1 Shein, SL, Ferguson NM, Kochanek PM, Bayir H, Clark RB, Fink EL, et al. Effectiveness of pharmacological therapies for intracranial hypertension in children with severe traumatic brain injury—results from an automated data collection system time-synched to drug administration. Pediatr Crit Care Med 2016; 17:236–245.

2 Wong JM, Panchmatia JR, Ziewacz JE, Bader AM, Dunn IF, Laws ER, et al. Patterns in neurosurgical adverse events: intracranial neoplasm surgery. Neurosurg Focus 2012; 33(5), E16.

3 Bell MJ, Adelson PD, Hutchison JS, et al. Multiple Medical Therapies for Pediatric Traumatic Brain Injury Workgroup: Differences in medical therapy goals for children with severe traumatic brain injury—an international study. Pediatr Crit Care Med 2013; 14:811–818.

4 Sousa LM, de Andrade AF, Belon AR, Soares MS, Amorim RL, Otochi JP, et al. Evaluation of the maintained effect of 3% hypertonic saline solution in an animal model of intracranial hypertension. Med Sci Monit Basic Res 2016; 22: 123-127.

5 Colton K, Yang S, Hu PF, Chen, HH, Bonds B, Stansbury LG, et al. Pharmacologic treatment reduces pressure times time dose and relative duration of intracranial hypertension. Journal of Intensive Care Medicine 2016; 31(4): 263-269.

6 Colton K, Yang S, Hu PF, Chen, HH, Bonds B, Stansbury LG, et al. Intracranial pressure response after pharmacologic treatment of intracranial hypertension. J Trauma Acute Care Surg. 2014; 77(1): 47-53.

7 Sakellaridis N, Pavlou E, Karatzas S, et al. Comparison of mannitol and hypertonic saline in the treatment of severe brain injuries. J Neurosurg 2011; 114:545–8.

8 Mangat HS, Chiu Y, Gerber LM, Alimi M, Ghajar J, Härtl R. Hypertonic saline reduces cumulative and daily intracranial pressure burdens after severe traumatic brain injury. J Neurosurg 2015; 122:202–210.

9 Jagannatha AT, Sriganesh K, Devi BI, Rao GS. An equiosmolar study on early intracranial physiology and long term outcome in severe traumatic brain injury comparing mannitol and hypertonic saline. Journal of Clinical Neuroscience 2016; 27: 68–73.

10 Roumeliotis N, Dong C, Pettersen G, Crevier L, Emeriaud G. Hyperosmolar therapy in pediatric traumatic brain injury: a retrospective study. Childs Nerv Syst 2016; 32:2363–2368.

11 Li Q, Chen H, Hao J, Yin N, Xu M, Zhou J. Agreement of measured and calculated serum osmolality during the infusion of mannitol or hypertonic saline in patients after craniotomy: a prospective, double-blinded, randomized controlled trial. BMC Anesthesiology 2015; 15:138.