Safety and Efficacy of Repeated Doses of 14.6 or 23.4 % Hypertonic Saline for Refractory Intracranial Hypertension
The efficacy of administering single bolus doses of 14.6 or 23.4 % hypertonic saline (HTS) to treat refractory intracranial hypertension has been demonstrated in the literature and has emerged as an important therapeutic option in treating these patients. However, many institutions lack experience with this therapy and there are few published studies evaluating the safety of repeated bolus dosing of HTS.
A retrospective review of patients admitted between January 2008 and July 2012 was conducted to evaluate the use of repeated dosing of HTS in patients with refractory intracranial hypertension. The primary objective was to evaluate the safety of repeated dosing of HTS assessed by documented adverse effects such as central pontine myelinolysis (CPM) and severe fluctuations in serum sodium concentrations. Secondary objectives were to evaluate the efficacy of repeated dosing HTS in reducing intracranial pressure (ICP) and to compare the dose–response relationship of 14.6 and 23.4 % doses.
Fifty-five patients were included for evaluation, each receiving an average of 8.9 (range 2–61) doses of HTS. A statistically significant increase in mean serum sodium concentration occurred with the administration of HTS (p < 0.0001). No cases of CPM were identified. The use of HTS was found to be effective based on decreases in ICP after administration (p < 0.0001, mean ICP reduction: 10.1 mmHg, range 3–23.6 mmHg). The efficacy of 23.4 % saline in decreasing ICP was not found to be significantly different than 14.6 % saline (p = 0.23).
Repeat bolus dosing of 14.6 or 23.4 % HTS appears to be relatively safe and effective for treating refractory intracranial hypertension assuming there is frequent electrolyte monitoring and concomitant fluid management.
KeywordsHypertonic saline Hyperosmolar agents Intracranial pressure Osmotherapy Intracranial hypertension Serum sodium
Intracranial hypertension resulting from neurologic injury is often associated with negative prognosis . Increased intracranial pressure (ICP) reduces cerebral perfusion pressure (CPP) and can lead to cerebral hypoxia and death [2, 3].
Cerebral edema after neurological injury (i.e., head trauma, stroke, or CNS infection) causes elevations in ICP when the compensatory mechanism of raising perfusion pressure is overwhelmed by increased volume . Cerebral edema develops by either a cytotoxic or a vasogenic mechanism and involves the swelling of cells in response to increased intracellular sodium levels [1, 3]. Vasogenic edema is extracellular edema leading to the breakdown of the blood brain barrier in response to increased vascular permeability [1, 3]. Products from tissue injury (i.e., lysed cells, intravascular blood) further add to the osmotic gradient, pulling in water and worsening the edema . This overall cascade effect leads to higher ICP, worsening ischemia and injury to additional tissue .
The Brain Trauma Foundation guidelines recommend the following therapies for treating ICP: cerebrospinal fluid drainage, sedation and analgesia, CPP optimization, osmotherapy, hyperventilation, high-dose barbiturate therapy, and hypothermia . Osmotherapy continues to be the standard of care in the management of patients with elevated ICP . Osmotic agents work by elevating serum osmolality, creating an osmotic gradient that pulls fluid out of the brain into intravascular space [4, 7]. This mechanism largely depends on an intact blood brain barrier.
Mannitol has been widely used in clinical practice since the 1960s and has been the traditional osmotic agent of choice for the control of elevated ICP . Unfortunately, mannitol has the ability to cross the disrupted blood brain barrier, raising concern for accumulation within the injured areas of the brain after multiple administrations [6, 7]. This accumulation often leads to a reversal of the osmotic gradient resulting in an increase in cerebral edema and in some cases an increase in midline shift [6, 7]. Furthermore, the use of mannitol is associated with the development of acute tubular necrosis and renal failure . If serum osmolarity exceeds 320 mOsm/L or if a patient has predisposing risk factors for renal failure, this risk is greatly increased. Due to this concern, maintaining serum osmolarity below 320 mOsm/L during mannitol therapy is recommended .
Recently, hypertonic saline (HTS) has been shown to be a potentially useful adjunctive therapy to mannitol [8, 10]. Studies have demonstrated that HTS can reduce ICP and provide potential beneficial hemodynamic, vasoregulatory, and immunomodulatory effects [1, 8]. Similarly to mannitol, the infusion of HTS increases the osmotic gradient between the brain and the blood and pulls fluid from the interstitial space into intravascular space. HTS counteracts the effects of accumulated extracellular osmolytes by increasing intravascular osmolarity to draw fluid from the interstitial space, thereby reducing ICP. Increased intracellular sodium also restores the normal function of the sodium/osmolyte co-transporters . Human trials comparing mannitol to HTS have found that HTS can be more effective than mannitol in reducing episodes of increased ICP, though there have been differences in published results [3, 8, 10]. While Ware et al.  found no difference between the ICP reductions observed with mannitol and 23.4 % HTS they did find that HTS resulted in a significantly longer duration of effect without complications. Kerwin et al.  described somewhat different results in their study where they found the mean reduction of ICP in the hour following administration to be greater following HTS therapy than with mannitol but found no difference in the duration of ICP reduction or incidence of adverse events with either therapy.
The use of HTS is not without risk of complications. The most serious potential adverse effect of HTS therapy is the potential development of neurologic complications due to central pontine myelinolysis (CPM), which is the destruction of myelinated fibers after a rapid rise in serum sodium [2, 4, 6, 9, 10, 11]. Human trials utilizing HTS have not documented development of CPM [2, 4, 9]. Renal insufficiency and even failure is another potential adverse effect, although it has been found to occur less commonly than with the use of other osmotic diuretics used to control cerebral edema [2, 4, 6, 9, 10, 11]. Electrolyte disturbance may also occur due to the sodium and chloride load being administered.
Valentino et al.  described a case report of a patient who received ten doses of 23.4 % HTS over a 48-h period. In this report, the patient did not experience hemodynamic or CNS complications. To date, additional literature supporting the safety of repeated bolus doses of HTS in reducing ICP are lacking. We evaluated the cases at our institution to describe the utilization of repeated dosing HTS, focusing on safety and efficacy. We were also interested in comparing the dose–response relationship with 14.6 and 23.4 % HTS in refractory ICP reduction.
The study design was a retrospective review of patients after Institutional Review Board approval using a prospective pharmaceutical protocol for HTS from January 2008 to July 2012. A list of dispensed HTS doses was generated by the pharmacy department and used to identify patients who received more than one dose in a 24-h period for reduction of ICP. Our institution previously approved an institutional guideline for safe administration of HTS, which utilized best-practice and available literature regarding HTS administration.
Inclusion criteria for this review were: (1) admission to the NeuroICU; (2) administration of more than one dose of 14.6 or 23.4 % saline within a 24-h period; (3) documented monitoring of ICP during administration of HTS; and (4) 18 years of age or older. Exclusion criteria were: (1) active participation in other clinical trials (i.e., receiving therapy under an investigational protocol) and (2) pregnant patients.
Concentration, Infusion, and Safety Monitoring
The dose of HTS was 60 or 120 mEq (8,008 mOsm/L) of sodium chloride (15 or 30 mL of 23.4 % NaCl, respectively) intravenous bolus over 20 min via controlled infusion pump through a central line. Due to a drug manufacturer shortage of commercially prepared 23.4 % saline in 2011, the use of commercially available 14.6 % saline (5,000 mOsm/L) was administered as a pharmaceutical interchange for patient care. The protocol at our institution recommends 120 mEq of sodium chloride dose as 30 mL of 23.4 % saline. During 23.4 % saline shortages, a therapeutic equivalent of 60 and 120 mEq of sodium chloride was provided using either 24 or 48 mL of 14.6 % saline, respectively. Patients also received baseline infusion of normal saline (0.9 %) at variable rates depending on the clinical situation. Standard of care intensive care unit (ICU) monitoring included invasive and noninvasive blood pressure monitoring, hourly neurological checks by nursing and frequent monitoring of laboratory tests including complete blood count (CBC), serum electrolytes including sodium, creatinine, blood urea nitrogen (BUN) and plasma osmolality. In addition, continuous ICP and electrocardiogram monitoring was recorded in the medical record.
Patient demographics, laboratory and dosing data and documented adverse events were obtained from the electronic medical record. Demographic data included age, gender, ethnicity, pregnancy status, past medical history, past surgical history, admission and discharge dates, and diagnoses. Baseline laboratory values were recorded (i.e., serum sodium, serum osmolality, and ICP). For each consecutive HTS dose administration, the following data points were recorded: dose and concentration, administration time, ICP peak and nadir with associated times and pre- and post-dose serum sodium and osmolality with associated times. To evaluate adverse effects, serum sodium increases of greater than or equal to 10 mEq/L per 24 h were recorded as well as cases of central or extra-pontine myelinolysis as reported in computed tomography (CT) or magnetic resonance imaging (MRI) readings or in clinician’s progress notes documentation.
Descriptive statistics (i.e., mean, median, ranges) were used for analysis of the safety and efficacy endpoints for this retrospective review of patients receiving treatment for a condition without comparison to a control group. In addition, continuous variables were assessed using paired t tests and the Spearman’s rank correlation was utilized to analyze correlation data. Unpaired, two-sided t tests were used to evaluate the HTS dose to ICP response relationship.
Baseline patient characteristics
n = 55
Age, years old mean (range)
Female, n (%)
Caucasian, n (%)
Intracranial pressure, mmHg (range)
Serum Na+, mEq/L (range)
Admission diagnosis, n (%)
Vertebral artery dissection
Past medical history, n (%)
Diabetes, type II
Noncontributory past medical history
Safety and Efficacy
An average of 8.9 (range 2–61; median 6) intravenous HTS bolus doses were administered per each included patient. With each dose administration, the serum sodium increased by an average of 1.8 %. The average pre-dose serum sodium of 141.7 mEq/L (range 128–151 mEq/L) increased to an average of 144.3 mEq/L (range 130–166 mEq/L) after each dose, see Supplementary Table 2. This change was found to be statistically significant (p < 0.0001, 95 % CI −3.53 to −1.62) but the average post-dose values were still less than the goal serum sodium levels of 145–155 mEq/L for this patient population. No correlation was found between the number of doses administered and increases in serum sodium (Rho: −0.205; p = 0.13, 95 % CI −0.45 to 0.06). The average incidence of a 10 mEq/L or greater rise in serum sodium over a 24-h period was found to be 1.06 (range 0–5). This was found to statistically correlate with the number of doses administered (Rho: 0.351; p = 0.01, 95 % CI 0.10–0.56).
Changes in serum osmolality were inconsistently documented with only six (10.9 %) patients having complete documentation of values. For this reason, further evaluation of changes in serum osmolality was not conducted.
No documented cases of central pontine or extra pontine myelinolysis were documented in the 55 patients included in this study. All patients in this study received CT head noncontrast studies for the main neuroimaging modality to monitor brain edema and structural changes. Out of n = 55 patients in the study, n = 18 (33 %) had MRI during their original hospital admission, with no patient having changes consistent with CPM. Of these 18 patients with MRI, nine had either global cerebral edema or bifrontal or localized brain edema. Another nine patients (four of whom overlapped with the group of nine patients with localized or global brain edema) also had vascular infarcts documented. One patient with global edema who had a combination of subarachnoid hemorrhage and cardiac arrest had MRI changes consistent with widespread anoxic–hypoxic brain injury.
Death occurred in 32.7 % (n = 18; 6 received 14.6 % saline, 12 received 23.4 % saline) of the patients included. All deceased patients received 120 mEq doses of HTS, most also received 60 mEq doses of HTS.
Because of the large range of HTS doses administered, a partial analysis was done of those patients receiving ten or more consecutive doses (n = 16). This analysis resulted in similar results as above. An average of 19.6 HTS doses were administered (range 10–61; median 15). Serum sodium increased by an average of 1.4 %. The average pre-dose serum sodium of 143.8 mEq/L (range 137–149 mEq/L) increased to an average of 145.2 mEq/L (range 138–151 mEq/L) after each dose. This change was found to be statistically significant (p = 0.0002) but similar to the previous analysis remained within serum sodium goals. ICP was significantly reduced from a mean ICP peak of 20.8 mmHg (range 8.8–27.9 mmHg) to a mean ICP nadir of 9.96 (range 4.5–15.4 mmHg), (p < 0.001).
A mean ICP decrease of 11.8 mmHg with each administration of 120 mEq of 23.4 % saline (n = 239) was not found to be statistically different from the mean ICP decrease of 10.7 mmHg associated each administration of 120 mEq of 14.6 % saline (n = 121); p = 0.23, 95 % CI −0.91 to 3.12.
The current study also demonstrates that repeated bolus doses of HTS are efficacious in reducing ICP with a mean reduction of 49.5 % after each dose. To date, this is the largest cohort of patients that demonstrate efficacy of repeat bolus dose HTS using concentrations of 14.6 and 23.4 %. A recently published meta-analysis by Lazaridis et al.  evaluated the efficacy of HTS in eleven studies on the use of 23.4 % saline in 263 neurocritically ill patients and found a similar ICP reduction: 56 % ICP decrease; p < 0.0001, 95 % CI 43.99–67.12. An original evaluation of the repeated boluses of 14.6 % HTS including 11 patients was also recently published. In this prospective cohort study, 14.6 % HTS was found to be safe and effective for treatment of refractory ICP . An evaluation of the duration of ICP lowering effect may have added to the efficacy assessment, thus adding to the limitations of this review.
The utilization of 120 mEq bolus doses of 23.4 % (30 mL) saline administered over 20 min used at our institution has demonstrated similar efficacy to that described in previous studies [7, 8, 10, 13, 16, 17]. Ware et al.  demonstrated efficacy of this same dose of 23.4 % saline provided in a 2-min intravenous infusion. At our institution, we have opted to utilize the more prolonged 20-min infusion to minimize the risk for extravasation with administration of concentrated sodium chloride since, we have demonstrated efficacy with this infusion rate. Also, we opted to utilize the same dose of 120 mEq of 14.6 % saline (48 mL) when we were unable to reliably obtain 23.4 % saline due to drug manufacturer shortages. The comparison evaluation in this study demonstrated no difference in efficacy for either concentration of HTS administered. Because there is more literature to support the use of 23.4 % saline it remains our preferred concentration and the 14.6 % concentration is administered as an alternative in times of drug manufacturer shortages [7, 8, 10, 13, 16, 17].
One of the goals of conducting this study was to increase the awareness of the utilization and safety of HTS in this patient population. This therapy has been utilized at our facility for some time but we have found that many institutions and practices lack clinical experience with using such a highly concentrated dose of HTS. At our institution, we also take precautions to prevent errors with this therapy by having pharmacy prepare and dispense the HTS in patient-specific intravenous bags for each order. These are hand-delivered to the nursing staff with labeling directing infusion via a central line. An infusion pump is used to precisely control the administration rate.
Due to its retrospective design, this study is limited by a potential for patient-selection bias and a lack of control for variables. Many patients received concomitant therapeutic intervention with HTS therapy including hyperventilation, mannitol, medical sedation, ventriculostomy, and surgical decompression. Therefore, the independent effect of HTS in reducing ICP could not be completely evaluated in this study. Nonetheless, there was a robust association between the increase in serum sodium concentration and reduction in ICP.
Another limitation of this study is its lack of a comparison group of patients who did not receive HTS. However, at our institution the widespread adoption of HTS as part of the medical therapy for refractory intracranial hypertension meant that we would be unable to identify a sufficient number of subjects for a control group.
This study is further limited by the inter-patient variability in the number and timing of consecutive dosing courses administered. Some patients included in this analysis received multiple courses of consecutive doses and others received only one consecutive set of HTS doses.
Intracranial hypertension can be fatal and relieving elevated ICP may improve outcomes for neurocritically ill patients. The superior agent to reduce ICP is part of ongoing investigations. Highly concentrated (14.6 or 23.4 %) HTS has been found to be an effective therapy but lack of clinical experience may cause it to be underutilized. This study was conducted to increase awareness of the safety and efficacy of HTS in this patient population. This study demonstrates that repeated intravenous bolus administration of HTS was not found to be associated with any major adverse events such as CPM and was effective at consistently lowering ICP in those with refractory intracranial hypertension. The effect of individual doses of 120 mEq of sodium chloride was found to be no different when provided as 30 mL of 23.4 % saline or as 48 mL of 14.6 % saline. Further randomized trials are needed to define the most appropriate agent, the optimal dose and administration and long-term neurological outcomes for treating refractory intracranial hypertension.
The authors would like to acknowledge the contributions of the following colleagues: Paula Fuqua Pharm. D., CCRC (Department of Pharmacy, Mayo Clinic, Jacksonville, FL, USA) and Jamila Russeau Pharm. D., BCPS (Department of Pharmacy, Mayo Clinic, Jacksonville, FL, USA) for guidance and assistance in study protocol development and manuscript review. Colleen Thomas, MS (Department of Biostatistics, Mayo Clinic, Jacksonville, FL, USA) for general advice on using appropriate statistics for this study.
Conflict of interest
J. J. Lewandowski-Belfer, A. V. Patel, R. M. Darracott, D. A. Jackson, J. D. Nordeen, and W. D. Freeman declare that they have no conflict of interest.
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