Efficacy and Renal Safety of Protocol-based 11.7% Hypertonic Saline Infusion Compared with 20% Mannitol in Patients with Elevated Intracranial Pressure: A Study Protocol for a Randomized Clinical Trial.

Sodium is the most abundant extracellular ion. Historically, therapy with hypertonic saline was widely used for a variety of conditions. Currently, there are 3 primary indications for its use in critical care: hyponatremia, volume resuscitation, and brain injury. SIADH and CSW syndrome may require sodium replacement, but most cases of hyponatremia can be managed without administration of hypertonic saline. Studies of use of hypertonic saline in hypovolemia and brain injury are promising, but additional research is needed to better define optimal dosing regimens and to determine the relative risks associated with hypertonic saline versus conventional treatment for the management of patients with head injuries and for volume resuscitation in shock states.

Hyperosmolar Therapy in the Management of Intracranial Hypertension.

An Update on Neurocritical Care for the Patient With Kidney Disease

Management of elevated intracranial pressure (ICP) in emergency settings often involves the administration of hyperosmolar agents such as mannitol and hypertonic saline (HTS). The choice between these agents and their safety profile, mainly when administered via peripheral intravenous (IV) lines, remains a clinical concern. Objective: To compare the safety and effectiveness of peripheral IV administration of mannitol and hypertonic saline in managing elevated intracranial pressure in the emergency department. Methods: A retrospective cohort study was conducted in the Emergency Department of Shifa International Hospital from June 2023 to June 2024. The study included 200 adult and pediatric patients who received hyperosmolar agents, specifically 110 patients administered with a 1 g/kg bolus dose of 20% or 25% mannitol and 90 patients with a 5 mL/kg bolus dose of 3% hypertonic saline. The administration was followed by repeated doses or continuous infusion at the attending physician's discretion. The primary endpoint was the incidence of extravasation. In contrast, secondary endpoints included hypokalemia, acute kidney injury (AKI) within two days of admittance, hypernatremia, hyperchloremia, ICP at admission and 24 hours post-administration, length of hospital and ICU stay, need for ventilator support, mortality rate, Glasgow Coma Scale (GCS) score at discharge, and severity of infusion-related adverse effects. Results: The mannitol group consisted of older patients (52.8 ± 21.3 years vs. 28.6 ± 23.1 years), who were also heavier (75.2 ± 21.8 kg vs. 57.5 ± 33 kilograms), had a higher prevalence of end-stage renal disease (ESRD) (7.3%), and were less likely to present with altered mental status (89.1% vs. 97.8%). There were no incidents of extravasation in either group (p > 1). No significant differences were observed between the groups concerning secondary outcomes. However, the mannitol group exhibited higher ICP after 24 hours (4.240 ± 7.9 vs. 2.111 ± 6), a lower GCS score at discharge (3 [3-14] vs. 13 [3-15]), a higher mortality rate (55.5% vs. 33.4%), and a longer duration of ventilator support (2 days vs. one day). Conclusion: Peripheral IV administration of hypertonic saline appears safer and more effective in reducing intracranial pressure than mannitol in emergency department settings. HTS demonstrated a more favorable safety profile with lower mortality and shorter ventilator support duration.

To describe acute cerebral hemodynamic effects of medications commonly used to treat intracranial hypertension in children with traumatic brain injury. Currently, data supporting the efficacy of these medications are insufficient. In this prospective observational study, intracranial hypertension (intracranial pressure ≥ 20 mm Hg for > 5 min) was treated by clinical protocol. Administration times of medications for intracranial hypertension (fentanyl, 3% hypertonic saline, mannitol, and pentobarbital) were prospectively recorded and synchronized with an automated database that collected intracranial pressure and cerebral perfusion pressure every 5 seconds. Intracranial pressure crises confounded by external stimulation or mechanical ventilator adjustments were excluded. Mean intracranial pressure and cerebral perfusion pressure from epochs following drug administration were compared with baseline values using Kruskal-Wallis analysis of variance and Dunn test. Frailty modeling was used to analyze the time to intracranial pressure crisis resolution. Mixed-effect models compared intracranial pressure and cerebral perfusion pressure 5 minutes after the medication versus baseline and rates of treatment failure. A tertiary care children's hospital. Children with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8). None. We analyzed 196 doses of fentanyl, hypertonic saline, mannitol, and pentobarbital administered to 16 children (median: 12 doses per patient). Overall, intracranial pressure significantly decreased following the administration of fentanyl, hypertonic saline, and pentobarbital. After controlling for administration of multiple medications, intracranial pressure was decreased following hypertonic saline and pentobarbital administration; cerebral perfusion pressure was decreased following fentanyl and was increased following hypertonic saline administration. After adjusting for significant covariates (including age, Glasgow Coma Scale score, and intracranial pressure), hypertonic saline was associated with a two-fold faster resolution of intracranial hypertension than either fentanyl or pentobarbital. Fentanyl was significantly associated with the most frequent treatment failure. Intracranial pressure decreased after multiple drug administrations, but hypertonic saline may warrant consideration as the first-line drug for treating intracranial hypertension, as it was associated with the most favorable cerebral hemodynamics and fastest resolution of intracranial hypertension.

Objective:To determine the hypertonic saline efficacy in children with cerebral edema and raised intracranial pressure.Method:Studies assessing the efficacy and safety of hypertonic saline in children with cerebral edema and elevated intracranial pressure were identified using Medline, Web of Science, Scopus, and Google Scholar databases. Two reviewers independently assessed papers for inclusion. The primary outcome was a reduction of elevated intracranial pressure by the administration of hypertonic saline.Results:We initially evaluated 1595 potentially relevant articles, and only 7 studies met the eligibility criteria for the final analysis. Out of the seven studies, three of them were randomized controlled trials. Three of the studies found that hypertonic saline significantly reduced elevated intracranial pressure compared to control. One study reported a resolution of the comatose state as a measure of reduced intracranial pressure. It also found a significantly higher resolution of coma in the hypertonic saline group rather than the control. Three studies reported that the reduction of intracranial pressure was comparable between the groups. The random-effects model using pooled estimates from four studies showed no difference in hypertonic saline and conventional therapy mortality outcomes. Hypertonic saline was administered as bolus-only therapy at a rate of 1–10 mL/kg/dose over 5 min to 2 h and or bolus followed by infusion therapy (0.5–2 mL/kg/h). One study reported a twofold faster resolution of high intracranial pressure following hypertonic saline administration compared to controls. The re-dosing schedule varied greatly in all included studies. However, three studies reported adverse events but not methodically, and there were no reports on neurological sequelae.Conclusion:Hypertonic saline appears to reduce intracranial pressure in children with cerebral edema. However, we cannot draw a firm conclusion regarding the safest dose regimens of hypertonic saline, including the safe and effective therapeutic hypernatremia threshold in the management of raised intracranial pressure with cerebral edema. Future clinical trials should focus on the appropriate concentration, dose, duration, mode of administration, and adverse effects of hypertonic saline to standardize the treatment.

To comparatively evaluate hypertonic sodium (HTS) and mannitol in patients following acute traumatic brain injury (TBI) on the outcomes of all-cause mortality, neurological disability, intracranial pressure (ICP) change from baseline, ICP treatment failure, and serious adverse events. PubMed, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and WHO ICTRP (World Health Organization International Clinical Trials Registry Platform) were searched (inception to November 2015) using hypertonic saline solutions, sodium chloride, mannitol, osmotic diuretic, traumatic brain injury, brain injuries, and head injury. Searches were limited to humans. Clinical practice guidelines and bibliographies were reviewed. Prospective, randomized trials comparing HTS and mannitol in adults (≥16 years) with severe TBI (Glasgow Coma Scale score ≤8) and elevated ICP were included. ICP elevation, ICP reduction, and treatment failure were defined using study definitions. Of 326 articles screened, 7 trials enrolling a total of 191 patients met inclusion criteria. Studies were underpowered to detect a significant difference in mortality or neurological outcomes. Due to significant heterogeneity and differences in reporting ICP change from baseline, this outcome was not meta-analyzed. No difference between HTS and mannitol was observed for mean ICP reduction; however, risk of ICP treatment failure favored HTS (risk ratio [RR] = 0.39; 95% CI = 0.18-0.81). Serious adverse events were not reported. Based on limited data, clinically important differences in mortality, neurological outcomes, and ICP reduction were not observed between HTS or mannitol in the management of severe TBI. HTS appears to lead to fewer ICP treatment failures.

Background:Intravenous indomethacin has been used in infants for many years as the pharmacological closure of ductus arteriosus, but the incidence, risk, and risk factors of acute kidney injury (AKI) among infants treated with indomethacin, were still scarce.Objectives:To determine the incidence, risk, and risk factors of AKI among infants treated with indomethacin (exposed group) for patent ductus arteriosus (PDA) closure compared with the matched non-exposed infants.Methods:A matched retrospective cohort study of infants admitted to the neonatal intensive care unit of Songklanagarind Hospital from January 2003 to December 2018 was performed. All data were collected from computerized medical records. A non-exposed infant was matched (1:1) by gestational age and birth weight to each exposed infant. AKI, the outcome of interest, was diagnosed according to neonatal AKI definitions. The incidence (95% CI) of AKI was estimated for each group. Conditional logistic regression was used to estimate the odds ratio (OR) of developing AKI among those who received indomethacin compared with those who did not, adjusted for potential confounders (concomitantly used nephrotoxic potential medications including aminoglycosides, amphotericin B, vancomycin, furosemide, systemic corticosteroids, and systemic vasopressors and inotropes). Kaplan-Meier estimate was performed to examine probability of recovery from AKI after AKI events.Results:The matching resulted in 193 pairs of exposed and non-exposed infants. The incidences [95% CI] of AKI in the exposed and the non-exposed group, were 33.7% [27.0%:40.4%] and 15.5% [10.4%:20.7%], respectively. Indomethacin statistically increased the risk for developing AKI, crude OR 2.94[95%CI 1.77:4.90], McNemar’s chi square p<0.001, and adjusted OR 2.73 [95%CI 1.55:4.80], p=0.001. The risk of AKI associated with potentially nephrotoxic medications were inconclusive. Time to recovery from AKI was relatively rapid, median recovery time was 3 days in both groups and all infants who developed AKI recovered within 6 days.Conclusions:The incidence of AKI among infants treated with indomethacin for PDA closure were doubled that in the indomethacin-nonexposed infants. Indomethacin significantly increased the risk of AKI, while the risk associated with other concomitant nephrotoxic medications were inconclusive. Transient nephrotoxicity associated with indomethacin should be balanced with the risk associated with delayed PDA closure. All infants receiving indomethacin should be routinely monitored for serum creatinine and/or urine output, throughout the treatment and one to two weeks after treatment cessation. Alternatives with better renal safety profiles should be considered in the population with higher risk of AKI.

In advanced congestive heart failure (CHF), intravenous (i.v.) inotropic agents, i.v. diuretics, ultrafiltration, and hemodialysis have been shown to not yield better clinical outcomes. In this scenario, the simultaneous administration of hypertonic saline solution (HSS) and furosemide may offer a more effective therapeutic option with a good safety profile. Therefore, a meta-analysis was performed to compare combined therapy, consisting of i.v. furosemide plus concomitant administration of HSS, with i.v. furosemide alone for acute decompensated heart failure (ADHF). The outcomes we chose were all-cause mortality, risk of re-hospitalization for ADHF, length of hospital stay, weight loss, and variation of serum creatinine. Based on five randomized controlled trials (RCTs) involving 1,032 patients treated with i.v. HSS plus furosemide vs. 1,032 patients treated with i.v. furosemide alone, a decrease in all-cause mortality in patients treated with HSS plus furosemide was proven [RR = 0.57; 95 % confidence interval (CI) = 0.44-0.74, p = 0.0003]. Likewise, combined therapy with HSS plus furosemide was shown to be associated with a reduced risk of ADHF-related re-hospitalization (RR = 0.51; 95 % CI = 0.35-0.75, p = 0.001). Besides, combined therapy with HSS plus furosemide was found to be associated with a reduced length of hospital stay (p = 0.0002), greater weight loss (p < 0.00001), and better preservation of renal function (p < 0.00001). HSS as an adjunct to i.v. furosemide for diuretic-resistant CHF patients led to a better renal safety profile and improved clinical endpoints such as mortality and heart failure-related hospitalizations.

Mannitol, an osmotic agent used to decrease intracranial pressure, can cause acute kidney injury (AKI). The objectives of this study were to assess the impact of mannitol on the incidence and severity of AKI and to identify risk factors and outcome for AKI in patients with intracranial hemorrhage (ICH). The authors retrospectively evaluated 153 adult patients who received mannitol infusion after ICH between January 2005 and December 2009 in the neurosurgical intensive care unit. Multivariate analysis was used to evaluate the risk factors for AKI after ICH. Based on the odds ratio, weighted scores were assigned to predictors of AKI. The overall incidence of AKI among study participants was 10.5% (n = 16). Acute kidney injury occurred more frequently in patients who received mannitol infusion at a rate ≥ 1.34 g/kg/day than it did in patients who received mannitol infusion at a rate < 1.34 g/kg/day. A higher mannitol infusion rate was associated with more severe AKI. Independent risk factors for AKI were mannitol infusion rate ≥ 1.34 g/kg/day, age ≥ 70 years, diastolic blood pressure (DBP) ≥ 110 mm Hg, and glomerular filtration rate < 60 ml/min/1.73 m(2). The authors developed a risk model for AKI, wherein patients with a higher risk score showed a graded association with a higher incidence of AKI. The incidence of AKI following mannitol infusion in patients with ICH was 10.5%. A higher mannitol infusion rate was associated with more frequent and more severe AKI. Additionally, age ≥ 70 years, DBP ≥ 110 mm Hg, and established renal dysfunction before starting mannitol therapy were associated with development of AKI.

To compare the effects of preoperatively administered pentastarch (10% concentration in isotonic saline [0.9% NaCl] solution) and hypertonic saline (7.2% NaCl) solutions on PCV and circulating total protein (TP) concentration in horses with colic undergoing emergency exploratory laparotomy and to assess survival rates of horses that received each treatment. Prospective, randomized study. 100 horses with signs of abdominal pain and PCV ≥ 0.46 L/L. Procedures-Horses received a 4 mL/kg (1.8 mL/lb) dose of pentastarch solution (n = 50) or hypertonic saline solution (50) over a 10- to 20-minute period before anesthetic induction. Blood samples were collected at the time of evaluation and ≤ 5 minutes after fluid resuscitation; changes in PCV and TP concentration were compared. Survival was evaluated by Kaplan-Meier and Cox proportional hazards analyses. Age, weight, sex, PCV, and heart rate on initial examination were similar between treatment groups. Hypertonic saline solution treatment resulted in a significantly greater reduction in PCV (median change, -0.14 L/L) than did pentastarch treatment (median change, -0.07 L/L). Reduction in TP concentration was also significantly greater after hypertonic saline solution treatment (median change, -16 g/L) than after pentastarch treatment (median change, -2 g/L). Long-term survival was not significantly different between groups. Despite a greater reduction in preanesthetic hemoconcentration following administration of hypertonic saline solution (4 mL/kg infusion, once), no difference in overall long-term survival was found between horses that received this treatment and those that received an equal volume of pentastarch solution. Findings suggested that, in a clinical setting, either of these fluids would be appropriate for preoperative fluid resuscitation in horses with colic.

Hypertonic Saline (HS) has been a proven and effective therapy and a safe alternative to mannitol in patients with increase intracranial pressure (ICP). We hereby present a case of 25-year-old women with intracranial bleed secondary to right parietal arteriovenous malformation. Patient underwent surgery for evacuation of hematoma and resection of arteriovenous malformation. Post- operative course was complicated by recurrent episodes of elevated ICP. She received total of 17 doses of 23.4% HS and 30 doses of mannitol with good outcome. Despite reluctance from some clinicians to use HS, hypertonic saline seems to be a safe and effective therapy.

The purpose of this study was to compare the effects of mannitol and hypertonic saline in doses of similar osmotic burden for the treatment of intracranial hypertension in patients with severe traumatic brain injury. The authors used an alternating treatment protocol to compare the effect of hypertonic saline with that of mannitol given for episodes of increased intracranial pressure in patients treated for severe head injury at their hospital during 2006-2008. Standard guidelines for the management of severe traumatic brain injury were followed. Elevated intracranial pressure (ICP) was treated either with mannitol or hypertonic saline. Doses of similar osmotic burden (mannitol 20%, 2 ml/kg, infused over 20 minutes, or saline 15%, 0.42 ml/kg, administered as a bolus via a central venous catheter) were given alternately to the individual patient with severe brain injury during episodes of increased pressure. The dependent variables were the extent and duration of reduction of increased ICP. The choice of agent for treatment of the initial hypertensive event was determined on a randomized basis; treatment was alternated for every subsequent event in each individual patient. Reduction of ICP and duration of action were recorded after each event. Results obtained after mannitol administration were statistically compared with those obtained after hypertonic saline administration. Data pertaining to 199 hypertensive events in 29 patients were collected. The mean decrease in ICP obtained with mannitol was 7.96 mm Hg and that obtained with hypertonic saline was 8.43 mm Hg (p = 0.586, equal variances assumed). The mean duration of effect was 3 hours 33 minutes for mannitol and 4 hours 17 minutes for hypertonic saline (p = 0.40, equal variances assumed). No difference between the 2 medications could be found with respect to the extent of reduction of ICP or duration of action.

Safety of Peripheral Line Administration of 3% Hypertonic Saline and Mannitol in the Emergency Department.

We tested the hypothesis that transtentorial herniation (TTH) represents a state of cerebral ischemia that can be reversed by hypertonic saline. Because of the high mortality associated with TTH, new therapeutic strategies need to be developed for rapid and effective reversal of this process. We produced TTH (defined by acute dilatation of one or both pupils) by creating supratentorial intracerebral hemorrhage with autologous blood injection in seven mongrel dogs anesthetized using intravenous pentobarbital and fentanyl. We measured serial rCBF (regional cerebral blood flow) using radiolabeled microspheres in regions around and distant to the hematoma. Cerebral oxygen extraction and oxygen consumption (CMRO2) were measured by serial sampling of cerebral venous blood from the sagittal sinus. Mean arterial pressure (MAP) and intracranial pressure (ICP) were continuously monitored. TTH was successfully reversed over a mean period of 25.7 +/- 4.9 minutes after intravenous administration of 23.4% sodium chloride (1.4 mL/kg) in all animals. All measurements were recorded 15, 30, 60, and 90 minutes after administration of 23.4% sodium chloride. Compared to prehematoma ICP (14.1 +/- 1.7 mm Hg, mean +/- SE), elevation in ICP was observed during TTH (36.2 +/- 7.2 mm Hg) with no change in cerebral perfusion pressure (CPP) (80.4 +/- 4.7 vs. 76.7 +/- 10.1 mm Hg) because of concomitant elevation in mean arterial pressure. Compared to baseline values, there was a reduction in rCBF (mL/100 gm/min +/- SE) in brainstem (12.1 +/- 2.0 vs. 21.4 +/- 1.4), gray matter (18.2 +/- 2.1 vs. 31.4 +/- 1.8), and white matter (8.6 +/- 1.7 vs.18.7 +/- 0.9) in the hemisphere contralateral to the hematoma; and gray matter (12.9 +/- 2.9 vs. 27.9 +/- 2.2) and white matter (8.3 +/- 2.0 vs.19.9 +/- 1.0) in the ipsilateral hemisphere distant from the hematoma. Administration of 23.4% sodium chloride resulted in reduced ICP at 15 minutes (12.7 +/- 1.4) and 30 minutes (15.6 +/- 3.1) after administration. RCBF values were restored in all regions studied after administration of 23.4% sodium chloride with an increase in CMRO2 (1.8 +/- 0.4 vs. 3.9 +/- 0.7 mL O2 /100 gm/min). Compared with baseline values, rCBF increased in the ipsilateral (31.7 +/- 2.5 vs. 63.4 +/- 11.7) and contralateral (28.7 +/- 1.9 vs. 45.5 +/- 5.7) thalamus at 15 minutes after administration of 23.4% sodium chloride. TTH represented a state of ischemia in brainstem and supratentorial gray and white matter in the presence of adequate CPP, suggesting mechanical compression of vessels at the level of tentorium. Hypertonic saline reversed TTH, and restored both rCBF and CMRO2, although hyperemia was observed immediately after reversal of TTH. Administration of hypertonic saline may preserve neurologic function during the interim period between TTH and surgical intervention.