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Objective: To compare the efficacy and safety of two hyperosmolar agents (hypertonic saline vs. mannitol) used for the reduction of elevated intracranial pressure (ICP) in children., Methods: A meta-analysis of randomized controlled trials (RCTs) was conducted and GRADE system (Grading of Recommendations, Assessment, Development and Evaluation) of evidence was applied. Relevant databases were searched till 31 st May 2022. Primary outcome was mortality rate., Results: Of 720 citations retrieved, 4 RCTs were included in the meta-analysis (n = 365, male = 61%). Traumatic and non-traumatic cases of elevated ICP were included. There was no significant difference in the mortality rate between the two groups [relative risk (RR), 1.09; (95% confidence interval (CI), 0.74 to 1.6)]. No significant difference was found for any of the secondary outcomes, except serum osmolality (being significantly higher in mannitol group). Adverse events like shock and dehydration were significantly higher in the mannitol group, and hypernatremia in the hypertonic saline group. The evidence generated for primary outcome was of "low certainty", and for secondary outcomes, it varied from "very-low to moderate certainty"., Conclusions: There is no significant difference between hypertonic saline and mannitol used for the reduction of elevated ICP in children. The evidence generated for primary outcome (mortality rate) was of "low certainty", and for secondary outcomes, it varied from "very-low to moderate certainty". More data from high-quality RCTs are needed to guide any recommendation., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Background: The objective was to determine the effects of continuous infusion of hypertonic saline solutions on outcomes of patients with brain injury., Methods: Preferred Reported Items for Systemic Reviews and Meta-Analysis guidelines were followed. We searched the MEDLINE and COCHRANE clinical trials register (through December 2021) and reference lists of articles. We included all clinical trials conducted in brain-injured patients hospitalized in intensive care units evaluating continuous infusion of hypertonic saline solution (osmolarity above 308 mOsm/L). Two reviewers extracted data that were checked by two others. The primary outcome was the in-hospital mortality rate. The main secondary outcomes were the rates of intracranial hypertension, an unfavorable neurological outcome at day 90, and adverse events., Results: We identified 23 clinical trials reporting the use of continuous infusion of hypertonic saline solution in brain-injured patients. The primary outcome was available in 10 studies (n = 1883 patients). The odds ratio (OR) for in-hospital death with the intervention was 0.68 (95% confidence interval (CI), 0.54-0.85, I 2  = 0%). In the subgroup of studies including only traumatic brain-injured patients (7 studies, n = 1521 patients), the OR for the primary outcome was 0.74 (95%CI 0.57-0.95) with the intervention. The OR for intracranial hypertension and unfavorable neurological outcome at day 90 were 0.66 (95%CI 0.49-0.88, I 2  = 42%, n = 787 patients) and 0.61 (95%CI 0.46-0.81, I 2  = 15%, n = 956 patients), respectively. Regarding safety, the OR of acute kidney injury and severe hypernatremia were 0.82 (95%CI 0.47-1.44, I 2  = 0%) and 3.38 (95%CI 2.16-5.27, I 2  = 24%)., Conclusions: Continuous hypertonic saline solution infusion reduced in-hospital mortality without increasing the risk of unfavorable neurological outcome at day 90 in brain-injured patients hospitalized in intensive care units. Given the inclusion of observational and heterogeneous studies, further randomized studies are needed before developing recommendations for implementation at the bedside., Systematic Review Registration: PROSPERO CRD42021221367. Registered 13 May 2021., (Copyright © 2022 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Hypertonic lactate (HL) is emerging as alternative treatment of intracranial hypertension following acute brain injury (ABI), but comparative studies are limited. Here, we examined the effectiveness of HL on main cerebral and systemic physiologic variables, and further compared it to that of standard hypertonic saline (HS). Retrospective cohort analysis of ABI subjects who received sequential osmotherapy with 7.5% HS followed by HL-given at equi-osmolar (2400 mOsmol/L) and isovolumic (1.5 mL/kg) bolus doses-to reduce sustained elevations of ICP (> 20 mmHg). The effect of HL on brain (intracranial pressure [ICP], brain tissue PO 2 [PbtO 2 ], cerebral microdialysis [CMD] glucose and lactate/pyruvate ratio [LPR]) and blood (chloride, pH) variables was examined at different time-points (30, 60, 90, 120 min vs. baseline), and compared to that of HS. A total of 34 treatments among 17 consecutive subjects (13 traumatic brain injury [TBI], 4 non-TBI) were studied. Both agents significantly reduced ICP (p < 0.001, at all time-points tested): when comparing treatment effectiveness, absolute ICP decrease in mmHg and the duration of treatment effect (median time with ICP < 20 mmHg following osmotherapy 183 [108-257] vs. 150 [111-419] min) did not differ significantly between HL and HS (all p > 0.2). None of the treatment had statistically significant effects on PbtO 2 and CMD biomarkers. Treatment with HL did not cause hyperchloremia and resulted in a more favourable systemic chloride balance than HS (Δ blood chloride - 1 ± 2.5 vs. + 4 ± 3 mmol/L; p < 0.001). This is the first clinical study showing that HL has comparative effectiveness than HS for the treatment of intracranial hypertension, while at the same time avoiding hyperchloremic acidosis. Both agents had no significant effect on cerebral oxygenation and metabolism., (© 2022. The Author(s).)

Background: The present study was performed to evaluate intracranial pressure (ICP) variations after antipyretic therapy and their relationship to ICP at baseline (ICPbas) in acute brain injury (ABI) patients., Methods: We completed a retrospective analysis on data derived from 2 previously published prospective observational studies. The first study involved 32 ABI patients and was performed to elucidate the cerebral and hemodynamic effects of intravenous (IV) paracetamol. The second study involved 30 ABI patients and was performed to investigate cerebral and hemodynamic effects of intramuscular IM diclofenac sodium (DCF). Overall patient population was divided into 2 groups: 1) group A (G-A) when ICPbas was ≤15 mmHg; and 2) group B (G-B) when ICPbas was >15 mmHg. The main objective was to evaluate if ICPbas affects the time course of ICP after antipyretics administration., Results: Data from 62 ABI patients were analyzed. We failed to observe a significant change in ICP after antipyretic treatment in the overall group of patients (P1=0.486). A significant difference, however, was found between the two groups (P2<0.001). We observed that in the G-A, ICP increased in response to antipyretic administration, whereas in the G-B, ICP decreased. These opposite responses are reflected in the statistically significant interaction (P3<0.001)., Conclusions: Variation in ICP after antipyretic therapy is influenced by ICPbas. Specifically, patients with ICPbas≤15 mmHg showed a significant increase in ICP after antipyretic therapy, while a significant reduction in ICP was observed in patients with ICPbas>15 mmHg.

Refractory intracranial hypertension after traumatic brain injury (TBI) is defined as recurrent increase of intracranial pressure above 20-22 mmHg for sustained period of time (10-15 min), despite conventional therapies, such as osmotic therapy, cerebral spinal fluid drainage and mild hyperventilation. As such, more aggressive treatments should be taken into consideration. In particular, therapeutic hypothermia, barbiturates administration and decompressive craniectomy are considered as tier-three or "salvage" interventions, as they have shown to be able to control refractory hypertension; however, they are also associated with an increased risk of significant side effects. Therefore, the aim of this review was to describe the evidence supporting the use of these tier-three therapies in the management of refractory intracranial hypertension in TBI patients.

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6-12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient's poor outcome either at discharge from the intensive care unit (ICU) or at 6-12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was <20 mmHg throughout the first 120 h. NOR+sdB prevented composite death in the ICU in patients with sTBI, and we may obtain novel insights into the beneficial role of prophylactic barbiturate therapy from suppression of the elevated ICP during the first 120 h.

Treatment with osmoactive agents such as mannitol or hypertonic saline (HTS) solutions is widely used to manage or prevent the increase of intracranial pressure (ICP) in central nervous system (CNS) disorders. We sought to evaluate the variability and mean plasma concentrations of the water and electrolyte balance parameters in critically ill patients treated with osmotic therapy and their influence on mortality. This cohort study covered patients hospitalized in an intensive care unit (ICU) from January 2017 to June 2019 with presumed increased ICP or considered to be at risk of it, treated with 15% mannitol (G1, n = 27), a combination of 15% mannitol and 10% hypertonic saline (HTS) (G2, n = 33) or 10% HTS only (G3, n = 13). Coefficients of variation (Cv) and arithmetic means (mean) were calculated for the parameters reflecting the water and electrolyte balance, i.e., sodium (NaCv/NaMean), chloride (ClCv/ClMean) and osmolality (mOsmCv/mOsmMean). In-hospital mortality was also analyzed. The study group comprised 73 individuals (36 men, 49%). Mortality was 67% (n = 49). Median NaCv (G1: p = 0.002, G3: p = 0.03), ClCv (G1: p = 0.02, G3: p = 0.04) and mOsmCv (G1: p = 0.001, G3: p = 0.02) were higher in deceased patients. NaMean ( p = 0.004), ClMean ( p = 0.04), mOsmMean ( p = 0.003) were higher in deceased patients in G3. In G1: NaCv (AUC = 0.929, p < 0.0001), ClCv (AUC = 0.817, p = 0.0005), mOsmCv (AUC = 0.937, p < 0.0001) and in G3: NaMean (AUC = 0.976, p < 0.001), mOsmCv (AUC = 0.881, p = 0.002), mOsmMean (AUC = 1.00, p < 0.001) were the best predictors of mortality. The overall mortality prediction for combined G1+G2+G3 was very good, with AUC = 0.886 ( p = 0.0002). The mortality of critically ill patients treated with osmotic agents is high. Electrolyte disequilibrium is the independent predictor of mortality regardless of the treatment method used. Variations of plasma sodium, chloride and osmolality are the most deleterious factors regardless of the absolute values of these parameters.

Background: Increased intracranial pressure has been shown to be strongly associated with poor neurological outcomes and mortality for patients with acute traumatic brain injury. Currently, most efforts to treat these injuries focus on controlling the intracranial pressure. Hypertonic saline is a hyperosmolar therapy that is used in traumatic brain injury to reduce intracranial pressure. The effectiveness of hypertonic saline compared with other intracranial pressure-lowering agents in the management of acute traumatic brain injury is still debated, both in the short and the long term., Objectives: To assess the comparative efficacy and safety of hypertonic saline versus other intracranial pressure-lowering agents in the management of acute traumatic brain injury., Search Methods: We searched Cochrane Injuries' Specialised Register, CENTRAL, PubMed, Embase Classic+Embase, ISI Web of Science: Science Citation Index and Conference Proceedings Citation Index-Science, as well as trials registers, on 11 December 2019. We supplemented these searches with searches of four major Chinese databases on 19 September 2018. We also checked bibliographies, and contacted trial authors to identify additional trials., Selection Criteria: We sought to identify all randomised controlled trials (RCTs) of hypertonic saline versus other intracranial pressure-lowering agents for people with acute traumatic brain injury of any severity. We excluded cross-over trials as incompatible with assessing long-term outcomes., Data Collection and Analysis: Two review authors independently screened search results to identify potentially eligible trials and extracted data using a standard data extraction form. Outcome measures included: mortality at end of follow-up (all-cause); death or disability (as measured by the Glasgow Outcome Scale (GOS)); uncontrolled intracranial pressure (defined as failure to decrease the intracranial pressure to target and/or requiring additional intervention); and adverse events e.g. rebound phenomena; pulmonary oedema; acute renal failure during treatment)., Main Results: Six trials, involving data from 287 people, met the inclusion criteria. The majority of participants (91%) had a diagnosis of severe traumatic brain injury. We had concerns about particular domains of risk of bias in each trial, as physicians were not reliably blinded to allocation, two trials contained participants with conditions other than traumatic brain injury and in one trial, we had concerns about missing data for important outcomes. The original protocol was available for only one trial and other trials (where registered) were registered retrospectively. Meta-analysis for both the primary outcome (mortality at final follow-up) and for 'poor outcome' as per conventionally dichotomised GOS criteria, was only possible for two trials. Synthesis of long-term outcomes was inhibited by the fact that two trials ceased data collection within two hours of a single bolus dose of an intracranial pressure-lowering agent and one at discharge from the intensive care unit (ICU). Only three trials collected data after participants were released from hospital, one of which did not report mortality and reported a 'poor outcome' by GOS criteria in an unconventional way. Substantial missing data in a key trial meant that in meta-analysis we report 'best-case' and 'worst-case' estimates alongside available case analysis. In no scenario did we discern a clear difference between treatments for either mortality or poor neurological outcome. Due to variation in modes of drug administration (including whether it followed or did not follow cerebrospinal fluid (CSF) drainage, as well as different follow-up times and ways of reporting changes in intracranial pressure, as well as no uniform definition of 'uncontrolled intracranial pressure', we did not perform meta-analysis for this outcome and report results narratively, by individual trial. Trials tended to report both treatments to be effective in reducing elevated intracranial pressure but that hypertonic saline had increased benefits, usually adding that pretreatment factors need to be considered (e.g. serum sodium and both system and brain haemodynamics). No trial provided data for our other outcomes of interest. We consider evidence quality for all outcomes to be very low, as assessed by GRADE; we downgraded all conclusions due to imprecision (small sample size), indirectness (due to choice of measurement and/or selection of participants without traumatic brain injury), and in some cases, risk of bias and inconsistency. Only one of the included trials reported data on adverse effects; a rebound phenomenon, which was present only in the comparator group (mannitol). None of the trials reported data on pulmonary oedema or acute renal failure during treatment. On the whole, trial authors do not seem to have rigorously sought to collect data on adverse events., Authors' Conclusions: This review set out to find trials comparing hypertonic saline to a potential range of other intracranial pressure-lowering agents, but only identified trials comparing it with mannitol or mannitol in combination with glycerol. Based on limited data, there is weak evidence to suggest that hypertonic saline is no better than mannitol in efficacy and safety in the long-term management of acute traumatic brain injury. Future research should be comprised of large, multi-site trials, prospectively registered, reported in accordance with current best practice. Trials should investigate issues such as the type of traumatic brain injury suffered by participants and concentration of infusion and length of time over which the infusion is given., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Increased intracranial pressure (ICP) has been shown to be strongly associated with poor neurological outcomes and mortality for patients with acute traumatic brain injury (TBI). Currently, most efforts to treat these injuries focus on controlling the ICP. Hypertonic saline (HTS) is a hyperosmolar therapy that is used in traumatic brain injury to reduce intracranial pressure. The effectiveness of HTS compared with other ICP-lowering agents in the management of acute TBI is still debated, both in the short and the long term., Objectives: To assess the comparative efficacy and safety of hypertonic saline versus other ICP-lowering agents in the management of acute TBI., Search Methods: We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, PubMed, Embase Classic+Embase (OvidSP), ISI Web of Science: Science Citation Index and Conference Proceedings Citation Index-Science, as well as trials registers, on 11 December 2019. We supplemented these searches using four major Chinese databases on 19 September 2018. We also checked bibliographies, and contacted study authors to identify additional studies., Selection Criteria: We sought to identify all randomised controlled trials (RCTs) of HTS versus other intracranial pressure-lowering agents for people with acute TBI of any severity. We excluded cross-over trials as incompatible with assessing long term outcomes., Data Collection and Analysis: Two review authors independently screened search results to identify potentially eligible trials and extracted data using a standard data extraction form. Outcome measures included: mortality at end of follow-up (all-cause); death or disability (as measured by the Glasgow Outcome Scale (GOS)); uncontrolled ICP (defined as failure to decrease the ICP to target and/or requiring additional intervention); and adverse events (AEs) (e.g. rebound phenomena; pulmonary oedema; acute renal failure during treatment)., Main Results: Six trials, involving data from 295 people, met the inclusion criteria. The majority of participants (89%) had a diagnosis of severe TBI. We had concerns about particular domains of risk of bias in each trial, as physicians were not reliably blinded to allocation, two trials contained participants with conditions other than TBI and in one trial, there were concerns about missing data for important outcomes. The original protocol was available for only one study and other trials (where registered) were registered retrospectively. Meta-analysis for both the primary outcome (mortality at final follow up) and for 'poor outcome' as per conventionally dichotomised GOS criteria, was only possible for two studies. Synthesis of long-term outcomes was inhibited by the fact that two ceased data collection within two hours of a single bolus dose of an ICP-lowering agent and one at discharge from ICU. Only three studies collected data after release from hospital. Due to variation in modes of drug administration, follow-up times, and ways of reporting changes in ICP, as well as no uniform definition of 'uncontrolled ICP', we did not perform meta-analysis for this outcome and report results narratively, by individual trial. Trials tended to report both treatments to be effective in reducing elevated ICP but that HTS had increased benefits, usually adding that pretreatment factors need to be considered (e.g. serum sodium and both system and brain hemodynamics). No trial provided data for our other outcomes of interest. Evidence for all outcomes is considered very low, as assessed by GRADE. All conclusions were downgraded due to imprecision (small sample size), indirectness (due to choice of measurement and/or selection of patients without TBI), and in some cases, risk of bias and inconsistency. Only one of the included trials reported data on adverse effects (AEs) - a rebound phenomenon, which was present only in the comparator group (mannitol). No data were reported on pulmonary oedema or acute renal failure during treatment. On the whole, investigators do not seem to have rigorously sought to collect data on AEs., Authors' Conclusions: This review set out to find trials comparing HTS to a potential range of other ICP-lowering agents, but only identified trials comparing it with mannitol or mannitol in combination with glycerol. Based on limited data, there is weak evidence to suggest that HTS is no better than mannitol in efficacy and safety in the long-term management of acute TBI. Future research should be comprised of large, multi-site trials, prospectively registered, reported in accordance with current best practice. Issues such as the type of TBI suffered by participants and concentration of infusion and length of time over which the infusion is given should be investigated., (Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Dexmedetomidine (DEX) is a selective α 2 adrenergic agonist that is commonly used for sedation in the intensive care unit (ICU). The role of DEX for adjunctive treatment of refractory intracranial hypertension is poorly defined. The primary objective of this study was to determine the effect of DEX on the need for rescue therapy (ie, hyperosmolar boluses, extraventricular drain [EVD] drainages) for refractory intracranial hypertension. Secondary objectives included the number of intracranial pressure (ICP) excursions, bradycardic, hypotensive, and compromised cerebral perfusion pressure episodes. This retrospective cohort study evaluated patients admitted to the neurosurgical ICU from August 1, 2009, to July 29, 2015, and who received DEX for refractory intracranial hypertension. The objectives were compared between the 2 time periods-before (pre-DEX) and during therapy (DEX). Twenty-three patients with 26 episodes of refractory intracranial hypertension met the inclusion criteria. The number of hyperosmolar boluses was decreased after DEX therapy was initiated. Mannitol boluses required were statistically reduced (1 vs 0.5, P = .03); however, reduction in hypertonic boluses was not statistically significant (1.3 vs 0.9, P = .2). The mean number of EVD drainages per 24 hours was not significantly different between the time periods (15.7 vs 14.0, P = .35). The rate of ICP excursions did not differ between the 2 groups (24.3 vs 22.5, P = .62). When compared to pre-DEX data, there was no difference in the median number of hypotensive (0 vs 0), bradycardic (0 vs 0), or compromised cerebral perfusion pressure episodes (0.5 vs 1.0). Dexmedetomidine may avoid increases in the need for rescue therapy when used as an adjunctive treatment of refractory intracranial hypertension without compromising hemodynamics.

Purpose of the Review: The aims of fluid management in acute brain injury are to preserve or restore physiology and guarantee appropriate tissue perfusion, avoiding potential iatrogenic effects. We reviewed the literature, focusing on the clinical implications of the selected papers. Our purposes were to summarize the principles regulating the distribution of water between the intracellular, interstitial, and plasma compartments in the normal and the injured brain, and to clarify how these principles could guide fluid administration, with special reference to intracranial pressure control., Recent Findings: Although a considerable amount of research has been published on this topic and in general on fluid management in acute illness, the quality of the evidence tends to vary. Intravascular volume management should aim for euvolemia. There is evidence of harm with aggressive administration of fluid aimed at achieving hypervolemia in cases of subarachnoid hemorrhage. Isotonic crystalloids should be the preferred agents for volume replacement, while colloids, glucose-containing hypotonic solutions, and other hypotonic solutions or albumin should be avoided. Osmotherapy seems to be effective in intracranial hypertension management; however, there is no clear evidence regarding the superiority of hypertonic saline over mannitol. Fluid therapy plays an important role in the management of acute brain injury patients. However, fluids are a double-edged weapon because of the potential risk of hyper-hydration, hypo- or hyper-osmolar conditions, which may unfavorably affect the clinical course and the outcome.

Background: The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear., Methods: From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively., Results: The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are reported descriptively. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. At 12 months, the GOS-E distributions were as follows: death, 30.4% among 194 surgical patients versus 52.0% among 179 medical patients; vegetative state, 6.2% versus 1.7%; lower severe disability, 18.0% versus 14.0%; upper severe disability, 13.4% versus 3.9%; moderate disability, 22.2% versus 20.1%; and good recovery, 9.8% versus 8.4%. Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mm Hg after randomization (median, 5.0 vs. 17.0 hours; P<0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P=0.03)., Conclusions: At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. (Funded by the Medical Research Council and others; RESCUEicp Current Controlled Trials number, ISRCTN66202560 .).

Introduction: Past work has shown the importance of the "pressure times time dose" (PTD) of intracranial hypertension (intracranial pressure [ICP] > 19 mm Hg) in predicting outcome after severe traumatic brain injury. We used automated data collection to measure the effect of common medications on the duration and dose of intracranial hypertension., Methods: Patients >17 years old, admitted and requiring ICP monitoring between 2008 and 2010 at a single, large urban tertiary care facility, were retrospectively enrolled. Timing and dose of ICP-directed therapy were recorded from paper and electronic medical records. The ICP data were collected automatically at 6-second intervals and averaged over 5 minutes. The percentage of time of intracranial hypertension (PTI) and PTD (mm Hg h) were calculated., Results: A total of 98 patients with 664 treatment instances were identified. Baseline PTD ranged from 27 (before administration of propofol and fentanyl) to 150 mm Hg h (before mannitol). A "small" dose of hypertonic saline (HTS; ≤250 mL 3%) reduced PTD by 38% in the first hour and 37% in the second hour and reduced the time with ICP >19 by 38% and 39% after 1 and 2 hours, respectively. A "large" dose of HTS reduced PTD by 40% in the first hour and 63% in the second (PTI reduction of 36% and 50%, respectively). An increased dose of propofol or fentanyl infusion failed to decrease PTD but reduced PTI between 14% (propofol alone) and 30% (combined increase in propofol and fentanyl, after 2 hours). Barbiturates failed to decrease PTD but decreased PTI by 30% up to 2 hours after administration. All reductions reported are significantly changed from baseline, P < .05., Conclusion: Baseline PTD values before drug administration reflects varied patient criticality, with much higher values seen before the use of mannitol or barbiturates. Treatment with HTS reduced PTD and PTI burden significantly more than escalation of sedation or pain management, and this effect remained significant at 2 hours after administration., (© The Author(s) 2014.)

Objective: To evaluate the clinical effectiveness of bolus-dose fentanyl and midazolam to treat episodic intracranial hypertension in children with severe traumatic brain injury., Design: Retrospective cohort., Setting: PICU in a university-affiliated children's hospital level I trauma center., Patients: Thirty-one children 0-18 years of age with severe traumatic brain injury (Glasgow Coma Scale score of ≤ 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic intracranial hypertension., Interventions: None., Measurements and Main Results: The area under the curve from high-resolution intracranial pressure-time plots was calculated to represent cumulative intracranial hypertension exposure: area under the curve for intracranial pressure above 20 mm Hg (area under the curve-intracranial hypertension) was calculated in 15-minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic intracranial hypertension. Our primary outcome measure, the difference between predrug and postdrug administration epochs (Δarea under the curve-intracranial hypertension), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism, and time after injury; time after injury correlated with Δarea under the curve-intracranial hypertension. In a mixed-effects model, with patient as a random effect, drug/dose combination as a fixed effect, and time after injury as a covariate, intracranial hypertension increased after administration of fentanyl and/or midazolam (overall aggregate mean Δarea under the curve-intracranial hypertension = +17 mm Hg × min, 95% CI, 0-34 mm Hg × min; p = 0.04). The mean Δarea under the curve-intracranial hypertension increased significantly after administration of high-dose fentanyl (p = 0.02), low-dose midazolam (p = 0.006), and high-dose fentanyl plus low-dose midazolam (0.007). Secondary analysis using age-dependent thresholds showed no significant impact on cerebral perfusion pressure deficit (mean Δarea under the curve-cerebral perfusion pressure)., Conclusions: Bolus dosing of fentanyl and midazolam fails to reduce the intracranial hypertension burden when administered for episodic intracranial hypertension. Paradoxically, we observed an overall increase in intracranial hypertension burden following drug administration, even after accounting for within-subject effects and time after injury. Future work is needed to confirm these findings in a prospective study design., Competing Interests: COPYRIGHT FORM DISCLOSURES: The remaining authors have disclosed that they do not have any potential conflicts of interest.

Object: Mannitol is commonly used to treat elevated intracranial pressure (ICP). The authors analyzed mannitol dosing errors at peripheral hospitals prior to or during transport to tertiary care facilities for intracranial emergencies. They also investigated the appropriateness of mannitol use based on the 2007 Brain Trauma Foundation guidelines for severe traumatic brain injury., Methods: The authors conducted a retrospective review of the Shock Trauma Air Rescue Society (STARS) electronic patient database of helicopter medical evacuations in Alberta, Canada, between 2004 and 2012, limited to patients receiving mannitol before transfer. They extracted data on mannitol administration and patient characteristics, including diagnosis, mechanism, Glasgow Coma Scale score, weight, age, and pupil status., Results: A total of 120 patients with an intracranial emergency received a mannitol infusion initiated at a peripheral hospital (median Glasgow Coma Scale score 6; range 3-13). Overall, there was a 22% dosing error rate, which comprised an underdosing rate (<0.25 g/kg) of 8.3% (10 of 120 patients), an overdosing rate (>1.5 g/kg) of 7.5% (9 of 120), and a nonbolus administration rate (>1 hour) of 6.7% (8 of 120). Overall, 72% of patients had a clear indication to receive mannitol as defined by meeting at least one of the following criteria based on Brain Trauma Foundation guidelines: neurological deterioration (11%), severe traumatic brain injury (69%), or pupillary abnormality (25%)., Conclusions: Mannitol administration at peripheral hospitals is prone to dosing error. Strategies such as a pretransport checklist may mitigate this risk.

Background/purpose: Mannitol is commonly used in patients with increased intracranial pressure (ICP), but its effect on cerebrovascular pressure reactivity (CVPR) is uncertain. We analyzed the changes of pressure reactivity index (PRx) during the course of mannitol treatment., Methods: Twenty-one patients who received mannitol treatment for increased ICP were recruited prospectively. Continuous waveforms of arterial blood pressure (ABP) and ICP were collected simultaneously for 60 minutes (10 minutes at baseline and 50 minutes since mannitol administration) during 37 events of mannitol treatment. The correlation coefficients between the mean ABP and ICP were averaged every 10 minutes and labeled as the PRx. The linear correlation of six time points of PRx in each event was calculated to represent the trend of CVPR changes. The negative slope of correlation was defined as improvement in CVPR under mannitol treatment and vice versa., Results: At baseline, the average of ICP was 26.0 ± 9.1 mmHg and the values of PRx were significantly correlated with ICP (p = 0.0044, r = 0.46). After mannitol administration, the average of ICP decreased significantly to 21.2 ± 11.1 mmHg (p = 0.036), and CVPR improved in 59.4 % of all events. Further analysis showed that low baseline cerebral perfusion pressure was the only hemodynamic parameter significant association with the improvement of CVPR after mannitol treatment (p = 0.039)., Conclusion: Despite lowering ICP, mannitol may have diverse effects on CVPR in patients with intracranial hypertension. Our study suggests that mannitol infusion may have a beneficial effect on CVPR, particularly in those with a low cerebral perfusion pressure at baseline., (Copyright © 2013. Published by Elsevier B.V.)

Hyperosmolar agents are commonly used as an initial treatment for the management of raised intracranial pressure (ICP) after severe traumatic brain injury (TBI). They have an excellent adverse-effect profile compared to other therapies, such as hyperventilation and barbiturates, which carry the risk of reducing cerebral perfusion. The hyperosmolar agent mannitol has been used for several decades to reduce raised ICP, and there is accumulating evidence from pilot studies suggesting beneficial effects of hypertonic saline (HTS) for similar purposes. An ideal therapeutic agent for ICP reduction should reduce ICP while maintaining cerebral perfusion (pressure). While mannitol can cause dehydration over time, HTS helps maintain normovolemia and cerebral perfusion, a finding that has led to a large amount of pilot data being published on the benefits of HTS, albeit in small cohorts. Prophylactic therapy is not recommended with mannitol, although it may be beneficial with HTS. To date, no large clinical trial has been performed to directly compare the two agents. The best current evidence suggests that mannitol is effective in reducing ICP in the management of traumatic intracranial hypertension and carries mortality benefit compared to barbiturates. Current evidence regarding the use of HTS in severe TBI is limited to smaller studies, which illustrate a benefit in ICP reduction and perhaps mortality., (© 2015 New York Academy of Sciences.)

Background: In recent years hypertonic saline has attracted increasing interest in the treatment of traumatic intracranial hypertension, and has a number of documented and theoretical advantages over other hyperosmolar agents. To date, no consensus has been achieved on the safest and most effective HTS concentration for administration., Aims: The purpose of this paper was to evaluate the efficacy of intravenous bolus administration of highly concentrated (30 %) hypertonic saline (HTS) in the treatment of refractory intracranial hypertension secondary to traumatic brain injury., Methods: Patients were treated with an intravenous bolus of 10 ml of 30 % hypertonic saline. Multiple physiological parameters were measured throughout, including intracranial pressure, mean arterial pressure, cerebral perfusion pressure, pulse and inotrope/pressor requirements. Laboratory investigation pre and post HTS administration included: arterial pH, pCO2, HCO3, base excess; serum biochemistry measurements of sodium, potassium, chloride, urea and creatinine; and coagulation studies., Results: TBI patients saw a rapid and significant reduction in ICP from a baseline value of 28 ± 5.31 to 18.44 ± 6.17 mmHg at 1 h post HTS, a statistically significant reduction that was maintained for up to 7 h. This response was maintained even with repeated HTS administration, which was also associated with an augmented cerebral perfusion pressure from a baseline of 58.0 ± 6.48 to 76.33 mmHg within 1 h of HTS administration., Conclusion: No associated harmful biochemical or haematological abnormalities were noted. In conclusion, highly concentrated 30 % HTS appears to be both effective and safe in the management of refractory intracranial hypertension.

We describe the protocolised use of 23.4% hypertonic saline solution (HTS) for intracranial hypertension in the context of traumatic brain injury in the paediatric population. This study represents the largest published data on the use of 23.4% HTS in the paediatric population. In this retrospective cohort, we focus on the efficacy, biochemical and metabolic consequences of 23.4% HTS administration in a Level 1 paediatric trauma centre. Mortality in the first seven days was 6% (2/32) with a mean intensive care unit length-of-stay of ten days (range 2 to 25, standard deviation [SD] 6). All-cause hospital mortality was 6%, with no deaths after the seven-day study period. Mean intracranial pressure (ICP) response to HTS was 10 mmHg (range 1 to 30, SD 8). For biochemistry data, the mean highest daily serum sodium was 148 mmol/l (139 to 161, SD 6), mean highest serum chloride was 115 mmol/l (range 101 to 132, SD 8) with matched mean serum base excess of -1.5 mmol/l (range 2 to -8, SD 3) and mean peak serum creatinine was 73 mmol/l (range 32 to 104, SD 32). Glasgow outcome scores of >3 (independent function) were achieved in 74% of patients. We describe the use of 23.4% HTS, demonstrating it to be a practical and efficacious method of delivering osmoles and may be advantageous in minimising total fluid volume. Thus, the bolus versus infusion debate may best be served via combining both approaches.

In patients with severe traumatic brain injury, increased intracranial pressure (ICP) is associated with poor functional outcome or death. Hypertonic saline (HTS) is a hyperosmolar therapy commonly used to treat increased ICP; this study aimed to measure initial patient response to HTS and look for association with patient outcome. Patients >17 years old, admitted and requiring ICP monitoring between 2008 and 2010 at a large urban tertiary care facility were retrospectively enrolled. The first dose of hypertonic saline administered after admission for ICP >19mmHg was recorded and correlated with vital signs recorded at the bedside. The absolute and relative change in ICP at 1 and 2h after HTS administration was calculated. Patients were stratified by mortality and long-term (≥6 months) functional neurological outcome. We identified 46 patients who received at least 1 dose of HTS for ICP>19, of whom 80% were male, mean age 34.4, with a median post-resuscitation GCS score of 6. All patients showed a significant decrease in ICP 1h after HTS administration. Two hours post-administration, survivors showed a further decrease in ICP (43% reduction from baseline), while ICP began to rebound in non-survivors (17% reduction from baseline). When patients were stratified for long-term neurological outcome, results were similar, with a significant difference in groups by 2h after HTS administration. In patients treated with HTS for intracranial hypertension, those who survived or had good neurological outcome, when compared to those who died or had poor outcomes, showed a significantly larger sustained decrease in ICP 2h after administration. This suggests that even early in a patient's treatment, treatment responsiveness is associated with mortality or poor functional outcome. While this work is preliminary, it suggests that early failure to obtain a sustainable response to hyperosmolar therapy may warrant greater treatment intensity or therapy escalation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Decompressive craniectomy and barbiturate coma are often used as second-tier strategies when intracranial hypertension following severe traumatic brain injury is refractory to first-line treatments. Uncertainty surrounds the decision to choose either treatment option. We investigated which strategy is more economically attractive in this context., Design: We performed a cost-utility analysis. A Markov Monte Carlo microsimulation model with a life-long time horizon was created to compare quality-adjusted survival and cost of the two treatment strategies, from the perspective of healthcare payer. Model parameters were estimated from the literature. Two-dimensional simulation was used to incorporate parameter uncertainty into the model. Value of information analysis was conducted to identify major drivers of decision uncertainty and focus future research., Setting: Trauma centers in the United States., Subjects: Base case was a population of patients (mean age = 25 yr) who developed refractory intracranial hypertension following traumatic brain injury., Interventions: We compared two treatment strategies: decompressive craniectomy and barbiturate coma., Measurements and Main Results: Decompressive craniectomy was associated with an average gain of 1.5 quality-adjusted life years relative to barbiturate coma, with an incremental cost-effectiveness ratio of $9,565/quality-adjusted life year gained. Decompressive craniectomy resulted in a greater quality-adjusted life expectancy 86% of the time and was more cost-effective than barbiturate coma in 78% of cases if our willingness-to-pay threshold is $50,000/quality-adjusted life year and 82% of cases at a threshold of $100,000/quality-adjusted life year. At older age, decompressive craniectomy continued to increase survival but at higher cost (incremental cost-effectiveness ratio = $197,906/quality-adjusted life year at mean age = 85 yr)., Conclusions: Based on available evidence, decompressive craniectomy for the treatment of refractory intracranial hypertension following traumatic brain injury provides better value in terms of costs and health gains than barbiturate coma. However, decompressive craniectomy might be less economically attractive for older patients. Further research, particularly on natural history of severe traumatic brain injury patients, is needed to make more informed treatment decisions.

Background: Rising intracranial pressure (ICP) is a poor prognostic indicator in traumatic brain injury (TBI). Both mannitol and hypertonic sodium solutions are used to treat raised ICP in patients with TBI., Objective: This meta-analysis compares the use of mannitol versus hypertonic sodium solutions for ICP control in patients with TBI., Data Sources and Study Eligibility: Randomised clinical trials in adults with TBI and evidence of raised ICP, which compare the effect on ICP of hypertonic sodium solutions and mannitol., Methods: The primary outcome measure is the pooled mean reduction in ICP. Studies were combined using a Forest plot., Results: Six studies were included, comprising 171 patients (599 episodes of raised ICP). The weighted mean difference in ICP reduction, using hypertonic sodium solutions compared with mannitol, was 1.39 mm Hg (95% CI -0.74 to 3.53)., Limitations: Methodological differences between studies limit the conclusions of this meta-analysis., Conclusions: The evidence shows that both agents effectively lower ICP. There is a trend favouring the use of hypertonic sodium solutions in patients with TBI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: 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., Methods: 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., Results: 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)., Conclusions: 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.

Background: Traumatic brain injury (TBI) is a significant cause of death and disability in young adults, but not much is known about the incidence and characteristics of blood-brain barrier (BBB) dysfunction in this group. In this proof of concept study, we sought to quantify the incidence of BBB dysfunction (defined as a cerebrospinal fluid (CSF)-plasma albumin quotient of ≥0.007) and examine the relationship between plasma and CSF levels of proteins and electrolytes, in patients with severe TBI., Methods: We recruited 30 patients, all of whom were receiving hypertonic 20 % saline infusion for intracranial hypertension and had external ventricular drains in situ. Simultaneous CSF and blood samples were obtained. Biochemical testing was performed for sodium, osmolality, potassium, glucose, albumin, immunoglobulin-G, and total protein., Results: Eleven patients (37 %) showed evidence of impairment of passive BBB function, with a CSF-plasma albumin quotient of ≥0.007. There were strong positive correlations seen among CSF-plasma albumin quotient and CSF-plasma immunoglobulin-G quotient and CSF-plasma total protein quotient (r = 0.967, P < 0.001 and r = 0.995, P < 0.001, respectively). We also found a higher maximum intracranial pressure (24 vs. 21 mmHg, P = 0.029) and a trend toward increased mortality (27 vs. 11 %, P = 0.33) in patients with BBB disruption., Conclusions: In summary, passive BBB dysfunction is common in patients with severe TBI, and may have important implications for effectiveness of osmotherapy and long-term outcomes. Also, our results suggest that the CSF-plasma total protein quotient, a measurement which is readily available, can be used instead of the CSF-plasma albumin quotient for evaluating BBB dysfunction.

Background: Refractory intracranial hypertension (RICH) is associated with high mortality in severe traumatic brain injury (sTBI). Indomethacin (INDO) can decrease intracranial cerebral pressure (ICP) improving cerebral pressure perfusion (CPP). Our aim was to determine modifications in ICP and CPP following INDO in RICH secondary to sTBI., Methods: INDO was administered in a loading dose (0.8 mg/kg/15 min), followed by continuous 2-h infusion period (0.5 mg/kg/h). Clinical outcome was assessed at 30 days according to Glasgow Outcome Scale (GOS). Differences in ICP and CPP values were assessed using repeated-measures ANOVA. Receiver operating characteristic curve (AUC) was used for discrimination in predicting 30-day survival and good functional outcome (GOS 4 or 5). Analysis of INDO safety profile was also conducted., Results: Thirty-two patients were included. Median GCS score was 6 (interquartile range: 4-7). The most frequent CT finding was the evacuated mass lesion (EML) according to Marshall classification (28.1 %). Mortality rate was 34.4 %. Within 15 min of INDO infusion, ICP decreased (Δ%: -54.6 %; P < 0.0001), CPP increased (Δ%: +44.0 %; P < 0.0001), and the remaining was stable during the entire infusion period. Patients with good outcome (n = 12) showed a greater increase of CPP during INDO test (P = 0.028). CPP response to INDO test discriminated moderately well surviving patients (AUC = 0.751; P = 0.0098) and those with good functional recovery (AUC = 0.763; P = 0.0035) from those who died and from those with worse functional outcome, respectively. No adverse events were observed., Conclusions: INDO appears effective in reducing ICP and improving CPP in RICH. INDO test could be a useful tool in identifying RICH patients with favorable outcome. Future studies are needed.

Object: The authors undertook this study to evaluate the effects of continuous intracranial pressure (ICP) monitoring-directed mannitol treatment on kidney function in patients with moderate or severe traumatic brain injury (TBI)., Methods: One hundred sixty-eight patients with TBI were prospectively assigned to an ICP monitoring group or a conventional treatment control group based on the Brain Trauma Foundation guidelines. Clinical data included the dynamic changes of patients' blood concentrations of cystatin C, creatinine (Cr), and blood urea nitrogen (BUN); mannitol use; and 6-month Glasgow Outcome Scale (GOS) scores., Results: There were no statistically significant differences with respect to hospitalized injury, age, or sex distribution between the 2 groups. The incidence of acute kidney injury (AKI) was higher in the control group than in the ICP monitoring group (p < 0.05). The mean mannitol dosage in the ICP monitoring group (443 ± 133 g) was significantly lower than in the control group (820 ± 412 g) (p < 0.01), and the period of mannitol use in the ICP monitoring group (3 ± 3.8 days) was significantly shorter than in the control group (7 ± 2.3 days) (p < 0.01). The 6-month GOS scores in the ICP monitoring group were significantly better than in the control group (p < 0.05). On the 7th, 14th, and 21st days after injury, the plasma cystatin C and Cr concentrations in the ICP-monitoring group were significantly higher than the control group (p < 0.05)., Conclusions: In patients with moderate and severe TBI, ICP-directed mannitol treatment demonstrated a beneficial effect on reducing the incidence of AKI compared with treatment directed by neurological signs and physiological indicators.

Object: Normal intracranial pressure (ICP) and cerebral perfusion pressure (CPP) have been identified as favorable prognostic factors in the outcome of patients with traumatic brain injuries (TBIs). Osmotic diuretics and hypertonic saline (HTS) are commonly used to treat elevated ICP in patients with TBI; however, sustained effects of repeated high-concentration HTS boluses for severely refractory ICP elevation have not been studied. The authors' goal in this study was to determine whether repeated 14.6% HTS boluses were efficacious in treating severely refractory intracranial hypertension in patients with TBI., Methods: In a prospective cohort study in a neurocritical care unit, adult TBI patients with sustained ICP > 30 mm Hg for more than 30 minutes after exhaustive medical and/or surgical therapy received repeated 15-minute boluses of 14.6% HTS over 12 hours through central venous access., Results: Response to treatment was evaluated in 11 patients. Within 5 minutes of bolus administration, mean ICP decreased from 40 to 33 mm Hg (30% reduction, p < 0.05). Intracranial pressure-lowering effects were sustained for 12 hours (41% reduction, p < 0.05) with multiple boluses (mean number of boluses 7 ± 5.5). The mean CPP increased 22% and 32% from baseline at 15 and 30 minutes, respectively (p < 0.05). The mean serum sodium level (SNa) at baseline was 155 ± 7.1 mEq/L, and after multiple boluses of 14.6% HTS, S(Na) at 12 hours was 154 ± 7.1 mEq/L. The mean heart rate, systolic blood pressure, blood urea nitrogen, and creatinine demonstrated no significant change throughout the study., Conclusions: The subset of TBI patients with intracranial hypertension that is completely refractory to all other medical therapies can be treated effectively and safely with repeated boluses of 14.6% HTS rather than a one-time dose.

Traditionally, the use of ketamine for patients with traumatic brain injuries is contraindicated due to the concern of increasing intracranial pressure (ICP). These concerns, however, originated from early studies and case reports that were inadequately controlled and designed. Recently, the concern of using ketamine in these patients has been challenged by a number of published studies demonstrating that the use of ketamine was safe in these patients. This article reviews the current literature in regards to using ketamine in patients with traumatic brain injuries in different clinical settings associated with anesthesia, as well as reviews the potential mechanisms underlying the neuroprotective effects of ketamine. Studies examining the use of ketamine for induction, maintenance, and sedation in patients with TBI have had promising results. The use of ketamine in a controlled ventilation setting and in combination with other sedative agents has demonstrated no increase in ICP. The role of ketamine as a neuroprotective agent in humans remains inconclusive and adequately powered; randomized controlled trials performed in patients undergoing surgery for traumatic brain injury are necessary., (© 2013 John Wiley & Sons Ltd.)

Background and Purpose: Intracranial hypertension and cerebral edema are known contributors to secondary brain injury and to poor neurologic outcomes. Small volume solutions of exceedingly high osmolarity, such as 23.4% saline, have been used for the management of intracranial hypertension crises and as a measure to prevent or reverse acute brain tissue shifts. We conducted a systematic literature review on the use of 23.4% saline in neurocritically ill patients and a meta-analysis of the effect of 23.4% saline on intracranial pressure reduction., Design: We searched computerized databases, reference lists, and personal files to identify all clinical studies in which 23.4% saline has been used for the treatment of neurocritical care patients. Studies that did not directly involve either effects on cerebral hemodynamics or the treatment of patients with clinical or radiographic evidence of intracranial hypertension and/or cerebral swelling were eliminated., Measurements and Main Results: We identified 11 clinical studies meeting eligibility criteria. A meta-analysis was performed to evaluate the percent decrease in intracranial pressure and the 95% confidence intervals, from baseline to 60 minutes or nadir from the six studies from which this information could be extracted. A fixed effects meta-analysis estimated that the percent decrease in intracranial pressure from baseline to either 60 minutes or nadir after administration of 23.4% saline was 55.6% (se 5.90; 95% confidence interval, 43.99-67.12; p < 0.0001)., Conclusions: Highly concentrated hypertonic saline such as 23.4% provides a small volume solution with low cost and an over 50% reduction effect on raised intracranial pressure. Side effects reported are minor overall in view of the potentially catastrophic event that is being treated. High quality data are still needed to define the most appropriate osmotherapeutic agent, the optimal dose, the safest and most effective mode of administration and to further elucidate the mechanism of action of 23.4% saline and of osmotherapy in general.

Objectives: To evaluate high-dose barbiturates as a second-tier therapy for pediatric refractory intracranial hypertension complicating severe traumatic brain injury., Design: This is a retrospective cohort study of children with refractory intracranial hypertension treated with high-dose barbiturates., Setting: A single center level I pediatric trauma from 2001 to 2010., Patients: Thirty-six children with refractory intracranial hypertension defined as intracranial pressure greater than 20 mm Hg despite standard management treated with high-dose barbiturates after severe traumatic brain injury., Interventions: High-dose barbiturates were administered for refractory intracranial hypertension for a minimum duration of 6 hours and monitored by continuous electroencephalography., Measurements and Main Results: Exposure was control of refractory intracranial hypertension defined as > 20 mm Hg within 6 hours after starting barbiturates. Pediatric cerebral performance category scores at hospital discharge and at 3 months (or longer) follow-up were the primary outcomes. Ten of 36 patients (28%) had control of refractory intracranial hypertension. Neither demographic nor injury characteristics were associated with refractory intracranial hypertension control. Children who responded received barbiturates significantly later after injury (76 vs. 29 median hours). Overall, 14 children died, 13 without control of intracranial pressure. Survival was more common in those who responded compared with those who did not respond to high-dose barbiturates, although this did not reach statistical significance (relative risk of death 0.2; 95% confidence interval; [0.03-1.3]). Of the 22 survivors, 19 had an acceptable survival (pediatric cerebral performance category less than 3) at 3 months or longer after injury; however, only three returned to normal function. Among survivors, control of refractory intracranial hypertension was associated with significantly better pediatric cerebral performance category scores and over two-fold likelihood of acceptable long-term outcome (relative risk 2.3; 95% confidence interval [1.4-4.0]) compared with uncontrolled refractory intracranial hypertension despite high-dose barbiturates., Conclusions: Addition of high-dose barbiturates achieved control of refractory intracranial hypertension in almost 30% of treated children. Control of refractory intracranial hypertension was associated with increased likelihood of an acceptable long-term outcome.

Background: Propofol infusion syndrome (PRIS) is well known, often associated with, lethal complication of sedation with propofol. PRIS seems to be associated with young age, traumatic brain injury (TBI), higher cumulative doses of propofol, and the concomitant use of catecholamines. Known manifestations of PRIS are metabolic acidosis, rhabdomyolysis, and cardiac failure. While fatal PRIS can occur suddenly and rapidly, there is no sensitive test or early warning sign, and the only preventive measure is to limit propofol dosage and its duration., Methods: DESCRIPTION OF A SINGLE CASE: A case report was used for investigation purposes of this study., Results: We report the case study of a young patient with severe TBI, receiving propofol sedation because of high intracranial pressure. Seven days after the trauma, the patient developed metabolic acidosis and refractory circulatory shock, probably caused by PRIS. Reversal of T-waves was seen on the electrocardiogram (ECG) 29 h before circulation failure occurred. In the absence of other signs of cardiac dysfunction or ischemia, these reversed T-waves probably represent an early warning sign of developing PRIS., Conclusion: From the findings of this study, we conclude that meticulous observation and analysis of the ECG during propofol sedation might result in earlier recognition of developing PRIS.

The use of hyperosmolar agents for intracranial hypertension was introduced in the early 20th century and remains a mainstay of therapy for patients with cerebral edema. Both animal and human studies have demonstrated the efficacy of two hyperosmolar agents, mannitol and hypertonic saline, in reducing intracranial pressure via volume redistribution, plasma expansion, rheologic modifications, and anti-inflammatory effects. However, because of physician and institutional variation in therapeutic practices, lack of standardized protocols for initiation and administration of therapy, patient heterogeneity, and a paucity of randomized controlled trials have yielded little class I evidence on which clinical decisions can be based, most current evidence regarding the use of hyperosmolar therapy is derived from retrospective analyses (class III) and case series (class IV). In this review, we summarize the available evidence regarding the use of hyperosmolar therapy with mannitol or hypertonic saline for the medical management of intracranial hypertension and present a comprehensive discussion of the evidence associated with various theoretical and practical concerns related to initiation, dosage, and monitoring of therapy.

Background: The present study evaluates the types and dynamics of intracranial pathological changes in patients with severe traumatic brain injury (sTBI) who participated in a prospective, randomized, double-blinded study of add-on treatment with prostacyclin. Further, the changes of brain CT scan and their correlation to Glasgow Coma Scale score (GCS), maximal intracranial pressure (ICP(max)), minimal cerebral perfusion pressure (CPP(min)), and Glasgow Outcome Score (GOS) at 3, 6, and 12 months were studied., Methods: Forty-eight subjects with severe traumatic brain injury were treated according to an ICP-targeted therapy protocol based on the Lund concept with the addition of prostacyclin or placebo. The first available CT scans (CT(i)) and follow-up scans nearest to 24 h (CT(24)) were evaluated using the Marshall, Rotterdam, and Morris-Marshall classifications., Results: There was a significant correlation of the initial Marshall, Rotterdam, Morris-Marshall classifications and GOS at 3 and 12 months. The CT(24) Marshall classification did not significantly correlate to GOS while the Rotterdam and the Morris-Marshall classification did. The CT(i) Rotterdam classification predicted outcome evaluated as GOS at 3 and 12 months. Prostacyclin treatment did not influence the dynamic of tissue changes., Conclusions: The Rotterdam classification seems to be appropriate for describing the evolution of the injuries on the CT scans and contributes in predicting of outcome in patients treated with an ICP-targeted therapy. The Morris-Marshall classification can also be used for prognostication of outcome but it describes only the impact of traumatic subarachnoid hemorrhage (tSAH).

Objectives: The purpose of this study was to describe the administration of 3% saline (3%S) during pediatric critical care transport., Methods: A retrospective study was performed on pediatric patients who underwent critical transport to Loma Linda University Children's Hospital from January 1, 2003, to June 30, 2007, and were given 3%S. Patients' demographics, admission diagnosis, route and amount of 3%S administration, serum electrolytes, vital signs, radiographic data, and Glasgow Coma Scale scores were collected and analyzed., Results: A total of 101 children who received 3%S infusions during pediatric critical care transport were identified. Mean patient age was 5.9 years, and mean patient weight was 27.6 kg. The main indications for infusing 3%S were suspected cerebral edema (41%), intracranial bleed with edema (51%), and symptomatic hyponatremia (6%). The amount of 3%S bolus ranged from 1.2 to 24 mL/kg, with a mean of 5.4 mL/kg. Serum electrolytes before and after 3%S infusion demonstrated significant increases in sodium, chloride, and bicarbonate levels (P < 0.05). A significant reduction was also seen in serum urea nitrogen levels and anion gap. Radiographic imaging performed before 3%S infusion demonstrated findings consistent with concerns of increased intracranial pressure such as intracranial bleed and cerebral edema. The route of initial 3%S infusions was mainly through peripheral intravenous lines (96%). No complications related to the 3%S delivery such as local reactions, renal abnormalities, or central pontine myelinolysis were observed., Conclusions: It seems 3%S may be administered safely during pediatric critical transport and administration routes can include peripheral lines. With the importance of initiating therapy early to improve patient outcomes, the use of 3%S may benefit transported children with brain injury and suspected intracranial hypertension.

Purpose of Review: Traumatic brain injury is the leading cause of death in young patients and stroke is the leading cause of major disability in elderly patients. Both injuries are often followed by cerebral plasticity changes and increased intracerebral pressure (ICP). Aim of the review is to present current knowledge about amphetamines and other therapeutics concerning the recovery of brain injury based on contemporary findings., Recent Findings: On the one hand beneficial effects for cognitive and physical outcome after brain injury by coupling amphetamine with physical therapy could be demonstrated; on the other hand its efficacy was shown in only two out of 10 clinical trials., Summary: Impairment after brain injury is reduced if adequate early treatment is established. On the basis of current findings amphetamine after brain injury cannot be recommended. In patients with an increased ICP the maintenance of an adequate cerebral perfusion pressure is required. In patients with increased ICP under controlled ventilation, the combination of ketamine with, for example, a short-acting benzodiazepine and opioid or methohexital is equally well tolerated. Ketamine decreases ICP without lowering blood pressure and cerebral perfusion pressure. Its neuroprotective property might reduce the exacerbation of brain injury following N-methyl-D-aspartate-receptor activation, neuronal apoptosis and systemic inflammatory responses.

Background: Hyponatremia may complicate brain injury and exacerbate cerebral edema and intracranial pressure (ICP). Vasopressin-receptor antagonists (such as conivaptan) are promising novel agents to treat hyponatremia that act by inducing aquaresis. It is unclear whether raising serum sodium in this way could also confer an acute osmotic benefit, reducing brain water and thereby ICP. We evaluated the effect of a bolus of conivaptan on ICP in a patient with hyponatremia after traumatic brain injury (TBI)., Methods: A 22-year-old suffered severe TBI with occlusive left carotid dissection. Her course was complicated by left hemispheric infarcts with cerebral edema and intermittently elevated ICP. Conivaptan 20-mg IV was given as a bolus when serum sodium rapidly dropped to 128 mEq/l., Results: This dose resulted in significant aquaresis, with over 1 l per hour of dilute urine peaking at 3-5 h after the dose. By 8 h, sodium had risen to 146 mEq/l. ICP had been stable at 11-15 mmHg for several hours prior to the dose, remained in this range for 2 h after, but then fell to 2 mmHg at 4 h, and remained reduced out to 8 h. Cerebral perfusion pressure, initially stable at 60-80 mmHg, rose to over 90 mmHg at 4 h., Conclusions: In this preliminary case report, a single dose of conivaptan not only resulted in rapid correction of acute hyponatremia, but also a significant fall in ICP temporally associated with peak aquaresis. Vasopressin-receptor antagonists, by reversing osmotic shifts, may be novel agents to control ICP and cerebral edema, especially in the setting of falling sodium.

Object: 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., Methods: 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., Results: 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)., Conclusions: No difference between the 2 medications could be found with respect to the extent of reduction of ICP or duration of action.

Traumatic brain injury (TBI) is a major cause of death and disability in the United States. While there are no pharmacotherapeutic options currently available for attenuating the neurologic injury cascade after TBI, numerous pharmacologic issues are encountered in these critically ill patients. Adequate fluid resuscitation, reversal of coagulopathy, maintenance of cerebral perfusion, and treatment of intracranial hypertension are common interventions early in the treatment of TBI. Other deleterious complications such as venous thromboembolism, extremes in glucose concentrations, and stress-related mucosal disease should be anticipated and avoided. Early provision of nutrition and prevention of drug or alcohol withdrawal are also cornerstones of routine care in TBI patients. Prevention of infections and seizures may also be helpful. Clinicians caring for TBI patients should be familiar with the pharmacologic issues typical of this vulnerable population in order to develop optimal strategies of care to anticipate and prevent common complications.