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Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep ( n =  24) were subject to 2-hours tMCAo and randomized ( n =  6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The NK1-R antagonist drug (EU-C-001) was kindly donated by PresSura Neuro, however, they had no input in the experimental design, conduct of the study, nor data analysis.

Background: Elevated intracranial pressure (ICP) is observed in many neurological pathologies, e.g. hydrocephalus and stroke. This condition is routinely relieved with neurosurgical approaches, since effective and targeted pharmacological tools are still lacking. The carbonic anhydrase inhibitor, acetazolamide (AZE), may be employed to treat elevated ICP. However, its effectiveness is questioned, its location of action unresolved, and its tolerability low. Here, we determined the efficacy and mode of action of AZE in the rat ., Methods: We employed in vivo approaches including ICP and cerebrospinal fluid secretion measurements in anaesthetized rats and telemetric monitoring of ICP and blood pressure in awake rats in combination with ex vivo choroidal radioisotope flux assays and transcriptomic analysis., Results: AZE effectively reduced the ICP, irrespective of the mode of drug administration and level of anaesthesia. The effect appeared to occur via a direct action on the choroid plexus and an associated decrease in cerebrospinal fluid secretion, and not indirectly via the systemic action of AZE on renal and vascular processes. Upon a single administration, the reduced ICP endured for approximately 10 h post-AZE delivery with no long-term changes of brain water content or choroidal transporter expression. However, a persistent reduction of ICP was secured with repeated AZE administrations throughout the day., Conclusions: AZE lowers ICP directly via its ability to reduce the choroid plexus CSF secretion, irrespective of mode of drug administration., (© 2022. The Author(s).)

[Figure: see text].

Background: The aim was to study the effects of barbiturate coma treatment (BCT) on intracranial pressure (ICP) and intracranial compensatory reserve (RAP index) in children (< 17 years of age) with traumatic brain injury (TBI) and refractory intracranial hypertension (RICH)., Methods: High-resolution monitoring data were used to study the effects of BCT on ICP, mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and RAP index. Four half hour long periods were studied: before bolus injection and at 5, 10, and 24 hours thereafter, respectively, and a fifth tapering period with S-thiopental between < 100 and < 30 μmol/L. S-thiopental concentrations and administered doses were registered., Results: Seventeen children treated with BCT 2007-2017 with high-resolution data were included; median age 15 (range 6-17) and median Glasgow coma score 7 (range 3-8). Median time from trauma to start of BCT was 44.5 h (range 2.5-197.5) and from start to stop 99.0 h (range 21.0-329.0). Median ICP was 22 (IQR 20-25) in the half hour period before onset of BCT and 16 (IQR 11-20) in the half hour period 5 h later (p = 0.011). The corresponding figures for CPP were 65 (IQR 62-71) and 63 (57-71) (p > 0.05). The RAP index was in the half hour period before onset of BCT 0.6 (IQR 0.1-0.7), in the half hour period 5 h later 0.3 (IQR 0.1-0.7) (p = 0.331), and in the whole BCT period 0.3 (IQR 0.2-0.4) (p = 0.004). Eighty-two percent (14/17) had favorable outcome (good recovery = 8 patients and moderate disability = 6 patients)., Conclusion: BCT significantly reduced ICP and RAP index with preserved CPP. BCT should be considered in case of RICH.

Background: Intravenous hypertonic saline is utilized commonly in critical care for treatment of acute or refractory elevations of intracranial pressure (ICP) in traumatic brain injury (TBI) patients. Though there is a clear understanding of the general physiological effects of a hypertonic saline solution over long periods of time, smaller epoch effects of hypertonic saline (HTS) have not been thoroughly analyzed. The aim of this study was to perform a direct evaluation of the high-frequency response of HTS on the cerebrovascular physiological responses in TBI., Methods: We retrospectively reviewed our prospectively maintained adult TBI database for those with archived high-frequency cerebral physiology and available HTS treatment information. We evaluated different epochs of physiology around HTS bolus dosing, comparing pre- with post-HTS. We assessed for changes in slow fluctuations in ICP, pulse amplitude of ICP (AMP), cerebral perfusion pressure (CPP), mean arterial pressure (MAP), cerebrovascular reactivity (as measured through pressure reactivity index (PRx)), and cerebral compensatory reserve (correlation (R) between AMP (A) and ICP (P)). Comparisons of mean measures and percentage time above clinically relevant thresholds for the physiological parameters were compared pre- and post-HTS using descriptive statistics and Mann-Whitney U testing. We assessed for subgroups of physiological responses using latent profile analysis (LPA)., Results: Fifteen patients underwent 69 distinct bolus infusions of hypertonic saline. Apart from the well-documented decrease in ICP, there was also a reduction in AMP. The analysis of cerebrovascular reactivity response to HTS solution had two main effects. For patients with grossly impaired cerebrovascular reactivity pre-HTS (PRx > + 0.30), HTS bolus led to improved reactivity. However, for those with intact cerebrovascular reactivity pre-HTS (PRx < 0), HTS bolus demonstrated a trend towards more impaired reactivity. This indicates that HTS has different impacts, dependent on pre-bolus cerebrovascular status. There was no significant change in metrics of cerebral compensatory reserve. LPA failed to demonstrate any subgroups of physiological responses to HTS administration., Conclusions: The direct decrease in ICP and AMP confirms that a bolus dose of a HTS solution is an effective therapeutic agent for intracranial hypertension. However, in patients with intact autoregulation, hypertonic saline may impair cerebral hemodynamics. These findings regarding cerebrovascular reactivity remain preliminary and require further investigation.

Background: Standardized volume dosing of 23.4% hypertonic saline (HTS) exists for adults, but the concentration, dosing and administration of HTS in pediatrics is variable. With emerging pediatric experience of 23.4% HTS, a standard volume dose approach may be helpful. Objective: To describe initial experience with a standardized 23.4% HTS weight-based volume dosing protocol of 10, 20, or 30 mL in the pediatric intensive care unit. Methods: Standard volume doses of 23.4% HTS were developed from weight dosing equivalents of 3% HTS. Pre and post sodium and intracranial pressure (ICP) measurements were compared with paired t-test or Wilcoxon rank-sum test. The site of administration and complications were noted. Results: A total of 16 pediatric patients received 37 doses of 23.4% HTS, with the smallest patient weighing 11 kg. For protocol compliance, 17 doses (46%) followed recommended dosing, 19 were less volume than recommended (51%), and 1 dose (3%) was more than recommended. Mean increase in sodium was 3.5 mEq/L (95% CI = 2-5 mEq/L); P < 0.0001. The median decrease in ICP was 10.5 mm Hg (interquartile range [IQR] 8.3-19.5) for a 37% (IQR 25%-64%) reduction. Most doses were administered through central venous access, although peripheral intravenous administrations occurred in 4 patients without complication. Conclusion and Relevance: Three standard-volume dose options of 23.4% HTS based on weight increases sodium and reduces ICP in pediatric patients. Standard-volume doses may simplify weight-based dosing, storage and administration for pediatric emergencies, although the optimum dose, and safety of 23.4% HTS in children remains unknown.

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: Hypertonic saline (HTS) and mannitol are effective in reducing intracranial pressure (ICP) after severe traumatic brain injury (TBI). However, their simultaneous effect on the cerebral perfusion pressure (CPP) and ICP has not been studied rigorously., Objective: To determine the difference in effects of HTS and mannitol on the combined burden of high ICP and low CPP in patients with severe TBI., Methods: We performed a case-control study using prospectively collected data from the New York State TBI-trac® database (Brain Trauma Foundation, New York, New York). Patients who received only 1 hyperosmotic agent, either mannitol or HTS for raised ICP, were included. Patients in the 2 groups were matched (1:1 and 1:2) for factors associated with 2-wk mortality: age, Glasgow Coma Scale score, pupillary reactivity, hypotension, abnormal computed tomography scans, and craniotomy. Primary endpoint was the combined burden of ICPhigh (> 25 mm Hg) and CPPlow (< 60 mm Hg)., Results: There were 25 matched pairs for 1:1 comparison and 24 HTS patients matched to 48 mannitol patients in 1:2 comparisons. Cumulative median osmolar doses in the 2 groups were similar. In patients treated with HTS compared to mannitol, total number of days (0.6 ± 0.8 vs 2.4 ± 2.3 d, P < .01), percentage of days with (8.8 ± 10.6 vs 28.1 ± 26.9%, P < .01), and the total duration of ICPhigh + CPPlow (11.12 ± 14.11 vs 30.56 ± 31.89 h, P = .01) were significantly lower. These results were replicated in the 1:2 match comparisons., Conclusion: HTS bolus therapy appears to be superior to mannitol in reduction of the combined burden of intracranial hypertension and associated hypoperfusion in severe TBI patients., (Copyright © 2019 by the Congress of Neurological Surgeons.)

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.)

Objective: To explore the effect of 23.4% hypertonic saline for management of elevated intracranial pressure in children admitted to our institution for severe traumatic brain injury., Design: Single-center, retrospective medical chart analysis., Setting: A PICU at a level 1 pediatric trauma center in the United States., Patients: Children admitted for severe traumatic brain injury from 2006 to 2016 who received 23.4% hypertonic saline and whose intracranial pressures were measured within 5 hours of receiving 23.4% hypertonic saline., Interventions: None., Measurements and Main Results: Over the 10-year period, 1,587 children were admitted for traumatic brain injury, 155 of whom were deemed severe per this study's criteria. Forty of these children received at least one dose of hypertonic saline, but 14 were excluded for insufficient intracranial pressure data. Among the remaining 26 children, one hundred one 23.4% hypertonic saline boluses were used in the analysis. Use of 23.4% hypertonic saline was associated with a decrease in intracranial pressure of approximately 7 mm Hg at both within 1 hour after the bolus (p < 0.01) and 4 hours after the bolus (p < 0.01) when compared with the intracranial pressure measured within 1 hour before the hypertonic saline bolus. These effects remained significant after adjusting for Functional Status Scale score and CT Marshall scores. There was no statistically significant association between adjunctive therapies, such as antiepileptics and analgesics, and changes in intracranial pressure. There was no laboratory evidence of hyperkalemia or renal injury after use of 23.4% hypertonic saline. Across all hospitalizations, 65% of the study population demonstrated an abnormally elevated creatinine at least once, but only three episodes of acute kidney injury occurred in total, all before hypertonic saline administration. Eight of the 26 children in this analysis died during their hospitalization. The Functional Status Scale scores ranged from 6 to 26 with a mean of 12.2 and SD of 5.7., Conclusions: Use of 23.4% hypertonic saline with children admitted for severe traumatic brain injury is associated with a statistically significant decrease in intracranial pressure within 1 hour of use.

Background: Severe traumatic brain injury (sTBI) is a major cause of morbidity and mortality. Intracranial pressure (ICP) monitoring and management form the cornerstone of treatment paradigms for sTBI in developed countries. We examine the available randomized controlled trial (RCT) data on the impact of ICP management on clinical outcomes after sTBI., Methods: A systematic review of the literature on ICP management following sTBI was performed to identify pertinent RCT articles., Results: We identified six RCT articles that examined whether ICP monitoring, decompressive craniectomy, or barbiturate coma improved clinical outcomes after sTBI. These studies support (1) the utility of ICP monitoring in the management of sTBI patients and (2) craniectomy and barbiturate coma as effective methods for the management of intracranial hypertension secondary to sTBI. However, despite adequate ICP control in sTBI patients, a significant proportion of surviving patients remain severely disabled., Conclusions: If one sets the bar at the level of functional independence, then the RCT data raises questions pertaining to the utility of decompressive craniectomy and barbiturate coma in the setting of sTBI.

Objective: In neurotrauma care, a better understanding of treatments after traumatic brain injury (TBI) has led to a significant decrease in morbidity and mortality in this population. TBI represents a significant medical problem, and complications after TBI are associated with the initial injury and postevent intracranial processes such as increased intracranial pressure and brain edema. Consequently, appropriate therapeutic interventions are required to reduce brain tissue damage and improve cerebral perfusion. We present a contemporary review of literature on the use of pharmacologic therapies to reduce intracranial pressure after TBI and a comparison of their efficacy., Methods: This review was conducted by PubMed query. Only studies discussing pharmacologic management of patients after TBI were included. This review includes prospective and retrospective studies and includes randomized controlled trials as well as cohort, case-control, observational, and database studies. Systematic literature reviews, meta-analyses, and studies that considered conditions other than TBI or pediatric populations were not included., Results: Review of the literature describing the current pharmacologic treatment for intracranial hypertension after TBI most often discussed the use of hyperosmolar agents such as hypertonic saline and mannitol, sedatives such as fentanyl and propofol, benzodiazepines, and barbiturates. Hypertonic saline is associated with faster resolution of intracranial hypertension and restoration of optimal cerebral hemodynamics, although these advantages did not translate into long-term benefits in morbidity or mortality. In patients refractory to treatment with hyperosmolar therapy, induction of a barbiturate coma can reduce intracranial pressure, although requires close monitoring to prevent adverse events., Conclusions: Current research suggests that the use of hypertonic saline after TBI is the best option for immediate decrease in intracranial pressure. A better understanding of the efficacy of each treatment option can help to direct treatment algorithms during the critical early hours of trauma care and continue to improve morbidity and mortality after TBI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Bolus doses of 23.4% sodium chloride (NaCl) are commonly used for the treatment of intracranial hypertension; however, delays in administration may occur in patients without central intravenous access. At our institution, equiosmolar bolus doses of 5% NaCl have emerged as potential alternatives to 23.4% NaCl because they may be safely administered through peripheral lines., Objectives: We sought to assess the efficacy in reducing intracranial pressure (ICP), time to administration, and safety of 5% NaCl as compared with 23.4% NaCl for the treatment of intracranial hypertension., Methods: Patients admitted from July 2012 to June 2014 who received boluses of 5% NaCl or 23.4% NaCl for a sustained ICP >20 mm Hg were included. Data collected included measurements of ICP, time to administration, and adverse events., Results: A total of 44 patients were identified; 11 received 5% NaCl, and 33 received 23.4% NaCl. The median percentage reductions in ICP at 30, 60, and 120 minutes in patients who received 5% versus 23.4% NaCl were 34% versus 26% ( P = 0.850), 48% versus 40% ( P = 0.700), and 46% versus 30% ( P = 0.064), respectively. The median time to administration was shorter in the 5% NaCl group (7 vs 11 minutes, P = 0.364). Both groups had a 27% rate of adverse events and no infusion site reactions., Conclusions: These data suggest that 5% NaCl may be as effective as 23.4% NaCl at lowering ICP if given at equiosmolar doses, has a shorter time to administration, and has no difference in the prevalence of adverse events.

The impact of hypertonic saline (HTS) on long term control of intracranial hypertension (ICH) is yet to be established. The current prospective randomized controlled study was carried out in 38 patients with severe traumatic brain injury (TBI). Over 450 episodes of refractory ICH were treated with equiosmolar boluses of 20% mannitol in 20 patients and 3.0% HTS in 18 subjects. Intracranial pressure (ICP) was monitored for 6days. ICP and cerebral perfusion pressure (CPP) were comparable between the groups. The mannitol group had a progressive increase in the ICP over the study period (p=0.01). A similar increase was not seen in the HTS group (p=0.1). The percentage time for which the ICP remained below a threshold of 20 mmHg on day6 was higher in the HTS group (63% versus 49%; p=0.3). The duration of inotrope requirement in the HTS group was less compared to the mannitol group (p=0.06). The slope of fall in ICP in response to a bolus dose at a given baseline value of ICP was higher with HTS compared to mannitol (p=0.0001). In-hospital mortality tended to be lower in the HTS group (3 versus 10; p=0.07) while mortality at 6 months was not different between the groups (6 versus 10; p=0.41). Dichotomized Glasgow Outcome Scale scores at 6months were comparable between the groups (p=0.21). To conclude, immediate physiological advantages seen with HTS over mannitol did not translate into long term benefit on ICP/CPP control or mortality of patients with TBI., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.)

Objectives: 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., Design: 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., Setting: A tertiary care children's hospital., Patients: Children with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8)., Interventions: None., Measurements and Main Results: 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., Conclusions: 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.

Neurovascular coupling is the relationship between the activity of the brain and the subsequent change in blood flow to the active region. The most common methods of detecting neurovascular coupling are cumbersome and noncontinuous. However, the integration of intracranial pressure (ICP) and electroencephalography (EEG) may serve as an indirect measure of neurovascular coupling.This study used data collected from burst-suppressed patients who received both ICP and depth EEG monitoring. An adaptive thresholding algorithm was used to detect the start and end of each EEG burst. The morphological clustering and analysis of ICP and pulse morphological template-matching algorithms were then applied to derive several metrics describing the shape of the ICP pulse waveform and track how it changed following an EEG burst. These changes were compared using a template obtained from patients undergoing CO2-induced vasodilation.All segments exhibited a significant period of vasodilation within 1-2 s after burst, and 4 of 5 had a significant period of vasoconstriction within 4-11 s of the EEG burst, suggesting that there might be a characteristic response of vasodilation and subsequent vasoconstriction after a spontaneous EEG burst. Furthermore, these findings demonstrate the potential of integrated EEG and ICP as an indirect measure of neurovascular coupling.

Continuous intracranial pressure (ICP) and electroencephalographic (EEG) monitoring are used in the management of patients with brain injury. It is possible that these two signals could be related through neurovascular coupling. To explore this mechanism, we modeled the ICP response to brain activity by treating spontaneous burst activity in burst-suppressed patients as an impulse, and identified the ICP response function (ICPRF) as the subsequent change in ICP.Segments of ICP were filtered, classified as elevating or stable, and suitable ICPRFs were identified. After calibration, each ICPRF was convolved with the EEG to produce the estimated ICP. The mean error (ME) versus distance from the selected ICPRF was calculated and the elevating and stable ICP segments compared.Eighty-four ICPRFs were identified from 15 data segments. The ME of the elevating segments increased at an average rate of 57 mmHg/min, whereas the average ME of the stable segments increased at a rate of 0.05 mmHg/min.These findings demonstrate that deriving an ICPRF from a burst-suppressed patient is a suitable approach for stable segments. To completely model the ICP response to EEG activity, a more robust model should be developed.

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.)

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.

Background: AF-16 is a 16-amino-acid-long peptide derived from the amino-terminal part of the endogenous protein, antisecretory factor (AF). AF-16 in vivo has been shown to regulate dysfunctions in the water and ion transport system under various pathological conditions and also to counteract experimentally increased tissue pressure., Methods: Rats were subjected to a cryogenic brain injury in order to increase the intracranial pressure (ICP). The distribution of AF-16 in blood and CSF after intravenous or intranasal administration was determined in injured and control rats. ICP was monitored in freely moving, awake rats, by means of an epidural pressure transducer catheter connected to a wireless device placed subcutaneously on the skull. The continuous ICP registrations were achieved by means of telemetry., Results: Intranasal administration of AF-16 resulted in a significantly higher CSF concentrations of AF-16 in injured than in control rats, 1.3 versus 0.6 ng/ml, whereas no difference between injured and control rats was seen when AF-16 was given intravenously. Rats subjected to cryogenic brain injury developed gradually increasing ICP levels. Intranasal administration of AF-16 suppressed the increased ICP to normal values within 30 min., Conclusion: Optimal AF-16 concentrations in CSF are achieved after intranasal administration in rats subjected to a cryogenic brain injury. The ability of AF-16 to suppress an increased ICP was manifested.

To evaluate the efficacy of intracranial pressure (ICP)-targeted treatment, compared to standard intensive care, in adults with community acquired acute bacterial meningitis (ABM) and severely impaired consciousness, a prospectively designed intervention-control comparison study was performed. Included were patients with confirmed ABM and severely impaired mental status on admission. Fifty-two patients, given ICP-targeted treatment at a neuro-intensive care unit, and 53 control cases, treated with conventional intensive care, were included. All patients received intensive care with me-chanical ventilation, sedation, antibiotics and corticosteroids according to current guidelines. ICP-targeted treatment was performed in the intervention group, aiming at ICP 50 mmHg. The mortality was significantly lower in the intervention group compared to controls, 5/52 (10%) versus 16/53 (30%). Furthermore, only 17 patients (32%) in the control group fully recovered, compared to 28 (54%) in the intervention group. Early neuro-intensive care using ICP-targeted therapy reduces mortality and improves the overall outcome in adult patients with ABM and severely impaired mental status on admission.

Background: The accepted treatment of increased intracranial pressure (ICP) in patients experiencing severe traumatic brain injury is multimodal and algorithmic, obscuring individual effects of treatment. Using continuous vital signs monitoring, we sought to measure treatment effect and ascertain the accuracy of manual data recording., Methods: Patients older than 17 years, admitted and requiring ICP monitoring between 2008 and 2010 at a high-volume urban trauma center, were retrospectively evaluated. Timing and dose of ICP-directed therapy were recorded from paper and electronic medical records. ICP data were collected automatically at 6-second intervals and from manual charts. A statistical mixed model was applied to all data to account for multiple sampling., Results: A total of 117 patients met inclusion criteria; 450 treatments were administered when nursing records indicate an ICP greater than 20 mm Hg, while 968 treatments were given when ICP was greater than 20 mm Hg by automated data. Pharmacologic treatments identified include hypertonic saline (HTS), mannitol, barbiturates, and dose escalations of propofol or fentanyl infusions. Treatment with HTS resulted in the largest ICP decrease of the treatments examined, with a 1-hour ICP reduction of 8.8/9.9 mm Hg (for a small/large dose) according to manual data and a reduction of 3.0/2.4 mm Hg according to automated data. Propofol and fentanyl escalations resulted in smaller but significant ICP reductions. Mannitol (n = 8) resulted in statistically insignificant trends down in the first hour but rebounded by the second hour after administration. The average ICP in the hour before medication administration was higher for barbiturates (27 mm Hg) and mannitol (32 mm Hg) than for the other interventions (18-19 mm Hg)., Conclusion: ICP fell after administration of HTS, mannitol, or barbiturates and showed continued improvement after 2 hours. ICP fell initially after treatment with short-acting propofol and fentanyl but trended back up after 2 hours. Manually recorded data consistently overestimated treatment effectiveness. Automated data collection gives a more accurate assessment of patient status and responsiveness to treatment., Level of Evidence: Therapeutic study, level IV.

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: 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.

Critical closing pressure (CCP) is the arterial blood pressure (ABP) at which brain vessels collapse and cerebral blood flow (CBF) ceases. Using the concept of impedance to CBF, CCP can be expressed with brain-monitoring parameters: cerebral perfusion pressure (CPP), ABP, blood flow velocity (FV), and heart rate. The novel multiparameter method (CCPm) was compared with traditional transcranial Doppler (TCD) calculations of CCP (CCP1). Digital recordings of ABP, intracranial pressure (ICP), and TCD-based FV from previously published studies of 29 New Zealand White rabbits were reanalyzed. Overall, CCP1 and CCPm showed correlation across wide ranges of ABP, ICP, and PaCO2 (R=0.93, P<0.001). Three physiological perturbations were studied: increase in ICP (n=29) causing both CCP1 and CCPm to increase (P<0.001 for both); reduction of ABP (n=10) resulting in decrease of CCP1 (P=0.006) and CCPm (P=0.002); and controlled increase of PaCO2 (n=8) to hypercapnic levels, which decreased CCP1 and CCPm, albeit insignificantly (P=0.123 and P=0.306 respectively), caused by a spontaneous significant increase in ABP (P=0.025). Multiparameter mathematical model of critical closing pressure explains the relationship of CCP on brain-monitoring variables, allowing the estimation of CCP during cases such as hypercapnia-induced hyperemia, where traditional calculations, like CCP1, often reach negative non-physiological values.

Background: Intracranial hypertension is the final pathway of many neurocritical entities, such as spontaneous intracerebral hemorrhage (sICH) and severe traumatic brain injury (sTBI)., Objective: This study aimed to (1) determine alterations in intracranial pressure (ICP) and cerebral hemodynamics after an indomethacin (INDO) infusion test and the related association with survival in patients with refractory intracranial hypertension (RICH) secondary to sICH or sTBI and (2) assess the safety profile after INDO., Methods: INDO was administered in a loading dose (0.8 mg/kg/15 min), followed by a 2-hour continuous infusion (0.5 mg/kg/h) in RICH patients with ICP greater than 20 mm Hg who did not respond to first-line therapies. Changes in ICP, cerebral perfusion pressure (CPP), and cerebrovascular variables (assessed by transcranial Doppler and jugular bulb saturation) were observed. Clinical outcome was assessed at 1 and 6 months according to the Glasgow Outcome Scale and correlated with INDO infusion test response. Analysis of INDO safety profile was conducted., Results: Thirteen sICH and 10 sTBI patients were studied. The median GCS score at admission was 6. Within 30 minutes of INDO infusion, ICP decreased (42.0 ± 13.5 vs 27.70 ± 12.7 mm Hg; Δ%: -48.4%; P < .001), and both CPP (57.7 ± 4.8 vs 71.9 ± 7.0 mm Hg; Δ%: +26.0%; P < .001) and middle cerebral artery velocity (35.2 ± 5.6 vs 42.0 ± 5.1 cm·s(-1); Δ%: +26.1%; P < .001) increased. The CPP response to a 2-hour INDO infusion test was correlated (R2 = 0.72, P < .001) with survival. No adverse events were observed after INDO., Conclusion: Our findings support the effectiveness and feasibility of an INDO test in decreasing ICP and improving cerebral hemodynamics in surviving RICH patients. Future studies to evaluate different doses, lengths of infusion, and longer term effects are needed.

Object: Currently, mannitol is the recommended first choice for a hyperosmolar agent for use in patients with elevated intracranial pressure (ICP). Some authors have argued that hypertonic saline (HTS) might be a more effective agent; however, there is no consensus as to appropriate indications for use, the best concentration, and the best method of delivery. To answer these questions better, the authors performed a review of the literature regarding the use of HTS for ICP reduction., Methods: A PubMed search was performed to locate all papers pertaining to HTS use. This search was then narrowed to locate only those clinical studies relating to the use of HTS for ICP reduction., Results: A total of 36 articles were selected for review. Ten were prospective randomized controlled trials (RCTs), 1 was prospective and nonrandomized, 15 were prospective observational trials, and 10 were retrospective trials. The authors did not distinguish between retrospective observational studies and retrospective comparison trials. Prospective studies were considered observational if the effects of a treatment were evaluated over time but not compared with another treatment., Conclusions: The available data are limited by low patient numbers, limited RCTs, and inconsistent methods between studies. However, a greater part of the data suggest that HTS given as either a bolus or continuous infusion can be more effective than mannitol in reducing episodes of elevated ICP. A meta-analysis of 8 prospective RCTs showed a higher rate of treatment failure or insufficiency with mannitol or normal saline versus HTS.

Background: In patients with aneurysmal subarachnoid hemorrhage (SAH), preliminary results indicate that the amplitude of the single intracranial pressure (ICP) wave is a better predictor of the early clinical state and 6-month outcome than the mean ICP., Objective: To perform a randomized and blinded single-center trial comparing the effect of mean ICP vs mean ICP wave amplitude (MWA)-guided intensive care management on early clinical state and outcome in patients with aneurysmal SAH., Methods: Patients were randomized to 2 different types of ICP management: maintenance of mean ICP less than 20 mm Hg and MWA less than 5 mm Hg. Early clinical state was assessed daily using the Glasgow Coma Scale. The primary efficacy variable was 12-month outcome in terms of the Rankin Stroke Score., Results: Ninety-seven patients were included in the study. There were no significant differences in treatment between the 2 groups apart from a larger volume of cerebrospinal fluid drained during week 1 in the MWA group. There was a tendency toward higher Glasgow Coma Scale scores in the MWA group during weeks 1 (P = .08) and 2 (P = .07). Outcome in terms of Rankin Stroke Score at 12 months was significantly better in the MWA group (P < .05)., Conclusion: This randomized and blinded trial disclosed a significant better primary efficacy variable (Rankin Stroke Score after 12 months) in the MWA patient group. We suggest that proactive intensive care management with MWA-tailored cerebrospinal fluid drainage during the first week improves aneurysmal SAH outcome.

Background: Raised intracranial pressure (ICP) is known to complicate both traumatic and non-traumatic encephalopathies. It impairs cerebral perfusion and may cause death due to global ischaemia and intracranial herniation. Osmotic agents are widely used to control ICP. In children, guidelines for their use are mainly guided by adult studies. We conducted this review to determine the current evidence of the effectiveness of osmotic agents and their effect on resolution of coma and outcome in children with acute encephalopathy., Methods: We searched several databases for published and unpublished studies in English and French languages, between January 1966 and March 2009. We considered studies on the use of osmotic agents in children aged between 0 and 16 years with acute encephalopathies. We examined reduction in intracranial pressure, time to resolution of coma, and occurrence of neurological sequelae and death., Results: We identified four randomized controlled trials, three prospective studies, two retrospective studies and one case report. Hypertonic saline (HS) achieved greater reduction in intracranial pressure (ICP) compared to mannitol and other fluids; normal saline or ringer's lactate. This effect was sustained for longer when it was given as continuous infusion. Boluses of glycerol and mannitol achieved transient reduction in ICP. Oral glycerol was associated with lower mortality and neurological sequelae when compared to placebo in children with acute bacterial meningitis. HS was associated with lower mortality when compared to mannitol in children with non-traumatic encephalopathies., Conclusion: HS appears to achieve a greater reduction in ICP than other osmotic agents. Oral glycerol seems to improve outcome among children with acute bacterial meningitis. A sustained reduction in ICP is desirable and could be achieved by modifying the modes and rates of administration of these osmotic agents, but these factors need further investigation.

Objective: This study aimed to study case reports and review the world literature concerning increased intracranial pressure secondary to unilateral radical neck dissection., Case Report: A male patient presented with a painless lump in the left side of his neck. Diagnostic investigation revealed papillary thyroid carcinoma and 4 x 2-cm left cervical lymph node. Total thyroidectomy with modified radical neck dissection on the left side that included removal of the internal jugular vein was undertaken. Eleven days after the operation, the patient presented with a history of headache and diplopia. Clinical examination showed bilateral papilledema and right-sided sixth cranial nerve palsy. A computed tomographic scan and magnetic resonance image of the brain was normal. Subsequent magnetic resonance venography revealed an aplastic contralateral transverse sinus., Conclusion: Based on our case, vascular anomalies should be considered in any patient who exhibits signs of increased intracranial pressure after unilateral neck dissection.

Object: Deepening sedation is often needed in patients with intracranial hypertension. All widely used sedative and anesthetic agents (opioids, benzodiazepines, propofol, and barbiturates) decrease blood pressure and may therefore decrease cerebral perfusion pressure (CPP). Ketamine is a potent, safe, rapid-onset anesthetic agent that does not decrease blood pressure. However, ketamine's use in patients with traumatic brain injury and intracranial hypertension is precluded because it is widely stated that it increases intracranial pressure (ICP). Based on anecdotal clinical experience, the authors hypothesized that ketamine does not increase-but may rather decrease-ICP., Methods: The authors conducted a prospective, controlled, clinical trial of data obtained in a pediatric intensive care unit of a regional trauma center. All patients were sedated and mechanically ventilated prior to inclusion in the study. Children with sustained, elevated ICP (> 18 mm Hg) resistant to first-tier therapies received a single ketamine dose (1-1.5 mg/kg) either to prevent further ICP increase during a potentially distressing intervention (Group 1) or as an additional measure to lower ICP (Group 2). Hemodynamic, ICP, and CPP values were recorded before ketamine administration, and repeated-measures analysis of variance was used to compare these values with those recorded every minute for 10 minutes following ketamine administration., Results: The results of 82 ketamine administrations in 30 patients were analyzed. Overall, following ketamine administration, ICP decreased by 30% (from 25.8 +/- 8.4 to 18.0 +/- 8.5 mm Hg) (p < 0.001) and CPP increased from 54.4 +/- 11.7 to 58.3 +/- 13.4 mm Hg (p < 0.005). In Group 1, ICP decreased significantly following ketamine administration and increased by > 2 mm Hg during the distressing intervention in only 1 of 17 events. In Group 2, when ketamine was administered to lower persistent intracranial hypertension, ICP decreased by 33% (from 26.0 +/- 9.1 to 17.5 +/- 9.1 mm Hg) (p < 0.0001) following ketamine administration., Conclusions: In ventilation-treated patients with intracranial hypertension, ketamine effectively decreased ICP and prevented untoward ICP elevations during potentially distressing interventions, without lowering blood pressure and CPP. These results refute the notion that ketamine increases ICP. Ketamine is a safe and effective drug for patients with traumatic brain injury and intracranial hypertension, and it can possibly be used safely in trauma emergency situations.

Animal and human studies suggest that hypertonic saline is a potential therapeutic agent to assist with the medical treatment of patients with traumatic brain injury. It may have a place as osmotherapy to decrease brain size, predominantly of uninjured brain and has several potential advantages over mannitol. Hypertonic saline has clinically desirable physiological effects on cerebral blood flow, intracranial pressure and inflammatory responses in models of neurotrauma. Animal studies support its use, but definitive human trials using mortality end-points in brain trauma are lacking. Hypertonic saline may be considered a therapeutic adjunct to the medical management of traumatic brain injury, awaiting definitive evidence to support routine use.

Object: The authors evaluated the initial intracranial pressure (ICP) and cerebral perfusion pressure (CPP) as prognostic factors in severe head injury in children and tried to determine the optimal CPP range., Methods: The authors performed a 9-year retrospective review of all patients with severe traumatic brain injuries (TBIs) who required invasive ICP monitoring and were admitted to the pediatric intensive care unit at their institution between January 1995 and December 2003. These patients had Glasgow Coma Scale scores lower than 8 and/or required ICP monitoring due to worsening neurological status or neuroimaging results suggestive of cerebral hypertension. Clinical summaries and imaging studies were reviewed. Data for 156 pediatric patients who ranged in age from 1 to 18 years were obtained. Half of these patients presented with normal initial ICPs (< 20 mm Hg), and a good outcome was achieved in 80% of these children. An unfavorable outcome was observed in more than 60% of patients with an initial CPP lower than 40 mm Hg. The proportion of patients with an unfavorable outcome decreased to 10% with initial CPPs higher than 60 mm Hg, but patients with initial CPPs higher than 70 mm Hg did not improve., Conclusions: Initial ICP and CPP measurements were useful as prognostic factors in pediatric patients with severe TBIs: patients with initial CPPs between 40 and 70 mm Hg were found to have a better neurological prognosis than those with CPPs either higher or lower than that range.

Osmotherapy, i.e. the intravenous administration of hyperosmolar solutions, is one of the mainstays of therapy for reduction of a pathologically increased intracranial pressure, in addition to analgosedation and raising the upper body of the patient. The administration of mannitol as a osmotherapeutic agent is, however, marred by considerable side-effects. A possible alternative is the use of hypertonic saline solution (NaCl). The advantages and disadvantages of this option are considered as well as points still in question.

Background: Osmotic agents are widely used to lower elevated intracranial pressure (ICP). However, little data are available regarding cerebral oxygenation and metabolism in the traumatized brains studied under clinical conditions. The present prospective, open-labeled clinical study was designed to investigate whether administration of mannitol, with the aim of reducing moderate intracranial hypertension, improves cerebral metabolism and oxygenation in patients after severe traumatic brain injury (TBI)., Methods: Multimodal cerebral monitoring (MCM), consisting of intraparenchymal ICP, tissue oxygenation (ptiO2), and micro dialysis measurements was initiated in six male TBI patients (mean age 45 years; Glasgow Coma Scale score <9). A total of 14 mannitol boli (20%, 0.5g/kg, 20 minutes infusion time) were administered to treat ICP exceeding 20 mm Hg (2.7 kPa). Temporal alterations determined by MCM after mannitol infusions were recorded for 120 minutes. Microdialysates were assayed immediately for extracellular glucose, lactate, pyruvate, and glutamate concentrations., Results: Elevated ICP was successfully treated in all cases. This effect was maximal 40 minutes after start of infusion (25 +/- 6 mm Hg [3.3 +/- 0.8 kPa] to 17 +/- 3 mm Hg [2.3 +/- 0.4 kPa], p < 0.05) and lasted up to 100 minutes. Cerebral ptiO2 remained unaffected (21 +/- 5 mm Hg [2.8 +/- 0.7 kPa] to 23 +/- 6 mm Hg [3.1 +/- 0.8 kPa], n.s.). Microdialysate concentrations of all analytes rose unspecifically by 10% to 40% from baseline, reaching maximum concentrations 40 to 60 minutes after start of the infusion., Conclusions: Mannitol efficiently reduces increased ICP. At an ICP of up to 30 mm Hg [4 kPa] it does not affect cerebral oxygenation. Unspecific increases of extracellular fluid metabolites can be explained by transient osmotic dehydration. Additional mechanisms, such as increased cerebral perfusion and blood volume, might explain an accelerated return to baseline.

The effect of indomethacin in reducing intracranial pressure (ICP) may be dependent on the choice of anesthetic regimen. We studied the effects of indomethacin on ICP and cerebral blood flow (CBF) during isoflurane or propofol anesthesia in a sheep model of intracranial hypertension. A crossover design was applied in which six sheep were anesthetized with isoflurane and propofol in a random order. Anesthetic depth was measured with response and state entropy. Changes in CBF, ICP, mean arterial blood pressure, arterio-venous oxygen difference, and Paco2 were measured at specific times before and after an IV indomethacin bolus (0.2 mg/kg). Response and state entropy values during anesthesia were similar in both groups. Isoflurane and propofol reduced CBF by 11% and 34%, respectively. Indomethacin caused a reduction in ICP within 15 s during both anesthetic regimens, with the decrease in ICP being significantly more pronounced during isoflurane (P = 0.009). In both anesthetic groups, indomethacin caused a simultaneous increase in mean arterial blood pressure and a further 17% versus 14% decrease in CBF from predrug values for isoflurane and propofol, respectively. The reduction in CBF was significantly more pronounced for propofol (P = 0.02). The effect on ICP, however, was most pronounced during isoflurane anesthesia. We suggest that the effect of indomethacin is partly mediated by an autoregulatory response.

Objectives: We investigated the relationship between stable decrease in intracranial pressure (ICP) following mannitol administration and variations in regional oxygenation (PtiO2) in severe traumatic brain injured (STBI) patients., Methods: Fourteen STBI patients (Glasgow Coma Scale score < or = 8) admitted to the neurointensive care unit during a 12-month period were studied. Multiparameter data, including parenchymal tissue oxygen (PtiO2) and carbon dioxide tension, cerebral perfusion pressure, mean arterial pressure; temperature, pH and pressure reactivity index were measured. Point values from 53 mannitol administrations were extracted every five seconds and divided into five consecutive 30-minute epochs. Mean values and trends were identified. Postadministration epoch with maximum decrease in ICP was selected along with the means of the corresponding variables. These data were compared with baseline to derive the delta values. Mean deltaICP was then compared with deltaPtiO2 in each patient using linear correlation., Findings: In patients with ICP0 > 20 mmHg (group A), PtiO2 increased in 69.6% of samples, whereas in group B (ICP0 < 20 mmHg), PtiO2 increased in only 50% of the samples. There was a significant negative correlation between mean deltaICP and deltaPtiO2 in both groups; Group A: r = -0.79 (P = 0.01); Group B: r = -0.92 (P = 0.01)., Conclusions: There is a strong negative correlation between stable decrease in ICP following mannitol administration and improvement in regional oxygenation around the peri-contusional area. The data suggest a potentially favourable interaction between mannitol therapy and cerebral internal milieu in STBI patients.

Objective: The aim of this pilot study was to compare the effects of equimolar doses of hypertonic saline and dextran solution (HSD, Rescueflow) with 20% mannitol solution for reduction of increased intracranial pressure., Design: Prospective, randomized, controlled, crossover trial in the intensive care unit of a large teaching hospital., Setting: Academic hospital and tertiary referral center for neuroscience., Patients: Nine patients with an intracranial pressure of >20 mm Hg were recruited and received two treatments of each, HSD and 20% mannitol, in a randomized order., Intervention: Equimolar, rapid intravenous infusions of either 200 mL of 20% mannitol or 100 mL of 7.5% saline and 6% dextran-70 solution (HSD) over 5 mins., Measurements: Intracranial pressure, blood pressure, serum and urine sodium and osmolality, and urine output., Main Results: Treatments reduced intracranial pressure with both mannitol (median decrease, 7.5 mm Hg, 95% confidence interval, 5.8-11.8) and HSD (median decrease, 13 mm Hg; 95% confidence interval, 11.5-17.3). HSD caused a significantly greater decrease in intracranial pressure than mannitol (p = .044). HSD had a longer duration of effect than mannitol (p = .044)., Conclusion: When given in an equimolar, rapid, intravenous infusion, HSD reduces intracranial pressure more effectively than mannitol.

Authors of recent studies have championed the importance of maintaining cerebral perfusion pressure (CPP) to prevent secondary brain injury following traumatic head injury. Data from these studies have provided little information regarding outcome following severe head injury in patients with an intracranial pressure (ICP) greater than 40 mm Hg, however, in July 1997 the authors instituted a protocol for the management of severe head injury in patients with a Glasgow Coma Scale score lower than 9. The protocol was focused on resuscitation from acidosis, maintenance of a CPP greater than 60 mm Hg through whatever means necessary as well as elevation of the head of the bed, mannitol infusion, and ventriculostomy with cerebrospinal fluid drainage for control of ICP. Since the institution of this protocol, nine patients had a sustained ICP greater than 40 mm Hg for 2 or more hours, and five of these had an ICP greater than 75 mm Hg on insertion of the ICP monitor and later experienced herniation and expired within 24 hours. Because of the severe nature of the injuries demonstrated on computerized tomography scans and their physical examinations, these patients were not aggressively treated under this protocol. The authors vigorously attempted to maintain a CPP greater than 60 mm Hg with intensive fluid resuscitation and the administration of pressor agents in the four remaining patients who had developed an ICP higher than 40 mm Hg after placement of the ICP monitor. Two patients had an episodic ICP greater than 40 mm Hg for more than 36 hours, the third patient had an episodic ICP greater than of 50 mm Hg for more than 36 hours, and the fourth patient had an episodic ICP greater than 50 mm Hg for more than 48 hours. On discharge, all four patients were able to perform normal activities of daily living with minimal assistance and experience ongoing improvement. Data from this preliminary study indicate that intense, aggressive management of CPP can lead to good neurological outcomes despite extremely high ICP. Aggressive CPP therapy should be performed and maintained even though apparently lethal ICP levels may be present. Further study is needed to support these encouraging results.

Hypertonic saline solution (HSS) has been investigated in the treatment of intracranial hypertension (ICH) in a limited number of studies, usually after failure of conventional treatment. HSS, used in concentrations that vary from 3% to 23.4%, seems to be effective in reducing refractory ICH and to be devoid of adverse effects. We treated a patient with refractory ICH with a small-volume infusion of 18% HSS, and performed magnetic resonance imaging (MRI) before and after HSS infusion. MRI showed a marked reduction in cerebral water content 1 h after the infusion. To our knowledge, this is the first MRI study in a patient with brain injury to evaluate the effect of HSS on brain water content. Further studies are necessary to test HSS efficacy and to identify, through MRI or computed tomography (CT) scan imaging, a subgroup of patients with brain injury who would be best treated with HSS.

To ascertain the effects of niravoline (RU 51599, a selective kappa-opioid receptor agonist) on elevated intracranial pressure with mass lesion, the authors experimentally induced intracranial hypertension in cats by progressive inflation of an extradural balloon with physiological saline at the constant rate of 0.5 ml/h for 2.5 h. After 2.5 h, inflation was discontinued, but the balloon remained inflated for an additional 3 h. Immediately after cessation of balloon inflation and while the balloon remained expanded, the control group (n = 8) received ringer's lactate solution only. In the treatment group (n = 8), each cat was treated with an intravenous administration of niravoline at a dose of 1.0 mg/kg immediately after the cessation of balloon inflation and every hour for 3 h in post-inflation period (three injections total). Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), electroencephalogram (EEG), pupil size, blood gasses and pH, plasma osmolality and electrolytes, and brain water content were studied in both groups. Compared with the untreated group, niravoline treatment produced significant decreases in ICP and significant increases in CPP at 1, 2, and 3 h post-inflation in the presence of an extradural mass lesion. Brain water content was significantly reduced both in the compressed and contralateral hemispheres following niravoline treatment. No significant changes were observed in plasma osmolality and systemic arterial blood pressure following niravoline administration. The results from this present study provide further evidence that niravoline is effective in reducing elevated intracranial pressure, brain water content, and maintaining an adequate cerebral perfusion pressure even in the presence of an extradural mass lesion. Niravoline may offer a new therapeutic modality in head-injury patients with an acute intracranial, expanding mass lesion by providing a safer extended time-period until the mass can be surgically evacuated.