Overview of Hypothermia, Its Role in Neuroprotection, and the Application of Prophylactic Hypothermia in Traumatic Brain Injury.

The current standard of practice is to maintain normothermia in traumatic brain injury (TBI) patients despite the theoretical benefits of hypothermia and numerous animal studies with promising results. While targeted temperature management or induced hypothermia to support neurological function is recommended for a select patient population postcardiac arrest, similar guidelines have not been instituted for TBI. In this review, we will examine the pathophysiology of TBI and discuss the benefits and risks of induced hypothermia in this patient population. In addition, we provide an overview of the largest randomized controlled trials testing-induced hypothermia. Our literature review on hypothermia returned a myriad of studies and trials, many of which have inconclusive results. The aim of this review was to recognize the effects of hypothermia, summarize the latest trials, address the inconsistencies, and discuss future directions for the study of hypothermia in TBI.

Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b.

BACKGROUND: Environmental factors contribute to autism spectrum disorder. Fentanyl, one of the most widely used opioid analgesics in anaesthesia, can induce neurotoxicity, but its role in autism remains unknown. We determined whether fentanyl induced autism-like behaviours in young mice and the underlying mechanisms. METHODS: Young male and female mice received fentanyl at postnatal days 6, 8, and 10, and performed behavioural tests, including three-chamber social preference, elevated plus maze, grooming behaviour, and open-field test, from postnatal days 30-32. Expression of Grin2b, the gene encoding the GluN2B subunit of the N-methyl-d-aspartate receptor, was assessed in the anterior cingulate cortex of male mice using fluorescence in situ hybridisation histochemistry. We used bisulfite target sequencing to determine Grin2b hypermethylation sites after fentanyl treatment. In the specific activation and rescue experiments, we injected the mu opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (DAMGO) or Grin2b overexpression lentivirus into the anterior cingulate cortex of male mice. RESULTS: Fentanyl induced autism-like behaviours in both young male and female mice, and downregulated Grin2b expression (0.49-fold [0.08] vs 1.00-fold [0.09]; P<0.01) and GluN2B protein amounts (0.38-fold [0.07] vs 1.00-fold [0.12]; P<0.01) in the anterior cingulate cortex through hypermethylation of Grin2b. The mu-opioid receptor antagonist naloxone and overexpression of Grin2b in anterior cingulate cortex attenuated the fentanyl-induced effects, whereas DAMGO injection into the anterior cingulate cortex induced autism-like behaviours. CONCLUSIONS: These data suggest that fentanyl induces autism-like behaviours in young mice via an epigenetic mechanism. Further research is required to determine possible clinical relevance to autism risk.

Detection of Brain Hypoxia Based on Noninvasive Optical Monitoring of Cerebral Blood Flow with Diffuse Correlation Spectroscopy.

BACKGROUND: Diffuse correlation spectroscopy (DCS) noninvasively permits continuous, quantitative, bedside measurements of cerebral blood flow (CBF). To test whether optical monitoring (OM) can detect decrements in CBF producing cerebral hypoxia, we applied the OM technique continuously to probe brain-injured patients who also had invasive brain tissue oxygen (PbO2) monitors. METHODS: Comatose patients with a Glasgow Coma Score (GCS) < 8) were enrolled in an IRB-approved protocol after obtaining informed consent from the legally authorized representative. Patients underwent 6-8 h of daily monitoring. Brain PbO2 was measured with a Clark electrode. Absolute CBF was monitored with DCS, calibrated by perfusion measurements based on intravenous indocyanine green bolus administration. Variation of optical CBF and mean arterial pressure (MAP) from baseline was measured during periods of brain hypoxia (defined as a drop in PbO2 below 19 mmHg for more than 6 min from baseline (PbO2 > 21 mmHg). In a secondary analysis, we compared optical CBF and MAP during randomly selected 12-min periods of "normal" (> 21 mmHg) and "low" (< 19 mmHg) PbO2. Receiver operator characteristic (ROC) and logistic regression analysis were employed to assess the utility of optical CBF, MAP, and the two-variable combination, for discrimination of brain hypoxia from normal brain oxygen tension. RESULTS: Seven patients were enrolled and monitored for a total of 17 days. Baseline-normalized MAP and CBF significantly decreased during brain hypoxia events (p < 0.05). Through use of randomly selected, temporally sparse windows of low and high PbO2, we observed that both MAP and optical CBF discriminated between periods of brain hypoxia and normal brain oxygen tension (ROC AUC 0.761, 0.762, respectively). Further, combining these variables using logistic regression analysis markedly improved the ability to distinguish low- and high-PbO2 epochs (AUC 0.876). CONCLUSIONS: The data suggest optical techniques may be able to provide continuous individualized CBF measurement to indicate occurrence of brain hypoxia and guide brain-directed therapy.

Transcranial Optical Monitoring of Cerebral Hemodynamics in Acute Stroke Patients during Mechanical Thrombectomy.

INTRODUCTION: Mechanical thrombectomy is revolutionizing treatment of acute stroke due to large vessel occlusion (LVO). Unfortunately, use of the modified Thrombolysis in Cerebral Infarction score (mTICI) to characterize recanalization of the cerebral vasculature does not address microvascular perfusion of the distal parenchyma, nor provide more than a vascular "snapshot." Thus, little is known about tissue-level hemodynamic consequences of LVO recanalization. Diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) are promising methods for continuous, noninvasive, contrast-free transcranial monitoring of cerebral microvasculature. METHODS: Here, we use a combined DCS/DOS system to monitor frontal lobe hemodynamic changes during endovascular treatment of 2 patients with ischemic stroke due to internal carotid artery (ICA) occlusions. RESULTS AND DISCUSSION: The monitoring instrument identified a recanalization-induced increase in ipsilateral cerebral blood flow (CBF) with little or no concurrent change in contralateral CBF and extracerebral blood flow. The results suggest that diffuse optical monitoring is sensitive to intracerebral hemodynamics in patients with ICA occlusion and can measure microvascular responses to mechanical thrombectomy.

Connecting the dots: an association between opioids and acute hippocampal injury.

Acute hippocampal injury represents a relatively rare cause of amnesia. Interestingly however, between 2012 and 2017, 18 patients were reported at hospitals in Massachusetts with sudden-onset amnesia in the setting of complete diffusion-weighted hyperintensity of both hippocampi on magnetic resonance imaging. Notably, 17 of the 18 patients tested positive for opioids or had a recorded history of opioid use. This observation suggests an association between opioids and acute hippocampal injury. With particular attention to the Massachusetts cluster and data on fentanyl and its congeners, the epidemiological and pathophysiological evidence that supports this hypothesis is presented, as are potential underlying mechanisms.

Toxicity of inhaled agents after prolonged administration.

Inhaled anesthetics have been utilized mostly for general anesthesia in the operating room and oftentimes for sedation and for treatment of refractory status epilepticus and status asthmaticus in the intensive care unit. These contexts in the ICU setting are related to potential for prolonged administration wherein potential organ toxicity is a concern. Over the last decade, several clinical and animal studies of neurotoxicity attributable to inhaled anesthetics have been emerging, particularly in extremes of age. This review overviews potential for and potential mechanisms of neurotoxicity and systemic toxicity of prolonged inhaled anesthesia and clinical scenarios where inhaled anesthesia has been used in order to assess safety of possible prolonged use for sedation. High dose inhaled agents are associated with postoperative cognitive dysfunction (POCD) and other situations. However, thus far no strong indication of problematic neuro or organ toxicity has been demonstrated after prolonged use of low dose volatile anesthesia.

Awake Craniotomy: A New Airway Approach.

Awake craniotomies have been performed regularly at the University of Pennsylvania since 2004. Varying approaches to airway management are described for this procedure, including intubation with an endotracheal tube and use of a laryngeal mask airway, simple facemask, or nasal cannula. In this case series, we describe the successful use (i.e., no need for endotracheal intubation related to inadequate gas exchange) of bilateral nasopharyngeal airways in 90 patients undergoing awake craniotomies. The use of nasopharyngeal airways can ease the transition between the asleep and awake phases of the craniotomy without the need to stimulate the airway. Our purpose was to describe our experience and report adverse events related to this technique.

Acousto-Optic Cerebral Blood Flow Monitoring During Induction of Anesthesia in Humans.

BACKGROUND: Past transcranial Doppler (TCD) studies have documented the effects of the sequence of anesthesia induction followed by intubation on cerebral blood flow (CBF) velocity. The purpose of this study was to determine whether acousto-optic CBF monitoring would detect changes in CBF which are known to occur with propofol and subsequent endotracheal intubation. METHODS: Seventy-two patients scheduled for elective non-intracranial surgery were evaluated. A Cerox 3215F (Ornim Medical) acousto-optic CBF monitor was used. The acousto-optic transducers were applied bifrontally prior to induction. Baseline cerebral flow index (CFI) values were obtained for at least 2 min prior to induction, set to a unitless value of 100. Subsequent relative changes in CFI from baseline were determined at the lowest value over 3 min after propofol injection but before laryngoscopy; and the highest value over 5 min after the start of laryngoscopy. CFI data were evaluated using Friedman's test. RESULTS: The median dose of propofol [interquartile range] given was 200 mg [160-250]. CFI decreased to 84 % of baseline after propofol and increased to 147 % of baseline after endotracheal intubation (both p < 0.001); MAP decreased after intravenous induction of anesthesia from 103 ± 15 to 86 ± 15 mmHg (p < 0.001) and then returned following endotracheal intubation to 104 ± 20 mmHg. CONCLUSIONS: Our data are congruent with previous observations made with TCD under similar experimental conditions. Such observations support the notion that acousto-optic monitoring yields valid real-time measures of changes in CBF in humans. Further validation against other quantitative measures of CBF would be appropriate.

Brief report: a comparison of clinical and research practices in measuring cerebral perfusion pressure: a literature review and practitioner survey.

BACKGROUND: Our objective was to determine whether there is variability in the foundational literature and across centers in how mean arterial blood pressure is measured to calculate cerebral perfusion pressure. METHODS: We reviewed foundational literature and sent an e-mail survey to members of the Neurocritical Care Society. RESULTS: Of 32 articles reporting cerebral perfusion pressure data, the reference point for mean arterial blood pressure was identified in 16: 10 heart and 6 midbrain. The overall survey response rate was 14.3%. Responses from 31 of 34 (91%) United Council for Neurologic Subspecialties fellowship-accredited Neurointensive Care Units indicated the reference point was most often the heart (74%), followed by the midbrain (16%). Conflicting answers were received from 10%. CONCLUSIONS: There is substantive heterogeneity in both research reports and clinical practice in how mean arterial blood pressure is measured to determine cerebral perfusion pressure.

Response of brain oxygen to therapy correlates with long-term outcome after subarachnoid hemorrhage.

BACKGROUND: Brain oxygen (PbtO2) monitoring can help guide care of poor-grade aneurysmal subarachnoid hemorrhage (aSAH) patients. The relationship between PbtO2-directed therapy and long-term outcome is unclear. We hypothesized that responsiveness to PbtO2-directed interventions is associated with outcome. METHODS: Seventy-six aSAH patients who underwent PbtO2 monitoring were included. Long-term outcome [Glasgow Outcome Score-Extended (GOS-E) and modified Rankin Scale (mRS)] was ascertained using the social security death database and structured telephone interviews. Univariate and multivariate regression were used to identify variables that correlated with outcome. RESULTS: Data from 64 patients were analyzed (12 were lost to follow-up). There were 530 episodes of compromised PbtO2 (<20 mmHg) during a total of 7,174 h of monitor time treated with 1,052 interventions. Forty-two patients (66 %) survived to discharge. Median follow-up was 8.5 months (range 0.1-87). At most recent follow-up 35 (55 %) patients were alive, and 28 (44 %) had a favorable outcome (mRS ≤3). In multivariate ordinal regression analysis, only age and response to PbtO2-directed intervention correlated significantly with outcome. Increased age was associated with worse outcome (coeff. 0.8, 95 % CI 0.3-1.3, p = 0.003), and response to PbtO2-directed intervention was associated with improved outcome (coeff. -2.12, 95 % CI -4.0 to -0.26, p = 0.03). Patients with favorable outcomes had a 70 % mean rate of response to PbtO2-directed interventions whereas patients with poor outcomes had a 45 % response rate (p = 0.005). CONCLUSIONS: Response to PbtO2-directed intervention is associated with improved long-term functional outcome in aSAH patients.

Microvascular reperfusion during endovascular therapy: the balance of supply and demand.

BACKGROUND: Endovascular therapy (EVT) has revolutionized the treatment of acute stroke, but large vessel recanalization does not always result in tissue-level reperfusion. Cerebral blood flow (CBF) is not routinely monitored during EVT. We aimed to leverage diffuse correlation spectroscopy (DCS), a novel transcranial optical imaging technique, to assess the relationship between microvascular CBF and post-EVT outcomes. METHODS: Frontal lobe CBF was monitored by DCS in 40 patients undergoing EVT. Baseline CBF deficit was calculated as the percentage of CBF impairment on pre-EVT CT perfusion. Microvascular reperfusion was calculated as the percentage increase in DCS-derived CBF that occurred with recanalization. The adequacy of reperfusion was defined by persistent CBF deficit, calculated as: baseline CBF deficit - microvascular reperfusion. A good functional outcome was defined as 90-day modified Rankin Scale score ≤2. RESULTS: Thirty-six of 40 patients achieved successful recanalization, in whom microvascular reperfusion in itself was not associated with infarct volume or functional outcome. However, patients with good functional outcomes had a smaller persistent CBF deficit (median 1% (IQR -11%-16%)) than patients with poor outcomes (median 28% (IQR 2-50%)) (p=0.02). Smaller persistent CBF deficit was also associated with smaller infarct volume (p=0.004). Multivariate models confirmed that persistent CBF deficit was independently associated with infarct volume and functional outcome. CONCLUSIONS: CBF augmentation alone does not predict post-EVT outcomes, but when microvascular reperfusion closely matches the baseline CBF deficit, patients experience favorable clinical and radiographic outcomes. By recognizing inadequate reperfusion, bedside CBF monitoring may provide opportunities to personalize post-EVT care aimed at CBF optimization.

Obesity is associated with reduced brain tissue oxygen tension after severe brain injury.

BACKGROUND: Obesity has been associated with compromised tissue oxygenation and reduced organ perfusion. The brain is critically dependent on oxygen delivery, and reduced brain tissue oxygen tension (P(bt)O(2)) may result in poor outcome after brain injury. We tested the hypothesis that obesity is associated with compromised P(bt)O(2) after severe brain injury. METHODS: Patients with severe brain injury (GCS score ≤ 8) who underwent continuous P(bt)O(2) monitoring were retrospectively identified from a prospective single-center database. Patients, were classified by body mass index (BMI = weight (kg)/m(2)) and were included if they were obese (BMI ≥ 30) or non-obese (BMI = < 30). RESULTS: Sixty-nine patients (mean age 46.4 ± 17.0 years) were included. Mean daily P(bt)O(2) was 25.8 (9.6) mmHg for the 28 obese and 31.8 (12.3) mmHg for the 41 non-obese patients (P = 0.03). Initial P(bt)O(2) and mean daily maximum P(bt)O(2) measurements also were significantly lower in obese patients than in non-obese patients. Univariate predictors of compromised P(bt)O(2) (defined as minutes P(bt)O(2) < 20 mmHg) included elevated BMI (P = 0.02), presence of ARDS (P < 0.01), mean PaO(2) (P < 0.01), maximum FiO(2) (P < 0.01), mean PaO(2):FiO(2) (P < 0.01), and mean CVP (P < 0.01). In multivariable analysis, BMI was significantly associated with compromised P(bt)O(2) (P = 0.02). Sex, age, and mean CVP were also identified as significant predictors of compromised P(bt)O(2); ARDS and PF ratio were not. CONCLUSIONS: In patients with severe brain injury, obesity was found to be an independent predictor of compromised P(bt)O(2). This effect may be mediated through obesity-related pulmonary dysfunction and inadequate compensatory mechanisms.

Comparison of optical measurements of critical closing pressure acquired before and during induced ventricular arrhythmia in adults.

Significance: The critical closing pressure (CrCP) of cerebral circulation, as measured by diffuse correlation spectroscopy (DCS), is a promising biomarker of intracranial hypertension. However, CrCP techniques using DCS have not been assessed in gold standard experiments. Aim: CrCP is typically calculated by examining the variation of cerebral blood flow (CBF) during the cardiac cycle (with normal sinus rhythm). We compare this typical CrCP measurement with a gold standard obtained during the drops in arterial blood pressure (ABP) caused by rapid ventricular pacing (RVP) in patients undergoing invasive electrophysiologic procedures. Approach: Adults receiving electrophysiology procedures with planned ablation were enrolled for DCS CBF monitoring. CrCP was calculated from CBF and ABP data by three methods: (1) linear extrapolation of data during RVP ( CrCP RVP ; the gold standard); (2) linear extrapolation of data during regular heartbeats ( CrCP Linear ); and (3) fundamental harmonic Fourier filtering of data during regular heartbeats ( CrCP Fourier ). Results: CBF monitoring was performed prior to and during 55 episodes of RVP in five adults. CrCP RVP and CrCP Fourier demonstrated agreement ( R = 0.66 , slope = 1.05 (95%CI, 0.72 to 1.38). Agreement between CrCP RVP and CrCP Linear was worse; CrCP Linear was 8.2 ± 5.9 mmHg higher than CrCP RVP (mean ± SD; p < 0.001 ). Conclusions: Our results suggest that DCS-measured CrCP can be accurately acquired during normal sinus rhythm.

Potential non-hypoxic/ischemic causes of increased cerebral interstitial fluid lactate/pyruvate ratio: a review of available literature.

Microdialysis, an in vivo technique that permits collection and analysis of small molecular weight substances from the interstitial space, was developed more than 30 years ago and introduced into the clinical neurosciences in the 1990s. Today cerebral microdialysis is an established, commercially available clinical tool that is focused primarily on markers of cerebral energy metabolism (glucose, lactate, and pyruvate) and cell damage (glycerol), and neurotransmitters (glutamate). Although the brain comprises only 2% of body weight, it consumes 20% of total body energy. Consequently, the ability to monitor cerebral metabolism can provide significant insights during clinical care. Measurements of lactate, pyruvate, and glucose give information about the comparative contributions of aerobic and anaerobic metabolisms to brain energy. The lactate/pyruvate ratio reflects cytoplasmic redox state and thus provides information about tissue oxygenation. An elevated lactate pyruvate ratio (>40) frequently is interpreted as a sign of cerebral hypoxia or ischemia. However, several other factors may contribute to an elevated LPR. This article reviews potential non-hypoxic/ischemic causes of an increased LPR.

Standardization of Neuroanesthesia Education: Need of the Hour and the Way Forward.

PURPOSE OF REVIEW: This review illustrates the evolution and progress with standardization of fellowship education in neuroanesthesiology. It provides a structured discussion around the need for curricula and framework which individual training programs in neuroanesthesiology can use to meet defined educational standards thus meeting criteria for accreditation. RECENT FINDINGS: Neuroanesthesiology training has traditionally been heterogenous around the world but international efforts from the community of neuroanesthesiology have culminated in the development of an international council for perioperative training in neuroscience in anesthesiology(ICPNT). This serves not only as an accrediting body but also creates a platform through their neuroanesthesia program relations committee for collaboration and engagement between various training programs internationally, increasing the educational standards of the individual programs and collectively increasing the overall level of standards for neuroanesthesia training. Standardized curriculum and competency-based assessments and milestones would help with narrowing the focus to quality education in neuroanesthesiology. SUMMARY: Structured training around the three pillars of neuroanesthesiology with concomitant accreditation is expected to lead to higher education standards with better patient care. The SNACC created milestones for neuroanesthesiology training during residency and the ICPNT can now use this as a foundation for fellowship training. Having a council to accredit and standardize will likely become indispensable in creating a set path for training in neuroanesthesiology. Additionally, the flexibility built in due to the international nature would allow modified and variable pathways depending upon individual capabilities and interests. The path forward will include widespread adoption of standardization supporting the overarching goal of excellent patient outcomes around the world.

Physiological Signatures of Brain Death Uncovered by Intracranial Multimodal Neuromonitoring.

BACKGROUND: The physiological and neurochemical changes that accompany brain death are not well described. MATERIALS AND METHODS: A retrospective observational study of patients with acute brain injury who underwent intracranial multimodality neuromonitoring between October 2015 and June 2018. Patients were included for analysis either if brain death was diagnosed or refractory intracranial hypertension with persistent equalization of intracranial pressure (ICP) and mean arterial pressure (MAP) developed. RESULTS: Of 114 patients who underwent invasive neuromonitoring, 11 cases with MAP/ICP equalization were identified. Of those, 9 were declared brain dead based on accepted national and institutional criteria. An additional 2 cases with MAP/ICP equalization who died after withdrawal of life-sustaining therapies were identified. Of the 11 identified patients, 10 had continuous monitoring data available for analysis. Cerebral microdialysis data were available for 4 patients.In the 10 cases with available continuous data, ICP/MAP equalization was associated with marked reduction of cerebral blood flow and brain tissue oxygen tension to near zero levels as well as a significant decrease in brain temperature compared with body temperature. In the 4 patients with microdialysis monitoring, ICP/MAP equalization resulted in a near complete depletion of cerebral glucose and pyruvate, as well as a marked rise in cerebral glycerol. Finally, ICP/MAP equalization was accompanied by complete loss of cerebrovascular pressure reactivity, decrease in intracranial pulse pressure, and a paradoxical improvement of ICP waveform morphology. CONCLUSIONS: A characteristic set of changes in cerebrovascular physiology and neurochemistry occurs during brain death. These changes can be identified by intracranial neuromonitoring.

Cerebrovascular pressure reactivity and intracranial pressure are associated with neurologic outcome after hypoxic-ischemic brain injury.

AIM: We evaluated the association of physiological parameters measured by intracranial multimodality neuromonitoring with neurologic outcome in a consecutive series of patients with hypoxic-ischemic brain injury (HIBI). METHODS: We retrospectively identified all patients with HIBI who underwent combined invasive intracranial pressure (ICP) and brain tissue oxygen (PbtO2) monitoring over a 3 year period. Cerebrovascular pressure reactivity index (PRx) was calculated continuously as a surrogate of cerebral autoregulation. Favorable outcome was defined as recovery of consciousness (Glasgow Coma Scale motor score = 6). Differences in mean ICP, PRx and PbtO2 for the entire monitoring period across outcomes were measured. Logistic regression and area under receiver operating characteristic (AUROC) curve were used to assess the association of each monitoring parameter with neurologic outcome. RESULTS: We analyzed data from 36 patients. Most (89%) had an antecedent sudden cardiac arrest. Favorable outcome occurred in 8 (22%) patients. ICP and PRx were higher in patients with unfavorable outcome (ICP: 26 ±â€¯4.1 mmHg vs 7.5 ±â€¯2 mmHg, p = 0.0002; PRx: 0.51 ±â€¯0.05 vs 0.11 ±â€¯0.05, p < 0.0001). There was no significant difference in PbtO2 between groups (unfavorable: 20 ±â€¯2.4 mmHg vs favorable: 25 ±â€¯1.5 mmHg, p = 0.12). Both ICP (AUROC 0.84, 95%CI 0.72-0.98, p = 0.003) and PRx (AUROC 0.94, 95%CI 0.85-1, p = 0.0002) discriminated between favorable and unfavorable outcome, in contrast to PbtO2, (AUROC 0.59, 95%CI 0.39-0.78, p = 0.52). ICP > 15 mmHg, PRx > 0.2, and PbtO2 < 18 mmHg had sensitivity/specificity of 68%/100%, 89%/88%, and 40%/100% respectively for discriminating outcomes. CONCLUSION: Cerebrovascular pressure reactivity and intracranial pressure appear to be associated with neurologic outcome in patients with HIBI.

Impaired cerebral blood flow autoregulation during posttraumatic arterial hypotension after fluid percussion brain injury is prevented by phenylephrine in female but exacerbated in male piglets by extracellular signal-related kinase mitogen-activated protein kinase upregulation.

OBJECTIVE: Traumatic brain injury contributes to morbidity and mortality in children and boys are disproportionately represented. Hypotension is common and worsens outcome after traumatic brain injury. Extracellular signal-related kinase mitogen-activated protein kinase is upregulated and reduces cerebral blood flow after fluid percussion brain injury in piglets. We hypothesized that increased cerebral perfusion pressure through phenylephrine sex dependently reduces impairment of cerebral autoregulation during hypotension after fluid percussion brain injury through modulation of extracellular signal-related kinase mitogen-activated protein kinase. DESIGN: Prospective, randomized animal study. SETTING: University laboratory. SUBJECTS: Newborn (1- to 5-day-old) pigs. INTERVENTIONS: Cerebral blood flow, pial artery diameter, intracranial pressure, and autoregulatory index were determined before and after fluid percussion brain injury in untreated, preinjury, and postinjury phenylephrine (1 microg/kg/min intravenously) treated male and female pigs during normotension and hemorrhagic hypotension. Cerebrospinal fluid extracellular signal-related kinase mitogen-activated protein kinase was determined by enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: Reductions in pial artery diameter, cerebral blood flow, cerebral perfusion pressure, and elevated intracranial pressure after fluid percussion brain injury were greater in males, which were blunted by phenylephrine pre- or postfluid percussion brain injury. During hypotension and fluid percussion brain injury, pial artery dilation was impaired more in males. Phenylephrine decreased impairment of hypotensive pial artery dilation after fluid percussion brain injury in females, but paradoxically caused vasoconstriction after fluid percussion brain injury in males. Papaverine-induced pial artery vasodilation was unchanged by fluid percussion brain injury and phenylephrine. Cerebral blood flow, cerebral perfusion pressure, and autoregulatory index decreased markedly during hypotension and fluid percussion brain injury in males but less in females. Phenylephrine prevented reductions in cerebral blood flow, cerebral perfusion pressure, and autoregulatory index during hypotension in females but increased reductions in males. Cerebrospinal fluid extracellular signal-related kinase mitogen-activated protein kinase was increased more in males than females after fluid percussion brain injury. Phenylephrine blunted extracellular signal-related kinase mitogen-activated protein kinase upregulation in females but increased extracellular signal-related kinase mitogen-activated protein kinase upregulation in males after fluid percussion brain injury. CONCLUSIONS: These data indicate that elevation of cerebral perfusion pressure with phenylephrine sex dependently prevents impairment of cerebral autoregulation during hypotension after fluid percussion brain injury through modulation of extracellular signal-related kinase mitogen-activated protein kinase. These data suggest the potential role for sex-dependent mechanisms in cerebral autoregulation after pediatric traumatic brain injury.

Successful management of refractory intracranial hypertension from acute hyperammonemic encephalopathy in a woman with ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is the most common of the urea cycle disorders and results in an accumulation of ammonia and its metabolites. Excess ammonia in the brain is metabolized to glutamine, which increases intracellular osmolarity and contributes to cytotoxic edema. METHODS: We report a case of a woman heterozygous for OTCD who developed acute hyperammonemic encephalopathy and increased intracranial pressure (ICP). RESULTS: Despite hemodialysis, protein restriction, and administration of pharmacologic nitrogen scavengers, she developed progressive cerebral edema and increased ICP that was refractory to maximal medical management. She underwent a bifrontal decompressive craniectomy resulting in resolution of her intracranial hypertension. CONCLUSION: Aggressive multimodality management of the patient coupled with bifrontal decompressive hemicraniectomy was a life-saving measure, offering the patient a reasonable outcome. At 6 month follow-up she had moderate disability on the Glasgow Outcome Score associated with cognitive difficulties.