A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Epoxyeicosatrienoates (EETs) are endogenous regulators of neuroinflammation and cerebral blood flow. Their metabolism to dihydroxyeicosatrienoates (DHETs) is catalyzed by soluble epoxide hydrolase (sEH). After subarachnoid hemorrhage (SAH), EETs' pathway amplification may be a therapeutic target for the prevention of delayed cerebral ischemia (DCI). We conducted a double-blind, placebo-controlled, phase Ib randomized trial of GSK2256294, a pharmacologic inhibitor of sEH, to evaluate the safety profile and to assess biomarkers of neurovascular inflammation in patients with aneurysmal SAH. METHODS: Patients were randomly assigned to receive 10 mg of GSK2256294 or a placebo treatment once daily for 10 days, beginning within 72 hours after aneurysm rupture. The primary study end point was safety. Secondary end points included serum and cerebrospinal fluid (CSF) EETs-to-DHETs ratio, cytokine levels, and serum endothelial injury biomarkers, measured at day 7 and day 10 after SAH. Tertiary end points included neurologic status, disposition, length of stay, incidence of DCI, and mortality; these were assessed at hospital discharge and at 90 days. RESULTS: Ten patients received GSK2256294 and nine patients received a placebo. There were no adverse events related to the study drug. GSK2256294 administration resulted in a significant increase in the EET/DHET ratio at day 7 and day 10 in serum, but not in the CSF. There was a trend for decreased CSF inflammatory cytokines following GSK2256294 administration, but this did not reach statistical significance. CONCLUSIONS: GSK2256294 administration was safe and well tolerated in critically ill patients with SAH, producing an increase in serum EETs and the EET-to-DHET ratio. Our findings support future studies in a larger population to evaluate the role of sEH inhibition in the prevention of DCI after SAH and other forms of brain injury and inflammatory conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03318783.

Implementation of the TaperGuard™ endotracheal tube in an unselected surgical population to reduce postoperative pneumonia.

BACKGROUND: Endotracheal tube (ETT) designs to decrease the risk of ventilator associated pneumonia (VAP) include supraglottic suctioning, and/or modifications of the cuff shape. The TaperGuard™ ETT has a tapered, polyvinylchloride cuff designed to reduce microaspiration around channels that form with a standard barrel-shaped cuff. We compared risk of postoperative pneumonia using the TaperGuard™ ETT and the standard ETT in surgical patients requiring general anesthesia with endotracheal intubation. METHODS: We used an interrupted time-series design to compare endotracheal intubation using the TaperGuard™ ETT (intervention cohort), and a historic cohort using the standard ETT (baseline cohort), among surgical patients requiring hospital admission. We compared the incidence of postoperative pneumonia in the intervention and baseline cohorts. Data were collected from the electronic health record and linked to patient-level data from National Surgical Quality Improvement Project. Additionally, we performed secondary analyses in a subgroup of patients at high risk of postoperative pneumonia. RESULTS: 15,388 subjects were included; 6351 in the intervention cohort and 9037 in the baseline cohort. There was no significant difference in the incidence of postoperative pneumonia between the intervention cohort (1.62%) and the baseline cohort (1.79%). The unadjusted odds ratio (OR) of postoperative pneumonia was 0.90 (95% CI: 0.70, 1.16; p = 0.423) and the OR adjusted for patient characteristics and potential confounders was 0.90 (95% CI: 0.69, 1.19; p = 0.469), comparing the intervention and baseline cohorts. There was no a priori selected subgroup of patients for whom the use of the TaperGuard™ ETT was associated with decreased odds of postoperative pneumonia relative to the standard ETT. Hospital mortality was higher in the intervention cohort (1.5%) compared with the baseline cohort (1.0%; OR 1.46, 95% CI: 1.09, 1.95; p = 0.010). CONCLUSIONS: The broad implementation of the use of the TaperGuard™ ETT for intubation of surgical patients was not associated with a reduction in the risk of postoperative pneumonia. In the setting of a low underlying postoperative pneumonia risk and the use of recommended preventative VAP bundles, further risk reduction may not be achievable by simply modifying the ETT cuff design in unselected or high-risk populations undergoing inpatient surgery. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT02450929 .

Clinical evaluation and airway management for adults with cervical spine instability.

Airway management of patients with cervical spine instability may be difficult as a result of immobilization, and may be associated with secondary neurologic injury related to cervical spine motion. Spinal cord instability is most common in patients with trauma, but there are additional congenital and acquired conditions that predispose to subacute cervical spine instability. Patients with suspected instability should receive immobilization during airway management with manual in-line stabilization. The best strategy for airway management is one that applies the technique with the highest likelihood of success on the first attempt and the lowest biomechanical influence on a potentially unstable spine.

Protective role of p450 epoxyeicosanoids in subarachnoid hemorrhage.

BACKGROUND: Patients recovering from aneurysmal subarachnoid hemorrhage (SAH) are at risk for developing delayed cerebral ischemia (DCI). Experimental and human studies implicate the vasoconstrictor P450 eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) in the pathogenesis of DCI. To date, no studies have evaluated the role of vasodilator epoxyeicosatrienoic acids (EETs) in DCI. METHODS: Using mass spectrometry, we measured P450 eicosanoids in cerebrospinal fluid (CSF) from 34 SAH patients from 1 to 14 days after admission. CSF eicosanoid levels were compared in patients who experienced DCI versus those who did not. We then studied the effect of EETs in a model of SAH using mice lacking the enzyme soluble epoxide hydrolase (sEH), which catabolizes EETs into their inactive diol. To assess changes in vessel morphology and cortical perfusion in the mouse brain, we used optical microangiography, a non-invasive coherence-based imaging technique. RESULTS: Along with increases in 20-HETE, we found that CSF levels of 14,15-EET were elevated in SAH patients compared to control CSF, and levels were significantly higher in patients who experienced DCI compared to those who did not. Mice lacking sEH had elevated 14,15-EET and were protected from the delayed decrease in microvascular cortical perfusion after SAH, compared to wild type mice. CONCLUSIONS: Our findings suggest that P450 eicosanoids play an important role in the pathogenesis of DCI. While 20-HETE may contribute to the development of DCI, 14,15-EET may afford protection against DCI. Strategies to enhance 14,15-EET, including sEH inhibition, should be considered as part of a comprehensive approach to prevent DCI.

Genetic variation in soluble epoxide hydrolase: association with outcome after aneurysmal subarachnoid hemorrhage.

OBJECT: Patients with aneurysmal subarachnoid hemorrhage (SAH) are at high risk for delayed cerebral ischemia (DCI) and stroke. Epoxyeicosatrienoic acids (EETs) play an important role in cerebral blood flow regulation and neuroprotection after brain injury. Polymorphisms in the gene for the enzyme soluble epoxide hydrolase (sEH), which inactivates EETs, are associated with ischemic stroke risk and neuronal survival after ischemia. This prospective observational study of patients with SAH compares vital and neurologic outcomes based on functional polymorphisms of sEH. METHODS: Allelic discrimination based on quantitative real-time polymerase chain reaction was used to differentiate wild-type sEH from K55R heterozygotes (predictive of increased sEH activity and reduced EETs) and R287Q heterozygotes (predictive of decreased sEH activity and increased EETs). The primary outcome was new stroke after SAH. Secondary outcomes were death, Glasgow Outcome Scale score, and neurological deterioration attributable to DCI. RESULTS: Multivariable logistic regression models adjusted for age at admission and Glasgow Coma Scale scores revealed an increase in the odds of new stroke (OR 5.48 [95% CI 1.51-19.91]) and death (OR 7.52 [95% CI 1.27-44.46]) in the K55R group, but no change in the odds of new stroke (OR 0.56 [95% CI 0.16-1.96]) or death (OR 3.09 [95% CI 0.51-18.52]) in patients with R287Q genotype, compared with wild-type sEH. The R287Q genotype was associated with reduced odds of having a Glasgow Outcome Scale score of ≤ 3 (OR 0.23 [95% CI 0.06-0.82]). There were no significant differences in the odds of neurological deterioration due to DCI. CONCLUSIONS: Genetic polymorphisms of sEH are associated with neurological and vital outcomes after aneurysmal SAH.

Targeting brain tissue oxygenation in traumatic brain injury.

The management of patients with traumatic brain injury has evolved in the last several years, due to the introduction of new, invasive monitoring devices. The ability to monitor parameters other than measurements related to pressures has generated substantial interest. Brain tissue oxygenation monitoring has been consistently shown to provide prognostic information, as indicated by poor prognosis associated with low brain tissue oxygen values. Furthermore, various physiologic manipulations, including increasing the P(aO(2)), have been associated with an increase in brain tissue oxygenation. Whether brain-oxygenation-guided therapy results in improvement in outcomes is debatable. Retrospective studies suggest benefit, while prospective studies have shown a higher intensity of therapeutic interventions with no outcome differences. Data from high quality randomized trials are necessary to determine if brain-oxygenation-guided therapy is beneficial. An oxygen challenge (transient increase in F(IO(2)) to 0.6 up to 1.0) to assess the responsiveness of the monitoring and ascertain the presence of technical malfunction is an accepted practice.

The association between fluid balance and outcomes after subarachnoid hemorrhage.

BACKGROUND: We sought to determine the association between early fluid balance and neurological/vital outcome of patients with subarachnoid hemorrhage. METHODS: Hospital admission, imaging, ICU and outcome data were retrospectively collected from the medical records of adult patients with aneurysmal SAH admitted to a level-1 trauma and stroke referral center during a 5-year period. Two groups were identified based on cumulative fluid balance by ICU day 3: (i) patients with a positive fluid balance (n = 221) and (ii) patients with even or negative fluid balance (n = 135). Multivariable logistic regression was used to adjust for age, Hunt-Hess and Fisher scores, mechanical ventilation and troponin elevation (>0.40 ng/ml) at ICU admission. The primary outcome was a composite of hospital mortality or new stroke. RESULTS: Patients with positive fluid balance had worse admission GCS and Hunt-Hess score, and by ICU day 3 had cumulatively received more IV fluids, but had less urine output when compared with the negative fluid balance group. There was no difference in the odds of hospital death or new stroke (adjusted OR: 1.47, 95%CI: 0.85, 2.54) between patients with positive and negative fluid balance. However, positive fluid balance was associated with increased odds of TCD vasospasm (adjusted OR 2.25, 95%CI: 1.37, 3.71) and prolonged hospital length of stay. CONCLUSIONS: Although handling of IV fluid administration was not an independent predictor of mortality or new stroke, patients with early positive fluid balance had worse clinical presentation and had greater resource use during the hospital course.

Management guided by brain tissue oxygen monitoring and outcome following severe traumatic brain injury.

OBJECT: The authors sought to describe changes in clinical management associated with brain tissue oxygen (PbO(2)) monitoring and how these changes affected outcomes and resource utilization. METHODS: The cohort study comprised 629 patients admitted to a Level I trauma center with a diagnosis of severe traumatic brain injury over a period of 3 years. Hospital mortality rate, neurological outcome, and resource utilization of 123 patients who underwent both PbO(2) and intracranial pressure (ICP) monitoring were compared with the same measures in 506 patients who underwent ICP monitoring only. The main outcomes were hospital mortality rate, functional independence at hospital discharge, duration of mechanical ventilation, hospital length of stay, and hospital cost. Multivariable regression with robust variance was used to estimate the adjusted differences in the main outcome measures between patient groups. The models were adjusted for patient age, severity of injury, and pathological features seen on head CT scan at admission. RESULTS: On average, patients who underwent ICP/PbO(2) monitoring were younger and had more severe injuries than patients who received ICP monitoring alone. Relatively more patients treated with PbO(2) monitoring received osmotic therapy, vasopressors, and prolonged sedation. After adjustment for baseline characteristics, the hospital mortality rate was, if anything, slightly higher in patients undergoing PbO(2)-guided management than in patients monitored with ICP only (adjusted mortality difference 4.4%, 95% CI -3.9 to 13%). Patients who underwent PbO(2)-guided management also had lower adjusted functional independence scores at hospital discharge (adjusted score difference -0.75, 95% CI -1.41 to -0.09). There was a 27% relative increase (95% CI 6-53%) in the median hospital length of stay when the PbO(2) group was compared with the ICP-only group. CONCLUSIONS: The mortality rate in patients with traumatic brain injury whose clinical management was guided by PbO(2) monitoring was not reduced in comparison with that in patients who received ICP monitoring alone. Brain tissue oxygen monitoring was associated with worse neurological outcome and increased hospital resource utilization.

Cue-elicited reward-seeking requires extracellular signal-regulated kinase activation in the nucleus accumbens.

The motivation to seek out rewards can come under the control of stimuli associated with reward delivery. The ability of cues to motivate reward-seeking behavior depends on the nucleus accumbens (NAcc). The molecular mechanisms in the NAcc that underlie the ability of a cue to motivate reward-seeking are not well understood. We examined whether extracellular signal-regulated kinase (ERK), an important intracellular signaling pathway in learning and memory, has a role in these motivational processes. We first examined p42 ERK (ERK2) activation in the NAcc after rats were trained to associate an auditory stimulus with food delivery and found that, as a consequence of training, presentation of the auditory cue itself was sufficient to increase ERK2 activation in the NAcc. To examine whether inhibition of ERK in the NAcc prevents cue-induced reward-seeking, we infused an inhibitor of ERK, U0126, into the NAcc before assessing rats' instrumental responding in the presence versus absence of the conditioned cue. We found that, whereas vehicle-infused rats showed increased instrumental responding during cue presentation, rats infused with U0126 showed a profound impairment in cue-induced instrumental responding. In contrast, intra-NAcc U0126 infusion had no effect on rats' food-reinforced instrumental responding or their ability to execute conditioned approach behavior. Our results demonstrate learning-related changes in ERK signaling in the NAcc, and that disruption of ERK activation in this structure interferes with the incentive-motivational effects of conditioned stimuli. The molecular mechanisms described here may have implications for cue-elicited drug craving after repeated exposure to drugs of abuse.