Raphael A. Carandang

Rapid Unexpected Brain Herniation in Association with Renal Replacement Therapy in Acute Brain Injury: Caution in the Neurocritical Care Unit

IntroductionWe aim to raise awareness for the potential for rapid brain edema and herniation in acutely brain-injured patients undergoing renal replacement therapy (RRT), including one case undergoing continuous veno-venous hemofiltration. Dialysis disequilibrium syndrome (DDS) may have been a possible cause for the brain edema.MethodsWe retrospectively reviewed four consecutive neurocritically ill patients in acute renal failure undergoing RRT between 2011 and 2013. Imaging, blood pressure, and laboratory data pre-, during, and post-RRT are presented in graphical form. We performed an extensive literature review.ResultsAll patients suffered rapidly progressive herniation and death from global brain edema closely related in time to RRT, without other identifiable causes even after detailed review by three neurointensivists. Common clinical symptoms included sudden onset fixed and dilated pupils with apnea, consistent with brain stem compression. Herniation was not reversed by high-dose osmotherapy, and all patients died. Our detailed literature review provides plausible mechanisms for DDS as the most likely cause for our patients’ brain edema.ConclusionsEven today, sudden brain edema and herniation may occur in association with RRT in neurocritically ill patients. We call for the establishment of RRT guidelines in patients with acute neurological injuries.

Cortical Vein Thrombosis as a Mimic for Isolated Cortical Subarachnoid Hemorrhage and Transient Ischemic Attack

Isolated cortical subarachnoid hemorrhage is rare and poorly understood. Differential diagnoses and proposed pathophysiology vary widely and the diagnostic work-up for these patients who present with transient ischemic attack-like episodes and characteristic imaging findings is still unclear. We report a case of isolated subarachnoid hemorrhage and transient neurologic deficits due to isolated cortical vein thrombosis that was not detected by noninvasive tests. A 75-year-old woman with a history of a lobar intracerebral hemorrhage presented to the Academic Medical Center with sudden-onset transient left upper extremity weakness. Head CT showed a linear hyperdensity in the right precentral gyrus suggestive of isolated subarachnoid hemorrhage. MRI showed susceptibility in the corresponding area. CT angiogram and MRV showed no evidence of a venous thrombosis. The main outcome measures were results of computerized tomography and CT angiogram, magnetic resonance parenchymal and vascular imaging, angiography findings and clinical follow-up at 3 months. Cortical vein thrombosis was detected on conventional angiography. MRI was negative for microhemorrhages. The patient was anticoagulated and had no recurrences of her symptoms. We conclude that cortical vein thrombosis can present as isolated subarachnoid hemorrhage and transient ischemic attack-like episodes and may require angiography for definitive diagnosis.

Nicotine Replacement Therapy After Subarachnoid Hemorrhage Is Not Associated With Increased Vasospasm

Background and Purpose— A significant number of patients with aneurysmal subarachnoid hemorrhage are active smokers and at risk for acute nicotine withdrawal. There is conflicting literature regarding the vascular effects of nicotine and theoretical concern that it may worsen vasospasm. The literature on the safety of nicotine replacement therapy and its effects on vasospasm is limited. Methods— A retrospective analysis was conducted of a prospectively collected database of aneurysmal subarachnoid hemorrhage patients admitted to the neurointensive care unit from 1994 to 2008. Paired control subjects matched for age, sex, Fisher score, aneurysm size and number, hypertension, and current medication were analyzed. The primary outcome was clinical and angiographic vasospasm and the secondary outcome was Glasgow Outcome Score on discharge. Conditional logistic models were used to investigate univariate and multivariate relationships between predictors and outcome. Results— Two hundred fifty-eight active smoking patients were included of which 87 were treated with transdermal nicotine replacement therapy. Patients were well matched for age, sex, gender, Fisher score, aneurysm size and number, hypertension, and current medications, but patients who received nicotine replacement therapy had less severe Hunt-Hess scores and Glasgow coma scores. There was no difference in angiographic vasospasm, but patients who received nicotine replacement therapy were less likely to have clinical vasospasm (19.5 versus 32.8%; P=0.026) and a Glasgow Outcome Score <4 on discharge (62.6% versus 81.6%; P=0.005) on multivariate analysis. Conclusions— Nicotine replacement therapy was not associated with increased angiographic vasospasm and was associated with less clinical vasospasm and better Glasgow Outcome Score scores on discharge.

Nitric Oxide and Mitochondrial Function in Neurological Diseases

Mitochondria are key cellular organelles that play crucial roles in the energy production and regulation of cellular metabolism. Accumulating evidence suggests that mitochondrial activity can be modulated by nitric oxide (NO). As a key neurotransmitter in biologic systems, NO mediates the majority of its function through activation of the cyclic guanylyl cyclase (cGC) signaling pathway and S-nitrosylation of a variety of proteins involved in cellular functioning including those involved in mitochondrial biology. Moreover, excess NO or the formation of reactive NO species (RNS), e.g., peroxynitrite (ONOO-), impairs mitochondrial functioning and this, in conjunction with nuclear events, eventually affects neuronal cell metabolism and survival, contributing to the pathogenesis of several neurodegenerative diseases. In this review we highlight the possible mechanisms underlying the noxious effects of excess NO and RNS on mitochondrial function including (i) negative effects on electron transport chain (ETC); (ii) ONOO--mediated alteration in mitochondrial permeability transition; (iii) enhanced mitochondrial fragmentation and autophagy through S-nitrosylation of key proteins involved in this process such as dynamin-related protein 1 (DRP-1) and Parkin/PINK1 (protein phosphatase and tensin homolog-induced kinase 1) complex; (iv) alterations in the mitochondrial metabolic pathways including Krebs cycle, glycolysis, fatty acid metabolism, and urea cycle; and finally (v) mitochondrial ONOO--induced nuclear toxicity and subsequent release of apoptosis-inducing factor (AIF) from mitochondria, causing neuronal cell death. These proposed mechanisms highlight the multidimensional nature of NO and its signaling in the mitochondrial function. Understanding the mechanisms by which NO mediates mitochondrial (dys)function can provide new insights into the treatment of neurodegenerative diseases.

The Modified Apnea Test During Brain Death Determination An Alternative in Patients With Hypoxia

Introduction: Conventional apnea testing in patients with severe hypoxemia or hemodynamic instability with removal from the ventilator support is unsafe. We describe an alternative approach to apnea testing, which may be used in patients with hypoxia unable to undergo conventional apnea testing. Methods: Case Report. A 42-year-old man had a severe traumatic brain injury resulting in diffuse cerebral edema and subarachnoid hemorrhage with herniation. His presentation was complicated by hypoxic respiratory failure from pulmonary contusions and hemorrhagic shock. On hospital day 2, the patient lost brain stem reflexes. Brain death testing with conventional apnea testing was attempted but aborted due to hypoxia. Results: A modified apnea test was applied, which had been approved by appropriate hospital committees including critical care operations, ethics, and the brain death protocol council. Minute ventilation was gradually decreased by ≥50% to attain a PaCo2 level ≥20 mm Hg above baseline. The ventilation mode was then switched from volume control to continuous positive airway pressure while observing the patient for signs of respiration for a duration of 60 seconds. Conclusion: The modified apnea test does not require circuit disconnection and can be successfully applied to determine brain death without compromising safety in high-risk patients having severe hypoxia.

Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial

Background Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in human aneurysmal subarachnoid haemorrhage (aSAH). We evaluated safety, feasibility and tolerability of intravenous dantrolene (IV-D) in patients with aSAH. Methods In this single-centre, randomised, double blind, placebo-controlled trial, 31 patients with aSAH were randomised to IV-D 1.25 mg every 6 h for 7 days (n=16) or equiosmolar free water/5% mannitol (placebo; n=15). Primary safety end points were incidence of hyponatraemia (sNa≤132 mmol/L) and liver toxicity (proportion of patients alanine transaminase, aspartate aminotransferase and AlkPhos >5× upper-limit-of-normal). Secondary end points included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored for clinical/radiological cVSP, delayed cerebral ischaemia (DCI), and 3-month functional outcomes. Quantitative analyses of angiograms and daily transcranial Doppler (TCD) were performed. Results Between IV-D versus placebo, no differences were observed in the primary outcomes (hyponatremia 44% vs 67% (p=0.29); liver toxicity 6% vs 0% (p=1.0)). Three patients in the IV-D versus two in the placebo group had severe adverse events possibly attributable to infusion and reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain oedema requiring osmotherapy. The majority of adverse events were not related to infusion (17 vs 5 (RR 2.2; 95% CI 0.7 to 6.7; p=0.16) in IV-D vs placebo). No differences in any categorical cVSP outcomes, DCI, 3-month outcomes or quantitative angiogram and TCD analyses were seen in this small safety trial not powered to detect efficacy. Conclusions In this small trial, IV-D after aSAH was feasible, tolerable and safe. Trial registration number http://clinicaltrials.gov NCT01024972.

The Modified Apnea Test During Brain Death Determination

Introduction: Conventional apnea testing in patients with severe hypoxemia or hemodynamic instability with removal from the ventilator support is unsafe. We describe an alternative approach to apnea testing, which may be used in patients with hypoxia unable to undergo conventional apnea testing. Methods: Case Report. A 42-year-old man had a severe traumatic brain injury resulting in diffuse cerebral edema and subarachnoid hemorrhage with herniation. His presentation was complicated by hypoxic respiratory failure from pulmonary contusions and hemorrhagic shock. On hospital day 2, the patient lost brain stem reflexes. Brain death testing with conventional apnea testing was attempted but aborted due to hypoxia. Results: A modified apnea test was applied, which had been approved by appropriate hospital committees including critical care operations, ethics, and the brain death protocol council. Minute ventilation was gradually decreased by ≥50% to attain a PaCo2 level ≥20 mm Hg above baseline. The ventilation mode was then switched from volume control to continuous positive airway pressure while observing the patient for signs of respiration for a duration of 60 seconds. Conclusion: The modified apnea test does not require circuit disconnection and can be successfully applied to determine brain death without compromising safety in high-risk patients having severe hypoxia.

“don’t lose hope early”: Hemorrhagic diffuse axonal injury on head Ct is not associated with poor outcome in moderate-severe Tbi patients

BACKGROUND Diffuse axonal injury (DAI) on magnetic resonance imaging has been associated with poor functional outcome after moderate-severe traumatic brain injury (msTBI). Yet, DAI assessment with highly sensitive magnetic resonance imaging techniques is unfeasible in the acute trauma setting, and computed tomography (CT) remains the key diagnostic modality despite its lower sensitivity. We sought to determine whether CT-defined hemorrhagic DAI (hDAI) is associated with discharge and favorable 3- and 12-month functional outcome (Glasgow Coma Scale score ≥4) after msTBI. METHODS We analyzed 361 msTBI patients from the single-center longitudinal Outcome Prognostication in Traumatic Brain Injury study collected over 6 years (November 2009 to November 2015) with prospective outcome assessments at 3 months and 12 months. Patients with microhemorrhages on CT were designated “CT-hDAI-positive” and those without as “CT-hDAI-negative.” For secondary analyses “CT-hDAI-positive” was stratified into two phenotypes according to presence (“associated”) versus absence (“predominant”) of concomitant large acute traumatic lesions to determine whether presence versus absence of additional focal mass lesions portends a different prognosis. RESULTS Seventy (19%) patients were CT-hDAI–positive (n = 36 predominant; n = 34 associated hDAI). In univariate analyses, CT-hDAI–positive status was associated with discharge survival (p = 0.004) and favorable outcome at 3 months (p = 0.003) and 12 months (p = 0.005). After multivariable adjustment, CT-hDAI positivity was no longer associated with discharge survival and functional outcome (all ps > 0.05). Stratified by hDAI phenotype, predominant hDAI patients had worse trauma severity, longer intensive care unit stays, and more systemic medical complications. Predominant hDAI, but not associated hDAI, was an independent predictor of discharge survival (adjusted odds ratio, 24.7; 95% confidence interval [CI], 3.2–192.6; p = 0.002) and favorable 12-month outcome (adjusted odds ratio, 4.7; 95% CI, 1.5–15.2; p = 0.01). Sensitivity analyses using Cox regression confirmed this finding for 1-year survival (adjusted hazard ratio, 5.6; 95% CI, 1.3–23; p = 0.048). CONCLUSION The CT-defined hDAI was not an independent predictor of unfavorable short- and long-term outcomes and should not be used for acute prognostication in msTBI patients. Predominant hDAI patients had good clinical outcomes when supported to intensive care unit discharge and beyond. LEVEL OF EVIDENCE Prognostic study, level III.

The Role of Invasive Monitoring in Traumatic Brain Injury

Severe traumatic brain injury is a complex disease that involves physical injury and distortion of tissues and cell membranes, gross hemodynamic changes including loss of autoregulation, cerebral edema and tissue shifts, changes in pressure and perfusion and multiple secondary cellular processes including electrolyte fluxes, inflammatory mediator release, neurotransmitter mediated excitotoxicity, apoptosis, mitochondrial dysfunction, and alterations in cellular metabolism. The optimal treatment of these patients who have severe neurological dysfunction or require sedation that compromises neurological functional assessment by physical examination requires the monitoring and management of multiple aspects of brain physiology including pressure, perfusion, oxygenation, cellular metabolism, and electrical activity. Invasive monitoring techniques, while still in various stages of development, can and will provide real-time trackable data that informs the management of these patients as well as contributes to our understanding of the pathophysiological processes that contribute to it.