H. Alex Choi

Hypothermia for acute brain injury—mechanisms and practical aspects

Hypothermia is widely accepted as the gold-standard method by which the body can protect the brain. Therapeutic cooling—or targeted temperature management (TTM)—is increasingly being used to prevent secondary brain injury in patients admitted to the emergency department and intensive care unit. Rapid cooling to 33 °C for 24 h is considered the standard of care for minimizing neurological injury after cardiac arrest, mild-to-moderate hypothermia (33–35 °C) can be used as an effective component of multimodal therapy for patients with elevated intracranial pressure, and advanced cooling technology can control fever in patients who have experienced trauma, haemorrhagic stroke, or other forms of severe brain injury. However, the practical application of therapeutic hypothermia is not trivial, and the treatment carries risks. Development of clinical management protocols that focus on detection and control of shivering and minimize the risk of other potential complications of TTM will be essential to maximize the benefits of this emerging therapeutic modality. This Review provides an overview of the potential neuroprotective mechanisms of hypothermia, practical considerations for the application of TTM, and disease-specific evidence for the use of this therapy in patients with acute brain injuries.

Prevention of Shivering During Therapeutic Temperature Modulation: The Columbia Anti-Shivering Protocol

BackgroundAs the practice of aggressive temperature control has become more commonplace, new clinical problems are arising, of which shivering is the most common. Treatment for shivering while avoiding the negative consequences of many anti-shivering therapies is often difficult. We have developed a stepwise protocol that emphasizes use of the least sedating regimen to achieve adequate shiver control.MethodsAll patients treated with temperature modulating devices in the neurological intensive care unit were prospectively entered into a database. Baseline demographic information, daily temperature goals, best daily GCS, and type and cumulative dose of anti-shivering agents were recorded.ResultsWe collected 213 patients who underwent 1388 patient days of temperature modulation. Eighty-nine patients underwent hypothermia and 124 patients underwent induced normothermia. In 18% of patients and 33% of the total patient days only none-sedating baseline interventions were needed. The first agent used was most commonly dexmeditomidine at 50% of the time, followed by an opiate and increased doses of propofol. Younger patients, men, and decreased BSA were factors associated with increased number of anti-shivering interventions.ConclusionsA significant proportion of patients undergoing temperature modulation can be effectively treated for shivering without over-sedation and paralysis. Patients at higher risk for needing more interventions are younger men with decreased BSA.

Quantitative Analysis of Hemorrhage Volume for Predicting Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Background and Purpose— Delayed cerebral ischemia (DCI) is an important complication after subarachnoid hemorrhage and appears to be associated with clot burden on CT. Quantification of hemorrhage on digitized images may be a more accurate method for predicting DCI than qualitative scales. Methods— Quantitative analysis of clot burden on CT was performed in 160 subarachnoid hemorrhage patients who were scanned within 24 hours from the symptom onset between June 25, 2005 and July 19, 2009. Cisternal plus intraventricular hemorrhage volumes (CIHV) were classified into quartiles to evaluate their association with DCI. DCI was defined as neurological deterioration or cerebral infarction, or both attributable to vasospasm. Results— DCI occurred in 25% of the patients included (age, 55.4±14.5; male, 36.3%). Compared to the lowest quartile of CIHV (<9.6 mL), the higher quartile (9.6 mL–16.5 mL, 16.5 mL–31.0 mL, and ≥31.0 mL) was associated with a greater risk of DCI (odds ratio, 2.6, 4.1, and 6.1, respectively; P=0.01). Receiver-operating characteristic curve analysis showed that quantitative CIHV performed equivalently to the modified Fisher scale. Patients who had DCI develop in a specific vascular territory had higher amounts of blood volume in the corresponding cisterns. Patients in the highest quartile of CIHV also had a higher risk of death or severe disability at 3 months (71%) compared to other groups (23%, 19%, and 40% for first, second, and third quartiles, respectively). Conclusions— CIHV is a reasonable predictor for DCI and 3-month functional outcome in subarachnoid hemorrhage patients.

Multimodality Monitoring for Cerebral Perfusion Pressure Optimization in Comatose Patients With Intracerebral Hemorrhage

Background and Purpose— Limited data exist to recommend specific cerebral perfusion pressure (CPP) targets in patients with intracerebral hemorrhage. We sought to determine the feasibility of brain multimodality monitoring for optimizing CPP and potentially reducing secondary brain injury after intracerebral hemorrhage. Methods— We retrospectively analyzed brain multimodality monitoring data targeted at perihematomal brain tissue in 18 comatose intracerebral hemorrhage patients (median monitoring, 164 hours). Physiological measures were averaged over 1-hour intervals corresponding to each microdialysis sample. Metabolic crisis was defined as a lactate/pyruvate ratio >40 with a brain glucose concentration <0.7 mmol/L. Brain tissue hypoxia (BTH) was defined as PbtO2 <15 mm Hg. Pressure reactivity index and oxygen reactivity index were calculated. Results— Median age was 59 years, median Glasgow Coma Scale score was 6, and median intracerebral hemorrhage volume was 37.5 mL. The risk of BTH, and to a lesser extent metabolic crisis, increased with lower CPP values. Multivariable analyses showed that CPP <80 mm Hg was associated with a greater risk of BTH (odds ratio, 1.5; 95% confidence interval, 1.1–2.1; P=0.01) compared to CPP >100 mm Hg as a reference range. Six patients died (33%). Survivors had significantly higher CPP and PbtO2 and lower ICP values starting on postbleed day 4, whereas lactate/pyruvate ratio and pressure reactivity index values were persistently lower, indicating preservation of aerobic metabolism and pressure autoregulation. Conclusions— PbtO2 monitoring can be used to identify CPP targets for optimal brain tissue oxygenation. In patients who do not undergo multimodality monitoring, maintaining CPP >80 mm Hg may reduce the risk of BTH.

Seizures and CNS hemorrhage: spontaneous intracerebral and aneurysmal subarachnoid hemorrhage.

Background:Convulsive and nonconvulsive seizures frequently complicate acute brain injury particularly central nervous system hemorrhages and both have been associated with poor outcome. No randomized controlled trials have been conducted to guide decisions on seizure prophylaxis or treatment. The magnitude of additional injury from nonconvulsive seizures remains controversial and some argue that these epileptiform patterns primarily represent surrogate markers of severely injured brain. The deleterious effects of seizures on brain recovering from a recent injury have to be weighed against the deleterious effects of antiepileptic medications when making decisions on prophylaxis and treatment. Review Summary:Currently seizure prophylaxis is not generally recommended for patients with spontaneous intracerebral hemorrhage (ICH) or aneurysmal subarachnoid hemorrhage (aSAH). However, short-term prophylaxis (during the acute critical illness) is commonly instituted for patients in whom seizures would likely lead to additional injury such as herniation or rebleeding. ICH or aSAH patients with seizures at the onset of their hemorrhage, patients with ICH in close proximity to the cortical surface, and aSAH patients with a poor clinical grade (poor neurologic examination and/or thick cisternal blood) are at high risk of seizures, especially nonconvulsive, and are frequently kept on short-term prophylaxis. Convulsive seizures occur in 7% to 17% of patients with spontaneous ICH and in between 6% and 26% of those with aneurysmal aSAH. These should be treated as soon as possible regardless of the underlying causative factors. Nonconvulsive seizures are seen in about 20% of patients with ICH and in 8% to 18% of those with aSAH. It is controversial how aggressively to treat nonconvulsive seizures. Conclusion:Convulsive and nonconvulsive seizures are frequent after central nervous system hemorrhage and treatment is controversial, particularly for nonconvulsive seizures. Randomized controlled trials need to be conducted to better allow evidence-based guidelines for these common neurologic conditions.

Global Cerebral Edema and Brain Metabolism After Subarachnoid Hemorrhage

Background and Purpose— Global cerebral edema is common among patients with poor-grade subarachnoid hemorrhage and is associated with poor outcome. Currently no targeted therapy exists largely due to an incomplete understanding of the underlying mechanisms. Methods— This is a prospective observational study including 39 consecutive patients with poor-grade subarachnoid hemorrhage with multimodal neuromonitoring. Levels of microdialysate lactate–pyruvate ratio, episodes of cerebral metabolic crisis (lactate-pyruvate ratio >40 and brain glucose <0.7 mmol/L), brain tissue oxygen tension, cerebral perfusion pressure, and transcranial Doppler sonography flow velocities were analyzed. Results— Median age was 54 years (range, 45 to 61 years) and 62% were female. Patients with global cerebral edema on admission (n=24 [62%]) had a higher incidence of metabolic crisis in the first 12 hours of monitoring (n=15 [15% versus 2%], P<0.05) and during the total time of neuromonitoring (20% versus 3%, P<0.001) when compared to those without global cerebral edema. There was no difference in brain tissue oxygen tension or cerebral perfusion pressure between the groups; however, in patients with global cerebral edema, a higher cerebral perfusion pressure was associated with lower lactate–pyruvate ratio (P<0.05). Episodes of metabolic crisis were associated with poor outcome (modified Rankin Scale score 5 or 6, P<0.05). Conclusions— In patients with poor-grade subarachnoid hemorrhage, global cerebral edema is associated with early brain metabolic distress.

Paroxysmal Sympathetic Hyperactivity After Acute Brain Injury

Paroxysmal sympathetic hyperactivity is a syndrome associated with brain trauma, stroke, encephalitis, and other forms of brain injury. It is characterized by uncontrolled episodes of unbalanced sympathetic surges causing hyperthermia, diaphoresis, tachycardia, hypertension, tachypnea, and dystonic posturing. Patients who develop paroxysmal sympathetic hyperactivity have worse neurologic outcomes, longer hospital stays, and more complications. Despite the clear negative impact on outcome, consensus regarding diagnostic criteria, risk factors, pathophysiology, and treatment approaches is lacking. Recently, the importance of consensus regarding diagnostic criteria has been emphasized, and new theories of pathophysiology have been proposed. Many treatment options are available, but only a few systemic studies of the efficacy of treatment algorithms exist. Treatments should focus on decreasing the frequency and intensity of episodes with regularly scheduled doses of medications, such as long-acting benzodiazepines, nonselective β-blockers, α2-agonists, morphine, baclofen, and gabapentin, usually in combination. Treatment of acute breakthrough episodes should focus on doses of as-needed morphine and short-acting benzodiazepines. A balance between control of symptoms without oversedation is the goal.

Status Epilepticus–Induced Hyperemia and Brain Tissue Hypoxia After Cardiac Arrest

OBJECTIVE To report changes of cerebral blood flow and metabolism associated with status epilepticus after cardiac arrest. DESIGN Case report. SETTING Neurological intensive care unit in a university hospital. PATIENT An 85-year-old man resuscitated from out-of-hospital cardiac arrest underwent brain multimodality monitoring and treatment with therapeutic hypothermia. MAIN OUTCOME MEASURES Changes of cerebral blood flow and metabolism. RESULTS Repetitive electrographic seizure activity detected at the start of monitoring was associated with dramatic reductions in brain tissue oxygen tension and striking surges in cerebral blood flow and brain temperature. Intravenous lorazepam and levetiracetam administration resulted in immediate cessation of the seizures and these associated derangements. The lactate to pyruvate ratio was initially elevated and trended down after administration of anticonvulsants. CONCLUSION Brain multimodality monitoring is a feasible method for evaluating secondary brain injury associated with seizure activity after cardiac arrest.

Hyperoxia may be related to delayed cerebral ischemia and poor outcome after subarachnoid haemorrhage.

Objective To determine the association between exposure to hyperoxia and the risk of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH). Methods We analysed data from a single centre, prospective, observational cohort database. Patient inclusion criteria were age ≥18 years, aneurysmal SAH, endotracheal intubation with mechanical ventilation, and arterial partial pressure of oxygen (PaO2) measurements. Hyperoxia was defined as the highest quartile of an area under the curve of PaO2, until the development of DCI (PaO2≥173 mm Hg). Poor outcome was defined as modified Rankin Scale 4–6 at 3 months after SAH. Results Of 252 patients, there were no differences in baseline characteristics between the hyperoxia and control group. Ninety-seven (38.5%) patients developed DCI. The hyperoxia group had a higher incidence of DCI (p<0.001) and poor outcome (p=0.087). After adjusting for modified Fisher scale, rebleeding, global cerebral oedema, intracranial pressure crisis, pneumonia and sepsis, hyperoxia was independently associated with DCI (OR, 3.16; 95% CI 1.69 to 5.92; p<0.001). After adjusting for age, Hunt–Hess grade, aneurysm size, Acute Physiology and Chronic Health Evaluation II score, rebleeding, pneumonia and sepsis, hyperoxia was independently associated with poor outcome (OR, 2.30; 95% CI 1.03 to 5.12; p=0.042). Conclusions In SAH patients, exposure to hyperoxia was associated with DCI. Our findings suggest that exposure to excess oxygen after SAH may represent a modifiable factor for morbidity and mortality in this population.

Time Course and Predictors of Neurological Deterioration After Intracerebral Hemorrhage

Background and Purpose— Neurological deterioration (ND) is a devastating complication after intracerebral hemorrhage but little is known about time course and predictors. Methods— We performed a retrospective cohort study of placebo patients in intracerebral hemorrhage trials. We performed computed tomographic scans within 3 hours of symptoms and at 24 and 72 hours; and clinical evaluations at baseline, 1-hour, and days 1, 2, 3, and 15. Timing of ND was predefined as follows: hyperacute (within 1 hour), acute (1–24 hours), subacute (1–3 days), and delayed (3–15 days). Results— We enrolled 376 patients and 176 (47%) had ND within 15 days. In multivariate analyses of ND by category, hyperacute ND was associated with hematoma expansion (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.7–7.6) and baseline intracerebral hemorrhage volume (OR, 1.04 per mL; 95% CI 1.02–1.06); acute ND with hematoma expansion (OR, 7.59; 95% CI, 3.91–14.74), baseline intracerebral hemorrhage volume (OR, 1.02 per mL; 95% CI, 1.01–1.04), admission Glasgow Coma Scale (OR, 0.77 per point; 95% CI, 0.65–0.91), and interventricular hemorrhage (OR, 2.14; 95% CI, 1.05–4.35); subacute ND with 72-hour edema (OR, 1.03 per mL; 95% CI, 1.02–1.05) and fever (OR, 2.49; 95% CI, 1.01–6.14); and delayed ND with age (OR, 1.11 per year; 95% CI, 1.04–1.18), troponin (OR, 4.30 per point; 95% CI, 1.71–10.77), and infections (OR, 3.69; 95% CI, 1.11–12.23). Patients with ND had worse 90-day modified Rankin scores (5 versus 3; P<0.001). Conclusions— ND occurs frequently and predicts poor outcomes. Our results implicate hematoma expansion and interventricular hemorrhage in early ND, and cerebral edema, fever, and medical complications in later ND.