Matthew A. Koenig

Reversal of transtentorial herniation with hypertonic saline

Objective: To evaluate the role of 23.4% saline in the management of transtentorial herniation (TTH) in patients with supratentorial lesions. Methods: Consecutive patients with clinically defined TTH treated with 23.4% saline (30 to 60 mL) were included in a retrospective cohort. Factors associated with successful reversal of TTH were determined. Results: Seventy-six TTH events occurred in 68 patients admitted with intracerebral hemorrhage (n = 29), subarachnoid hemorrhage (n = 16), stroke (n = 8), brain tumor (n = 8), subdural hematoma (n = 5), epidural hematoma (n = 1), and meningitis (n = 1). In addition to 23.4% saline, TTH management included hyperventilation (70% of events), mannitol (57%), propofol (62%), pentobarbital (15%), ventriculostomy drainage (27%), and decompressive hemicraniectomy (18%). Reversal of TTH occurred in 57/76 events (75%). Intracranial pressure decreased from 23 ± 16 mm Hg at the time of TTH to 14 ± 10 mm Hg at 1 hour (p = 0.002), and 11 ± 12 mm Hg at 24 hours (p = 0.001) among 22 patients with intracranial pressure monitors. Reversal of TTH was predicted by a ≥5 mmol/L rise in serum sodium concentration (p = 0.001) or an absolute serum sodium of ≥145 mmol/L (p = 0.007) 1 hour after 23.4% saline. Adverse effects included transient hypotension in 13 events (17%); no evidence of central pontine myelinolysis was detected on post-herniation MRI (n = 18). Twenty-two patients (32%) survived to discharge, with severe disability in 17 and mild to moderate disability in 5. Conclusion: Treatment with 23.4% saline was associated with rapid reversal of transtentorial herniation (TTH) and reduced intracranial pressure, and had few adverse effects. Outcomes of TTH were poor, but medical reversal may extend the window for adjunctive treatments.

Management of Brain Injury After Resuscitation From Cardiac Arrest

The devastating neurologic injury in survivors of cardiac arrest has been recognized since the development of modern resuscitation techniques. After numerous failed clinical trials, two trials showed that induced mild hypothermia can ameliorate brain injury and improve survival and functional neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. This article provides a comprehensive review of the advances in the care of brain injury after cardiac arrest, with updates on the process of prognostication, the use of therapeutic hypothermia and adjunctive intensive care unit care for cardiac arrest survivors.

Quantitative EEG and neurological recovery with therapeutic hypothermia after asphyxial cardiac arrest in rats.

We test the hypothesis that quantitative electroencephalogram (qEEG) can be used to objectively assess functional electrophysiological recovery of brain after hypothermia in an asphyxial cardiac arrest rodent model. Twenty-eight rats were randomly subjected to 7-min (n = 14) and 9-min (n = 14) asphyxia times. One half of each group (n = 7) was randomly subjected to hypothermia (T = 33 degrees C for 12 h) and the other half (n = 7) to normothermia (T = 37 degrees C). Continuous physiologic monitoring of blood pressure, EEG, and core body temperature monitoring and intermittent arterial blood gas (ABG) analysis was undertaken. Neurological recovery after resuscitation was monitored using serial Neurological Deficit Score (NDS) calculation and qEEG analysis. Information Quantity (IQ), a previously validated measure of relative EEG entropy, was employed to monitor electrical recovery. The experiment demonstrated greater recovery of IQ in rats treated with hypothermia compared to normothermic controls in both injury groups (P < 0.05). The 72-h NDS of the hypothermia group was also significantly improved compared to the normothermia group (P < 0.05). IQ values measured at 4 h had a strong correlation with the primary neurological outcome measure, 72-h NDS score (Pearson correlation 0.746, 2-tailed significance <0.001). IQ is sensitive to the acceleration of neurological recovery as measured NDS after asphyxial cardiac arrest known to occur with induced hypothermia. These results demonstrate the potential utility of qEEG-IQ to track the response to neuroprotective hypothermia during the early phase of recovery from cardiac arrest.

Safety of Induced Hypertension Therapy in Patients With Acute Ischemic Stroke

IntroductionThe management of blood pressure in acute stroke is controversial. Small pilot studies have suggested that blood pressure augmentation improves short-term neurological function, but the rate of adverse events with induced hypertension (IH) therapy is unknown.Methods and ResultsWe reviewed 100 consecutive patients who underwent perfusion magnetic resonance imaging for acute ischemic stroke. IH therapy was employed in 46 patients and standard therapy (ST) in 54. The two groups had similar baseline characteristics, but more patients in the IH group had significant large-artery stenoses. The IH group achieved significantly higher mean arterial pressure (MAP) than the ST group within 3 days of initiation of therapy with a variety of vasopressor agents. Only 35% of patients in the IH group actually achieved the target MAP augmentation of 10–20% above baseline, however. All patients survived to discharge. Four patients experienced major adverse events in each group. Two patients in the IH group experienced intracerebral hemorrhage compared to none in the ST group. Two patients in the ST group experienced myocardial ischemia, compared to none in the IH group. The National Institutes of Health Stroke Scale during the hospitalization and place of discharge were similar in both groups. Patients in the IH group were more likely to be admitted to the intensive care unit and had a longer hospital stay by nearly 4 days compared to the ST group.ConclusionThese data demonstrate the relative safety of IH therapy in acute stroke patients. Given the greater use of resources, however, the role of IH in improving clinical outcomes requires a prospective, randomized trial.

Early electrophysiologic markers predict functional outcome associated with temperature manipulation after cardiac arrest in rats.

Objective:Therapeutic hypothermia after cardiac arrest improves survival and functional outcomes, whereas hyperthermia is harmful. The optimal method of tracking the effect of temperature on neurologic recovery after cardiac arrest has not been elucidated. We studied the recovery of cortical electrical function by quantitative electroencephalography after 7-min asphyxial cardiac arrest, using information quantity (IQ). Design:Laboratory investigation. Setting:University medical school and animal research facility. Subjects:A total of 28 male Wistar rats. Interventions:Using an asphyxial cardiac arrest rodent model, we tracked quantitative electroencephalography of 6-hr immediate postresuscitation hypothermia (at 33°C), normothermia (37°C), or hyperthermia (39°C) (n = 8 per group). Neurologic recovery was evaluated using the Neurologic Deficit Score. Four rats were included as a sham control group. Measurements and Main Results:Greater recovery of IQ was found in rats treated with hypothermia (IQ = 0.74), compared with normothermia (IQ = 0.60) and hyperthermia (IQ = 0.56) (p < .001). Analysis at different intervals demonstrated a significant separation of IQ scores among the temperature groups within the first 2 hrs postresuscitation (p < .01). IQ values of >0.523 at 60 mins postresuscitation predicted good neurologic outcome (72-hr Neurologic Deficit Score of ≥60), with a specificity of 100% and sensitivity of 81.8%. IQ was also significantly lower in rats that died prematurely compared with survivors (p < .001). IQ values correlated strongly with 72-hr Neurologic Deficit Score as early as 30 mins post–cardiac arrest (Pearson’s correlation 0.735, p < .01) and maintained a significant association throughout the 72-hr experiment. No IQ difference was noted in sham rats with temperature manipulation. Conclusions:The enhanced recovery provided by hypothermia and the detrimental effect by hyperthermia were robustly detected by early quantitative electroencephalographic markers. IQ values during the first 2 hrs after cardiac arrest accurately predicted neurologic outcome at 72 hrs.

Coma After Global Ischemic Brain Injury: Pathophysiology and Emerging Therapies

Cardiac arrest is a major cause of death and morbidity in the United States, and neurological injury contributes significantly to this. Neurological complications associated with global cerebral ischemia include disorders of responsiveness, such as coma and the vegetative state, seizures, motor deficits, and brain death. Coma, complete unresponsiveness, is the most pervasive of these. Therapies that improve neurological outcomes in general after cardiac arrest and therapies that stimulate arousal from coma could have enormous clinical impact. The authors review the physiology of arousal and describe the biochemical and pathophysiological derangements that develop after global cerebral ischemia. We then describe the potential therapeutic mechanisms of hypothermia and deep brain stimulation, which provide hope for better neurological outcomes after global cerebral ischemia.

Post-cardiac arrest temperature manipulation alters early EEG bursting in rats

OBJECTIVES Hypothermia improves outcomes after cardiac arrest (CA), while hyperthermia worsens injury. EEG recovers through periodic bursting from isoelectricity after CA, the duration of which is associated with outcome in normothermia. We quantified burst frequency to study the effect of temperature on early EEG recovery after CA. METHODS Twenty-four rats were divided into three groups, based on 6h of hypothermia (T=33 degrees C), normothermia (T=37 degrees C), or hyperthermia (T=39 degrees C) immediately post-resuscitation from 7-min asphyxial CA. Temperature was maintained using surface cooling and re-warming. Neurological recovery was defined by 72-h neurological deficit score (NDS). RESULTS Burst frequency was higher during the first 90min in rats treated with hypothermia (25.6+/-12.2min(-1)) and hyperthermia (22.6+/-8.3min(-1)) compared to normothermia (16.9+/-8.5min(-1)) (p<0.001). Burst frequency correlated strongly with 72-h NDS in normothermic rats (p<0.05) but not in hypothermic or hyperthermic rats. The 72-h NDS of the hypothermia group (74, 61-74; median, 25-75th percentile) was significantly higher than the normothermia (49, 47-61) and hyperthermia (43, 0-50) groups (p<0.001). CONCLUSIONS In normothermic rats resuscitated from CA, early EEG burst frequency is strongly associated with neurological recovery. Increased bursting followed by earlier restitution of continuous EEG activity with hypothermia may represent enhanced recovery, while heightened metabolic rate and worsening secondary injury is likely in the hyperthermia group. These factors may confound use of early burst frequency for outcome prediction.

Quantitative assessment of somatosensory-evoked potentials after cardiac arrest in rats: Prognostication of functional outcomes

Objective:High incidence of poor neurologic sequelae after resuscitation from cardiac arrest underscores the need for objective electrophysiological markers for assessment and prognosis. This study aims to develop a novel marker based on somatosensory evoked potentials (SSEPs). Normal SSEPs involve thalamocortical circuits suggested to play a role in arousal. Due to the vulnerability of these circuits to hypoxic-ischemic insults, we hypothesize that quantitative SSEP markers may indicate future neurologic status. Design:Laboratory investigation. Setting:University Medical School and Animal Research Facility. Subjects:Sixteen adult male Wistar rats. Interventions:None. Measurements and Main Results:SSEPs were recorded during baseline, during the first 4 hrs, and at 24, 48, and 72 hrs postasphyxia from animals subjected to asphyxia-induced cardiac arrest for 7 or 9 mins (n = 8/group). Functional evaluation was performed using the Neurologic Deficit Score (NDS). For quantitative analysis, the phase space representation of the SSEPs—a plot of the signal vs. its slope—was used to compute the phase space area bounded by the waveforms recorded after injury and recovery. Phase space areas during the first 85–190 mins postasphyxia were significantly different between rats with good (72 hr NDS ≥50) and poor (72 hr NDS <50) outcomes (p = .02). Phase space area not only had a high outcome prediction accuracy (80–93%, p < .05) during 85–190 mins postasphyxia but also offered 78% sensitivity to good outcomes without compromising specificity (83–100%). A very early peak of SSEPs that precedes the primary somatosensory response was found to have a modest correlation with the 72 hr NDS subscores for thalamic and brainstem function (p = .066) and not with sensory-motor function (p = .30). Conclusions:Phase space area, a quantitative measure of the entire SSEP morphology, was shown to robustly track neurologic recovery after cardiac arrest. SSEPs are among the most reliable predictors of poor outcome after cardiac arrest; however, phase space area values early after resuscitation can enhance the ability to prognosticate not only poor but also good long-term neurologic outcomes.

Evolution of somatosensory evoked potentials after cardiac arrest induced hypoxic-ischemic injury

AIM We tested the hypothesis that early recovery of cortical SEP would be associated with milder hypoxic-ischemic injury and better outcome after resuscitation from CA. METHODS Sixteen adult male Wistar rats were subjected to asphyxial cardiac arrest. Half underwent 7min of asphyxia (Group CA7) and half underwent 9min (Group CA9). Continuous SEPs from median nerve stimulation were recorded from these rats for 4h immediately following CA, and at 24, 48, and 72h. Clinical recovery was evaluated using the Neurologic Deficit Scale. RESULTS All rats in group CA7 survived to 72h, while only 50% of rats in group CA9 survived to that time. Mean NDS values in the CA7 group at 24, 48, and 72h after CA were significantly higher than those of CA9. The N10 (first negative potential at 10ms) amplitude was significantly lower within 1h after CA in rats that suffered longer CA durations. SEPs were also analyzed by separating the rats into good (NDS>or=50) vs. bad (NDS<50) outcomes at 72h, again showing significant difference in N10 and peak-to-peak amplitudes between the two groups. In addition, a smaller N7 potential was consistently observed to recover earlier in all rats. CONCLUSIONS The diminished recovery of N10 is associated with longer CA times in rats. Higher N10 and peak-to-peak amplitudes during early recovery are associated with better neurologic outcomes. N7, which may represent thalamic activity, recovers much earlier than cortical responses (N10), suggesting failure of thalamocortical conduction during early recovery.

Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus

Objective: To investigate the feasibility, safety, and efficacy of a ketogenic diet (KD) for superrefractory status epilepticus (SRSE) in adults. Methods: We performed a prospective multicenter study of patients 18 to 80 years of age with SRSE treated with a KD treatment algorithm. The primary outcome measure was significant urine and serum ketone body production as a biomarker of feasibility. Secondary measures included resolution of SRSE, disposition at discharge, KD-related side effects, and long-term outcomes. Results: Twenty-four adults were screened for participation at 5 medical centers, and 15 were enrolled and treated with a classic KD via gastrostomy tube for SRSE. Median age was 47 years (interquartile range [IQR] 30 years), and 5 (33%) were male. Median number of antiseizure drugs used before KD was 8 (IQR 7), and median duration of SRSE before KD initiation was 10 days (IQR 7 days). KD treatment delays resulted from intravenous propofol use, ileus, and initial care received at a nonparticipating center. All patients achieved ketosis in a median of 2 days (IQR 1 day) on KD. Fourteen patients completed KD treatment, and SRSE resolved in 11 (79%; 73% of all patients enrolled). Side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss. Five patients (33%) ultimately died. Conclusions: KD is feasible in adults with SRSE and may be safe and effective. Comparative safety and efficacy must be established with randomized placebo-controlled trials. Classification of evidence: This study provides Class IV evidence that in adults with SRSE, a KD is effective in inducing ketosis.