Therapeutic Coma Research Articles

Status epilepticus bei Erwachsenen: klinisch orientierte Übersichtsarbeit zu Ätiologie, diagnostischen Herausforderungen und therapeutischen Fortschritten

AbstractStatus epilepticus (SE) is a neurological emergency associated with a high mortality rate. Collaborative efforts have been made to establish standardized definitions, classifications, and treatment protocols to improve management and reduce mortality. In 2015, the International League Against Epilepsy (ILAE) developed a new definition and classification system for SE, taking into account the pathophysiology of SE and setting time points for treatment decision-making, while considering the variability in seizure semiology.Timely identification of the underlying cause of SE would facilitate more targeted treatment, as almost half of all SE cases require specific therapy for the underlying cause in addition to providing symptomatic treatment.A stepwise algorithm for seizure management is proposed, with the initial stage involving the administration of benzodiazepines (BZD), followed by the use of non-sedating anti-seizure medications (ASM) as the second line of treatment. The decision to resort to therapeutic coma is made on a case-by-case basis, as most invasive treatments may not always be the best approach.This comprehensive review provides an overview of SE and its definition, pathophysiology, diagnostic challenges, and recent treatment advances.

Propofol versus sodium thiopentone for the treatment of status epilepticus and refractory status epilepticus in dogs

ABSTRACT Aims To compare the effect on mortality and length of hospital stay of propofol with that of sodium thiopentone for the management of dogs with status epilepticus (SE) and refractory status epilepticus (RSE). Methods In this cohort study, medical records of a veterinary referral clinic in Argentina were retrospectively searched for dogs that were hospitalised and required induction of therapeutic coma (TC) with either propofol or sodium thiopentone for the management of SE or RSE of any cause. A logistic regression model was performed to evaluate the association between the type of anaesthetic used and in-hospital mortality adjusting for the type of epilepsy (idiopathic, structural, or reactive). Kaplan-Meier estimated survival curves for the length of hospital stay by the type of anaesthetic drug were compared using the log-rank test (deaths were considered censored events). Cox proportional hazards regression was used to estimate hazard ratios for time to hospital discharge, unadjusted and adjusted for type of epilepsy. Results A total of 24 dogs with SE were included in the study: eight treated with propofol and 16 treated with sodium thiopentone. Four dogs treated with propofol (proportion = 0.50; 95% CI = 0.15–0.84), and eight treated with sodium thiopentone (proportion = 0.50; 95% CI = 0.50–0.74) died during hospitalisation. The median hospitalisation time was 43 (IQR 24–56) hours for dogs that were treated with propofol and 72 (IQR 64–96) hours for dogs that were treated with sodium thiopentone. There was no evidence of a difference in the median duration of TC in dogs treated with propofol (12 (IQR 8–24) hours) or with sodium thiopentone (12 (IQR 7.5–20) hours; p = 0.946). In the logistic regression model, no evidence of association between the anaesthetic protocol for the management of RSE and in-hospital mortality, adjusted for the type of epilepsy, was found (OR 1.09 (95% CI = 0.17–6.87); p = 0.925). Cox regression analysis revealed a difference in the time to hospital discharge, adjusted by the type of epilepsy, between treatment groups (HR = 0.05 (95% CI = 0.01–0.54); p = 0.013). Conclusions and clinical relevance The time spent in hospital before discharge was longer in dogs with RSE treated with sodium thiopentone compared to those treated with propofol. However, as the sample size was very small, the results obtained in the present study should be analysed with caution. Further studies including a greater number of dogs are required.

Management of status epilepticus: a narrative review.

Status epilepticus causes prolonged or repetitive seizures that, if left untreated, can lead to neuronal injury, severe disability, coma and death in paediatric and adult populations. While convulsive status epilepticus can be diagnosed using clinical features alone, non-convulsive status epilepticus requires confirmation by electroencephalogram. Early seizure control remains key in preventing the complications of status epilepticus. This is especially true for convulsive status epilepticus, which has stronger evidence supporting the benefit of treatment on outcomes. When status epilepticus becomes refractory, often due to gamma-aminobutyric acid and N-methyl-D-aspartate receptor modulation, anaesthetic drugs are needed to suppress seizure activity, of which there is limited evidence regarding the selection, dose or duration of their use. Seizure monitoring with electroencephalogram is often needed when patients do not return to baseline or during anaesthetic wean; however, it is resource-intensive, costly, only available in highly specialised centres and has not been shown to improve functional outcomes. Thus, the treatment goals and aggressiveness of therapy remain under debate, especially for non-convulsive status epilepticus, where prolonged therapeutic coma can lead to severe complications. This review presents an evidence-based, clinically-oriented and comprehensive review of status epilepticus and its definitions, aetiologies, treatments, outcomes and prognosis at different stages of the patient's journey.

S2k-Leitlinie: Status Epilepticus im Erwachsenenalter

Diese S2k-Leitlinie (LL) zum Status epilepticus (SE) im Erwachsenenalter schreibt die letzte DGN-LL zum SE von 2012 fort. Neue Definitionen und Evidenz wurden bei der Erstellung der LL und des Clinical Pathway berücksichtigt. Jeder epileptische Anfall, der länger als 5 Minuten anhält (oder ≥ 2 Anfälle über einen Zeitraum von mehr als 5 Minuten ohne Wiedererlangen des neurologischen Ausgangsstatus), soll als SE behandelt werden.In der Diagnostik sollte initial eine CCT oder, wenn möglich, eine MRT erfolgen. Das EEG spielt bei der Diagnosestellung und beim Therapiemonitoring von non-konvulsiven SE und zum Ausschluss bzw. Nachweis psychogener nichtepileptischer Anfälle eine wesentliche Rolle. Der prognostische Einfluss von insbesondere entzündlichen Begleiterkrankungen (z. B. Pneumonie) wurde besser belegt, weshalb entsprechende Laborparameter auch im Verlauf kontrolliert werden sollten und ggf. frühzeitig eine antibiotische Therapie initiiert werden sollte.Die Therapie erfolgt in 4 Stufen: 1. Initialer SE: Gabe eines ausreichend hoch dosierten Benzodiazepins i. m., i. v. oder i. n.; 2. Benzodiazepin-refraktärer SE: 1. Wahl ist die i.v. Gabe von Levetiracetam oder Valproat; 3. Refraktärer SE (RSE) und 4. Superrefraktärer SE (SRSE): I.v. Propofol oder Midazolam alleine oder in Kombination oder Thiopental in anästhetischen Dosen. Beim fokalen non-konvulsiven RSE kann unter Umständen auf die Einleitung eines therapeutischen Komas verzichtet werden. Bei SRSE sollte die ketogene Diät zum Einsatz kommen. I.v. Ketamin oder inhalatives Isofluran kann erwogen werden. In Einzelfällen kann die elektrokonvulsive Therapie und, bei resektabler epileptogener Zone, ein Epilepsie chirurgischer Eingriff erwogen werden. I.v. Allopregnanolon oder die Hyperthermie sollen nicht eingesetzt werden.

Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.

Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care―all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.

Long-term prognosis related to deep sedation in refractory status Epilepticus.

To evaluate long-term prognosis in patients with refractory status epilepticus according to the level of sedation reached during drug-induced coma. Longitudinal study of patients with status epilepticus who received anesthetics to induce therapeutic coma. Demographic data, clinical, and electroencephalographic characteristics were collected, as well as variables related to sedation. We considered as deep sedation the EEG burst-suppression patterns (suppression ratio>50%). A GOSE (Glasgow Outcome Scale Extended) score of 7 or 8 was considered as good prognosis. A comparative study was carried out to identify predictors of good or poor prognosis at discharge, at 1 and 2years of follow-up. We included 61 patients: 63.9% were men; mean age 53.5±16.8years (range 16-86years), 39.3% reached deep sedation; 62.3% had>48 h induced coma. The median hospital stay was 21days, while 10days in the intensive care unit (ICU). In the multiple regression analysis, an ICU length of stay≥7days was associated with poor prognosis at discharge and at long-term (P<.05), while deep sedation was associated only with poor long-term prognosis (1 and 2years, P<.05). The Kaplan-Meier curve showed higher survival in the group that did not undergo deep sedation (P<.05). In refractory status epilepticus, deep sedation is associated with poor prognosis at long-term.

Duration of therapeutic coma and outcome of refractory status epilepticus.

Examine the association of duration of therapeutic coma (TC) with seizure recurrence, morbidity, and mortality in refractory status epilepticus (RSE). Define an optimal window for TC that provides sustained seizure control and minimizes complications. Retrospective, observational cohort study involving patients who presented with RSE to the University of Alabama at Birmingham or the University of California at San Francisco from 2010 to 2016. Relationship of duration of TC with primary and secondary outcomes was evaluated using two-sample t tests, simple linear regression, and chi-square tests. Multivariable linear and logistic regression models were used to identify independent predictors. Predictive ability of TC for seizure recurrence was quantified using a receiver-operating characteristic curve. Youden index was used to determine an optimal cutoff value. Multivariable analysis of clinical and treatment characteristics of 182 patients who were treated predominantly with propofol as anesthetic agent showed that longer duration of the first trial of TC (27.2 vs 15.6hours) was independently associated with a higher chance of seizure recurrence following the first weaning attempt (P=0.038) but not with poor functional neurologic outcome upon discharge, in-hospital complications, or mortality. Furthermore, higher doses of anesthetic utilized during the first trial of TC were independently associated with fewer in-hospital complications (P=0.003) and associated with a shorter duration of mechanical ventilation and total length of stay. Duration of TC was identified as an independent predictor of seizure recurrence with an optimal cutoff point at 35hours. This study suggests that a shorter duration yet deeper TC as treatment for RSE may be more effective and safer than the currently recommended TC duration of 24-48hours. Prospective and randomized trials should be conducted to validate these assertions.

864. Therapeutic Immunosupression to Treat Rabies Encephalitis

BackgroundRabies is nearly universally fatal with about 60,000 annual deaths globally; <0.1% cases survive. Reports of therapeutic coma leading to survival are outnumbered by reports of failure. On the basis of personal discussions with a leading rabies expert (Dr Rodney Willoughby), we hypothesized that limiting CNS immune response based on CSF antibody titre (ABT) might prove useful. We report on successful use of immunosuppression in 1 patient.MethodsA 26-year-old male was admitted with 2-day history of flu-like syndrome. He had category III dog bite on face 17 days prior. RIG was not given due to nonavailability; he had received ARV day 0, 3, 7, and 14 on time. On 4th day of admission (day 0), neurological features started—difficulty in walking and diplopia; hydrophobia was noted. Working diagnosis of rabies was made. MRI brain on day 1 showed subtle abnormal T2 and flair hyper intensities in pons, medulla, and left hippocampus. CSF (day 1) showed 105 cells; all lymphocytes. The RFFIT serum and CSF ABTs and rabies PCRs are tabulated below. Since ADEM was a possibility, he was begun on IVIg. Work up for other viral encephalitis was negative. Repeat CSF ABT on day 6 confirmed rabies. Postulating risk of death due to cerebral edema due to CNS immune response, dexamethasone (dexa) 6 mg/kg/day in 4 divided doses was begun on day 8. Serial MRI and CSF were done. Dexa taper was done based on MRI and CSF ABT. Intensive supportive care was given.ResultsMRI on day 9 and day 12 showed no cerebral edema. Dexa taper was started from day 13 by half every alternate day; it was given till day 28. By day 17, there was intermittent eye opening, withdrawal to pain and some orofacial and limb movements. Further recovery had waxing and waning course. Now he is nearly 1 year post rabies encephalitis. He is unable to talk or comprehend, but can sit independently and is able to walk with support.ConclusionImmunosuppressive therapy with dexa to improve outcomes in rabies seems an exciting option. Optimal dose, time of start, and taper schedule need further studies. CSF ABT-based tapering appears promising. Larger studies with this approach are needed.Table 1Day13613172055Serum ABT2048X81923276816384163848192CSF ABT64X10248192X40964096Saliva PCRNegative (Neg)XNegXXXXCSF PCRNegXNegXXXXNuchal biospyxNegxXXXX Disclosures All authors: No reported disclosures.

High dose phenobarbitone coma in pediatric refractory status epilepticus; a retrospective case record analysis, a proposed protocol and review of literature

BackgroundOngoing refractory status epilepticus is associated with significant morbidity and mortality. Therapeutic coma induction with midazolam, thiopentone, phenobarbitone or propofol is indicated when conventional antiepileptics fail to abort seizure. Of these, the most extensively studied is midazolam. Amongst the remaining three, phenobarbitone has the most favourable pharmacological profile, but has not been studied adequately, more so in the pediatric age group. The current retrospective case records analysis is an attempt to describe use of phenobarbitone coma in pediatric refractory status epilepticus. MethodsCase records of patients, admitted with status epilepticus to the pediatric inpatient services of a tertiary care teaching hospital of North India between January 2014 and December 2016 were reviewed. Those with refractory status epilepticus who failed to respond to midaolam infusion and phenobarbitone coma was used were included for analysis. ResultsOverall, 108 children presented in status, of which 34 developed refractory status epilepticus. Of these 34, 21 responded to midazolam infusion and in 13 high dose phenobarbitone coma following a standardised protocol was used. Amongst these 13 (8 males and 5 females, median age 6 years, IQR: 2.5–9.5), 12 responded and 1 succumbed. The median time to clinical seizure resolution and desired electroencephalographic changes post phenobarbitone initiation were 16 (IQR: 12–25) and 72 h (IQR: 48–120) respectively. ConclusionHigh dose phenobarbitone appears to be an effective therapeutic modality in pediatric refractory status epilepticus. The current study provides a protocol for its use which can be validated in future studies with larger sample size.

Therapeutic burst-suppression coma in pediatric febrile refractory status epilepticus

BackgroundEvidence for the beneficial effect of therapeutic burst-suppression coma in pediatric patients with febrile refractory status epilepticus is limited, and the clinical outcomes of this treatment strategy are largely unknown. Therefore, the aim of this study was to explore the outcomes of therapeutic burst-suppression coma in a series of children with febrile refractory status epilepticus. MethodsWe retrospectively reviewed consecutive pediatric patients with febrile refractory status epilepticus admitted to our pediatric intensive care unit between January 2000 and December 2013. The clinical characteristics were analyzed. ResultsThirty-five patients (23 boys; age range: 1–18years) were enrolled, of whom 28 (80%) developed super-refractory status epilepticus. All of the patients received the continuous administration of intravenous antiepileptic drugs for febrile refractory status epilepticus, and 26 (74.3%) achieved therapeutic burst-suppression coma. All of the patients received mechanical ventilatory support, and 26 (74.3%) received inotropic agents. Eight (22.9%) patients died within 1month. The neurologically functional outcomes at 6months were good in six (27.3%) of the 22 survivors, of whom two returned to clinical baseline. The patients with therapeutic burst-suppression coma were significantly associated with hemodynamic support than the patients with electrographic seizures control (p=0.03), and had a trend of higher 1-month mortality rate, worse 6months outcomes, and a longer duration of hospitalization. ConclusionsOur results suggest that therapeutic burst-suppression coma to treat febrile refractory status epilepticus may lead to an increased risk of hemodynamic instability and a trend of worse outcomes.

Author response: Therapeutic coma for status epilepticus: Differing practices in a prospective multicenter study.

We thank Dr. Sethi for the interest in our article.1 We agree the management of status epilepticus (SE) should be progressive using successive lines of antiseizure drugs (ASD), as recommended by the European and American guidelines.2,3 Therapeutic coma (TC) is sometimes needed; however, since the benefits of TC are not yet clear,4 we strongly believe that a “shotgun” approach should be avoided because it might harm the patient.5 We demonstrated that a more conservative approach was not associated with increased mortality, but avoiding TC correlated with a shorter length of hospital stay and a trend towards a better functional outcome.1 The best approach, as Dr. Sethi suggests, is probably to strictly adhere to the proposed treatment algorithms,3 using correctly dosed benzodiazepines followed by one nonsedating ASD. Eventually, after a careful case-by-case risk–benefit assessment, a decision to start TC may be taken. TC is often designated for patients with refractory generalized convulsive SE (awaiting further studies); nevertheless, in patients with focal SE and partly preserved consciousness, subsequent trials of nonsedating ASD before considering TC appears more appropriate.4

Editors' Note

Editors' Note: In China, the most common reason for eligible patients with acute strokes to not receive tissue plasminogen activator is patient or family refusal, while in the United States, it is mild or resolving symptoms. Hu et al. and article authors Messé and Schwamm discuss possible reasons for this difference. In reference to “Therapeutic coma for status epilepticus: Differing practices in a prospective multicenter study,” Dr. Sethi states that since the study showed that therapeutic coma in status epilepticus resulted in an increased length of stay and associated costs with no change in mortality, the recommendation to follow published evidence-based guidelines in the treatment of status epilepticus should remain in place, with the use of therapeutic coma considered on a case-by-case basis. Authors Alvarez et al. agree. —Megan Alcauskas, MD, and Robert C. Griggs, MD Editors' Note: In China, the most common reason for eligible patients with acute strokes to not receive tissue plasminogen activator is patient or family refusal, while in the United States, it is mild or resolving symptoms. Hu et al. and article authors Messé and Schwamm discuss possible reasons for this difference.

Letter re: Therapeutic coma for status epilepticus: Differing practices in a prospective multicenter study.

The article by Alvarez et al.1 compared the use of therapeutic coma (TC) for status epilepticus (SE) in tertiary care centers belonging to Harvard Affiliated Hospitals (HAH) and the Centre Hospitalier Universitaire Vaudois (CHUV). TC for SE was used more in HAH hospitals as compared to CHUV, and did not affect mortality, but resulted in increased length of stay and related costs.1 I frequently advise residents to avoid a shotgun approach (hasty use of wide-ranging, nonselective, and haphazard techniques) to SE treatment. Evidence-based standardized protocols need to be followed, but treatment must be tailored to the patient. Benzodiazepines (first-line) and nonsedating antiseizure drugs (ASD) should be dosed based on weight and at the recommended rate to rapidly achieve therapeutic CNS concentrations. A second loading dose of the initial nonsedating ASD, such as phenytoin (usually half the initial loading dose), or a second ASD (i.e., levetiracetam, valproic acid, levetiracetam, lacosamide) sometimes terminates SE. The decision to use TC in patients who are in electrographic partial SE or displaying electrographic patterns thought to be in the interictal to ictal continuum, such as periodic lateralized discharges and generalized epileptiform discharges, needs to be individualized after carefully considering the risk–benefit profile.

Evolution of Cerebral Atrophy in a Patient with Super Refractory Status Epilepticus Treated with Barbiturate Coma

Introduction. Status epilepticus is associated with neuronal breakdown. Radiological sequelae of status epilepticus include diffusion weighted abnormalities and T2/FLAIR cortical hyperintensities corresponding to the epileptogenic cortex. However, progressive generalized cerebral atrophy from status epilepticus is underrecognized and may be related to neuronal death. We present here a case of diffuse cerebral atrophy that developed during the course of super refractory status epilepticus management despite prolonged barbiturate coma. Methods. Case report and review of the literature. Case. A 19-year-old male with a prior history of epilepsy presented with focal clonic seizures. His seizures were refractory to multiple anticonvulsants and eventually required pentobarbital coma for 62 days and midazolam coma for 33 days. Serial brain magnetic resonance imaging (MRI) showed development of cerebral atrophy at 31 days after admission to our facility and progression of the atrophy at 136 days after admission. Conclusion. This case highlights the development and progression of generalized cerebral atrophy in super refractory status epilepticus. The cerebral atrophy was noticeable at 31 days after admission at our facility which emphasizes the urgency of definitive treatment in patients who present with super refractory status epilepticus. Further research into direct effects of therapeutic coma is warranted.

Therapeutic coma for status epilepticus: Differing practices in a prospective multicenter study.

Our aim was to analyze and compare the use of therapeutic coma (TC) for refractory status epilepticus (SE) across different centers and its effect on outcome. Clinical data for all consecutive adults (>16 years) with SE of all etiologies (except postanoxic) admitted to 4 tertiary care centers belonging to Harvard Affiliated Hospitals (HAH) and the Centre Hospitalier Universitaire Vaudois (CHUV) were prospectively collected and analyzed for TC details, mortality, and duration of hospitalization. Two hundred thirty-six SE episodes in the CHUV and 126 in the HAH were identified. Both groups were homogeneous in demographics, comorbidities, SE characteristics, and Status Epilepticus Severity Score (STESS); TC was used in 25.4% of cases in HAH vs 9.75% in CHUV. After adjustment, TC use was associated with younger age, lower Charlson Comorbidity Index, increasing SE severity, refractory SE, and center (odds ratio 11.3 for HAH vs CHUV, 95% confidence interval 2.47-51.7). Mortality was associated with increasing Charlson Comorbidity Index and STESS, etiology, and refractory SE. Length of stay correlated with STESS, etiology, refractory SE, and use of TC (incidence rate ratio 1.6, 95% confidence interval 1.22-2.11). Use of TC for SE treatment seems markedly different between centers from the United States and Europe, and did not affect mortality considering the whole cohort. However, TC may increase length of hospital stay and related costs. This study provides Class III evidence that for patients with SE, TC does not significantly affect mortality. The study lacked the precision to exclude an important effect of TC on mortality.

Rabies encephalitis

Abstract: Rabies is an acute infection of the nervous system in human and animals caused by rabies virus. Transmission usually occurs via a bite of an infected animal; transmission via aerosols and by tissue or organ transplantation are rare. Worldwide, endemic dog rabies is responsible for the vast majority of human cases, particularly in Asia and Africa. There are about 60,000 fatal human cases annually, and almost half are in children. Dog rabies can become well controlled by mass vaccination of dogs, which has proved to be very successful in Latin America. However, dog rabies remains uncontrolled in Asia and Africa. Rabies can be very effectively prevented after recognized exposures in humans by wound cleansing and active and passive immunization with rabies vaccine and rabies immune globulin, respectively. Human rabies has characteristic clinical features, including hydrophobia, and there are both encephalitic and paralytic forms of disease with progressive illness to death. Antemortem diagnostic laboratory tests include detection of rabies virus RNA (by reverse transcription - polymerase chain reaction amplification) in saliva or skin biopsies, rabies virus antigen detection in skin biopsies, and/or detection of neutralizing anti-rabies virus antibodies in serum and cerebrospinal fluid. When patients are treated aggressively in critical care units, there often are cardiac and/or respiratory complications and progression to multisystem organ dysfunction. Rabies is virtually always fatal and most survivors have received one or more doses of rabies vaccine prior to the onset of their clinical illness. There is no established effective therapy for rabies. The Milwaukee protocol, which includes therapeutic coma, lacks a clear scientific rationale and has proven to be ineffective and should no longer be used for the management of human rabies. Our understanding of basic mechanisms involved in the pathogenesis of rabies are quite limited and have proven to be an important barrier for the development of novel therapeutic approaches for the disease. There is recent evidence that rabies virus induces mitochondrial dysfunction in infected cells, which results in oxidative stress due to generation of reactive oxygen species and neuronal injury. This advance may lead to new approaches to the therapy of rabies.

Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned.

The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol.

Single Center Outcomes of Status Epilepticus at a Paediatric Intensive Care Unit.

Status epilepticus (SE) is a frequent admission diagnosis to paediatric intensive care units (PICUs) and is associated with variable outcomes. We have audited our experience of patients presenting in SE at a Canadian PICU to determine unfavorable outcome variables. Charts of patients <18 years of age presenting in SE to a tertiary care PICU over a 10-year period were audited. Data were analyzed at three care-points: transport, the emergency department (ED) and the PICU. Patient outcome before PICU discharge was categorized as "favorable" for return to pre-status functioning level or "unfavorable" for new deficit/death. Student's t-test and the Kruskal-Wallis test were used for analysis of normal and skewed continuous variables, respectively, and either Chi-square test or Fisher's exact test for categorical variables. 189 patients (54% males) were identified with a median age of 1.9 years. Idiopathic SE had the highest incidence; infectious/vascular etiologies were associated with more unfavorable outcomes. Progression to refractory SE in the ED had a higher incidence of death (p<0.05). Patients with an unfavorable outcome had a higher incidence of apnea during transport (p=0.01), longer hospital stays (p<0.05), need for therapeutic coma (p=0.01), longer duration of therapeutic coma (p<0.05), need for mechanical ventilation (p<0.05), and recurrent or refractory seizures during inpatient stay (p<0.05). Multivariate analysis of unfavorable outcomes of patients in SE presenting to the PICU included renal failure, cerebral edema, apnea during transport, refractory seizures, and recurrent seizures. Refractory seizures in children presenting with SE are associated with worsened outcomes in the PICU.

Status epilepticus: impact of therapeutic coma on outcome.

Therapeutic coma is advocated in guidelines for management of refractory status epilepticus; this is, however, based on weak evidence. We here address the specific impact of therapeutic coma on status epilepticus outcome. Retrospective assessment of a prospectively collected cohort. Academic hospital. Consecutive adults with incident status epilepticus lasting greater than or equal to 30 minutes, admitted between 2006 and 2013. We recorded prospectively demographics, clinical status epilepticus features, treatment, and outcome at discharge and retrospectively medical comorbidities, hospital stay, and infectious complications. Associations between potential predictors and clinical outcome were analyzed using multinomial logistic regressions. Of 467 patients with incident status epilepticus, 238 returned to baseline (51.1%), 162 had new disability (34.6%), and 67 died (14.3%); 50 subjects (10.7%) were managed with therapeutic coma. Therapeutic coma was associated with poorer outcome in the whole cohort (relative risk ratio for new disability, 6.86; 95% CI, 2.84-16.56; for mortality, 9.10; 95% CI, 3.17-26.16); the effect was more important in patients with complex partial compared with generalized convulsive or nonconvulsive status epilepticus in coma. Prevalence of infections was higher (odds ratio, 3.81; 95% CI, 1.66-8.75), and median hospital stay in patients discharged alive was longer (16 d [range, 2-240 d] vs 9 d [range, 1-57 d]; p < 0.001) in subjects managed with therapeutic coma. This study provides class III evidence that therapeutic coma is associated with poorer outcome after status epilepticus; furthermore, it portends higher infection rates and longer hospitalizations. These data suggest caution in the straightforward use of this approach, especially in patients with complex partial status epilepticus.

Can anesthetic treatment worsen outcome in status epilepticus?

Status epilepticus refractory to first-line and second-line antiepileptic treatments challenges neurologists and intensivists as mortality increases with treatment refractoriness and seizure duration. International guidelines advocate anesthetic drugs, such as continuously administered high-dose midazolam, propofol, and barbiturates, for the induction of therapeutic coma in patients with treatment-refractory status epilepticus. The seizure-suppressing effect of anesthetic drugs is believed to be so strong that some experts recommend using them after benzodiazepines have failed. Although the rationale for the use of anesthetic drugs in patients with treatment-refractory status epilepticus seems clear, the recommendation of their use in treating status epilepticus is based on expert opinions rather than on strong evidence. Randomized trials in this context are lacking, and recent studies provide disturbing results, as the administration of anesthetics was associated with poor outcome independent of possible confounders. This calls for caution in the straightforward use of anesthetics in treating status epilepticus. However, there are still more questions than answers, and current evidence for the adverse effects of anesthetic drugs in patients with status epilepticus remains too limited to advocate a change of treatment algorithms. In this overview, the rationale and the conflicting clinical implications of anesthetic drugs in patients with treatment-refractory status epilepticus are discussed, and remaining questions are elaborated. This article is part of a Special Issue entitled "Status Epilepticus".