Yield of intermittent versus continuous EEG in comatose survivors of cardiac arrest treated with hypothermia.

INTRODUCTION: Electroencephalography (EEG) has a central role in the outcome prognostication in subjects with anoxic/hypoxic encephalopathy following a cardiac arrest (CA). Continuous EEG monitoring (cEEG) has been consistently developed and studied; however, its yield as compared to repeated standard EEG (sEEG) is unknown. METHODS: We studied a prospective cohort of comatose adults treated with therapeutic hypothermia (TH) after a CA. cEEG data regarding background activity and epileptiform components were compared to two 20 minute sEEG extracted from the cEEG recording (one during TH, and one in early normothermia). RESULTS: In this cohort, 34 recordings were studied. During TH, the agreement between cEEG and sEEG was 97.1% (95% CI: 84.6 - 99.9%) for background discontinuity and reactivity evaluation, while it was 94.1% (95% CI 80.3 - 99.2%) regarding epileptiform activity. In early normothermia, we did not find any discrepancies. Thus, concordance was very good during TH (kappa 0.83), and optimal during normothermia (kappa=1). The median delay between CA and the first EEG reactivity testing was 18 hours (range: 4.75 - 25) for patients with perfect agreement and 10 hours (range: 5.75 - 10.5) for the three patients in whom there were discordant findings (P=0.02, Wilcoxon). CONCLUSION: Standard intermittent EEG has comparable performance than continuous EEG both for variables important for outcome prognostication (EEG reactivity) and identification of epileptiform transients in this relatively small sample of comatose survivors of CA. This finding has an important practical implication, especially for centers where EEG resources are limited.

Cardiorespiratory arrest and vitamin D deficiency rickets: A case report

Vitamin D deficiency rickets became a rare disease in industrialized countries due to vitamin D supplementation in infants and nutritional guidelines. Symptoms of hypocalcemia due to vitamin D deficiency rickets may be life threatening. We report a case of a 16 months old infant who initially presented with stridor that was misdiagnosed as viral laryngitis. He presented, two weeks later, a cardiorespiratory arrest related to a laryngospasm secondary to severe hypocalcemia (ionized calcium level: 0.42 mmol/l,total calcium level: 1.15 mmol/). He was successfully resuscitated and vitamin D deficiency rickets was diagnosed. The medical history revealed that the infant was exclusively breast fed without vitamin D supplementation till the age of 10 months and also deprived from other milk products intentionally by the parents due to cultural habits. The laboratory investigations showed an elevated alkaline phosphatase level at 577 U/l, a normal phosphatemia level at 2 mmol/l, a decreased 25 (OH) cholecalciferol at 5.7 mcg/l,a normal calciuria level at 0.35 mol/mol of creatinine and an increased parathyroid hormone level at 325 ng/l. Cardiocirculatory arrest secondary to vitamin D deficiency rickets is very rare. The aim of this presentation is to highlight the symptoms of vitamin D deficiency rickets and to raise pediatricians' awareness to the necessity of including the diagnosis of hypocalcemia in case of stridor especially if the nutritional history or ethnic origin of the infant predispose to vitamin D deficiency. Vitamin D supplementation is important for some ethnic minority population, whom are faced with the risk of developing this disease

Prognostic value of continuous eeg monitoring during therapeutic hypothermia in patients with coma after cardiac arrest

INTRODUCTION: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. METHODS: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). RESULTS: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). CONCLUSIONS: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

Neurological Prognostication after Cardiac Arrest and Therapeutic Hypothermia: a Prospective Validation Study

Introduction: Clinical examination and electroencephalography study (EEG) have been recommended to predict functional recovery in comatose survivors of cardiac arrest (CA), however their prognostic value in patients treated with induced hypothermia (IH) has not been evaluated. Hypothesis: We aimed to validate the prognostic ability of clinical examination and EEG in predicting outcome of patients with coma after CA treated with IH and sought to derive a score with high predictive value for poor functional outcome in this setting. Methods: We prospectively studied 100 consecutive comatose survivors of CA treated with IH. Repeated neurological examination and EEG were performed early after passive rewarming and off sedation. Mortality was assessed at hospital discharge, and functional outcome at 3 to 6 months with Cerebral Performance Categories (CPC), and was dichotomized as good (CPC 1-2) vs. poor (CPC 3-5). Independent predictors of outcome were identified by multivariable logistic regression and used to assess the prognostic value of a Reproducible Electro-clinical Prognosticators of Outcome Score (REPOS). Results: Patients (20/100) with good outcome had all a reactive EEG background. Incomplete recovery of brainstem reflexes, myoclonus, time to return of spontaneous circulation (ROSC) > 25 min, and unreactive EEG background were all independent predictors of death and severe disability, and were added to construct the REPOS. Using a cut-off of 0 or 1 variables for good vs. 2 to 4 for poor outcome, the REPOS had a positive predictive value of 1.00 (95% CI: 0.92-1.00), a negative predictive value of 0.43 (95% CI: 0.29-0.58) and an accuracy of 0.81 for poor functional recovery at 3 to 6 months. Conclusions: In comatose survivors of CA treated with IH, a prognostic score, including clinical and EEG examination, was highly predictive of death and poor functional outcome at 3 to 6 months. Lack of EEG background reactivity strongly predicted poor neurological recovery after CA. Our findings show that clinical and electrophysiological studies are effective in predicting long-term outcome of comatose survivors after CA and IH, and suggest that EEG improves early prognostic assessment in the setting of therapeutic cooling.

Outcome Prediction after Cardiac Arrest Treated with Hypothermia

Rationale: Clinical and electrophysiological prognostic markers of brain anoxia have been mostly evaluated in comatose survivors of out hospital cardiac arrest (OHCA) after standard resuscitation, but their predictive value in patients treated with mild induced hypothermia (IH) is unknown. The objective of this study was to identify a predictive score of independent clinical and electrophysiological variables in comatose OHCA survivors treated with IH, aiming at a maximal positive predictive value (PPV) and a high negative predictive value (NPV) for mortality. Methods: We prospectively studied consecutive adult comatose OHCA survivors from April 2006 to May 2009, treated with mild IH to 33-34_C for 24h at the intensive care unit of the Lausanne University Hospital, Switzerland. IH was applied using an external cooling method. As soon as subjects passively rewarmed (body temperature >35_C) they underwent EEG and SSEP recordings (off sedation), and were examined by experienced neurologists at least twice. Patients with status epilepticus were treated with AED for at least 24h. A multivariable logistic regression was performed to identify independent predictors of mortality at hospital discharge. These were used to formulate a predictive score. Results: 100 patients were studied; 61 died. Age, gender and OHCA etiology (cardiac vs. non-cardiac) did not differ among survivors and nonsurvivors. Cardiac arrest type (non-ventricular fibrillation vs. ventricular fibrillation), time to return of spontaneous circulation (ROSC) >25min, failure to recover all brainstem reflexes, extensor or no motor response to pain, myoclonus, presence of epileptiform discharges on EEG, EEG background unreactive to pain, and bilaterally absent N20 on SSEP, were all significantly associated with mortality. Absent N20 was the only variable showing no false positive results. Multivariable logistic regression identified four independent predictors (Table). These were used to construct the score, and its predictive values were calculated after a cut-off of 0-1 vs. 2-4 predictors. We found a PPV of 1.00 (95% CI: 0.93-1.00), a NPV of 0.81 (95% CI: 0.67-0.91) and an accuracy of 0.93 for mortality. Among 9 patients who were predicted to survive by the score but eventually died, only 1 had absent N20. Conclusions: Pending validation in a larger cohort, this simple score represents a promising tool to identify patients who will survive, and most subjects who will not, after OHCA and IH. Furthermore, while SSEP are 100% predictive of poor outcome but not available in most hospitals, this study identifies EEG background reactivity as an important predictor after OHCA. The score appears robust even without SSEP, suggesting that SSEP and other investigations (e.g., mismatch negativity, serum NSE) might be principally needed to enhance prognostication in the small subgroup of patients failing to improve despite a favorable score.

Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.

Introduction: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. Methods: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Results: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). Conclusions: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

Contemporary approach to neurologic prognostication of coma after cardiac arrest.

Coma after cardiac arrest (CA) is an important cause of admission to the ICU. Prognosis of post-CA coma has significantly improved over the past decade, particularly because of aggressive postresuscitation care and the use of therapeutic targeted temperature management (TTM). TTM and sedatives used to maintain controlled cooling might delay neurologic reflexes and reduce the accuracy of clinical examination. In the early ICU phase, patients' good recovery may often be indistinguishable (based on neurologic examination alone) from patients who eventually will have a poor prognosis. Prognostication of post-CA coma, therefore, has evolved toward a multimodal approach that combines neurologic examination with EEG and evoked potentials. Blood biomarkers (eg, neuron-specific enolase [NSE] and soluble 100-β protein) are useful complements for coma prognostication; however, results vary among commercial laboratory assays, and applying one single cutoff level (eg, > 33 μg/L for NSE) for poor prognostication is not recommended. Neuroimaging, mainly diffusion MRI, is emerging as a promising tool for prognostication, but its precise role needs further study before it can be widely used. This multimodal approach might reduce false-positive rates of poor prognosis, thereby providing optimal prognostication of comatose CA survivors. The aim of this review is to summarize studies and the principal tools presently available for outcome prediction and to describe a practical approach to the multimodal prognostication of coma after CA, with a particular focus on neuromonitoring tools. We also propose an algorithm for the optimal use of such multimodal tools during the early ICU phase of post-CA coma.

Proportion of out-of-hospital adult non-traumatic cardiac or respiratory arrest among calls for seizure.

OBJECTIVES: To measure the proportion of adult non-traumatic cardiac or respiratory arrest among calls for seizure to an emergency medical dispatch centre and to record whether known epileptic patients present cardiac or respiratory arrest together with seizure. METHODS: This 2-year prospective observational investigation involved the collection of tape recordings of all incoming calls to the emergency medical dispatch centre, in which an out-of-hospital non-traumatic seizure was the chief complaint in patients >18 years, in addition to the paramedics' records of all patients who presented with respiratory or cardiac arrest. The authors also recorded whether the bystander spontaneously mentioned to the dispatcher that the victim was known to have epilepsy. RESULTS: During the 24-month period, the call centre received 561 incoming calls for an out-of-hospital non-traumatic seizure in an adult. Twelve cases were classified as cardiac or respiratory arrest by paramedics. In one case, the caller spontaneously mentioned that the victim had a history of epilepsy. The proportion of cardiac or respiratory arrest among calls for seizure was 2.1%. CONCLUSION: Although these cases are rare, dispatchers should closely monitor seizure patients with the help of bystanders to exclude an out-of-hospital cardiac or respiratory arrest, in which case the dispatcher can offer telephone cardiopulmonary resuscitation advice until the paramedics arrive. Whenever the activity of the centre allows it and no new incoming call is on hold, this can be achieved by staying on the line with the caller or by calling back. A history of epilepsy should not modify the type of monitoring performed by the dispatcher as those patients may also have an arrest together with seizure.

Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.

The role of Notch signaling in growth/differentiation control of mammalian epithelial cells is still poorly defined. We show that keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia and deregulated expression of multiple differentiation markers. In differentiating primary keratinocytes in vitro endogenous Notch1 is required for induction of p21WAF1/Cip1 expression, and activated Notch1 causes growth suppression by inducing p21WAF1/Cip1 expression. Activated Notch1 also induces expression of 'early' differentiation markers, while suppressing the late markers. Induction of p21WAF1/Cip1 expression and early differentiation markers occur through two different mechanisms. The RBP-Jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-Jkappa-dependent transcription. Expression of early differentiation markers is RBP-Jkappa-independent and can be induced by both activated Notch1 and Notch2, as well as the highly conserved ankyrin repeat domain of the Notch1 cytoplasmic region. Thus, Notch signaling triggers two distinct pathways leading to keratinocyte growth arrest and differentiation.

Prognostication in comatose survivors of cardiac arrest: An advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine.

OBJECTIVES: To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy. METHODS: GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included. RESULTS AND CONCLUSIONS: Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at ?72h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron specific enolase at 48-72h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients.

Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06).

BACKGROUND: Pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients. METHODS: Bevacizumab (10 mg/kg) and PLD (20 mg/m(2)) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination. RESULTS: Thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%. CONCLUSIONS: In this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this setting.

L'arrêt cardiaque: quelle réalité et quelle formation pour le praticien [Heart arrest: which reality and which training for the practitioner?]

Sudden death related to out-of hospital cardiac arrest is an important cause of mortality, which is mainly caused by ventricular fibrillation, a potentially reversible condition. The prognosis of out-of-hospital cardiac arrest remains dismal despite well developed emergency medical services. Witnessed arrest, ventricular fibrillation as the initial arrhythmia, cardiopulmonary resuscitation and early defibrillation are systematically associated with better survival. Key interventions must therefore be enforced to improve survival from out-of-hospital cardiac, introducing the concept of a "chain of survivals". The aim of the present article, which is illustrated by local results, is to review this important public health issue, to emphasize the role of the general practitioner in the chain of survival, and to promote education and training of basic and advanced life support.

Islands of euchromatin-like sequence and expressed polymorphic sequences within the short arm of human chromosome 21.

The goals of the human genome project did not include sequencing of the heterochromatic regions. We describe here an initial sequence of 1.1 Mb of the short arm of human chromosome 21 (HSA21p), estimated to be 10% of 21p. This region contains extensive euchromatic-like sequence and includes on average one transcript every 100 kb. These transcripts show multiple inter- and intrachromosomal copies, and extensive copy number and sequence variability. The sequencing of the "heterochromatic" regions of the human genome is likely to reveal many additional functional elements and provide important evolutionary information.