Kim An

Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.

BACKGROUND Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. METHODS We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2.5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. FINDINGS Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10.3%, 95% CI -24.0 to 3.4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. INTERPRETATION The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. FUNDING UCB Pharma.

A prehospital randomized trial in convulsive status epilepticus.

Therapeutic strategies for patients with generalized convulsive status epilepticus (GCSE) need to be improved. We present the design of an add‐on, randomized, double‐blind, placebo‐controlled, phase III clinical trial, to compare the efficacy for GCSE of intravenous levetiracetam in association with clonazepam versus clonazepam alone. In the therapeutic arm, 1 mg clonazepam is injected together with 2500 mg levetiracetam over 5 min. In the control arm, 1 mg clonazepam is injected together with a placebo over 5 min. This ongoing study is managed by prehospital physicians within emergency mobile units (SAMU). Adult patients with GCSE lasting more than 5 minutes are included in the study. The primary outcome measure is the percentage of patients with cessation of convulsions within 15 minutes of the onset of initial injections. Emergency medical consent is obtained from family members. An informed consent for continued participation is also obtained from patients when they wake. The study is currently recruiting participants.

A new approach for early onset cardiogenic shock in acute colchicine overdose: place of early extracorporeal life support (ECLS)?

Dear Editor, Colchicine belongs to the family of spindle poisons, which are mainly used to treat and prevent forms of microcrystalline arthritis, such as gout. It has a narrow therapeutic index. Colchicine overdose is associated with a high mortality rate [1]. Early symptoms usually include gastrointestinal pain; multiorgan failure typically occurs next, alongside metabolic derangements and bone marrow suppression. Prognostic factors include a supposed ingested dose of [0.8 mg/kg, cardiogenic shock, and ARDS [1]. Death from acute colchicine poisoning is usually due to hemodynamic collapse and cardiac arrhythmias. A 51-year-old male pharmacist (medical history of depression, high blood pressure, and gout treated with colchicine) was admitted to the ICU for an acute and unexplained circulatory shock. Over the course of his admission he continued to deteriorate and required high doses of norepinephrine (4.2 lg/kg/min), epinephrine (0.4 lg/kg/min), and dobutamine (10 lg/kg/min). After the first 24 h, his wife found a bottle of 1 mg Colchimax (17 tablets missing). The patient then admitted to ingesting those tablets, which was later confirmed by laboratory investigations: 9.7 nmol/L at day 1; 9.25 nmol/L at day 3; 5.75 nmol/L at day 6; and less than 1.25 nmol/L at day 16. Following the confirmation of a colchicine overdose, the patient’s clinical condition worsened. He quickly developed multiorgan failure and was hemodynamically unstable. In the ICU, it was decided to resort to a bedside-to-bench process. For the following 10 days he received extracorporeal life support (ECLS) (CARDIOHELP, Maquet, Rastatt, Germany), which was achieved through femoral venous arterial cannulation surgery with an initial rate of 3 L/min, 3,700 rev/min. He made a good recovery and showed normal organ function by day 6. The ECLS was removed on day 10 and the mechanical ventilator on day 20. He did not present any hematological failure. He suffered from an acute renal failure due to tubular necrosis that required dialysis for 36 days. The patient was discharged on day 52 with a CPC score of 1. Recent studies have proved that human [1] and animal [2] immunotherapy antibodies can be successfully used to treat colchicine overdose. However, there are a few limitations on the use of immunotherapy antibodies:

Early detection of brain death using the Bispectral Index (BIS) in patients treated by extracorporeal cardiopulmonary resuscitation (E-CPR) for refractory cardiac arrest☆

BACKGROUND Despite increasing use of extracorporeal cardiopulmonary resuscitation (E-CPR) for treatment of refractory cardiac arrest patients, prognosis remains dismal, often resulting in brain-death. However, clinical assessment of brain-death occurence is difficult in post-cardiac arrest patients, sedated, paralyzed, under mild therapeutic hypothermia (MTH). Our objective was to assess the usefulness of Bispectral-Index (BIS) monitoring at bedside for an early detection of brain-death occurrence in refractory cardiac arrest patients treated by E-CPR. METHODS This prospective study was performed in an intensive care unit of an university hospital. Forty-six patients suffering from refractory cardiac arrest treated by E-CPR were included. BIS was continuously recorded during ICU hospitalization. Clinical brain-death was confirmed when appropriate by EEG and/or cerebral CT angiography. RESULTS Twenty-nine patients evolved into brain-death and had average BIS values under MTH and after rewarming (temperature ≥35°C) of 4 (0-47) and 0 (0-82), respectively. Among these, 11 (38%) entered into a procedure of organs donation. Among the 17 non-brain-dead patients, the average BIS values at admission and after rewarming were 39 (0-65) and 59 (22-82), respectively. Two patients had on admission a BIS value equal to zero and evolved to a poor prognostic (CPC 4) and died after care limitations. BIS values were significantly different between patients who developed brain death and those who did not. In both groups, no differences were observed between the AUCs of ROC curves for BIS values under MTH and after rewarming (respectively 0.86 vs 0.83, NS). CONCLUSIONS Initial values of BIS could be used as an assessment tool for early detection of brain-death in refractory cardiac arrest patients treated by mild therapeutic hypothermia and E-CPR.

Coronary lesions in refractory out of hospital cardiac arrest (OHCA) treated by extra corporeal pulmonary resuscitation (ECPR)

PURPOSE Extracorporeal cardiopulmonary resuscitation (ECPR) is a second line treatment for refractory cardiac arrest (R-OHCA). Timing of ECPR before performing coronary angiography (CAG) is still debated. The aim of the study was to describe the clinical and angiographic characteristics of the largest cohort of out-of-hospital cardiac arrest (OHCA) patients undergoing ECPR. METHODS All refractory OHCA patients with ECPR managed by the prehospital mobile intensive care unit (MoICU of the SAMU) in Paris (France) were prospectively included from October 2014 to December 2016. RESULTS Among 74 patients included over the period, 54 patients had coronary artery disease (CAD). There is a trend toward the CAD patients being older but it did not meet statistical significance (55.3 ± 11.8 vs. 50.6 ± 12.8, p = 0,14). Patients were more frequently men and smokers (p = 0.03 for both). The proportion of initial shockable rhythm tended to be higher in patients with CAD (71% vs. 55%). The rate of 1-, 2-, and 3-vessel disease were 43%, 35% and 22% respectively. The Syntax Score was 18 ± 9 and the lesions in each epicardial vessel were mainly proximal. Percutaneous coronary intervention was performed ad hoc in 49 patients (91%). Complete revascularization was performed in 64%. Inhospital death was numerically lower (65% vs. 75%) in patients with CAD, especially in patients with initial shockable rhythm. CONCLUSION In 74 refractory OHCA patients treated with ECPR implanted by a prehospital mobile intensive care unit, the rate of CAD was high (54/74) especially in patients with shockable rhythm. The majority of patients presented with double or triple vessel disease and proximal lesions. The severity and extension of CAD may explain the refractory nature of the cardiac arrest.

Reply to Mégarbane: is early implementation of extracorporeal life support in severely colchicine-poisoned patients lifesaving? Definitive evidence is still lacking

Dear Editor, We thank Dr. Mégarbane [1] for his interest in our letter [2]. The ingested dose was estimated by the discovery by the patient’s wife of an empty bottle of Colchimax 1 mg; probably other bottles had been hidden by the patient and were not discovered. Furthermore, the patient first confessed the isolated ingestion of Colchimax to all members of our medical team and then confirmed it to the psychiatric team. He related he did not remember the time and the ingested dose after the coma. Moreover, by virtue of his profession (pharmacist), he well knew the toxic effects of colchicine and the kinetics of these effects. Colchicine intoxication is marked by a cardiovascular shock classically occurring between day 2 and day 7 as described by Megarbane (http://www. orpha.net/data/patho/FR/fr-colchicine. pdf). In our case, the ECLS could be removed at day 10, consistent with previous clinical description. The journal’s word limits for correspondence prevented us mentioning the usual prognosticators in colchicine poisoning: prothrombin rate 10 % and leukocytosis 19,100/mm at day 2; transient bone marrow suppression: thrombocytopenia (44,000/ mm) and leucopenia (1,500/mm) at day 5; and the alopecia that occurred at day 12. As we described, the patient required high doses of catecholamine without achieving a normal hemodynamic profile, for which reason we decided to use ECLS.