Philippe Hantson

Determinants of recovery from severe posterior reversible encephalopathy syndrome.

Objective Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. Design 70 patients with severe PRES admitted to 24 ICUs in 2001–2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. Main Results Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105–143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3–5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS<5 were highest glycaemia on day 1 (OR, 1.22; 95%CI, 1.02–1.45, pu200a=u200a0.03) and time to causative-factor control (OR, 3.3; 95%CI, 1.04–10.46, pu200a=u200a0.04), whereas GOSu200a=u200a5 was associated with toxaemia of pregnancy (preeclampsia/eclampsia) (OR, 0.06; 95%CI, 0.01–0.38, pu200a=u200a0.003). Conclusions By day 90 after admission for severe PRES, 44% of survivors had severe functional impairments. Highest glycaemia on day 1 and time to causative-factor control were strong early predictors of outcomes, suggesting areas for improvement.

Hypokalaemia related to acute chloroquine ingestion

Large doses of chloroquine can cause poisoning. Our aim was to determine the possible relation between the plasma potassium concentration on admission with the severity of acute chloroquine poisoning and to assess the mechanism of chloroquine-induced hypokalaemia. We conducted a retrospective study of 191 consecutive cases. The main data included the occurrence of vomiting before admission, plasma, and urinary potassium concentration at admission, whole blood chloroquine concentration on admission, haemodynamic parameters and ECG, administration of catecholamines and outcome. Mean blood chloroquine level was 20.1 mumol/L (SD 14.3) (therapeutic level < or = 6 mumol/L). Mean plasma potassium concentration was 3.0 mmol/L (0.8) and was lower in the subjects who died than in those who survived (p = 0.0003). Plasma potassium varied directly with the systolic blood pressure and inversely with the QRS and QT. Plasma potassium varied inversely with the blood chloroquine (p = 0.0001; tau = -0.42). Acute chloroquine intoxication is responsible for a hypokalaemia which correlates with the gravity of the intoxication and may be due to a transport-dependent mechanism. Plasma potassium concentrations should be carefully observed, particularly among patients who also receive catecholamine infusions. We should keep in mind, however, that overzealous repletion invokes the risk of subsequent hyperkalaemia and thus should be avoided.

Diltiazem poisoning treated with hyperinsulinemic euglycemia therapy and intravenous lipid emulsion.

Intravenous lipid emulsion (ILE) has been proposed as a rescue therapy for severe local anesthetic drugs toxicity, but experience is limited with other lipophilic drugs. An 18-year-old healthy woman was admitted 8 h after the voluntary ingestion of sustained-release diltiazem (3600 mg), with severe hypotension refractory to fluid therapy, calcium salts, and high-dose norepinephrine (6.66 μg/kg/min). Hyperinsulinemic euglycemia therapy was initiated and shortly after was followed by a protocol of ILE (intralipid 20%, 1.5 ml/kg as bolus, followed by 0.25 ml/kg over 1h). The main finding attributed to ILE was an apparent rapid decrease in insulin resistance, despite a prolonged serum diltiazem elimination half-life. Diltiazem is a lipophilic cardiotoxic drug, which could be sequestered in an expanded plasma lipid phase. The mechanism of action of ILE is not known, including its role in insulin resistance and myocardial metabolism in calcium-channel blocker poisoning.

Lipid emulsion as rescue therapy in lamotrigine overdose.

BACKGROUNDnLamotrigine is a sodium channel blocking agent that is widely prescribed for treatment of seizure. Although life-threatening effects are rarely observed in overdose, some previous reports have described the occurrence of cardiac toxicity. The management of sodium channel blocking agent-induced cardiotoxicity conventionally requires sodium bicarbonate administration. Recent case reports describe intravenous lipid administration as a successful treatment for refractory cardiovascular collapse induced by sodium channel blocking medications.nnnOBJECTIVEnThe objective of this study is to report the use of intravenous lipid emulsion as adjunctive therapy in a case of lamotrigine overdose in which electrocardiographic changes were unresponsive to bicarbonate therapy.nnnCASE REPORTnWe report a case of intentional lamotrigine overdose in a 50-year-old woman who lost consciousness and developed electrocardiographic aberrations, including widening of QRS with occurrence of left bundle branch block. The patient was initially treated with sodium bicarbonate without effect. Recovery of cardiac conduction was rapidly achieved after infusion of a 20% lipid emulsion. The exact mechanism of action of lipid emulsion is not fully understood. The lipophilic properties of lamotrigine suggest that it was partially removed by the plasmatic lipid emulsion.nnnCONCLUSIONnThis case provides additional insightxa0into the potential benefit of using lipid emulsion in refractory sodium channel blocking intoxications.

CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants

Abstract Introduction. Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates. Objective. This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants in humans. Methods. PubMed (up to August 2013) was searched with the following selection criteria: ‘CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)’. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amfetamines, opioid analgesics and antidepressants. amfetamines. While some in vitro studies suggest that CYP2D6-mediated metabolites of 3,4-methylenedioxymethamfetamine (MDMA) are substantially more cytotoxic compared with unchanged MDMA, it is not yet confirmed in human cases of MDMA intoxication that extensive/ultra-rapid CYP2D6 metabolisers could be at higher risk. This would also apply to methamfetamine exposure and the related cardiac and central nervous system toxicity. Opioid analgesics. CYP2D6 ultra-rapid metabolisers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. Antidepressants. CYP2D6 poor metabolisers are generally more prone to adverse effects. Among them, the four drugs with the highest level of evidence are amitriptyline, nortriptyline, venlafaxine and fluoxetine. Further data are needed, however, for doxepin and paroxetine, while citalopram adverse effects seem definitely less influenced by CYP2D6 genetic polymorphisms. Conclusions. Either poor or extensive/ultra-rapid CYP2D6 metabolisers may be exposed to toxic effects of amfetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.

Severe acute cardiomyopathy associated with venlafaxine overdose and possible role of CYP2D6 and CYP2C19 polymorphisms.

Introduction. Venlafaxine (VEN) is a serotonin-norepinephrine-dopamine reuptake inhibitor that causes usually a mild cardiotoxicity when ingested in overdose. We report a patient who developed acute heart failure following overdose. As the toxicokinetic data suggested a prolonged metabolism, genetic polymorphisms for cytochrome P450 isoenzymes CYP2D6 and CYP2C19 were also investigated. Case report. A 34-year-old woman was admitted to the hospital 10 hours after the ingestion of an 11.25 g overdose of VEN. She was comatose and suffered two self-limited seizures. The electrocardiogram showed diffuse ST segment depression, but normal QRS and QTc duration. The plasma levels on admission were 18u2009015 and 3u2009846 ng/ml for VEN and the metabolite O-desmethylvenlafaxine (ODV), respectively. The patient developed severe cardiodepression. The left ventricular shortening fraction was only 9% on echocardiography. The patient was oliguric and required continuous venovenous hemofiltration. The administration of milrinone was required for 12 days, and norepinephrine for 10 days. Left ventricular function recovered. The calculated elimination half-life was 30.8 and 72.2 hours for VEN and ODV, respectively. The patient genotype was CYP2D6*1/*5, the *5 allele corresponding to a complete deletion of CYP2D6 gene. Conclusions. Severe and sustained cardiotoxicity following VEN overdose may be related to the amount ingested, as well as to the genetic polymorphism for CYP2D6 leading to a delayed elimination of active metabolite.

Breakthrough in cardiac arrest: reports from the 4th Paris International Conference.

Jean-Luc Diehl The French Intensive Care Society organized on 5th and 6th June 2014 its 4th “Paris International Conference in Intensive Care”, whose principle is to bring together the best international experts on a hot topic in critical care medicine. The 2014 theme was “Breakthrough in cardiac arrest”, with many high-quality updates on epidemiology, public health data, pre-hospital and in-ICU cares. The present review includes short summaries of the major presentations, classified into six main chapters:Epidemiology of CAPre-hospital managementPost-resuscitation management: targeted temperature managementPost-resuscitation management: optimizing organ perfusion and metabolic parametersNeurological assessment of brain damagesPublic healthcare

Reversible splenial lesion syndrome in cerebral malaria.

A 71-year-old Caucasian man living in Congo was investigated by serial magnetic resonance imaging (MRI) after having presented cerebral malaria due to Plasmodium falciparum. The clinical picture was characterized initially by coma and seizures. The patient developed multiple organ failure. There was, at 4 months follow-up only, a minimal neurological improvement consistent with minimally conscious state. The first cerebral MRI on day 17 showed a lesion of the splenium of corpus callosum with high signal intensity on DWI and FLAIR sequence and reduced ADC, and small cortical infarcts in the internal occipital regions. Follow-up MRI obtained 36 days later showed a complete resolution of splenial lesion, though without clinical improvement. Cerebral malaria should be added to the list of possible causes of reversible lesion of the splenium of corpus callosum.

Aerosol delivery with two ventilation modes during mechanical ventilation: a randomized study

AbstractBackgroundVolume-controlled ventilation has been suggested to optimize lung deposition during nebulization although promoting spontaneous ventilation is targeted to avoid ventilator-induced diaphragmatic dysfunction. Comparing topographic aerosol lung deposition during volume-controlled ventilation and spontaneous ventilation in pressure support has never been performed. The aim of this study was to compare lung deposition of a radiolabeled aerosol generated with a vibrating-mesh nebulizer during invasive mechanical ventilation, with two modes: pressure support ventilation and volume-controlled ventilation.MethodsSeventeen postoperative neurosurgery patients without pulmonary disease were randomly ventilated in pressure support or volume-controlled ventilation. Diethylenetriaminepentaacetic acid labeled with technetium-99m (2xa0mCi/3xa0mL) was administrated using a vibrating-mesh nebulizer (Aerogen Solo®, provided by Aerogen Ltd, Galway, Ireland) connected to the endotracheal tube. Pulmonary and extrapulmonary particles deposition was analyzed using planar scintigraphy.ResultsLung deposition was 10.5xa0±xa03.0 and 15.1xa0±xa05.0xa0% of the nominal dose during pressure support and volume-controlled ventilation, respectively (pxa0<xa00.05). Higher endotracheal tube and tracheal deposition was observed during pressure support ventilation (27.4xa0±xa06.6 vs. 20.7xa0±xa06.0xa0%, pxa0<xa00.05). A similar penetration index was observed for the right (pxa0=xa00.210) and the left lung (pxa0=xa00.211) with both ventilation modes. A high intersubject variability of lung deposition was observed with both modes regarding lung doses, aerosol penetration and distribution between the right and the left lung.ConclusionsIn the specific conditions of the study, volume-controlled ventilation was associated with higher lung deposition of nebulized particles as compared to pressure support ventilation. The clinical benefit of this effect warrants further studies.n Clinical trial registration NCT01879488

Drug-drug interactions in the intensive care unit: Do they really matter?

Purpose: To describe prevalence and patterns of potential drug‐drug interactions (pDDIs) in the intensive care unit (ICU), occurrence of adverse drug events (ADEs), and agreement between different compendia and intensivists perceptions. Methods: A cross‐sectional study. Drug profiles of all adult patients from 2 academic ICUs were screened on day 3 upon admission. We identified pDDIs using 3 compendia (Stockleys, Micromedex, and Epocrates) and documented their mechanism of action, clinical consequences, severity, level of evidence, and management. Medical records were searched to identify ADEs potentially related to major pDDIs. Agreement between information sources (compendia, intensivists) was evaluated. Results: We identified 1120 pDDIs among 275 patients. Median number of pDDIs per patient was 3.0 (interquartile range, 1‐6), with 79% of patients presenting with at least 1 pDDI. Major pDDIs were detected in 18% of patients, with potentially related to ADEs in 4% of patients. Only 13% of all pDDIs were documented simultaneously in all 3 compendia. Different information sources (compendia, clinicians) showed “no” to “fair” agreement. Conclusions: Potential drug‐drug interactions occurred in most ICU patients, contrasting with low rates of potentially related ADEs, which may have been underestimated. Sources of information are inconsistent, challenging the identification of pDDIs.