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ethanol intoxication
Posters / Toxicologie Analytique & Clinique (2014) 26, S31-S55
S47
P39
P40
Predictive value of meconium concentrations of buprenorphine and methadone in neonatal abstinence syndrome (NAS)
A case report of persistent near-fatal anion gap acidosis due to a massive gamma-butyrolactone (GBL)/ethanol intoxication
A. Cesbron (1), A. Benoit (1, 2), M. Fiant (3), B. Guillois (3), A. Coquerel (1), M. Loilier (1) (1) Laboratoire de pharmacologie-toxicologie, centre hospitalier universitaire, Caen, France; (2) UMR 1075 Comete, université de Caen Basse-Normandie, France; (3) Service de néonatalogie, centre hospitalier universitaire, Caen, France.
H. Neels (1, 2), L. Heytens (3), G. Dockx (2), S. Schouwers (3), C. L. Crunelle (1) (1) Toxicological centre, university of Antwerp, Wilrijk, Belgium; (2) Toxicology laboratory, ZNA Stuivenberg, Antwerp, Belgium; (3) Department of intensive care, Sint-Augustinus hospital, Antwerp, Belgium.
Introduction. – Buprenorphine (BPN) and methadone (MTD) are two drugs authorized during pregnancy for opioid-dependence treatment. Substitution by MTD or BPN reduce fetal heroin exposure, obstetric complications, and neonatal morbidity and mortality (OFDT, 2003 ; Lejeune, 2004). Few days after birth newborns exposed in utero to MTD or BPN may suffered of neonatal abstinence syndrome (NAS), consisting in hyperirritability, gastrointestinal dysfunction, respiratory distress, and neurovegetative dysregulations and sometimes convulsions. NAS is treated with morphine, depending of the intensity of the symptoms (measured with Lipsitz scale). Previous studies show that maternal buprenorphine or methadone dose does not predict the severity or duration of NAS. Aim. – Meconium, the first neonatal feces, could represent the cumulative exposure to drugs in utero all along the gestation. A cohort of 80 opioid-dependent women and their newborn was enrolled for an inter-regional clinical assay managed by Caen university hospital. We assayed in meconium MTD and BPN concentrations, their metabolites and other drugs, and try to correlate them as prognostic factors of time, severity and duration of NAS. Methods. – 10 women treated with buprenorphine, 12 with methadone, and their newborns were currently included. NAS was followed by repeated Lipsitz scores (positive when >4). Meconium sample preparation included deproteinization followed by solidphase extraction (SPE) with Strata XC® column. BPN, MTD with their main metabolites norbuprenorphine and EDDP, and morphine were quantified by a liquid chromatography – tandem mass spectrometry (LC-MS/MS) method, developed and validated for this study. Separation was done with a Macherey-Nagel Nucleodur Polartec® (150 mm × 2,1 mm, 5 m) column using 10mM ammonium formiate, 0,2 % formic acid and acetonitrile, 0,1 % formic acid as mobile phases at a flow rate of 0,35 mL/min in a gradient mode. The analytes were identified and quantified by LC-MS/MS on an ABSciex® QTRAP3200 instrument with a TurboIon-Spray source operating in positive mode. Total time for each chromatograph was 15 min. Correlations were determined between meconium concentrations and 3 parameters : NAS onset, peak NAS score, and total amount of morphine used for NAS treatment. Other illicit substances and drugs which may have an impact on NAS are screened in maternal and newborn urines. Results. – For MTD mean meconium concentrations were 4200 ng/g, for EDDP 11700 ng/g (with a mean ratio MTD/EDDP = 0.42). EDDP meconium concentration and methadone/EDDP ratio were correlated with the peak NAS score (p=0.034 and p=0.029 respectively), and with the total amount of morphine used for NAS treatment (p=0.020 and p=0.013). There was no correlation with MTD meconium concentrations. Results are unavailable for buprenorphine at this time. Urine drug screens revealed frequently tobacco, opiates, cannabis, cocaine, hydroxyzine and benzodiazepines, confirming drugs of abuse are commonly used in opioid-dependent pregnant women. Conclusion. – These results show that measurement of meconium concentrations of EDDP and methadone/EDDP ratio may help clinicians to predict the severity of NAS, and so adapt earlier treatment with morphine. These preliminary results must be confirmed on large cohorts, higher than 30 newborns per group, including buprenorphine results.
Case. – We report a case of an intentional massive gamma-butyrolactone (GBL) intoxication, the precursor of the recreational drug gamma-hydroxybutyric acid (GHB), resulting in life-threatening metabolic acidosis (pH 6.5) with a highly increased anion- and osmolal gap. Rapid analysis using gas chromatography revealed no methanol nor ethylene glycol but a GHB plasma concentration of 4398 mg/L, far above the upper limit concentration found in fatalities attributed to GBL. Full recovery was established following supportive treatment including hemodialysis. This is the first report of GBL intoxication as a cause of high serum anion- and osmolal gap metabolic acidosis. Conclusions. – GHB/GBL is not a substance classically associated with high anion gap metabolic acidosis (HAGMA), but the finding of the massive GHB concentration was a direct result of the method used in this lab, allowing the simultaneous detection of several substances potentially causing HAGMA (P. Van Hee et al., Clin. Chem. Lab. Med. 2004; 42(11):1341-1345). Classical ethylene glycol methods would not measure GHB and suitable GC-MS techniques for rapid detection of this illicit drug are not widely available. Here, we propose that GBL/GHB intoxication should be considered in the differential diagnosis of this acid-base disorder. In view of the persistent acidosis, hemodialysis was life-saving. P41
Comparison of respiratory toxicity induced by two paraoxons in rat – research of toxicokinetic/ toxicodynamic relation S. Salle (1), L. Chevillard (2), P. Risede (2), F. Cottin (1), O. Roussel (1, 2), P. Houze (3, 4) (1) IRCGN, Rosny sous Bois, France; (2) INSERM U705, Paris, France; (3) Hospital Saint-Louis, Paris, France; (4) Laboratoire C-TAC E4463, Paris, France. Introduction. – Organophosphorus (OPs) are a major public health problem due to their toxicity and their massive use as pesticides. Both diethylparaoxon (DEPOX) and dimethylparaxon (DMPOX) have very close physicochemical properties. In rats, they induce similar respiratory toxicity from a dynamic standpoint, those effects being different considering kinetics. We suggested that this kinetic difference may occur because of DEPOX and DMPOX blood toxicokinetics (TK) differences. To test this hypothesis, we perform a toxicokinetic/ toxicodynamic (TK/TD) study, based on measurement of free blood concentrations of these two OPs and residual activity of total blood cholinesterases related to their effects on breathing rest. Methods. – For each study, Sprague-Dawley male rats, were spread out over three groups of six animals: DEPOX and DMPOX at 50 % of lethal dose (215 g/kg and 250 g/kg for DEPOX and DMPOX, respectively), and vehicle administered by subcutaneous route. For TD study, respiratory parameters were measured between 5 and 90 minutes using whole body plethysmography at rest. For TK studies, blood was collected by jugular catheter from 2.5 to 90 minutes. Free OPs blood concentrations were assayed by a HPLC-QTOF method, validated from 0.1 to 50 ng/mL using EnovalTM software, and whole blood cholinesterases activity by radioenzymology. Statistics (t-test) and kinetic modeling were performed using GraphPad PrismTM and Adapt 5TM softwares, respectively.
S47
P39
P40
Predictive value of meconium concentrations of buprenorphine and methadone in neonatal abstinence syndrome (NAS)
A case report of persistent near-fatal anion gap acidosis due to a massive gamma-butyrolactone (GBL)/ethanol intoxication
A. Cesbron (1), A. Benoit (1, 2), M. Fiant (3), B. Guillois (3), A. Coquerel (1), M. Loilier (1) (1) Laboratoire de pharmacologie-toxicologie, centre hospitalier universitaire, Caen, France; (2) UMR 1075 Comete, université de Caen Basse-Normandie, France; (3) Service de néonatalogie, centre hospitalier universitaire, Caen, France.
H. Neels (1, 2), L. Heytens (3), G. Dockx (2), S. Schouwers (3), C. L. Crunelle (1) (1) Toxicological centre, university of Antwerp, Wilrijk, Belgium; (2) Toxicology laboratory, ZNA Stuivenberg, Antwerp, Belgium; (3) Department of intensive care, Sint-Augustinus hospital, Antwerp, Belgium.
Introduction. – Buprenorphine (BPN) and methadone (MTD) are two drugs authorized during pregnancy for opioid-dependence treatment. Substitution by MTD or BPN reduce fetal heroin exposure, obstetric complications, and neonatal morbidity and mortality (OFDT, 2003 ; Lejeune, 2004). Few days after birth newborns exposed in utero to MTD or BPN may suffered of neonatal abstinence syndrome (NAS), consisting in hyperirritability, gastrointestinal dysfunction, respiratory distress, and neurovegetative dysregulations and sometimes convulsions. NAS is treated with morphine, depending of the intensity of the symptoms (measured with Lipsitz scale). Previous studies show that maternal buprenorphine or methadone dose does not predict the severity or duration of NAS. Aim. – Meconium, the first neonatal feces, could represent the cumulative exposure to drugs in utero all along the gestation. A cohort of 80 opioid-dependent women and their newborn was enrolled for an inter-regional clinical assay managed by Caen university hospital. We assayed in meconium MTD and BPN concentrations, their metabolites and other drugs, and try to correlate them as prognostic factors of time, severity and duration of NAS. Methods. – 10 women treated with buprenorphine, 12 with methadone, and their newborns were currently included. NAS was followed by repeated Lipsitz scores (positive when >4). Meconium sample preparation included deproteinization followed by solidphase extraction (SPE) with Strata XC® column. BPN, MTD with their main metabolites norbuprenorphine and EDDP, and morphine were quantified by a liquid chromatography – tandem mass spectrometry (LC-MS/MS) method, developed and validated for this study. Separation was done with a Macherey-Nagel Nucleodur Polartec® (150 mm × 2,1 mm, 5 m) column using 10mM ammonium formiate, 0,2 % formic acid and acetonitrile, 0,1 % formic acid as mobile phases at a flow rate of 0,35 mL/min in a gradient mode. The analytes were identified and quantified by LC-MS/MS on an ABSciex® QTRAP3200 instrument with a TurboIon-Spray source operating in positive mode. Total time for each chromatograph was 15 min. Correlations were determined between meconium concentrations and 3 parameters : NAS onset, peak NAS score, and total amount of morphine used for NAS treatment. Other illicit substances and drugs which may have an impact on NAS are screened in maternal and newborn urines. Results. – For MTD mean meconium concentrations were 4200 ng/g, for EDDP 11700 ng/g (with a mean ratio MTD/EDDP = 0.42). EDDP meconium concentration and methadone/EDDP ratio were correlated with the peak NAS score (p=0.034 and p=0.029 respectively), and with the total amount of morphine used for NAS treatment (p=0.020 and p=0.013). There was no correlation with MTD meconium concentrations. Results are unavailable for buprenorphine at this time. Urine drug screens revealed frequently tobacco, opiates, cannabis, cocaine, hydroxyzine and benzodiazepines, confirming drugs of abuse are commonly used in opioid-dependent pregnant women. Conclusion. – These results show that measurement of meconium concentrations of EDDP and methadone/EDDP ratio may help clinicians to predict the severity of NAS, and so adapt earlier treatment with morphine. These preliminary results must be confirmed on large cohorts, higher than 30 newborns per group, including buprenorphine results.
Case. – We report a case of an intentional massive gamma-butyrolactone (GBL) intoxication, the precursor of the recreational drug gamma-hydroxybutyric acid (GHB), resulting in life-threatening metabolic acidosis (pH 6.5) with a highly increased anion- and osmolal gap. Rapid analysis using gas chromatography revealed no methanol nor ethylene glycol but a GHB plasma concentration of 4398 mg/L, far above the upper limit concentration found in fatalities attributed to GBL. Full recovery was established following supportive treatment including hemodialysis. This is the first report of GBL intoxication as a cause of high serum anion- and osmolal gap metabolic acidosis. Conclusions. – GHB/GBL is not a substance classically associated with high anion gap metabolic acidosis (HAGMA), but the finding of the massive GHB concentration was a direct result of the method used in this lab, allowing the simultaneous detection of several substances potentially causing HAGMA (P. Van Hee et al., Clin. Chem. Lab. Med. 2004; 42(11):1341-1345). Classical ethylene glycol methods would not measure GHB and suitable GC-MS techniques for rapid detection of this illicit drug are not widely available. Here, we propose that GBL/GHB intoxication should be considered in the differential diagnosis of this acid-base disorder. In view of the persistent acidosis, hemodialysis was life-saving. P41
Comparison of respiratory toxicity induced by two paraoxons in rat – research of toxicokinetic/ toxicodynamic relation S. Salle (1), L. Chevillard (2), P. Risede (2), F. Cottin (1), O. Roussel (1, 2), P. Houze (3, 4) (1) IRCGN, Rosny sous Bois, France; (2) INSERM U705, Paris, France; (3) Hospital Saint-Louis, Paris, France; (4) Laboratoire C-TAC E4463, Paris, France. Introduction. – Organophosphorus (OPs) are a major public health problem due to their toxicity and their massive use as pesticides. Both diethylparaoxon (DEPOX) and dimethylparaxon (DMPOX) have very close physicochemical properties. In rats, they induce similar respiratory toxicity from a dynamic standpoint, those effects being different considering kinetics. We suggested that this kinetic difference may occur because of DEPOX and DMPOX blood toxicokinetics (TK) differences. To test this hypothesis, we perform a toxicokinetic/ toxicodynamic (TK/TD) study, based on measurement of free blood concentrations of these two OPs and residual activity of total blood cholinesterases related to their effects on breathing rest. Methods. – For each study, Sprague-Dawley male rats, were spread out over three groups of six animals: DEPOX and DMPOX at 50 % of lethal dose (215 g/kg and 250 g/kg for DEPOX and DMPOX, respectively), and vehicle administered by subcutaneous route. For TD study, respiratory parameters were measured between 5 and 90 minutes using whole body plethysmography at rest. For TK studies, blood was collected by jugular catheter from 2.5 to 90 minutes. Free OPs blood concentrations were assayed by a HPLC-QTOF method, validated from 0.1 to 50 ng/mL using EnovalTM software, and whole blood cholinesterases activity by radioenzymology. Statistics (t-test) and kinetic modeling were performed using GraphPad PrismTM and Adapt 5TM softwares, respectively.