Kai Knudsen

The clinical toxicology of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol

Introduction. Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), are drugs of abuse which act primarily as central nervous system (CNS) depressants. In recent years, the rising recreational use of these drugs has led to an increasing burden upon health care providers. Understanding their toxicity is therefore essential for the successful management of intoxicated patients. We review the epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to GHB and its analogs and discuss the features and management of GHB withdrawal. Methods. OVID MEDLINE and ISI Web of Science databases were searched using the terms “GHB,” “gamma-hydroxybutyrate,” “gamma-hydroxybutyric acid,” “4-hydroxybutanoic acid,” “sodium oxybate,” “gamma-butyrolactone,” “GBL,” “1,4-butanediol,” and “1,4-BD” alone and in combination with the keywords “pharmacokinetics,” “kinetics,” “poisoning,” “poison,” “toxicity,” “ingestion,” “adverse effects,” “overdose,” and “intoxication.” In addition, bibliographies of identified articles were screened for additional relevant studies including nonindexed reports. Non-peer-reviewed sources were also included: books, relevant newspaper reports, and applicable Internet resources. These searches produced 2059 nonduplicate citations of which 219 were considered relevant. Epidemiology. There is limited information regarding statistical trends on world-wide use of GHB and its analogs. European data suggests that the use of GHB is generally low; however, there is some evidence of higher use among some sub-populations, settings, and geographical areas. In the United States of America, poison control center data have shown that enquiries regarding GHB have decreased between 2002 and 2010 suggesting a decline in use over this timeframe. Mechanisms of action. GHB is an endogenous neurotransmitter synthesized from glutamate with a high affinity for GHB-receptors, present on both on pre- and postsynaptic neurons, thereby inhibiting GABA release. In overdose, GHB acts both directly as a partial GABAb receptor agonist and indirectly through its metabolism to form GABA. Toxicokinetics. GHB is rapidly absorbed by the oral route with peak blood concentrations typically occurring within 1 hour. It has a relatively small volume of distribution and is rapidly distributed across the blood–brain barrier. GHB is metabolized primarily in the liver and is eliminated rapidly with a reported 20–60 minute half-life. The majority of a dose is eliminated completely within 4–8 hours. The related chemicals, 1,4-butanediol and gamma butyrolactone, are metabolized endogenously to GHB. Clinical features of poisoning. GHB produces CNS and respiratory depression of relatively short duration. Other commonly reported features include gastrointestinal upset, bradycardia, myoclonus, and hypothermia. Fatalities have been reported. Management of poisoning. Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Airway protection, intubation, and/or assisted ventilation may be indicated for severe respiratory depression. Gastrointestinal decontamination is unlikely to be beneficial. Pharmacological intervention is rarely required for bradycardia; however, atropine administration may occasionally be warranted. Withdrawal syndrome. Abstinence after chronic use may result in a withdrawal syndrome, which may persist for days in severe cases. Features include auditory and visual hallucinations, tremors, tachycardia, hypertension, sweating, anxiety, agitation, paranoia, insomnia, disorientation, confusion, and aggression/combativeness. Benzodiazepine administration appears to be the treatment of choice, with barbiturates, baclofen, or propofol as second line management options. Conclusions. GHB poisoning can cause potentially life-threatening CNS and respiratory depression, requiring appropriate, symptom-directed supportive care to ensure complete recovery. Withdrawal from GHB may continue for up to 21 days and can be life-threatening, though treatment with benzodiazepines is usually effective.

High mortality rates among GHB abusers in Western Sweden.

Background. GHB is a drug of abuse and acute poisonings have been an increasing medical problem over the last decade in Sweden. Objectives. To document all cases of GHB poisonings in Gothenburg during 1995–2004 and to record drug-related deaths to compare the toxicity of GHB with other illicit drugs, such as heroin and amphetamine. Methods. The number of GHB-poisoned patients treated at the Sahlgrenska University Hospital has been recorded with the help of an in-house database. The number of deaths by illicit drugs was recorded during 2004. Seizures of the drugs GHB, 1,4-butanediol, and GBL were registered between 1996 and 2004. Results. The number of poisoned patients was 259. The number of seizures with GHB was 743, GBL 343, and 1,4-butanediol 236. In 2004 the number of deaths was 6 with heroin, 7 with GHB, 32 with amphetamine, 6 with cocaine, and one with methadone. One patient with GHB poisoning died during hospital care. Conclusions. Intoxication by GHB has substantial morbidity and abuse of GHB has substantial mortality. The acute prognosis is good but long-term prognosis is insecure with an increased risk for drug dependency and an early death.

Epinephrine and sodium bicarbonate independently and additively increase survival in experimental amitriptyline poisoning

OBJECTIVES Cardiac depression is the main adverse effect of severe tricyclic antidepressant poisoning. The aim of this study was to investigate whether treatment with epinephrine or norepinephrine increases survival as compared with standard treatment with sodium bicarbonate in experimental amitriptyline poisoning. DESIGN Nonrandomized, controlled intervention trial. SETTING University laboratory. SUBJECTS Male, anesthetized, paralyzed, and mechanically ventilated Sprague-Dawley rats (n = 91). INTERVENTIONS Rats subjected to a 60-min infusion of amitriptyline (2 mg/kg/min) were treated with a continuous infusion of either epinephrine, norepinephrine, sodium bicarbonate, epinephrine plus sodium bicarbonate, norepinephrine plus sodium bicarbonate, or placebo. MEASUREMENTS AND MAIN RESULTS Inotropic drug treatment was associated with an increased survival rate as compared with treatment with sodium bicarbonate and treatment with placebo. Epinephrine treatment was superior to norepinephrine. Additional treatment with sodium bicarbonate increased survival rate for each inotropic drug. Sodium bicarbonate and inotropic drug treatment independently increased the survival rate (p < .001 for both effects). No interaction between these two treatment effects was observed. CONCLUSIONS Both epinephrine and norepinephrine increased the survival rate in tricyclic antidepressant poisoning in rats. Sodium bicarbonate increased the survival rate independent of inotropic drug treatment. Furthermore, epinephrine was superior to norepinephrine when used both with and without sodium bicarbonate, and the most effective treatment was epinephrine plus sodium bicarbonate.

Severe amitriptyline overdose: Relationship between toxicokinetics and toxicodynamics

The clinical features and toxicokinetics of amitriptyline were studied in nine patients with severe amitriptyline poisoning. Amitriptyline and amitriptyline metabolites were studied in plasma, red blood cells, and cerebral spinal fluid. Eight patients were intubated and six required assisted ventilation. Two patients had ventricular arrhythmias, three patients convulsions and two were hypotensive. All complications developed within four hours of admission. Early in the course of the intoxication the QRS duration correlated with plasma, unbound and red blood cell nortriptyline concentration. The QRS duration also correlated with unbound but not the plasma amitriptyline concentration. The level of consciousness correlated with the plasma and unbound amitriptyline both in alpha and beta phase and with red blood cell amitriptyline in alpha phase. There was no correlation between nortriptyline concentration and level of consciousness. No correlation between coma grade or QRS duration and cerebral spinal fluid concentration of amitriptyline was found. There was no correlation between any hydroxymetabolite in blood or cerebral spinal fluid and QRS duration or coma grade. The beta half-life for amitriptyline was shorter for two patients with high concentrations of hydroxymetabolites. Although intubated, neither patient required assisted ventilation or developed complications. Because of the wide range of concentrations of amitriptyline and amitriptyline metabolites observed between individuals, it is not possible to predict outcome based on a single tricyclic antidepressant concentration.

Effects of magnesium sulfate and lidocaine in the treatment of ventricular arrhythmias in experimental amitriptyline poisoning in the rat.

ObjectivesAmitriptyline poisoning is associated with ventricular arrhythmias. Standard treatment is sodium bicarbonate but further intervention may be necessary. The present study compared the actions of lidocaine and magnesium sulfate on ventricular tachycardia induced by amitryptline. DesignNonrandomized, controlled, intervention trial. SettingUniversity laboratory. SubjectsThirty male Wistar rats anesthetized with pentobarbital and mechanically ventilated. InterventionsAfter pretreatment with nore-pinephrine, the animals were subjected to a continuous infusion of amitriptyline. After the appearance of ventricular tachycardia, they were treated with magnesium sulfate (45 mg/kg + 15 mg/kg/min) or lidocaine (1 mg/kg + 0.5 mg/kg/ min) or glucose infusion as a control. Measurements and Main ResultsIn the group treated with magnesium sulfate, electrocardiogram tracings demonstrated that nine often animals converted from ventricular tachycardia to sinus rhythm compared with one of ten in both the lidocaine- and glucose-treated groups (p < .001). The animals treated with magnesium sulfate also had a significantly longer total time in sinus rhythm (10.0 ± 1.6 mins) than those rats treated with lidocaine (1.7 ± 1.5 mins) or glucose (1.5 ± 1.5 mins). Magnesium sulfate significantly decreased blood pressure and heart rate, but no severe hemodynamic side effects were observed. ConclusionsMagnesium sulfate is effective in converting ventricular tachycardia in hyperadrenergic amitriptyline poisoning. in contrast, lidocaine had no effect on arrhythmias. (Crit Care Med 1994; 22:494–498)

Effects of Epinephrine and Norepinephrine on Hemodynamic Parameters and Arrhythmias During a Continuous Infusion of Amitriptyline in Rats

Epinephrine and norepinephrine were evaluated in treatment of hemodynamic compromise in amitriptyline intoxication. One hundred and one male Wistar rats were monitored hemodynamically during amitriptyline intoxication and given one of three infusion rates (0.1, 0.5 or 5.0 mg/kg/min) of either epinephrine or norepinephrine. Sixteen rats served as controls and received only glucose after intoxication. Amitriptyline intoxication lowered mean arterial pressure, heart rate, left ventricular max dP/dt, and increased left ventricular end-diastolic pressure. All doses of norepinephrine and the two higher doses of epinephrine increased mean arterial blood pressure and left ventricular max dP/dt. Heart rate increased with both drugs, more with epinephrine, but not beyond pre-intoxicated levels at any dose. Left ventricular end-diastolic pressure was unaltered by both drugs. Malignant arrhythmias appeared in 7% of all animals, whereas a progressive decline of cardiac contractility caused cardiac arrest in 36% of all animals. This suggests that myocardial depression is the aspect most likely to cause death. At intermediate doses epinephrine resulted in significantly fewer arrhythmias and lower mortality compared to norepinephrine. We conclude that epinephrine and norepinephrine each appeared effective in reversing amitriptyline-induced hemodynamic alterations. Epinephrine had fewer arrhythmogenic properties than norepinephrine and may be preferable to norepinephrine.

Effects of epinephrine, norepinephrine, magnesium sulfate, and milrinone on survival and the occurrence of arrhythmias in amitriptyline poisoning in the rat.

Objectives: Cardiac depression is the main adverse effect of severe tricyclic antidepressant poisoning. The aim of this study was to compare the effects of several inotropic drugs on survival and the occurrence of arrhythmias in the treatment of amitriptyline poisoning. Design: Nonrandomized, controlled intervention trial. Setting: University laboratory. Subjects: Eighty‐six male Wistar rats anesthetized with pentobarbital and mechanically ventilated. Interventions: Rats subjected to a 60‐min continuous infusion of amitriptyline (1.25 mg/kg/min) were treated with a continuous infusion of either epinephrine, norepinephrine, milrinone, magnesium, epinephrine + magnesium, or norepinephrine + magnesium. Measurements and Main Results: Without treatment, all animals exhibited arrhythmias on the electrocardiogram within 20 mins. All treatment drugs delayed the onset of arrhythmias, but significant differences were only observed after administration of epinephrine, epinephrine + magnesium sulfate, and norepinephrine + magnesium sulfate. All the inotropic drugs markedly increased survival. Sodium concentrations were unaffected by all treatments. In control animals, potassium concentrations increased during amitriptyline infusion. Norepinephrine treatment had no effect on potassium concentrations, whereas all other treatments resulted in decreased potassium concentrations. Conclusions: All inotropic drugs used in the study increased survival in tricyclic antidepressant poisoning in rats without increasing the risk of arrhythmias. Furthermore, epinephrine and norepinephrine + magnesium sulfate were effective in preventing arrhythmias, possibly due to improved hemodynamic performance or potassium homeostasis. (Crit Care Med 1994; 22:1851–1855)

Use of intravenous lipid emulsion in the resuscitation of a patient with cardiovascular collapse after a severe overdose of quetiapine

Abstract Background. Quetiapine is an atypical antipsychotic medication that is increasingly being used in the treatment of psychotic disorders and depression. An overdose of quetiapine is associated with hypotension, sinus tachycardia, and sedation. The clinical effects of its overdose are often mild to moderate, but a severe overdose can cause cardiovascular collapse and death.Intravenous lipid emulsion (ILE) is a proposed treatment for potentially lethal cardiotoxicity after severe overdoses with lipophilic drugs, such as quetiapine, mainly by the sequestration of the lipophilic toxin to an expanded intravascular lipid phase. Objectives. To report a case where ILE was successfully used in the resuscitation of a patient with cardiovascular collapse after a severe quetiapine overdose. Case report. A 42-year-old woman was admitted to the Emergency Department after being found unconscious at home, due to an estimated ingestion of 24 g of quetiapine (Seroquel). She was initially cardiorespiratory stable and unresponsive with a Glasgow Coma Scale of 3. The woman was immediately admitted to the Intensive Care Unit, where her condition quickly deteriorated. She was intubated, due to loss of airway. In addition, a gastric lavage was performed and activated charcoal was administered. The patient presented with cardiovascular collapse refractory to vasopressor treatment and volume resuscitation. ILE bolus followed by continuous infusion was administered. Her blood pressure started increasing 5 min after ILE was initiated and within an hour circulation was stabilized. The patient recovered completely without any residual symptoms, after 3 days in the ICU. Conclusions. ILE may potentially be life-saving in cases of severe quetiapine poisoning and should be considered as a treatment for severe cardiovascular instability resulting from quetiapine poisoning refractory to maximum conventional therapy.

Amitriptyline and amitriptyline metabolites in blood and cerebrospinal fluid following human overdose.

The toxicokinetics of amitriptyline were studied in nine patients admitted to hospital in Matthew-Lawson Coma Scale grade III-IV after an estimated ingestion of 1-5 g amitriptyline. Gastric lavage was performed and 50 g activated charcoal were given orally. Venous blood samples were taken on admission and at 1, 2, 4, 8, and 24 h, and in some patients at 36 and 48 h after admission. Arterial blood samples were taken at 1, 4, 8, and 24 h after admission. Lumbar punctures were performed 1 h after admission in 8 patients and again 4 h later in 5 patients. A urine sample was screened for other drugs. The bound and unbound fraction of amitriptyline and its metabolites nortriptyline, E and Z forms of 10-OH-amitriptyline and nortriptyline were analyzed in plasma, whole blood, red blood cells, and cerebrospinal fluid using an HPLC technique. The T1/2 alpha and T1/2 beta for amitriptyline were 1.5 - 3.1 and 15 - 43 h respectively. The rate of elimination of amitriptyline was not dose-dependent. The arteriovenous differences in the total amitriptyline+nortriptyline concentration were maximal in patients admitted soon after intake of drugs. Amitriptyline concentrations in cerebrospinal fluid were quantitatively similar to the unbound amitriptyline concentration in blood. The highest cerebrospinal fluid amitriptyline concentration was 506 nmol/L. There were large individual differences in plasma, blood and cerebrospinal fluid concentrations between different individuals. Repeated quantitative analysis of amitriptyline and its metabolites is unlikely to contribute to the clinical management of most patients with amitriptyline overdose.

Severe overdose of quetiapine treated successfully with extracorporeal life support

Background. Quetiapine is a second-generation antipsychotic drug, used mainly in the treatment of psychotic disorders. Overdose is associated with sedation, tachycardia and a prolonged QT-interval on the ECG. Cardiovascular symptoms are uncommon but in severe cases profound cardiovascular depression may occur. Objectives. To report a case where extracorporeal circulatory support (ECCS) was used successfully in severe quetiapine overdose. Case report. A 40-year-old woman was admitted to the emergency department (ED) with reduced consciousness apparently due to intoxication. She had a history of schizophrenia and was treated with 900 mg of quetiapine daily. In the ED, she presented with immeasurable low blood pressure, irregular bradycardia, hypothermia and a Glasgow Coma Scale (GCS) of 8. An immunoassay test for tricyclic antidepressive agents (TCA) was positive. Despite resuscitation with intravenous fluids, intensive vasopressor treatment and renal replacement therapy (CRRT) the patients condition deteriorated. The patient was quickly moved to an intensive care unit where ECCS could be instituted. The patient subsequently recovered after 4 days in the ICU without any residual symptoms. Further laboratory analysis did not confirm the immunoassay finding. Conclusions. Severe poisoning with quetiapine may imitate tricyclic antidepressant poisoning, and drug screening methods may be falsely positive for TCA. In case of cardiovascular collapse due to quetiapine overdose, ECCS may be life saving.