Concomitant Acute Toxic Leukoencephalopathy and Posterior Reversible Encephalopathy Syndrome.

BACKGROUND AND PURPOSE: Posterior reversible encephalopathy syndrome (PRES) and acute toxic leukoencephalopathy (ATL) are both potentially reversible clinicoradiologic entities. Although their magnetic resonance imaging (MRI) findings differ, rarely both may occur simultaneously in acutely encephalopathic patients. Our aim was to determine the incidence and causes of concomitant "ATL-PRES." METHODS: Retrospective search of suspected acutely encephalopathic adults since 1998 throughout our picture archiving and communication system revealed 167 patients with PRES and 106 patients with ATL. Images of these patients were retrospectively evaluated by two neuroradiologists and a fellow to identify the cases which carry both features of PRES and ATL. Imaging findings were scored based on previously reported scoring system as mild, moderate, and severe. The clinical outcome of the patients was determined according to the modified Rankin scale. RESULTS: Our search revealed a series of 6 patients (%2.2) in 273 patients who presented acutely with either encephalopathy or seizures, caused by various etiologies, including immunosuppression following transplantation (n = 2), hypertensive crisis (n = 2), chemotherapy (n = 1), and sepsis (n = 1). MRI demonstrated findings consistent with both PRES and ATL simultaneously on FLAIR and diffusion weighted imaging. Severity of imaging findings of concomitant "ATL-PRES" was concordant with each other (rho ≈ 1.0, P < .00001), and each patient eventually returned to clinical baseline. This finding, along with their similar etiologies, raises the possibility of an underlying common pathophysiologic thread, perhaps being endothelial toxicity. CONCLUSIONS: Concomitant "ATL-PRES" was found in 2.2% of the patients in a large cohort of ATL and PRES. Etiologies varied. Clinical symptoms and MRI findings were potentially reversible.

Risk assessment of accidental nortriptyline poisoning: the importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator.

It is not possible to make a prospective clinical study that reveals the importance of the nortriptyline metabolising cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) in relation to attaining potential toxic nortriptyline concentrations with a possibly fatal outcome. Therefore to study this we have applied the population based pharmacokinetic simulator Simcyp. The objective was to estimate how important CYP2C19 and CYP2D6 phenotype status, hepatic activity of CYP3A4, body weight, CYP2D6 phenotype dose adjustment, and drug-drug interactions are with regard to accidental poisoning in a virtual population receiving a daily dose of 100mg nortriptyline. Accidental poisoning is here defined as intake of a normal dose which because of slow metabolism may lead to potentially toxic concentrations. The input parameters values for Simcyp were based on average literature in vitro and in vivo data. The Simcyp simulations of nortriptyline pharmacokinetics reflected reported clinical concentration-time profiles, therapeutic drug monitoring data, and the consequence of CYP2D6 poor metaboliser (PM) and ultrarapid metaboliser status. Of the investigated factors, the simulations indicate that having CYP2D6 PM status is a major risk factor for attaining high concentrations and thereby possibly becoming poisoned by nortriptyline. Of the CYP2D6 PM subjects 16% would attain plasma concentrations exceeding the toxic limit. Individuals with the combination of CYP2D6 PM status and 10% of the average liver CYP3A4 expression had a 90% risk of becoming poisoned. The results point towards the combination of low CYP3A4 activity and CYP2D6 PM status of major importance for attaining possibly toxic nortriptyline concentrations. In a forensic toxicological context, the results indicate that both the activity of CYP3A4, information on possible drug-drug interactions, and the genotype of CYP2D6 are needed in order to elucidate whether an individual might have been accidentally poisoned because of slow metabolism. In a clinical context, the simulations suggest that precise individual dose adjustment of nortriptyline requires information regarding the activity of both CYP3A4 and CYP2D6. This underlines the value of therapeutic drug monitoring for nortriptyline. Population based pharmacokinetic simulations are considered useful tools for risk assessment in clinical and forensic toxicology.

Detection of amitriptyline, nortriptyline and bromazepam in liver, CSF and hair in the homicidal poisoning of a one-month-old girl autopsied 8 months after death.

We reported on the death by poisoning of a one-month-old baby that had followed the death of one of her sister (due to cyamemazine overdose). Exhumation of the corpse was done 8 months after burial and revealed the presence of amitriptyline. Parent drug and its metabolite were analysed by HPLC-MS/MS in positive ionisation mode on a C(18) analytical column using a gradient of acetonitrile and 2mM formate buffer at pH=3. Quantification is based on the main ion m/z=233, the common product ion of nortriptyline (MH(+), m/z 264), amitriptyline (MH(+), m/z 278) and nortriptyline D3 used as internal standard (MH(+), m/z 267). Amitriptyline and nortriptyline in the liver were measured at a concentration of 29.8 and 3.6 µg/g, respectively. Hair analyses revealed the presence of amitriptyline and nortriptyline at concentrations of 1811 and 43 pg/mg, respectively, while complementary analyses showed the presence of bromazepam in the hair at a concentration of 740 pg/mg, thus documenting previous administrations. The mother confessed later having used the drinkable form of the pharmaceutical LAROXYL(®) by pouring the content of a 20 ml bottle (at 40 mg/ml) into the feeding-bottle of her child. The milk was sweet but still bitter and following the testimony of a close relative, the whole family helped to feed the crying baby.

Tricyclic antidepressants intoxication in Tehran, Iran: epidemiology and associated factors.

BACKGROUND: Tricyclic antidepressant (TCA) intoxication contributes a large number of drug toxicities with serious complications. There are a few studies about factors associated with TCA intoxication. This study therefore aimed to identify determinants of this type of intoxication. METHODS: A cross-sectional study was carried out at Loghman-Hakim Poison Hospital during a 6-month period. All poisoned patients aged >12 years presented to this hospital during the mentioned period were evaluated. Then, TCA-poisoned patients were compared with other drug intoxications as the control group to determine factors associated with TCA intoxications. RESULTS: There were 9809 admissions, of which 1583 (16.1%) patients including 601 (38%) males were intoxicated with TCAs. Mean age of the subjects was 26.5 + 10 years. Most of the TCA intoxications (74.4%) were intentional (p = 0.01). Amitriptyline was the most frequent agent followed by Nortriptyline. There was no significant difference between TCA and non-TCA intoxications regarding the mortality (1.3% in TCA vs. 1.1% in others, p = 0.45). Logistic regression analysis revealed that sex, addiction status, and history of psychological problems have association with TCA intoxication. CONCLUSIONS: The results of this study are helpful in identifying individuals who are prone to TCA intoxication and may be useful in implementation of preventive strategies.

Tako-tsubo syndrome following nortriptyline overdose.

BACKGROUND: Tako-tsubo syndrome (TTS) refers to the apical ballooning of the left ventricle observed when angiographic ventriculography is performed in patients presenting with electrocardiographic changes suggestive of acute coronary syndrome (new transient ST-segment deviation (>0.05 mV) or T-wave inversion (>0.2 mV)), mild elevation of cardiac markers, but normal coronary arteries at the angiogram. CASE REPORT: A 54-year-old woman developed the characteristic features of TTS 44 hours following nortriptyline overdose. The admission ECG showed increased QRS duration rapidly reversible after sodium bicarbonate infusion. There was a minimal increase in troponin I level. The ECG performed at the time of chest pain revealed deeply negative T waves in leads I, II, III, aVF, V1 to V6 and remained abnormal at 5 weeks follow-up. In contrast, a complete recovery of left ventricular function was observed within one week. DISCUSSION: The pathophysiology of TTS, a variant of myocardial stunning, is still incompletely understood but could be related to sympathetic overstimulation. The possibility of TTS following toxic exposure is discussed.

Effects of amiodarone in a swine model of nortriptyline [corrected] toxicity.

OBJECTIVES: Antiarrhythmics can have devastating effects in cardiotoxic poisonings. Amiodarone is recommended for treatment of wide complex tachycardia, but its hemodynamic effects in wide complex tachycardia induced by tricyclic antidepressant poisoning are unknown. The objective of this study was to compare the effects of sodium bicarbonate, amiodarone, and normal saline in treating wide complex tachycardia secondary to nortriptyline poisoning. METHODS: This unblended randomized controlled animal study involved 18 anesthetized, intubated pigs with arterial and venous lines. Nortriptyline (2 mg/mL) was infused at 20 mg/min until the onset of toxicity, defined as a systolic blood pressure < or =50 mmHg or QRS > or =120 ms. At that point, the pigs were randomized into three groups of six. Group I received 0.9% normal saline, 10 ml/kg. Group II received hypertonic sodium bicarbonate, 1 mEq/kg. Group III received amiodarone, 15 mg/kg. The pigs were observed until death or survival at 60 minutes. RESULTS: After treatment, the changes in QRS were as follows: Group I, -2.0 ms; Group II, -33.0 ms; Group III, -21.7 ms. ANOVA demonstrated no significant difference between the groups (p = 0.28). Mean arterial pressures 10 minutes after treatment were as follows: Group I, 19.4 mmHg; Group II, 23.7 mmHg; Group III, 12.5 mmHg. Based on ANOVA, there was no significant difference between any of the groups (p = 0.50). CONCLUSIONS: In this model of nortriptyline poisoning, the administration of amiodarone to correct wide complex tachycardia did not have a harmful effect.

Excess fatality from desipramine and dosage recommendations.

Higher case fatality rates (CFR) were previously reported from desipramine than for 3 other tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, and imipramine. The database of the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) for the 20 years 1983-2002 was used to evaluate the CFR of desipramine and the other TCAs. The CFR of desipramine was 2.25-, 2.31-, and 2.62-fold the CFR for amitriptyline, nortriptyline, and imipramine, respectively (P < 0.001). Mechanisms of desipramine toxicity and its dosage recommendations are discussed. Desipramine and nortriptyline have higher distribution volumes and erythrocyte/plasma ratios than their parent compounds imipramine and amitriptyline. This implies lower therapeutic plasma levels and reduced doses for desipramine and nortriptyline compared with their parent compounds. Such adjustments have been done for nortriptyline, but not for desipramine. The authors suggest that the high CFR of desipramine might be reduced by lowering its dose, therapeutic plasma level, and maximal pill content.

Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution.

A 29-year-old woman ingested 8 g of nortriptyline and presented to the emergency department with coma, hypotension, and widened QRS interval. After intubation, gastric lavage, hyperventilation, and therapy with intravenous normal saline solution, sodium bicarbonate boluses (rapid intravenous push), and high doses of norepinephrine and dopamine, she transiently improved, only to deteriorate on arrival to the ICU. Because her arterial pH was alkalemic at 7.5 at this point, she was given additional sodium in the form of 200 mL of 7.5% NaCl by means of rapid intravenous infusion (intravenous push) to treat hypotension and widening QRS interval with ventricular ectopy. A continuous 12-lead ECG documented narrowing of her QRS interval with concomitant improvement of hypotension within 3 minutes of hypertonic saline solution infusion. Hypertonic saline solution should be considered for wide complex QRS and hypotension caused by tricyclic antidepressant-induced cardiotoxicity that is unresponsive to standard therapies.

Toxicokinetics of nortriptyline and amitriptyline: two case reports.

Two cases are presented of intentional intoxications with the tricyclic antidepressants (TCAs) nortriptyline (NT) and amitriptyline (AT). The peak plasma concentrations were 2290 microg/L and 2900 microg/L, respectively. The active metabolites E-10-hydroxynortriptyline (EHNT) and Z-10-hydroxynortriptyline (ZHNT) profiles were quite different as monitored for 5 to 10 days after presumed drug intake. In conclusion, these cases illustrate that (1) metabolite formation and elimination after intake of an overdose dose of NT and AT are stereoselective, and (2) NT and EHNT toxicokinetics and toxicodynamics are quite different. It also shows that a patient with a severe TCA overdose can still survive if he or she receives appropriate and quick supportive care, even if the prognostic markers QRS time, coma grade, and serum TCA levels predict poor outcome.

[Progressive cerebellar atrophy following acute antidepressant intoxication].

A 37-year-old woman presented with acute cerebellar atrophy after ingesting toxic doses of tricyclic antidepressants in an attempt of suicide. Two hours after ingestion, she was comatose and showed myoclonus of the limbs, and eventually developed status epileptics. The patient underwent general anesthesia with thiopental, she had hyperpyrexia with elevated muscle enzymes and leukocytosis. These clinical and laboratory features suggested that she had serotonin syndrome (SS). After recovery from coma and hyperpyrexia that had lasted for 7 days, she showed cerebellar ataxia, and progressive cerebellar atrophy of CT scan. As well as neuroleptic malignant syndrome, the SS may cause cerebellar degeneration, probably due to sustained hyperpyrexia.

Falsely elevated lithium levels in plasma samples obtained in lithium containing tubes.

CASE REPORT: We present a case of lithium poisoning in a 15-month-old child. Delayed elevation of the plasma lithium concentration at 13 hours after admission to a hospital was noted. This appeared to be factitiously related to the collection of samples in a speckled green top tube which contains lithium heparin as an anticoagulant. CONCLUSION: This type of false elevation has not been reported in the medical literature. A follow-up study in five healthy volunteers showed that the lithium concentrations of plasma samples obtained in speckled green top tubes are increased by approximately 1.5 mEq/L (1.5 mmol/L).

Recurrent hypotension immediately after seizures in nortriptyline overdose.

Cardiovascular deterioration after seizures in tricyclic overdose has long been suspected. The investigators studied a patient with a nortriptyline HCI level of 1,205 ng/mL who had four generalized grand mal seizures, each lasting between 60 and 90 seconds that were immediately followed by hypotension requiring norepinephrine support. When the seizures were controlled with midazolam, the hypotension subsided and norepinephrine was decreased. The metabolic acidosis associated with the seizures may have caused hypotension by direct cardiotoxicity, an increase in bioavailability of tricyclic antidepressant because of changes in protein binding, an alteration of the effects of tricyclic antidepressant on cardiac membrane sodium channels, or a combination of these mechanisms.

The study of tricyclic antidepressants in formalin-fixed human liver and formalin solutions.

The stability of amitriptyline, nortriptyline, desipramine and imipramine in formalin-fixed human liver tissue and formalin solutions was investigated. The levels of the tricyclic and its primary demethylated metabolite in the frozen liver were determined and compared with levels obtained in the formalin-fixed liver and formalin solutions in which the liver was stored. It was obvious that some methylation of the secondary amine, nortriptyline, to the corresponding tertiary amine, amitriptyline, and of desipramine to imipramine took place in the formalin environment. Nortriptyline was not detected in most cases, suggesting that it may degrade more rapidly than desipramine. There was no consistent ratio between the concentration of the drug in the frozen liver tissue versus formalin-preserved tissue or versus formalin solution. The methylation rates of the secondary amines could not be quantitated. Storage of the liver tissue in formalin at room temperature resulted in leaching of the drugs into the formalin solution. The drugs tested may be detected for up to 22 months in the formalin-fixed liver and in the formalin medium.

Profound alkalemia during treatment of tricyclic antidepressant overdose: a potential hazard of combined hyperventilation and intravenous bicarbonate.

Two patients with cardiovascular and neurologic toxicity from intentional tricyclic antidepressant overdose received bicarbonate infusions in association with hyperventilation for alkalinization. Both patients developed profound alkalemia. One patient died, and the other patient's alkalemia resolved prior to her death. Bicarbonate infusions have become the standard of care for symptomatic tricyclic antidepressant toxicity. Severe alkalemia (pH greater than 7.60) in other settings has been reported to correlate with higher rates of mortality. Careful monitoring of the pH is imperative when bicarbonate therapy is used. It is probably prudent to keep the pH level in the range 7.45 to 7.60. Capnography may also be useful in monitoring patients during alkalinization.