Mixed Overdose Research Articles

Gabapentinoid prescribing patterns and predictors utilizing neural networks: An analysis across emergency departments Nationwide between 2012 and 2021

BackgroundGabapentinoids increasingly utilized for neuropathic pain, possibly to curb opioid prescribing. At the same time, data suggest subsequent increases in misuse and overdose of gabapentinoids, often in mixed overdoses. We sought to determine national trends and characteristics of gabapentinoid prescribing, including co-use with opioids, from the emergency department (ED). MethodsThis is a retrospective review of the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2012 to 2021. Our primary outcome was the trend in ED visits in which gabapentinoids were prescribed at discharge. Secondarily, we identified trends in gabapentinoid and opioid co-prescribing and gabapentin and pregabalin prescribing at ED discharge. We examined demographic data and used descriptive statistics, Shapiro Wilke's test, Pearson's Spearman's rho (SR) or Pearson's correlation coefficient (PC) as applicable. Neural networks were used to identify the most important predictors of opioid utilization during the same visit. ResultsBetween 2012 and 2021, there were an estimated 7,242,694 (0.53% of all ED visits) visits in which gabapentinoids were prescribed at ED discharge. Prescriptions increased from a total of 138,479 (0.1%) in 2012 to 893,495 (0.63%) in 2021 (PC: 0.85, p < 0.001). Opioids were co-prescribed in 27.2% of all visits in which gabapentinoids were prescribed, with no change over time (PC: −0.47, p = 0.09). Pregabalin prescription increased linearly over time (PC: 0.64, p = 0.02).The most important predictors of opioid administration or co-prescribing were whether an alternative provider (e.g., consult or nurse practitioner) saw the patient (100%), insurance (94.4%), age (75.9%), and region (75.2%). ConclusionDespite an association of misuse and overdose, often associated with opioids, gabapentinoids were increasingly prescribed at ED discharge. While these agents may be safer alternatives to opioids, misuse may be an associated consequence of increased prescribing, which warrants further investigation.

A case of a mixed overdose involving kratom (Mitragyna speciosa) leading to serotonin syndrome

Objective: Drug overdose deaths have risen precipitously over the past two years in the United States. Polysubstance overdose with opiates and amphetamines have been of particular concern. Kratom (Mitragyna speciosa) is an unregulated widely available herb with both stimulant and opiate μ-receptor activity. Studies suggest that its use is quickly increasing. Case: We describe a patient who presented to a psychiatric hospital with a mixed toxic syndrome due to chronic kratom and prescribed SSRI use compounded by acute intake of methamphetamine. The patient displayed psychosis, tremulousness, myoclonus, and extreme anxiety. Her clinical picture was consistent with both serotonin syndrome and opiate withdrawal. Conclusion: We call attention to this case because polysubstance overdoses are common, and kratom is widely available. Complex toxic presentations that involve kratom are likely to be increasingly encountered.

Angiotensin axis antagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channel blocker poisoning

Context Amlodipine, a dihydropyridine calcium channel blocker (CCB), is the leading cause of cardiovascular drug-related overdose deaths in the USA. In contrast, angiotensin-II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) cause minimal toxicity in overdose. ACEIs/ARBs are often combined with dihydropyridines in hypertension treatment. Co-ingested ARBs/ACEIs may significantly contribute to the toxicity of dihydropyridine, but this has not been investigated. Objective To investigate the clinical outcomes from dihydropyridine overdoses with ARBs/ACEIs versus dihydropyridine overdoses alone. Methods This was a retrospective study of patients reported to the New South Wales Poisons Information Centre (NSW PIC) and 3 toxicology units (Jan 2016 to Jun 2019) in Australia. Patients >14 years who took an overdose of dihydropyridines (amlodipine, felodipine, lercanidipine, nifedipine) were included. Concurrent overdoses with non-dihydropyridine CCBs, alpha-blockers and beta-blockers were excluded. Patient demographics, drugs exposure details, serial vital signs, treatments and outcome were collected. Results There were 100 patients. 68 took mixed overdoses of dihydropyridines with ARBs/ACEIs and 32 took single overdoses of dihydropyridines without ARBs/ACEIs. The mixed group had lower median nadir mean arterial pressures (62 vs 75 mmHg, p < 0.001), more frequently had hypotension (OR 4.5, 95%CI: 1.7–11.9) or bradycardia (OR 8.8, 95%CI: 1.1–70). Multivariable analysis indicated the mixed overdoses had an 11.5 mmHg (95%CI: 4.9–18.1) lower minimum systolic blood pressure (SBP) compared with the single group; other factors associated with a lower minimum SBP were higher doses [2.3 mmHg (95%CI: 1.1–3.5) lower per 10 defined daily doses] and younger age [2.2 mmHg (95%CI: 0.3–4.2) higher per decade]. A larger proportion of the mixed ingestion group received intravenous fluids (OR 5.7, 95%CI: 1.8–18.6) and antidotes and/or vasopressors (OR 2.9, 95%CI: 1.004–8.6). Conclusion Combined overdoses of dihydropyridines with ARBs/ACEIs caused more significant hypotension and required more haemodynamic support than overdoses of dihydropyridines alone.

LIVING OFF THE FAT OF THE LAND: LIPID INFUSION FOR THE UNKOWN OVERDOSE

SESSION TITLE: Fellows Critical Care Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Lipid infusions are incorporated in the treatment of a variety of medication overdoses. We have found no study to date examining the use of lipids for unknown overdoses or ingestions that present lacking the signs and symptoms of a definitive toxidrome CASE PRESENTATION: A 30-year-old male with a history of drug abuse, ADHD, Crohn disease, and diverticulitis, presented to the ED from a drug and alcohol rehabilitation center with encephalopathy and incontinence. He admitted to taking a “Party Box” containing unknown hallucinogens and random pills. Urine drug screen was positive for benzodiazepine, cocaine, cannabinoid, opiate, and barbiturates. Labs showed a WBC of 16.7, chloride of 109, and bicarbonate of 21. He received IV fluids, lorazepam, and haloperidol before admission. On day 2 a rapid response was initiated for unresponsiveness. The patient had bradycardia, closed eyes, and involuntary lower extremity movement. EKG showed junctional bradycardia with rate of 38 bpm. A 1 Liter 20% IV lipid emulsion was administered over 2 hours. After 1 hour the bradycardia resolved. At 2 hours involuntary movements ceased. He was intubated for airway protection despite some improvement in mentation. By day 3 he was hemodynamically stable, awake, calm, and was extubated. DISCUSSION: For over 20 years, lipid infusions have been administered in animal models to reverse bupivacaine related cardiovascular collapse resulting in return of spontaneous circulation. Human case reports show efficacy treating lamotrigine, bupropion, calcium channel blocker, beta blocker, antipsychotic, tricyclic antidepressant, and local anesthesia systemic toxicity. Large scale human studies are absent. Although reported in the popular press for decades, parties where individuals trade various drugs—prescription or illicit—the incidence of this activity is unclear. Regulatory agencies and medical societies do not this behavior. PubMed searches for “pill party”, “fruit-salad party”, and “pharm party” returned no relevant results CONCLUSIONS: Our patient reported taking an unknown quantity of unspecified pills with subsequent cardiovascular and neurologic disturbances. Polypharmacy was manifest in our patient and drawing on the clinical signs and symptoms iabove, there was concern that this presentation could not be explained by drugs of abuse alone. To explain his bradycardia, we suspect that he may have ingested an AV nodal blocking agent. There is established benefit in using lipid infusions for specific overdoses. Data are inadequate in the routine use of lipids for unknown overdoses. The use of lipids for unknown overdoses that are associated with hemodynamic anomalies and neurological disorders merits further study, as it appears to carry a favorable risk-benefit potentia Reference #1: Weinberg GL. Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology. 2012;117(1):180–187 Reference #2: Lashari BH, Minalyan A, Khan W, Naglak M, Ward W. The Use of High-dose Insulin Infusion and Lipid Emulsion Therapy in Concurrent Beta-blocker and Calcium Channel Blocker Overdose. Cureus. 2018;10(11):e3534. Published 2018 Nov 1. doi:10.7759/cureus.3534 Reference #3: Hopkins LE, Sunkersing J, Jacques A. Too many pills to swallow: A case of a mixed overdose. J Intensive Care Soc. 2017;18(3):247–250. doi:10.1177/1751143717693860 DISCLOSURES: No relevant relationships by Firth Bowden, source=Web Response No relevant relationships by Edward Gray, source=Web Response No relevant relationships by Ali Nabavi, source=Web Response

Age-related differences in self-harm presentations and subsequent management of adolescents and young adults at the emergency department

BackgroundCharacteristics of self-harm differ across ages, but there is little work identifying age-related differences in younger people. Young people entering adolescence face emotionally and developmentally different challenges to those entering adulthood. This study investigates how Emergency Department (ED) presentations and management of self-harm differ through adolescence and early adulthood. Methods3782 consecutive self-harm episodes involving 2559 people aged 12–25 years were identified from an existing database of Leeds ED attendances from 2004 to 2007. Odds ratios for each of four age bands were compared to the remaining young people. ResultsThe female to male ratio was 6.3:1 at 12–14 years old, decreasing with successive age groups to 1.2:1 at 22–25 years old. Self-poisoning was commoner in those under 18 years old. 18–25 year olds were more likely to self-poison with prescribed medications, mixed overdoses, alcohol or recreational drugs. 18–25 year olds more often required medical treatment for the effects of the self-harm. 12–14 year olds were more often seen urgently by ED medical staff and offered high intensity mental health aftercare. Repetition of self-harm was commonest in 12–14 year olds, although multiple repetition of self-harm was commonest in 22–25 year olds. LimitationsData were not collected on whether the aftercare offered was received. The study sample included hospital attenders only. ConclusionsThe large excess of females over males in young people's self-harm is only true at the younger age range. Older adolescents present with more severe acts of self-harm, yet receive the lowest intensity of assessment and after care.

Tramadol Overdose Induced Transient Paresthesia and Decreased Muscle Strength: A Case Series

Background: Tramadol overdose is relatively common in Iran. A series of tramadol poisoned patients with paresthesia and decreased muscle strength are described. Methods: In this prospective cross-sectional study, all referred cases to Mashhad Medical Toxicology Center with suspected tramadol poisoning between 1st July 2010 and 1st September 2012 were included. Patients with mixed overdose, history of neurologic and musculoskeletal disorders including primary seizure, and history of addiction were excluded. Patients were visited on admission, 6 and 12 hours later. All cases underwent complete neurologic examination. Muscle strength was assessed with manual muscle testing. Results: Tramadol overdose accounted for 1026 cases during the study period. Eight hundred eighty nine cases were excluded and finally 137 cases were tramadol only overdose. Most patients (92%) were men. Mean (SD, min-max) age was 24.5 (6.9, 10-42) years. The strength of upper and lower limbs symmetrically declined in the first visit and increased gradually in 6 and 12 hours post-admission, but the strength of lower limbs was more significantly affected on admission and after 6 hours (P < 0.001) compared to upper limbs. Paresthesia happened in 64%, 9% and 0% in upper limbs and 86%, 35% and 3% in lower limbs on admission, and after 6 and 12 hours. No spasticity and flaccidity were observed. On admission, pupils were symmetrically reactive and 6.7 (2.3, 1-11) mm wide. Pupil size significantly declined to 5.6 (2.1, 1.3-9.0) mm 6 hours later (P < 0.001). Conclusion: Transient paresthesia and transient symmetrical decline in muscle strength of upper and lower limbs are potential neurologic complications following tramadol abuse and overdose. Further studies are needed to fully clarify the pathogenesis and mechanism of these complications following tramadol overdose.

Quantification of Pregabalin Using Hydrophilic Interaction HPLC-High-Resolution MS in Postmortem Human Samples: Eighteen Case Reports

Pregabalin is a drug for treating epilepsy, anxiety disorders and neuropathic pain. Cases of poisoning are rare, though some have been fatal. Concentrations of pregabalin in postmortem human samples and its distribution have very rarely been documented. As the literature is so scarce, we propose to report the concentrations in autopsy samples of 18 people who had been taking Lyrica(®), including one case of a mixed overdose involving pregabalin. Analysis was carried out using an original Hydrophilic Interaction LIquid Chromatography (HILIC) technique coupled with a high-resolution mass spectrometer (m/z 160.1334 ± 5 ppm). The sensitivity of the technique enables a quick and simple treatment of the samples by protein precipitation. The method was validated in the whole blood with detection and quantification limits of 0.025 and 0.060 µg/mL, respectively. Pregabalin was a likely factor in the cause of death in 3 of the 18 cases. In the other individuals, the concentrations ranged from 0.4 to 17.0 in the peripheral blood, 1.5 to 11.1 in the central blood, 126.6 to 2004.6 in the urine and 10.5 to 58.3 µg/mL in the bile, with median values of 5.6, 4.6, 534.6 and 17.7, respectively.

Intentional overdose of azathioprine in a patient with systemic lupus erythematosus

A 14-year-old girl with systemic lupus erythematosus presented with a mixed overdose of paracetamol, ibuprofen and azathioprine (1500 mg) following a deliberate self-harm attempt. The patient was admitted and monitored. No adverse effects were observed. A review of the literature showed very few reported azathioprine overdoses. Lupus patients are at risk of developing low mood and depression (and related self-harm including overdose of medication). This can be as a consequence of the disease process itself or in reaction to the stresses of living with a chronic disease, which are perhaps particularly acute in some adolescents with the disease. An intentional overdose in a patient with lupus is clearly a cry for help and should be appropriately managed. Counselling of young people and their parents about possible mood disorders is an important part of the management of this chronic disease. Despite the theoretical risk of significant myelosuppression as well as other potential adverse effects, azathioprine in acute overdose seems to be generally well tolerated.

Intravenous Lipid Emulsion (ILE) Therapy for Severe Felodipine Toxicity

Intravenous lipid emulsion (ILE) is increasingly used for the treatment of poisoning caused by lipid-soluble drugs. We report a case of reversal of cardiovascular collapse after the use of ILE in a patient with a mixed overdose, mainly of the calcium channel blocker felodipine. Conclusions that can be drawn from a single case are limited, but this report provides circumstantial evidence of benefit of ILE for felodipine poisoning. The use of ILE appears justified in cases refractory to conventional therapy.

Towards Safer and More Predictable Drug Treatment - Reflections from Studies of the First BCPT Prize Awardee

This MiniReview is a personal recollection of selected research topics, which the author in collaboration with colleagues has studied, aiming to improve the predictability of drug therapy. In early studies, we found bi- and trivalent cations to reduce the absorption of various tetracyclines and fluoroquinolones. Certain antacids elevated the bioavailability of some non-steroidal anti-inflammatory drugs and sulphonylureas. Various brands of phenytoin tablets revealed great differences in their bioavailability, causing clinical consequences. Numerous factors affecting the antidotal effect of activated charcoal were also studied, with charcoal compared to other gastrointestinal decontamination methods, including ipecac and gastric lavage. Effect of age and diseases on the pharmacokinetics of drugs was a research topic. Acute sotalol intoxications revealed its QT-prolonging properties, and even small mixed overdoses of moclobemide with serotonergic drugs proved fatal. Itraconazole and other potent inhibitors of CYP3A4 could drastically increase exposure to drugs like midazolam, triazolam, buspirone, lovastatin, simvastatin and oxycodone, whereas rifampicin greatly reduced their plasma concentrations. A change from potent inhibition to induction caused a 400-fold change in the exposure to oral midazolam. CYP2C8 was revealed to be crucial in the metabolism and interactions of several drugs. Many interactions affecting statins are CYP3A4-mediated, but transporters are important in certain interactions. Tizanidine is very susceptible to CYP1A2 inhibition. Fruit juices such as grapefruit juice can raise or lower exposure to different drugs. Both drug interactions and pharmacogenetics can modify the activity of cell membrane transporters and cause variability in the pharmacokinetics of and response to their substrate drugs.

925 Deliberate Self-Harm and Drug Overdose

Background: DSH is the second most leading cause of death in young people in developed countries outside the USA. NICE have provided guidelines on the management and prevention of DSH. Aim: To re-audit the care of children with DSH in an in-patient setting with view of adherence to the NICE guidelines. Methodology: We analysed 32 children admitted with DSH to a paediatric ward in a 2-year period extending from January 2007 - December 2009. 32 case notes were analysed and compared to the NICE guidelines and the original 2007 audit. Results: The age range was between 10-16 years (median 14) with 78% being females. 37.5% presented with paracetamol overdose, 43.7% mixed overdose and 18.7% physical harm. In the original audit 100% referrals were made to CAMHs compared to 93.7% (30/32) in 2010 of which 93.3% were made within 2 days of admission. 29 patients were assessed prior to discharge and were followed up in OP by CAMHs. Only 6% (11% in 2007) had clear consent for referral to CAMHs documented in the notes. Conclusion: Mixed overdose is the most common mode of DSH, with females the most prevalent demography. NICE guidelines recommend that all children with DSH should be admitted to an acute paediatric ward and be assessed by CAMHs prior to discharge. This audit illustrates that standards are not being met satisfactorily (93.7%). Furthermore as per the guidelines better documentation is required. The availability of an out-of-hours CAMHs team would benefit the management of DSH in children.

The Use of Intralipid in the Management of a Mixed Overdose

A 34-year-old man took a mixed overdose of multiple lipid-soluble drugs. He did not respond to maximal medical therapy but improved after the introduction of Intralipid. The possible mechanisms of action and potential adverse consequences of using Intralipid in this context are reviewed.

Intralipid reverses coma associated with zopiclone and venlafaxine overdose

Intralipid reverses coma associated with zopiclone and venlafaxine overdose

Brugada Syndrome and Brugada ECG Pattern: Unusual Causes of ST Elevation

Brugada Syndrome is a channelopathy that leads to ST elevation or right bundle branch block pattern in the right ventricular leads on ECG analysis and predisposes to ventricular tachyarrhythmias and sudden death. The ECG pattern can also be drug induced with several agents. This case describes a patient who presented after a mixed overdose of amitriptyline, olanzapine and alimemazine with ST elevation and T wave inversion on his ECG that were initially thought to be due to an Acute Coronary Syndrome.

The use of Intralipid for unconsciosness after a mixed overdose

The use of Intralipid for unconsciosness after a mixed overdose

Refractory hypotension and ECG changes in a case of nicorandil and lisinopril overdose and role of vasopressor in management

We present a rare case of a 13-year-old girl who took an intentional mixed overdose of nicorandil, lisinopril and metoclopramide. This is the first reported case in the literature of nicorandil overdose in the paediatric age group. The chief presenting clinical signs were hypoxia, peripheral hypoperfusion and hypotension with tachycardia unresponsive to aggressive intravenous volume expansion. Subsequent ECG changes suggested evolving myocardial ischaemia and were accompanied by complaints of back pain and worsening shortness of breath. Vasopressor therapy led to an immediate resolution of the ECG changes and improved the hypotension. This was continued for a further 24 h, until haemodynamic stability was achieved.

Significant lamotrigine overdose associated with acute pancreatitis

In March 2007, a 24-year{old woman was admitted via the Emergency Department after an act of deliberate self{harm. Five hours prior to admission she had taken 4200 mg of lamotrigine. She denied taking any other medication at the time of this overdose. Her relevant medical history included two previous episodes of mixed overdoses (July 2002 and May 2006), depression and a psychotic episode for which she was treated with mirtazepine 30 mg once daily, lamotrigine 100 mg twice daily and risperidone 2 mg twice daily. At the time of admission she reported a regular intake of two 750 mL bottles of wine per evening, but had no previous history of alcohol{related liver or pancreatic problems. She had drunk two bottles of wine with her overdose. On admission, she was tachycardic, lethargic, dehydrated, showed slurred speech, with cerebellar signs of nystagmus and ataxia. She had no evidence of abdominal tenderness. Arterial blood gas measurements revealed a compensated metabolic acidosis. Full blood count, urea, electrolyte and liver function tests were normal. Her blood alcohol level was 100 mg/100 mL. Paracetamol and salicylate were not detected. A lamotrigine level was not taken because it is not routinely available in our institution. An electrocardiogram showed a sinus tachycardia only. Within 24 hours of admission she complained of upper abdominal pain and vomiting. Serum amylase was 1043 U/L (0–110 U/L). Liver transaminase, full blood count, calcium, glucose, urea and electrolyte levels were within reference ranges. The patient was diagnosed with acute pancreatitis, and at 48 hours achieved a Ranson score of 1 on assessment of severity, predicting a good prognosis, with less than 1% mortality. General supportive treatment was started with intravenous fluid resuscitation, analgesia and antiemetics. Abdominal ultrasound two days after onset of symptoms showed a thickened gall bladder wall, with some surrounding fluid and no evidence of gallstones. Her symptoms as well as amylase levels settled within three days and the patient was discharged five days after the initial overdose. An endoscopic ultrasound of the pancreas was performed six weeks after discharge. This showed a normal gallbladder and common bile duct. The pancreas had no features of chronic pancreatitis and had a normal calibre pancreatic duct. In the 12 months following discharge she was seen twice in the Emergency Department with symptoms and signs consistent with significant alcohol abuse, however on both occasions her amylase was normal.

Coma cocktail: a role for flumazenil?

A common clinical scenario in the emergency department is a patient with a presumed drug overdose. Patients are often unresponsive with respiratory depression and hence unable to give a clear history. When the culprit toxin is known, rapid reversal with administration of the relevant antidote may be life saving. The empirical administration of a ‘coma cocktail’ consisting of naloxone, glucose and thiamine is common in many emergency departments. It is tempting to add flumazenil to this cocktail if there is a suspicion of benzodiazepine misuse; however, the possibility of mixed overdose or any suggestion of long-term benzodiazepine use should influence management choices.

L-carnitine was safely administered in the setting of valproate toxicity

Background l-Carnitine is a carnitine replacement that has been used in carnitine deficiency states. We conducted a review of patients with acute valproate (VPA) poisoning that had an elevated ammonia level and received l-carnitine to address safety. Methods After a brief training of systematic chart review, reviewers blinded to the purpose of the study completed a standardized data collection sheet. Ages, outcomes, side effects, presence of hyperammonemia, and total carnitine doses were recorded. Results Three years of poison center charts from more than 300 000 patients were reviewed; 674 patients ingested valproic acid. The median age was 26.2 years (range, 1-58 years). l-Carnitine was routinely recommended if the ammonia level was elevated. Fifty-five doses of carnitine were administered to 19 patients who had isolated VPA ingestions and 196 doses of carnitine were administered to patients with mixed overdoses that included VPA, all with an elevated ammonia level. No patient had a documented allergic reaction or side effects. Conclusions Two hundred fifty-one l-carnitine doses were not associated with adverse or toxic effects in our VPA toxic patients.

Use of flumazenil in the treatment of drug overdose

To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. An 800-bed, teaching, university-affiliated hospital. Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant "waking" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.