Acute isoniazid toxicity and the need for adequate pyridoxine supplies

A 25-year-old, 54-kg Hispanic man who had recently started multidrug therapy for pulmonary tuberculosis presented in status epilepticus after ingesting 9 g of isoniazid in a suicide attempt. Successful management of this patient required collaboration between several institutions to provide the large amount of necessary intravenous pyridoxine. Ultimately, this single overdose depleted the supply of intravenous pyridoxine for a significant region of the state of Nebraska. Isoniazid is commonly used to treat tuberculosis, but it is encountered relatively infrequently as the cause of an acute overdose. Severe isoniazid overdoses may present as seizure activity that is refractory to conventional antiepileptic therapy. Although intravenous pyridoxine is an effective antidote for isoniazid overdoses in patients presenting with status epilepticus, this agent has few indications and is typically stocked in limited quantities. In regions with large populations of patients who receive antituberculosis therapy, collaborative networks must be created to ensure that adequate supplies of intravenous pyridoxine (> or = 20 g) are available for effective treatment of isoniazid poisonings.     

Isoniazid overdose : a case series, literature review and survey of antidote availability

Tuberculosis has re-emerged as a significant public health threat over the last decade both globally and within Australia. This is thought to be largely due to the HIV epidemic, a growing itinerant population, and immigration. The antibiotic isoniazid remains an integral part of drug therapy. With the numbers of patients receiving isoniazid remaining high, the number of cases of acute poisoning is expected to be significant. This paper presents a series of two cases of isoniazid poisoning presenting to a tertiary referral centre in North Queensland. Isoniazid toxicity produces a triad of coma, metabolic acidosis and seizures. The seizures are often refractory to traditional antiepileptics. A specific antidote is available (pyridoxine [vitamin B6]) and both patients were administered this as part of their treatment. We also surveyed all hospitals in Australia with an accredited adult Emergency Department to assess the availability of pyridoxine.     

Inadequate stocking of antidotes in Taiwan: is it a serious problem?

OBJECTIVE: Insufficient hospital stock of a variety of poisoning antidotes is a worldwide problem. In an attempt to establish an antidote storage and distribution system for the response of the various poisoning accidents, we conducted a nationwide survey to characterize the current availability of selected antidotes and their anticipated need in Taiwan. MATERIALS AND METHODS: A questionnaire was mailed to 834 hospitals to gather information on the availability, anticipated need, and preferred purchase policy of 20 selected antidotes. A survey on the availability of cyanide antidote in 523 cyanide-handling facilities and their neighboring hospitals was also conducted. RESULTS: Hospitals of different size and service levels had a statistically significant difference in response rates. Except for pyridoxine, the availability and anticipated need for antidotes also varied significantly among different hospital groups. We found that physostigmine, cyanide antidote kit, BAL, EDTA, methylene blue, Vipera Russell formosensis antivenin, and botulism antitoxin were not available in most (>90%) hospitals. Interestingly, these antidotes are also among the most needed antidotes. Most hospitals preferred a government-ordered purchase of antidotes. In the survey of cyanide-processing facilities, a response rate of 24.1% was obtained and only 9.3% of these 107 facilities that both replied to the questionnaire and continued handling cyanide products had stocked cyanide antidote. It is noteworthy that cyanide antidote was also frequently lacking in the neighboring hospitals. CONCLUSIONS: The appropriate storage of antidotes in hospitals or workplaces in rural areas is instrumental in the timely treatment of certain poisonings, while nationwide unavailability is the critical problem. Raising awareness of the importance of antidotes by education, regular review of antidote storage, distribution plans, and appropriate legislation might provide solutions.     

Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs

Treatments for acute isoniazid (INH) intoxication have included, singly and in various combinations, a great variety of drugs. As a consequence it is difficult to evaluate the efficacy of these antidotes, except for pyridoxine, the most commonly recommended one. In some cases of INH poisoning evaluation is further complicated because of concurrent alcohol ingestion. The objectives of this investigation were to determine whether ethanol enhances the toxic effects of acute INH overdose, as suggested by some clinical reports, and to evaluate the antidotal efficacy of phenobarbital, pentobarbital, phenytoin, ethanol, or diazepam when each is administered in combination with pyridoxine. Male dogs were either pretreated with iv ethanol and challenged 1 hr later with po INH, 50 or 75 mg/kg, or they were given INH, 75 mg/kg, and injected iv 30 min later with the test drugs, alone or in combination with pyridoxine. Ethanol pretreatment not only did not enhance the toxicity of INH but, in fact, it reduced the severity of convulsions, although it did not change the mortality rate. In the antidotal study, none of the five CNS depressants or anticonvulsants protected against clonic-tonic seizures or death. Pyridoxine, however, reduced the severity of the seizures and prevented death, although it did not completely block convulsions. The combination antidotal treatments (pyridoxine plus each of the CNS drugs) were the most effective; they prevented both convulsions and lethality. It is suggested that pyridoxine is the basic antidote for treatment of acute INH poisoning, and that the addition of an anticonvulsant or a CNS depressant to the therapy enhances effectiveness.     

Extracorporeal treatments for isoniazid poisoning: Systematic review and recommendations from the EXTRIP workgroup

Isoniazid toxicity from self-poisoning or dosing errors remains common in regions of the world where tuberculosis is prevalent. Although the treatment of isoniazid poisoning is centered on supportive care and pyridoxine administration, extracorporeal treatments (ECTRs), such as hemodialysis, have been advocated to enhance elimination of isoniazid. No systematic reviews or evidence-based recommendations currently exist on the benefit of ECTRs for isoniazid poisoning. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup systematically collected and rated the available evidence on the effect of and indications for ECTRs in cases of isoniazid poisoning. We conducted a systematic review of the literature, screened studies, extracted data on study characteristics, outcomes, and measurement characteristics, summarized findings, and formulated recommendations following published EXTRIP methods. Forty-three studies (two animal studies, 34 patient reports or patient series, and seven pharmacokinetic studies) met inclusion criteria. Toxicokinetic or pharmacokinetic analysis was available for 60 patients, most treated with hemodialysis (n = 38). The workgroup assessed isoniazid as “Moderately Dialyzable” by hemodialysis for patients with normal kidney function (quality of evidence = C) and “Dialyzable” by hemodialysis for patients with impaired kidney function (quality of evidence = A). Clinical data for ECTR in isoniazid poisoning were available for 40 patients. Mortality of the cohort was 12.5%. Historical controls who received modern standard care including appropriately dosed pyridoxine generally had excellent outcomes. No benefit could be extrapolated from ECTR, although there was evidence of added costs and harms related to the double lumen catheter insertion, the extracorporeal procedure itself, and the extracorporeal removal of pyridoxine. The EXTRIP workgroup suggests against performing ECTR in addition to standard care (weak recommendation, very low quality of evidence) in patients with isoniazid poisoning. If standard dose pyridoxine cannot be administered, we suggest performing ECTR only in patients with seizures refractory to GABA_A receptor agonists (weak recommendation, very low quality of evidence).     

Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dogs

Because information regarding efficacious treatment of acute isoniazid (INH) toxicity is incomplete and controversial, diazepam and pyridoxine were investigated as iv antidotes in rats and dogs following administration of po lethal doses of INH. There is a marked species variation in the lethality of INH; the lowest consistently lethal dose is 1500 mg/kg for rats and 75 mg/kg for dogs. Of the two species, the dog more closely approximates man's sensitivity to the lethal effect of INH overdose (80–150 mg/kg). Species variation was also observed in the effects of the antidotes. Diazepam exerted dose-related protection against convulsions in rats; paradoxically, survival was increased by the lowest dose (1 mg/kg) but not by higher doses. In dogs, however, diazepam failed to prevent convulsions but provided dose-related protection against death. Pyridoxine, in rats, did not protect against INH toxicity, but in dogs it showed dose-related effectiveness against convulsions, and all doses (75–300 mg/kg) prevented lethality. Significantly, the highest dose of pyridoxine tested in rats (750 mg/kg) was substantially below the optimal pyridoxine-to-INH antidotal ratio recommended for man (a dose that at least equals the amount of INH ingested), but that dose of pyridoxine would be larger than its LD50 for rats. Combined administration of diazepam with pyridoxine protected against convulsions and death in rats and dogs. Used concurrently, the two antidotes are clearly synergistic for controlling the manifestations of experimental INH overdose. These results have important implications for the management of acute INH intoxication in man.     

Treatment of acute isoniazid toxicity.

The clinical symptoms and treatment of acute isoniazid toxicity are presented. The use of supportive measures and chemotherapy are discussed in detail. The pharmacology and biochemistry underlying the symptons of isoniazid poisoning are aslo presented. It is concluded that diazepam in combination with pyridoxine is the treatment of choice for the management of convulsions associated with isoniazid toxicity. Pyridoxine should be administered intravenously in amounts equal to the estimated quantity of isoniazid ingested, even if seizures have not occurred.     

Measurement of insulin wastage in five Ontario hospitals

This study was designed to determine the extent of insulin wastage and the extrapolated cost of wastage for Ontario hospitals. The five hospitals in the study were chosen to include differences in patient mix and drug distribution systems. Beginning and ending inventories of all insulin types were taken spanning a six-week period. The quantity of insulin dispensed and wasted during this time period was recorded. Partial vials were measured using a calibrated scale. Wastage was calculated as insulin discarded divided by the amount of insulin used in the time period. Insulin wastage averaged 34.1%. This was equivalent to up to $8,000 a year for the largest hospital surveyed and translates to an estimated cost of $360,000 a year in all Ontario hospitals. Therefore, hospitals should estimate their insulin wastage and seek ways to reduce it. The pharmaceutical industry should be encouraged to develop cost-effective insulin delivery systems.     

Availability of antidotes in hospital pharmacies in Greece

We determined the availability of poisoning antidotes in the pharmacies of state hospitals in Greece and in Health Centers of the island of Crete. A questionnaire survey was sent to all pharmacy directors of hospitals with emergency departments, asking them to report anonymously the amount currently in stock of each of 12 common antidotes. Questionnaires were sent to 100 pharmacy directors and 68 (68%) of them replied. Only 2 (3%) of the 68 hospitals stocked all 12 antidotes. The percentage of sufficient stocking for individual antidotes ranged from 6% (for digoxin immune fab) to 91% (for methylene blue). Recent circulation of government guidelines for antidote stocking and hospital type had no significant effect on antidote stocking. In a multiple regression analysis, hospital type (prefectural, regional, university hospital) and smaller hospital size were not predictors of the number of antidotes sufficiently stocked. Storing of key poisoning antidotes is inadequate in regional as well as in prefectural hospitals in Greece. Antidotes, including those which should be used without delay to be effective, are often not available, even for the commoner poisons in Greece such as pesticides.     

Relationship between Serum Acetaminophen Concentration and N‐Acetylcysteine‐Induced Adverse Drug Reactions

Abstract: Intravenous N‐acetylcysteine is usually regarded as a safe antidote. However, during the infusion of the loading dose, different types of adverse drug reactions (ADR) may occur. The objective of this study was to investigate the relation between the incidence of different types of ADR and serum acetaminophen concentration in patients presenting to the hospital with acetaminophen overdose. This is a retrospective study of patients admitted to the hospital for acute acetaminophen overdose over a period of 5 years (1 January 2004 to 31 December 2008). Parametric and non‐parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis. Of 305 patients with acetaminophen overdose, 146 (47.9%) were treated with intravenous N‐acetylcysteine and 139 (45.6%) were included in this study. Different types of ADR were observed in 94 (67.6%) patients. Low serum acetaminophen concentrations were significantly associated with cutaneous anaphylactoid reactions but not other types of ADR. Low serum acetaminophen concentration was significantly associated with flushing (p < 0.001), rash (p < 0.001) and pruritus (p < 0.001). However, there were no significant differences in serum acetaminophen concentrations between patients with and without the following ADR: gastrointestinal reactions (p = 0.77), respiratory reactions (p = 0.96), central nervous reactions (p = 0.82) and cardiovascular reactions (p = 0.37). In conclusion, low serum acetaminophen concentrations were associated with higher cutaneous anaphylactoid reactions. Such high serum acetaminophen concentrations may be protective against N‐acetylcysteine‐induced cutaneous ADR.     

Increasing resistance of M. tuberculosis to anti-TB drugs in Saudi Arabia

The incidence of drug resistance in Mycobacterium tuberculosis (MTB) isolated from our hospital between April 1996 and March 1998 was compared with an earlier study (1993-1995). Thirty (29.7%) of 101 MTB isolates were resistant to one or more anti-TB drugs and 21 (20%) of 101 were multi-drug resistant M. tuberculosis (MDR-TB). Resistance was most common to isoniazid (28.7%), followed by streptomycin (22.8%) and rifampicin (20.8%). Resistance to pyrazinamide and ethambutol was 7.9 and 6.9%, respectively. There was a three-fold increase in resistance compared with the earlier study.     

Acute pancreatitis after nifedipine and acetaminophen poisoning — case report

The incidence of drug-induced pancreatitis is rare. There have been several reports of acute pancreatitis as a complication in acute poisoning with drugs or toxins. We present a case of a young woman with acute pancreatitis secondary to an overdose of nifedipine and acetaminophen in a suicide attempt. We excluded other causes of acute pancreatitis by clinical history, serum toxicology, serology, and abdominal imaging. The most likely underlying pathophysiological mechanism was ischemic injury of the pancreas secondary to severe collapse induced by nifedipine and possible acetaminophen-induced direct pancreatotoxicity. The pancreatitis resolved with treatment that included continuous veno-venous haemofiltration in an intensive care unit. Emergency and intensive care units should be aware of this unusual complication of such poisoning. To our knowledge, this is the first reported association between massive nifedipine overdose and acute pancreatitis.     

Acute opiate overdose in Tehran: the forgotten role of opium

INTRODUCTION: The global epidemic of opiate use continues to spread and is an increasing burden especially in developing countries. Acute opiate overdose (AOO) is one of the most dramatic complications of drug abuse. The purpose of this study is to examine the epidemiology of acute opiate overdose in a poisoning center in Tehran. METHODS: In this cross-sectional survey, patients who attended the emergency room of Loghman-Hakim hospital - the only poisoning center in Tehran - and diagnosed with acute opiate overdose over a six month period were included. RESULTS: Overdose was more common among men (91.2%). The mean and standard deviation of age was 36.9+/-15. The most frequent opiate agent was opium (56.5%) followed by heroin. Opium was most commonly used by regular users, as a single agent and through ingestion. Benzodiazepines, antidepressants and alcohol were the most common agents consumed accompanied with opiates. The mortality rate was 8.8% which was not significantly different between cases of heroin and opium overdose. CONCLUSION: Opium was the major cause of overdose in our study. This result suggests that opium is not a harmless form of addiction although it is regarded as a thing of the past in many countries.     

New product opportunities with DRGs.

Medicare's new payment scheme for hospitals and other cost-containment pressures have changed the way that hospitals do business. The number and duration of hospital patient admissions have declined. Hospitals are more carefully considering the cost of their supplies. As a result, demand for many types of hospital supplies has declined; however, new market conditions have also created opportunities for innovation in the device and pharmaceutical industry. This paper describes the new economic incentives for hospitals and how these translate into new product opportunities in the areas of outpatient care, less-invasive surgical procedures, decreasing length of stay in hospitals or substituting for high labor costs during hospital stays, and generally, products that provide the same quality of care as before but at much lower cost. Specific examples of such products from Rorer Group Inc. are chosen to illustrate the company's attempts to meet the new needs of the hospital marketplace.     

Expanding the accessibility of harm reduction services in the United States: Measuring the impact of an automated harm reduction dispensing machine

BackgroundIn 2021, approximately 107,622 Americans died from drug overdose in the United States. With overdose deaths rising rapidly, it is imperative that prevention efforts focus on expanding proven, evidence-based strategies to curb overdose death rates such as targeted naloxone distribution and syringe service programs (SSPs). The COVID-19 pandemic placed additional strain on SSPs, increasing the need for programs that minimize direct contact and potential COVID-19 exposure. The purpose of this study is to evaluate the impact of an automated harm reduction dispensing machine on the local accessibility of harm reduction services.ObjectivesThe primary outcome of the study is the number of harm reduction supplies distributed to the community by the dispensing machine in its first year compared to the number of supplies distributed by the same organization in the previous year. Secondary outcomes include the countywide incidence of fatal drug overdose and human immunodeficiency virus (HIV) compared to previous years.MethodsThe machine is located outside, in the same location as a once weekly, in-person SSP. Clients register with the program over the phone with a harm reduction coordinator. Each client is connected to products and services such as naloxone, sharps containers, safer injection/smoking kits, pregnancy tests, HIV tests, substance use disorder treatment, and more.ResultsSince installation, 637 individuals registered with the program, 12% of whom had never reportedly used harm reduction services before. Within its first year of use, the machine dispensed 3360 naloxone doses and 10,155 fentanyl test strips, more than any other SSP in the county.ConclusionThe implementation of an automated harm reduction dispensing machine led to an increased accessibility of harm reduction products and services and was associated with a lower countywide incidence of unintentional overdose death and HIV. The association with decreased overdose death and HIV incidence should be further investigated to assess causality.     

Convulsions as the etiology of lactic acidosis in acute isoniazid toxicity in dogs.

The mechanism by which acute isoniazid (INH) overdose causes lactic acidosis is unknown. This study examines the role of convulsion in the development of lactic acidosis in dogs given po lethal doses of INH (75 mg/kg). Following INH, dogs did not develop acidosis until after they had experienced clonic-tonic convulsions. Acidosis, which became more pronounced with successive convulsions, was associated with marked increase of serum lactate (immediate postconvulsive level, 12.3 meq/liter, compared to control of 1.83 meq/liter). Diazepam, 0.5 mg/kg, plus pyridoxine HCl, 150 mg/kg, injected iv immediately following po INH, prevented both convulsions and changes in pH and lactate. When the antidotes were administered after the second convulsion of INH toxicity no further convulsions occurred and blood pH and lactate returned to control levels in 2 hr. “Curarization” of INH-treated dogs prevented both motor seizures and marked increase of lactate. In animals treated with INH and allowed to convulse two times to develop severe acidosis, correction of the acidosis with NaHCO₃ failed to prevent further convulsions and death. Diazepam and pyridoxine combinations, in doses that were ineffective for terminating INH-induced convulsions, became effective when given after correction of acidosis with NaHCO₃. It is concluded that convulsion is the main cause of lactic acidosis in acute INH toxicity and that correction of acidosis does not terminate acute INH toxicity. Although correction of acidosis increases the antidotal effectiveness of diazepam plus pyridoxine, increasing the dose of either or both of these two drugs achieves the same antidotal advantage without the potential problems of metabolic alkalosis which may result from NaHCO₃ administration.     

Seizures induced by theophylline and isoniazid in mice.

Isoniazid-induced seizures respond poorly to anticonvulsants but well to pyridoxine (Vitamin B6); theophylline produces difficult-to-treat seizures with substantial morbidity and mortality. Theophylline therapy depresses plasma pyridoxal-5'-phosphate (PLP), the active metabolite of pyridoxine, suggesting that theophylline-induced seizures might be amenable to treatment with pyridoxine. Our study established the dose-response relationship for convulsions due to isoniazid and theophylline in mice and determined if pyridoxine antagonized such seizures. Female CD-1 outbred mice weighing 25 to 30 g were used. Clonic seizures had clonic activity lasting 5 sec; tonic seizures had loss of the righting reflex with tonic hindlimb extension. Groups of 10 mice received single doses of 50, 100, 150, 200, 250 or 300 mg aminophylline/kg i.p. or 100, 150, 200, 250, 300 or 350 mg isoniazid/kg i.p. and were observed for seizures or death. Pyridoxine or saline with aminophylline or isoniazid were administered simultaneously. The LD50 for aminophylline was 266 mg/kg; for isoniazid it was 160 mg/kg. Doses of 150 mg aminophylline/kg or 100 mg isoniazid/kg did not induce seizures. Pyridoxine with aminophylline or isoniazid did not alter the frequency or time of onset of seizures or death. This was unexpected because pyridoxine antagonizes theophylline-induced seizures in mice and reverses isoniazid-induced seizures in humans. We found no evidence that PLP depletion in mice is a mechanism for seizures induced by isoniazid or aminophylline in a fashion similar to isoniazid in humans.     

Satisfactions and dissatisfactions with public and private hospitals

A fully national sample of 1255 people were questioned about their degree of satisfaction with hospital care in New Zealand. Questions covered both public and private hospitals and concerned actual experience of care as well as general attitudes to that care. Almost half the sample (49%) rated public hospital care as "excellent" or "very good", and a similar proportion (48%) assigned those grades to private hospitals. Only 7% of the sample rated public hospital care as "poor" or "very poor" and only 1% rated private hospitals in this way. Major reasons for satisfaction with public hospital care were the high standard of nursing care (41% of sample), the high qualifications of staff (34%) and the availability of appropriate equipment for emergencies (17%). The most common complaints were that hospitals are short-staffed/overworked (15%) and there are long waiting lists (14%). Reasons for satisfaction with private hospital care were no waiting (26%), good standard of care (20%) and good hotel facilities (14%). In general, both public and private hospitals were highly regarded. Dissatisfaction with public hospitals was most evident amongst younger, working people and amongst those in the north and central regions. Dunedin respondents were more satisfied with their hospital care than those in other parts of the country.