Theophylline toxicity: Successful management of a patient with distributive shock secondary to drug overdose.

Presenting a case of acute theophylline and salbutamol overdose with distributive shock. Twenty one years old lady presented with history of consumption of 3 gram of theophylline and 40 mg of salbutamol. On admission she had altered sensorium with the systolic blood pressure of 60 mmHg, unrecordable diastolic blood pressure and heart rate of 147/min. Investigations revealed severe metabolic acidosis, hypokalemia, hypocalcemia which was managed by intravenous fluids, vasopressors, infusion of injection calcium gluconate and injection potassium chloride. As her hemodynamic status did not improve, she has been initiated on 1.5 mL/kg of lipid emulsion as bolus and then 0.5 mL/kg/h as infusion. Her hemodynamic status improved gradually and she was discharged in 24 h. Lipid emulsion had been used in local anesthetics and many tablet overdoses. In this patient timely administration of lipid emulsion resulted in early recovery of shock.

Availability and cost of extracorporeal treatments for poisonings and other emergency indications: a worldwide survey.

BACKGROUND: Extracorporeal treatments (ECTRs) are used for different conditions, including replacement of organ function and poisoning. Current recommendations for ECTRs in various poisonings suggest that intermittent haemodialysis (IHD) is the most efficient technique. However, the practicality of these recommendations is poorly defined in view of limited information on availability and cost worldwide. METHODS: A survey invitation to an Internet-based questionnaire was emailed between January 2014 and March 2015 to members of international societies to determine the availability, time to initiation and cost of ECTRs (including filters, dialysate, catheter, anticoagulant and nursing/physician salary). The median cost ratio of every ECTR compared with IHD performed in the same institution were presented. RESULTS: The view rate was estimated at 28.1% (2532/9000), the participation rate was 40.1% (1015/2532) and the completion rate was 16.0% (162/1015). Respondents originated from 89 countries, and nearly three-fourths practiced in a tertiary care centre. A total of 162 respondents provided sufficient data for in-depth analysis. IHD was the most available acute ECTR (96.9%), followed by therapeutic plasma exchange (TPE; 68.3%), continuous renal replacement therapy (CRRT; 62.9%), peritoneal dialysis (PD; 44.8%), haemoperfusion (HP; 30.9%) and liver support devices (LSDs; 14.7%). IHD, CRRT and HP were the shortest to initiate (median = 60 min). The median cost ratios of each ECTR compared with IHD were 1.7 for CRRT and HP, 2.8 for TPE, 6.5 for LSDs and 1.4 for PD (P < 0.001 for all). The median cost ratio of a 4-h IHD treatment compared with 1 day in the intensive care unit was 0.6 (P = 0.2). CONCLUSIONS: IHD appears to be the most widely available ECTR worldwide and is at least 30% less expensive than other ECTRs. The superior efficacy of IHD for enhanced elimination, added to its lower cost and wider availability, strengthens its preference as the ECTR of choice in most cases of acute poisoning. KEYWORDS: costing, CRRT, EXTRIP, hemodialysis, hemoperfusion.

[Myocardial infarction in the course of digoxin and theophylline poisoning].

The aim of this paper is to present a case of the patient who was hospitalized in the Toxicology and Cardiology Department because of suicidal digoxin and theophylline intoxication. Both drugs have complicated mechanism of action and affect cardiovascular system differently, but both predispose to ventricular and supraventricular arrhythmias. In the presented patient conduction disorders, cardiac muscle repolarization disorders and ventricular arrhythmias typical to digoxin poisoning were observed. During hospitalization the patient experienced the ECG and biochemical abnormalities resulting from myocardial infarction. In our paper we have analyzed digoxin and theophylline mechanisms of action and possible impact of each of these drugs on the clinical symptoms that our patient presented.

Severe theophylline poisoning treated with continuous venovenous hemodialysis in a child.

Theophylline poisoning generally occurs due to acute high dose intake as well as chronic intake of the medication. Toxicity symptoms can be seen with a plasma concentration of theophylline over 20 µg/ml. The consequences of theophylline toxicity include metabolic disturbances (hypokalemia, hyperglycemia, and metabolic acidosis), nausea, vomiting, and in severe cases seizures, cardiac arrhythmias, and death. Theophylline poisoning in children is rarely described in the literature. A 3-year-old girl was referred from another hospital to our pediatric intensive care unit (PICU) due to prolonged refractory status epilepticus and respiratory failure linked with severe theophylline poisoning. The patient was admitted to our PICU 24 hours after the patient took theophylline. The referring center could not measure the serum theophylline level. The patient's first serum theophylline level that was checked at admission was 54 µg/ml. We started continuous venovenous hemodialysis (CVVHD) 3 hours after PICU admission and the patient's theophylline level successfully decreased within 9 hours. The patient was discharged at the 40th day of admission from our hospital with severe neurological disability. In conclusion, severe theophylline poisoning may be seen in children. We must consider CVVHD in critically ill children with severe theophylline poisoning.

Intermittent haemodialysis and sustained low-efficiency dialysis (SLED) for acute theophylline toxicity.

INTRODUCTION: Theophylline overdose can result in significant cardiovascular and neurologic toxicity and is potentially fatal. Clearance of theophylline can be enhanced by the administration of multiple-dose activated charcoal (MDAC) and extracorporeal elimination techniques. We report a case of severe theophylline toxicity initially treated with MDAC and intermittent haemodialysis. Subsequent to this, sustained low-efficiency dialysis (SLED) was undertaken. This is a prolonged renal replacement therapy that uses blood and dialysate flow rates between those of intermittent haemodialysis and continuous renal replacement therapy. CASE REPORT: A 61-year-old man presented following ingestion of 24 g of theophylline SR (300 mg/kg), 240 mg of diazepam and 2 g of gabapentin. He required intubation and developed a supraventricular tachycardia treated with esmolol, but suffered no seizures. Serum theophylline concentration peaked at 636 µmol/L (55-110) at 9.5 h post-ingestion. Intermittent haemodialysis was performed for 4 h and resulted in a theophylline extraction ratio of 0.57 with elimination half-life of 2.3 h. SLED was subsequently performed on two occasions for 7 h. Theophylline extraction ratio ranged from 0.46 (half-life 5.3 h during the first cycle) to 0.61 (half-life 10.6 h during the second cycle). After cessation of SLED, elimination half-life was 26 h. The patient made an uneventful recovery. DISCUSSION: Intermittent haemodialysis is the current recommended extracorporeal technique for enhancing theophylline elimination in the absence of charcoal haemoperfusion. However, SLED produced similar apparent extraction ratios with longer associated elimination half-life for theophylline than for intermittent haemodialysis. SLED is undertaken by intensive care unit (ICU) staff and may be a useful extracorporeal elimination technique in cases where access to intermittent haemodialysis, requiring specialist dialysis nursing staff, is limited or may be delayed.

Extracorporeal treatment for theophylline poisoning: systematic review and recommendations from the EXTRIP workgroup.

BACKGROUND: The Extracorporeal Treatments in Poisoning workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTRs) in poisoning. Here, the workgroup presents its systematic review and recommendations for theophylline. METHODS: After a systematic review of the literature, a subgroup reviewed articles, extracted data, summarized findings, and proposed structured voting statements following a pre-determined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Anonymous votes were compiled, returned, and discussed. A second vote determined the final recommendations. RESULTS: 141 articles were included: 6 in vitro studies, 4 animal studies, 101 case reports/case series, 7 descriptive cohorts, 4 observational studies, and 19 pharmacokinetic studies, yielding a low-to-very-low quality of evidence for all recommendations. Data on 143 patients were reviewed, including 10 deaths. The workgroup concluded that theophylline is dialyzable (level of evidence = A) and made the following recommendations: ECTR is recommended in severe theophylline poisoning (1C). Specific recommendations for ECTR include a theophylline concentration [theophylline] > 100 mg/L (555 µmol/L) in acute exposure (1C), the presence of seizures (1D), life-threatening dysrhythmias (1D) or shock (1D), a rising [theophylline] despite optimal therapy (1D), and clinical deterioration despite optimal care (1D). In chronic poisoning, ECTR is suggested if [theophylline] > 60 mg/L (333 µmol/L) (2D) or if the [theophylline] > 50 mg/L (278 µmol/L) and the patient is either less than 6 months of age or older than 60 years of age (2D). ECTR is also suggested if gastrointestinal decontamination cannot be administered (2D). ECTR should be continued until clinical improvement is apparent or the [theophylline] is < 15 mg/L (83 µmol/L) (1D). Following the cessation of ECTR, patients should be closely monitored. Intermittent hemodialysis is the preferred method of ECTR (1C). If intermittent hemodialysis is unavailable, hemoperfusion (1C) or continuous renal replacement therapies may be considered (3D). Exchange transfusion is an adequate alternative to hemodialysis in neonates (2D). Multi-dose activated charcoal should be continued during ECTR (1D). CONCLUSION: Theophylline poisoning is amenable to ECTRs. The workgroup recommended extracorporeal removal in the case of severe theophylline poisoning.

Successful treatment of life threatening theophylline intoxication in a pregnant patient by hemodialysis.

High-flux hemodialysis is the extracorporeal treatment of choice for various life threatening intoxications. Most published reports support the use of hemoperfusion in the context of severe theophylline poisoning, but the technique is limited by its significant side-effects. We present a potentially life threatening theophylline overdose treated with hemodialysis in a pregnant patient. For the first time the amount of theophylline removed was measured in the total collected spent dialysate, after a 3.75 hour hemodialysis and an 8 hour extended dialysis.

Iatrogenic intravenous medication errors reported to the GIZ-Nord Poisons Center Göttingen.

BACKGROUND: We analyzed the iatrogenic intravenous medication errors (IIME) reported to the GIZ-Nord Poisons Center Göttingen. METHODS: IIME over a ten year period were analyzed retrospectively and categorized into error types, age groups, drugs involved, and severity of IIME at registration and after known outcome. RESULTS: 265 IIME were registered from 1997 to 2006. They rose from 12 in 1997 to 45 in 2006 corresponding to an increase from 0.058 to 0.148% of all calls of the respective year. Children were affected in (21.1%) and adults in 78.9% of all cases. The drug classes (ATC classification) involved most frequently were antipsychotics (7.9%) and antithrombotic agents (6.0%). The main types of IIME were dosing error (37.7%) and wrong route of administration (28.7%). The severity of IIME at registration was none (33.6%), minor (32.5%), moderate (13.6%), severe (13.6%), fatal (1.5%), and unratable (5.2%). In the 46 cases followed to a known outcome, 15 were asymptomatic and 27 were symptomatic with minor (11 cases), moderate (5 cases) and severe features (11 cases). Four cases of IIME were already fatal at registration and one severe case died in the further course. Dosing error of theophylline was often observed in severe outcomes. CONCLUSION: IIME increased from 1997 to 2006. Intravenous use of antipsychotics and theophylline should be restricted to a minimum.

Overdose of methyldopa, indapamide and theophylline resulting in prolonged hypotension, marked diuresis and hypokalaemia in an elderly patient.

An 89-year-old man with a history of hypertension, chronic obstructive pulmonary disease, personality disorder and previous attempts of self-poisoning attempted suicide by swallowing two mouthfuls of tablets (methyldopa 250 mg, theophylline SR 200 mg, indapamide 2.5 mg and paracetamol 500 mg). He had prolonged, severe hypotension, necessitating the use of 3000 ml of Gelofusine and almost 2 days of intravenous norepinephrine infusion. He had marked diuresis for 4.5 days, requiring continuous and bolus infusions of intravenous fluids. He had marked renal potassium loss, requiring vigorous potassium replacement therapy. Multiple-dose activated charcoal was used to enhance theophylline elimination. The plasma paracetamol level was below the treatment line. Methyldopa via its metabolite stimulates postsynaptic alpha-adrenergic receptors in cardiovascular control centres in the brain, causing a reduction in peripheral sympathetic tone and a fall in arterial blood pressure and heart rate. In overdose, it causes hypotension, bradycardia and drowsiness. The natriuretic, kaliuretic and vasodilatory effects of indapamide are exaggerated in overdose, resulting in diuresis, hypokalaemia and hypotension. Theophylline markedly increases the level of circulating catecholamines, which stimulate the vascular beta(2)-adrenergic receptors with decreased peripheral vascular resistance. Peripheral vasodilation and hypotension occur in significant theophylline poisoning. Intracellular shift of potassium results in hypokalaemia. The prescribing physicians should recognise elderly patients at a high risk of self-poisoning and avoid using drugs with a high toxicity in overdose (e.g. theophylline and methyldopa). Restricting access to hazardous drugs (in overdose) would be of paramount importance to reduce the number of severe acute poisoning cases and case-fatalities.

[Hypokalaemia in a suicide attempt of an adolescent girl]. / Hypokalémie u suicidálního pokusu dospívající dívky.

In acute theophylline poisoning hypokalaemia, hyperglycaemia, and other electrolyte disturbances may occur. These abnormalities have been attributed to catecholamine excess with intracellular movement of potassium and catecholamine-stimulated gluconeogenesis. Herein we describe a female teenager, who developed metabolic disturbances with significant toxic response to oral theophylline overdose in a suicide attempt. Severe hypokalaemia (1.8 mmol/L) was among the leading pathological findings, at peak theophylline concentration (68 mg/L). There was high plasma glucose (10.2 mmol/L). Creatinine-kinase was evidently abnormal (8.60 microkat/L) several hours post poisoning, while serum myoglobin was markedly elevated (74.8 microg/L) despite the decrease in the drug level. Ventricular arrhythmia with marked extra systoles has been confirmed on electrocardiograph. Finally, the patient recovered through intensive care management with theophylline level (21.1 mg/L) falling close to reference range after 48 hours, but relative hypokalaemia persisted despite potassium supplementations even after the drug level fall below detection limit. In conclusion, timely gastrointestinal decontamination, determination of serum drug levels in intervals, electrocardiography evaluation followed by treatment of arrhythmias, supportive care including balancing of metabolic disturbances, follow-up assessment of serum electrolytes, in particular potassium and creatinine-kinase parallel with myoglobin level assessment even after significant decrease in theophylline level are very important measures.

The role of continuous renal replacement therapy in the treatment of poisoning.

Extracorporeal elimination of drugs and toxins is a critical component in the management of poisonings, though specific techniques and indications remain a matter of debate. Conventional hemodialysis is frequently the treatment of choice because of its widespread availability and proven effectiveness for certain drugs and toxins. With the increased availability of continuous renal replacement therapy (CRRT) modalities, there is yet another therapeutic option, but one that has yet to find a definitive role in this field. The continuous nature of these therapies is attractive for the management of acute renal failure, but the relatively slower clearance rates as compared to conventional hemodialysis is a distinct drawback in patients with acute xenobiotic-induced toxicity. There are abundant case reports as well as a few small case series in the medical literature documenting the use of CRRT, but specific techniques and the clinical outcomes vary considerably. Therefore one cannot draw definitive conclusions regarding benefit. Some patients, particularly those who are hemodynamically unstable and are not candidates for conventional hemodialysis, may warrant a trial of CRRT. However, at the present time, routine use for the treatment of poisoning is not supported. Controlled trials to better clarify its role would be beneficial, though such studies would be extremely difficult to conduct in this field. We believe that the intelligent application of extracorporeal modalities requires a thorough knowledge of drug pharmacokinetics, of the techniques utilized, and a skeptical analysis of the available literature.

The use of therapeutic plasmapheresis in the treatment of poisoned and snake bite victims: an academic emergency department's experiences.

The objective of this study is to describe the clinical status, procedural interventions, and outcomes of critically ill patients with poisoning and snake bite injuries presenting to a tertiary-care emergency department for treatment with therapeutic plasmapheresis. Records of 20 patients who presented to our academic emergency department over a 2-year period and who underwent plasmapheresis for poisoning or snake bite were retrospectively reviewed. Plasmapheresis was performed using centrifugation technology via an intravenous antecubital venous or subclavian vein catheter access. Human albumin or fresh frozen plasma were used as replacement fluids. Data extracted from the patient record included demographic data, clinical status, and outcome measures. Sixteen patients underwent plasmapheresis because of toxicity from snake bite. Three patients were treated for drug poisoning (phenytoin, theophylline, bipyridene HCl) and one patient for mushroom poisoning. Haematologic parameters such as platelet count, PT, and INR resolved rapidly in victims of snake bite injuries after treatment with plasmapheresis. Loss of limbs did not occur in these cases. Seven patients required admission to the intensive care unit. One patient with mushroom poisoning died. Mean length of hospital stay was 14.3 days (range 3-28 days) for all cases. Plasmapheresis was a clinically effective and safe approach in the treatment of snake bite envenomation and other drug poisoning victims especially in the management of hematologic problems and in limb preservation/salvage strategies. In addition to established conventional therapies, emergency physicians should consider plasmapheresis among the therapeutic options in treatment strategies for selected toxicologic emergencies.

[For which cases should clinicians perform blood purification in the management of acute poisoning? Clinical and pharmacological analyses].

Indications for performing blood purification such as direct hemoperfusion (DHP), hemodialysis (HD) and hemodiafiltration (HDF) in patients with acute poisoning were retrospectively analyzed. Although a quick improvement in consciousness level was achieved by an intensive treatment with DHP for three hours in 27 patients suffering from acute tranquilizer poisoning, a slow but safe recovery was surely obtained in another 111 cases who received general supportive care. The medical costs of patients treated by DHP were 2.07 times greater than those of cases treated by general supportive care. Plasma and urine concentrations of theophylline could be obtained simultaneously during the treatment by DHP. The excretion rate of DHP at 1, 2, 3 and 6 hours after starting DHP ranged from 99.4% to 96.0%. At the end of DHP, the clinical findings markedly improved and sufficient elimination from the body could be obtained. The rebound phenomenon was observed after three hours DHP in one case of acute anilin poisoning and the patient died of fatal fulminant hepatic failure at 9th hospital day. In this case, further DHP was needed. DHP is presently becoming less prevalent due to concerns over such issues as rapid metabolism and elimination efficacy in acute organophosphate and aconitine poisoning. In a case of 23-year old female who took a potentially fatal dose of 100 g of acetaminophen, blood purification was not performed and oral N acetylcysteine antidotal therapy was quite effective in order to prevent hepatic injury. The serum acetaminophen concentration was 287 microg/ml on her admission and the value fell to 28.8 microg/ml after 35 hours. These results indicate that blood purification is not always necessary because of it's poor elimination efficacy in some kinds poisoning. Nevertheless, in severe cases it was quite an effective and useful extracorporeal elimination technique for both improvement of clinical outcome and clearance of poisons. Although it is difficult to draw a definitive conclusion from this study, it is suggested that a rapid and prudent decision should be made as to perform blood purification.