This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chu, J. Articles by Hill, N. S. Search for Related Content PubMed PubMed Citation Articles by Chu, J. Articles by Hill, N. S.

Update in Clinical Toxicology

Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts–New England Medical Center, Boston, Massachusetts; New York City Poison Control Center, Department of Health, New York; Division of Emergency Medicine, New York University School of Medicine, New York, New York; and Grady Health System, Department of Emergency Medicine, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Nicholas S. Hill, M.D., Pulmonary, Critical Care, and Sleep Division, Tufts–New England Medical Center, 750 Washington Street, #257, Boston, MA 02111. E-mail: nhill{at}lifespan.org

Each year, new agents are added to the pharmacopoeia, expanding the list of possible toxicologic reactions. In response, new antidotes are introduced, uses of more established antidotes evolve, and new therapeutic approaches to well-established toxicologic syndromes are developed. This brief update on critical care toxicology focuses on a few of the most important new developments. The recognition and management of the serotonin syndrome are discussed as an example of a toxicologic syndrome that is occurring more frequently as a consequence of the introduction of new pharmacotherapies. New developments in the therapy of well-known toxicologic reactions are next considered in relation to acetaminophen overingestion. Examples of evolving uses of older antidotes include octreotide to treat sulfonylurea overdose and glucose and insulin to treat calcium channel blocker overdose. Finally, we examine new antidotes including fomepizole to inhibit alcohol dehydrogenase, and snake antivenom antibodies to treat envenomations. Critical care specialists must keep abreast of these trends to most effectively care for patients with toxicologic exposures.

GENERAL APPROACH TO TOXICOLOGIC SYNDROMES

The approach to therapy of acute toxicologic syndromes has gradually evolved. The need to obtain a complete history and to seek clues on physical examination remains essential (Table 1). The prehospital care record is important because this represents the patient's status before institution of therapy. On arrival at the hospital, pharmacologic intervention can confound the clinical findings and make it difficult to recognize a specific toxicologic syndrome. The use of emetics is now discouraged, but gastric lavage is still performed routinely in many centers for the prompt removal of pills and fragments. However, even this practice is becoming more selective because of controlled trials indicating that outcomes are not improved by performing gastric evacuation in all patients (1, 2). Gavage should still be performed in patients arriving within an hour of a potentially significant ingestion or after ingestion of toxins that do not adsorb to charcoal, such as heavy metals or lithium (3, 4). Prompt administration of activated charcoal into the gastrointestinal tract remains a mainstay of therapy for most other overingestions, with the exception of small organic compounds that are readily absorbed by the gut (e.g., methanol, ethylene glycol) but adsorb poorly to charcoal (3). A prompt consultation with either the regional poison center or a medical toxicologist as soon as a toxic reaction or overdose is suspected helps to assure that clinicians are providing optimal therapy in a timely fashion.

The medical therapy of psychiatric disorders such as depression and bipolar affective disorders includes agents that increase central nervous system (CNS) serotonin transmission and activity. The serotonin syndrome is a complication of the use or misuse of such medications and is characterized by confusion, autonomic instability, and neuromuscular abnormalities (Table 2). This constellation of symptoms was first seen in the 1950s in patients receiving iproniazid and pethidine (meperidine) and in the 1960s in patients receiving L-tryptophan (5–8). The pathophysiology of the serotonin syndrome is not entirely clear, but animal studies have confirmed the role of serotonin and the identity of the responsible receptors. In rats, serotonin syndrome is blocked by the nonspecific 5-hydroxytryptamine antagonists methysergide and metergoline, but not by specific 5-hydroxytryptamine₂ receptor antagonists such as ketanserin and pipamperone (9). This implicates 5-hydroxytryptamine_1A receptor activation in the brainstem and spinal cord as playing an important role in the genesis of the syndrome.

N-ACETYLCYSTEINE FOR FULMINANT HEPATIC FAILURE FROM ACETAMINOPHEN TOXICITY

Acetaminophen is one of the most commonly used pharmaceutical agents, and it is found in multiple over-the-counter and prescription medications. Not surprisingly, it is also the most common cause of drug overdose reported to the American Association of Poison Control Centers. Management of acetaminophen overdose consists of appropriate gastric decontamination, supportive care, and administration of N-acetylcysteine therapy, based on an adaptation of the Rumack–Matthew nomogram (13). At therapeutic doses, acetaminophen is metabolized primarily by glucuronidation and sulfation in the liver, with a minor proportion of drug undergoing P-450 metabolism to the toxic metabolite N-acetylbenzoquinoneimine, which is detoxified by hepatic glutathione. When excessive quantities of acetaminophen are ingested (i.e., acute ingestions of greater than 7.5 g in an adult or 150 mg/kg in a child) (14), endogenous glutathione stores are depleted, allowing N-acetylbenzoquinoneimine to accumulate and react with cellular proteins, causing hepatic and renal dysfunction.

N-acetylcysteine serves as an antidote by repleting glutathione reserves and acting as a glutathione substitute intracellularly. If given within 8 hours of acetaminophen ingestion, N-acetylcysteine prevents hepatotoxicity (15). Patients who begin N-acetylcysteine therapy later than 8 hours postingestion or have ingested large doses of acetaminophen chronically are at risk of hepatotoxicity despite therapy. A small subset of hepatotoxic patients will develop fulminant hepatic failure. Previously, patients developing fulminant hepatic failure had high morbidity and mortality rates. However, advances in orthotopic liver transplantation and the increasingly liberal use of prolonged intravenous as opposed to limited courses of oral N-acetylcysteine have decreased the mortality of these patients and have led to the development of a set of prognostic criteria to identify those at risk of mortality (16). Patients with the single criterion of a systemic pH less than 7.30 after fluid and hemodynamic resuscitation have a 95% mortality.

In addition, a combination of a prothrombin time greater than 100 seconds, serum creatinine greater than 3.3 mg/dl, and grade III or IV hepatic encephalopathy predicts a mortality of 77% (16).

Although it was long thought that initiation of N-acetylcysteine beyond the first 16 hours after ingestion was probably futile, evidence supporting the idea that late administration might be effective was provided in 1990, when a retrospective analysis showed a significant reduction in mortality of patients with fulminant acetaminophen-induced hepatic failure treated with late intravenous N-acetylcysteine (37% in the treatment group compared with 58% in the untreated group) (17). Among survivors, the mean time from ingestion to the beginning of therapy was 15.5 hours, with a delay of up to 36 hours in one patient (17). Subsequently, a prospective trial randomized 50 patients with fulminant acetaminophen-induced hepatic failure to receive late intravenous N-acetylcysteine versus vehicle control (18). Experimental therapy was continued until each patient either recovered, died, or underwent liver transplantation. The treatment group had a median time from overdose to N-acetylcysteine therapy of 53 hours (range, 36 to 80 hours). Compared with the untreated group, those treated with N-acetylcysteine had reduced mortality (52 versus 80%), a lower incidence of cerebral edema (40 versus 68%), and required less inotropic medication for blood pressure support (all p < 0.05). The beneficial effect of N-acetylcysteine in these patients may be from improved oxygen transport and consumption at the tissue level, as suggested by the increase in the oxygen-extraction ratio among treated patients observed in another trial (19).

Patients who develop fulminant hepatic failure after acetaminophen ingestion, regardless of how much time has passed since the ingestion, should be treated with N-acetylcysteine, preferably via the intravenous route. However, practical constraints or product unavailability may necessitate initiation of therapy by the oral or enteral route. We recommend a loading dose of 140 mg/kg, followed by a maintenance dose of 70 mg/kg every 4 hours. This is continued until the biochemical indicators of hepatotoxicity have improved substantially. If the enteral route is not functioning and intravenous medication is unavailable, it is possible to create an intravenous solution from the oral preparation (20). However, it is important to have an experienced pharmacist prepare the solution because adverse reactions occur frequently, including cutaneous reactions in 10% and bronchospasm in 5%, with a 2.8-fold increased risk in patients with asthma (21). Preparation of a dilute solution with a 0.2-µm pore size filter, slowed infusion of the bolus (over 30–60 minutes), and pretreatment of asthma patients with antihistamines are recommended.

OCTREOTIDE FOR SULFONYLUREA OVERDOSE

The number of different medications to treat diabetes mellitus has increased dramatically, but sulfonylureas remain a mainstay of therapy and overdoses are common. Sulfonylureas inhibit potassium ion efflux in vitro and increase pancreatic ß cell sensitivity to glucose in vivo (22), potentiating the secretion of insulin. Thus, sulfonylurea overdose leads to a hyperinsulinemic state that causes hypoglycemia, the severity and duration of which is related to the potency and half-life of the specific drug ingested. In past studies, the overall mortality of patients experiencing severe hypoglycemia from sulfonylureas was approximately 10% (23). Treatment of sulfonylurea-induced hypoglycemia starts with glucose therapy, oral or intravenous or both, and gastrointestinal decontamination. Other commonly used therapies include glucagon, diazoxide, corticosteroids, and urinary alkalinization to enhance urinary elimination for chlopropamide overdose. In the past, hypokalemia, hypophosphatemia, and rebound hypoglycemia have been problematic, particularly after overdoses of sulfonylureas with prolonged half-lives.

Octreotide is a synthetic analog of somatostatin that has greater potency and a longer duration of action. Besides their inhibitory action on insulin release, somatostatin and octreotide both inhibit CNS release of growth hormone and thyrotropin and secretion of gastrointestinal tract hormones such as gastrin, secretin, and motilin (24). In addition to its emerging role as a therapy for sulfonylurea overdose, octreotide is currently used in the treatment of growth hormone- and thyrotropin-secreting pituitary adenomas, metastatic pancreatic islet cell and carcinoid tumors, bleeding esophageal varices, and secretory diarrhea (25).

Studies examining the effects of somatostatin and octreotide on sulfonylurea-induced hypoglycemia have included animal and volunteer human studies. These have demonstrated the short-term inhibitory effect of somatostatin on insulin release during glucose infusions or tolbutamide administration (26, 27). Compared with somatostatin, octreotide has an equal inhibitory effect on insulin release but a longer duration of action, averaging 6 to 8 hours. In a randomized cross-over study of eight healthy subjects given glipizide orally on three separate days, octreotide infusion lowered insulin levels and glucose infusion requirements significantly more than treatment with glucose alone or diazoxide plus glucose. When therapy was stopped 13 hours after glipizide ingestion, only two of eight subjects developed hypoglycemia after therapy with octreotide, whereas all subjects had rebound hypoglycemia within 90 minutes of stopping therapy with glucose alone or diazoxide plus glucose (28).

Octreotide has now been used successfully in many cases of hypoglycemia secondary to sulfonylurea overdose (29, 30). In these reports, the adult doses ranged from 40 to 100 µg, administered subcutaneously, and frequency of administration ranged from every 6 to every 12 hours. The duration of therapy depends on the duration of action of the sulfonylurea agent, but it can last from 48 to 72 hours. Octreotide is well tolerated and, as long as blood sugars are closely monitored and therapy is continued until hypoglycemia resolves, complications are few and mortality nil. Most of the complications of octreotide occur in patients with acromegaly or insulinomas receiving high-dose long-term therapy, in whom it may worsen glycemic control (31, 32). These problems are rarely encountered in patients undergoing short-term therapy for sulfonylurea overdose. Adverse effects that may be seen during acute administration include injection site pain, nausea, vomiting, diarrhea, and possibly hyperglycemia. Because some patients experience delayed hypoglycemia after cessation of octreotide therapy, they should be observed for rebound hypoglycemia for at least 12 to 24 hours after the last dose (28).

Although octreotide offers mainly convenience advantages and would not be expected to lower the mortality rate compared with a carefully monitored glucose infusion, it is also economical, costing less than $150.00 for a 3-day course of therapy, and potentially reducing the need for frequent glucose measurements. For these reasons, it should now be considered first-line therapy for any patient who ingests a sulfonylurea agent and develops symptomatic hypoglycemia or a serum glucose concentration less than 60 mg/dl that is refractory to dextrose supplementation.

INSULIN AND GLUCOSE IN CALCIUM CHANNEL BLOCKER TOXICITY

Calcium channel blockers inhibit calcium influx by blocking L-type voltage-sensitive calcium channels on the outer cell membrane. This blockade decreases vascular smooth muscle tone, leading to arterial dilation, and has a negative inotropic effect on the myocardium. It also inhibits sinoatrial and atrioventricular nodal functions, causing decreased chronotropy (mainly by the phenylalkylamine and benzothiazepine class agents). In the setting of calcium channel blocker overdose, these effects translate into hypotension and myocardial conduction defects.

The therapy of calcium channel blocker overdose focuses on restoring cardiac function and systemic blood pressure and involves multiple additive therapies. Calcium salts (e.g., chloride, gluconate), glucagon, atropine, catecholamines, phosphodiesterase inhibitors, cardiac pacing, and intra-aortic balloon counterpulsation have all been tried, but no one modality has demonstrated superiority over the others. More recently, insulin and glucose have been added to the list of therapies.

Insulin and glucose have been used in futile attempts to minimize myocardial damage after infarction. This approach was based on the observations that although myocytes normally utilize free fatty acids as substrates for energy metabolism, stressed myocardium shifts to glucose as the preferred substrate (33). More recently, however, experimental studies have shown improved myocardial inotropy and survival in experimental animals with verapamil poisoning treated with insulin infusions as compared with controls (34, 35). In one study, all dogs treated with insulin for their verapamil-induced myocardial toxicity survived, whereas mortality was 100 and 67% among those treated with glucagon and epinephrine, respectively (p < 0.05) (34). These favorable effects may be attributable to counteraction by exogenous insulin of the diabetogenic effect of acute verapamil poisoning, including blockade of pancreatic insulin release and increased systemic insulin resistance (36). In these experimental models, insulin also improved lactate oxidation and reversed the diminished fatty acid uptake of verapamil-toxic myocardium (37).

Although clinical data on the use of insulin and glucose for calcium channel blocker toxicity are scanty, a study of calcium channel blocker toxicity in patients who failed traditional treatments suggests that the beneficial actions that were observed in animals also occur in humans (38). In this case series, the mean insulin infusion rate was 0.5 IU/kg per hour (range, 0.1–10 IU/kg per hour), with systemic blood pressure improving within 60 to 90 minutes. The duration of the insulin infusion depended on the patient's clinical condition and response to therapy, but ranged from 9 to 49 hours with a mean of 27 hours. The major adverse effects were hypoglycemia and hypokalemia (as low as 2.2 mEq/L). Although glucose was infused throughout the insulin infusion, serum glucose concentration fell to less than 60 mg/dl in four of five patients, with the lowest being 29 mg/dl, underscoring the need for close glucose monitoring. The glucose infusion was adjusted accordingly, with peak glucose infusion rates ranging from 10 to 75 g/hour (38).

Based on the current evidence, patients experiencing bradycardia or hypotension after ingesting calcium channel blockers should be initially resuscitated with traditional therapies such as intravenous crystalloid fluids, calcium salts, and glucagon. Those who have persistent hypotension, bradyarrhythmias, or conduction disturbances should be infused with insulin and glucose. Severely bradycardic and hypotensive patients may require vasopressor agents, cardiac pacing, or temporary intra-aortic balloon counterpulsation until they can metabolize the calcium channel blocker.

4-METHYLPYRAZOLE (FOMEPIZOLE) FOR METHANOL OR ETHYLENE GLYCOL INGESTIONS

The traditional management of toxic alcohol ingestions uses ethanol infusions and hemodialysis if serum levels exceed certain thresholds. The two most commonly ingested toxic alcohols, methanol and ethylene glycol (found mostly in windshield washer fluid and automobile antifreeze, respectively), are not themselves highly toxic; however, they produce toxic metabolites when metabolized by alcohol dehydrogenase (see Figure 1) . Therefore, initial therapy is directed at decreasing the production of the toxic metabolites. Ethanol is an effective inhibitor of toxic metabolite production from the toxic alcohols because it has a higher affinity as a substrate for alcohol dehydrogenase. However, to achieve effective inhibition of toxic alcohol metabolism by alcohol dehydrogenase, ethanol levels must be high (at least 100 mg/dl or 25% of the serum toxic alcohol concentration, whichever is higher).

View larger version (16K): [in this window] [in a new window]   Figure 1. Schematic of pathways for methanol and ethylene glycol metabolism. Ethanol saturates and fomepizole inhibits alcohol dehydrogenase (ADH), and both thereby block the formation of toxic intermediates such as formic and glycolic acids. If unmetabolized, methanol and ethylene are slowly excreted intact in the urine, but hemodialysis is often used to speed clearance. Several metabolic intermediates have been omitted for clarity of presentation.

Two prospective, observational multicenter trials have evaluated the effectiveness of fomepizole in toxic alcohol poisoning. In the first (42), 19 patients with ethylene glycol poisoning had substantial improvements of their metabolic acidoses within hours of initiation of fomepizole therapy. In addition, the mean serum glycolate level fell from 89.7 mg/dl (range, 0–264.4 mg/dl) to 0 mg/dl over 24 hours. Seventeen patients underwent concomitant hemodialysis, and nine, who presented later after ingestion and had higher plasma glycolate concentrations (> 97 mg/dl), had impaired kidney function. Eighteen of the 19 patients survived, one succumbing to complications of an acute myocardial infarction that occurred before the initiation of therapy. Fomepizole therapy was administered intravenously, using a loading dose of 15 mg/kg, followed by maintenance bolus doses of 10 mg/kg every 12 hours for 48 hours. The bolus doses were then increased to 15 mg/kg every 12 hours because of autoinduction of fomepizole hepatic metabolism. Therapy was continued until the serum ethylene glycol concentration was less than 20 mg/dl, requiring a mean of 3.5 doses of fomepizole per patient (range, 1–7 doses) (42).

The second study was another prospective observational trial of 11 patients poisoned with methanol (43). Fomepizole treatment was associated with a decrease in serum formic acid concentration, normalization of blood pH from the initial acidemia, and return of visual acuity abnormalities to baseline status by the time of hospital discharge. Seven patients underwent hemodialysis and nine patients survived, with two succumbing to anoxic brain injury that was present at the time of enrollment. The fomepizole dosing regimen was the same as for ethylene glycol described here previously, with patients in the methanol study receiving a median of four doses per patient (range, 1–10 doses). Fomepizole was well tolerated in both studies. Adverse side effects included headache, rash, tachycardia, anxiety, and seizures, but these were deemed more likely to be related to the alcohol ingestion than to the fomepizole.

These studies support the clinical safety and efficacy of fomepizole as an alcohol dehydrogenase inhibitor. It effectively inhibits the formation of toxic metabolites, rapidly improves metabolic imbalances, and prevents end-organ damage (e.g., renal failure or blindness). As shown in Table 4, fomepizole markedly prolongs the elimination half-lives of ethylene glycol and methanol, even more on average than ethanol (44–46), thus effectively preventing the generation of toxic metabolites. Concomitant hemodialysis is still usually required in patients with high alcohol levels or high anion gap acidoses, however, to accelerate the removal of the alcohols and toxic metabolites (44, 46). Although the studies have been uncontrolled and provide no direct comparison to traditional therapy with ethanol, they demonstrate that fomepizole has several advantages over ethanol therapy, including easier administration and monitoring and the avoidance of mental status changes, hypoglycemia, and hepatotoxicity. For these reasons, fomepizole is preferred to ethanol infusion for the therapy of toxic alcohol ingestions. The recommended dosing regimen is the same as that used in the study protocols (42, 43). Patients receiving hemodialysis require an additional bolus dose of 15 mg/kg at the end of each dialysis session, and therapy is continued until the serum ethylene glycol or methanol concentration is less than 20 mg/dl.

SNAKE Fab ANTIVENOM

Most of the roughly 10,000 venomous snake bites reported annually in the United States are caused by members of the subfamily Crotalinae (pit vipers). Pit vipers are divided into three genera: Crotalus (rattlesnakes), Sistrurus (pygmy rattlesnakes and massasauga), and Agkistrodon (copperheads and water moccasins). Crotaline venom is complex and composed of proteolytic enzymes, neurotoxins, cardiotoxins, direct lytic factors, hemolysins, and coagulation and anticoagulation factors (47, 48). Standard treatment for envenomations includes generalized wound care and antivenom therapy. For years, the only antivenom available in the United States has been an equine-derived serum IgG (Antivenin Crotalidae Polyvalent [ACP]; Wyeth, Paoli, PA). Although this antivenin has been effective, its use is associated with a high occurrence (23%) of acute hypersensitivity reactions, including urticaria, anaphylactoid reactions, and anaphylaxis (49). In addition, the incidence of serum sickness can be as high as 80% when more than five vials of ACP are administered (50, 51). Consequently, physicians have hesitated to use antivenom unless patients show moderate to severe signs of envenomation or progression of envenomation (see Table 5).

The treatment regimen for the Fab antivenom is an initial intravenous dose of four to six vials, which can be repeated within 1 hour if the manifestations (e.g., local swelling, coagulopathy) are not controlled after the first dose. An additional two vials are administered every 6 hours for 18 hours to prevent the recurrence of manifestations. Retreatment with two more vials of Fab antivenom is recommended if any of the following occur: fibrinogen less than 50 µg/ml, platelet count less than 25,000/mm³, international normalized ratio (INR) greater than 3.0, activated partial thromboplastin time (aPTT) greater than 50 seconds, or if the coagulopathy worsens (54). All patients treated with Fab antivenom require hospitalization for close monitoring of symptoms and the need for further therapy, and monitoring up to 2 weeks after envenomation may be necessary.

The more favorable side effect profile of the Fab antivenom has established it as the antivenin of first choice for Crotalinae envenomations and, from a risk–benefit perspective, favors earlier initiation of therapy and treatment of milder envenomations. In addition, the manufacturer has stopped production of ACP, so the Fab antivenom has become the only antivenin available for Crotalinae envenomations. However, the Fab antivenom has some disadvantages, including a high rate of coagulopathy and considerable expense. Each two-vial kit costs approximately $1,700 (U.S.), and therefore the drug cost for a complete course of Fab antivenin therapy can be as much as $14,000. Therefore, from a cost–effectiveness perspective, therapy should still be reserved for patients with moderate to severe envenomations.

CONCLUSION

As is the case with most fields in medicine, clinical toxicology has rapidly evolved as the number of toxicologic syndromes and antidotes has increased in response to the ever-expanding pharmacopoeia. In the current update, we have focused on several areas in which significant changes have occurred. In the case of serotonin syndrome, the rapidly increasing use of serotonin reuptake inhibitors in the therapy of depression necessitates that clinicians recognize the manifestations of the syndrome and be aware of potential drug interactions that are likely to produce it. The use of late N-acetylcysteine for fulminant liver injury from acetaminophen overdose is a change in the approach, reflecting new evidence that some amelioration of injury and improved survival may occur, even when used in cases that previously would have been considered irreversible. Octreotide for sulfonylurea overdoses and insulin and glucose for calcium channel blocker overingestions represent newer, inexpensive applications of older therapies. Fomepizole for toxic alcohol ingestions is a new antidote that is becoming a standard of care because of its efficacy and safety in comparison with ethanol infusions, despite its greater expense. Finally, with regard to pit viper envenomations, the older polyvalent antivenom has been replaced with a newer Fab antivenom that is associated with a much lower risk of allergic reactions. The topics covered in this update were selected to highlight developments in the field of clinical toxicology that impact on critical care medicine, but the list is far from exhaustive. Approaches to the management of toxicologic syndromes will undoubtedly continue to expand and evolve, and critical care clinicians are encouraged to keep abreast of new developments.

Acknowledgments

The authors thank Jan Hayden for assistance in preparation of the manuscript.

Received in original form August 31, 2001; accepted in final form March 27, 2002

REFERENCES

1. Merigian KS, Woodard M, Hedges JR, Stuebing R, Rushkin MC. Prospective evaluation of gastric emptying in the self-poisoned patient. Am J Emerg Med 1990;8:479–483.[CrossRef][Medline]
2. Pond SM, Lewis-Driver DJ, Williams GM, Green AC, Stevenson NW. Gastric emptying in acute overdose: a prospective randomized controlled trial. Med J Aust 1995;163:345–349.[Medline]
3. Kulig K, Bar-Or D, Cantrill SV, Rosen P, Rumack BH. Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 1985;14:562–567.[CrossRef][Medline]
4. Decker WJ, Combs HF, Corby DG. Adsorption of drugs and poisons by activated charcoal. Toxicol Appl Pharmacol 1968;13:454–460.[CrossRef][Medline]
5. Sporer KA. The serotonin syndrome: implicated drugs, pathophysiology and management. Drug Saf 1995;13:94–104.[Medline]
6. Oates JA, Sjoerdsma A. Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology 1960;10:1076–1078.[Free Full Text]
7. Smith B, Prockop DJ. Central nervous effects of ingestion of L-tryptophan by normal subjects. N Engl J Med 1962;267:1338–1341.[Medline]
8. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705–713.[Abstract/Free Full Text]
9. Lucki I, Nobler MS, Frazer A. Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat. J Pharmacol Exp Ther 1984;1:133–139.
10. Lejoyeux M, Rouillon F, Ades J. Prospective evaluation of the serotonin syndrome in depressed patients treated with clomipramine. Acta Psychiatr Scand 1993;88:369–371.[Medline]
11. Dowling GP, McDonough ET, Bost RO. "Eve" and "ecstasy": a report of five deaths associated with the use of MDEA and MDMA. JAMA 1987;257:1615–1617.[Abstract]
12. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 1998;16:615–619.[CrossRef][Medline]
13. Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen overdose. Arch Intern Med 1981;141:380–385.[Abstract]
14. Anker AL, Smilkstein MJ. Acetaminophen concepts and controversies. Emerg Med Clin North Am 1994;12:335–349.[Medline]
15. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study (1976–1985). N Engl J Med 1988; 319:1557–1562.[Abstract]
16. O'Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–445.[Medline]
17. Harrison PM, Keays R, Bray GP, Alexander GJ, Williams R. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet 1990;335:1572–1573.[CrossRef][Medline]
18. Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991;330:1026–1030.
19. Harrison PM, Wendon JA, Gimson AES, Alexander GJ, Williams R. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852–1857.[Abstract]
20. Yip L, Dart RC, Hurlbut KM. Intravenous administration of oral N-acetylcysteine. Crit Care Med 1998;26:40–43.[CrossRef][Medline]
21. Schmidt LE, Dalhoff K. Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol 2001;51:87–91.[CrossRef][Medline]
22. Gerich JE. Oral hypoglycemic agents. N Engl J Med 1989;321:1231–1245.[Medline]
23. Seltzer HS. Drug-induced hypoglycemia: a review of 1418 cases. Endocrinol Metab Clin North Am 1989;18:163–183.[Medline]
24. Katz M, Erstad BL. Octreotide, a new somatostatin analogue. Clin Pharm 1989;8:255–273.[Medline]
25. Lamberts SWJ, Van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996;334:246–254.[Free Full Text]
26. Alberti KGMM, Christensen NJ, Christensen SE, Hansen AP, Iversen J, Lanbaek K, Seyer-Hansen K, Orskou H. Inhibition of insulin secretion by somatostatin. Lancet 1973;2:1299–1301.[CrossRef][Medline]
27. Gerich JE, Lorenzi M, Schneider V, Forsham PH. Effect of somatostatin on plasma glucose and insulin responses to glucagons and tolbutamide in man. J Clin Endocrinol Metab 1974;39:1057–1060.[Medline]
28. Boyle PJ, Justice K, Krentz AJ, Nagy RJ, Schade DS. Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab 1993;76:752–756.[Abstract]
29. Krentz AJ, Boyle PJ, Justice KM, Wright AD, Schade DS. Successful treatment of severe refractory sulfonylurea-induced hypoglycemia with octreotide. Diabetes Care 1993;16:184–186.[Abstract]
30. McLaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for sulfonylurea-induced hypoglycemia. Ann Emerg Med 2000;36:133–138.[CrossRef][Medline]
31. Stehouwer CD, Lems WF, Fischer HR, Hackeng WH, Naafs MA. Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (Sandostatin). Acta Endocrinol 1989; 121:34–40.
32. Gama R, Marks V, Wright J, Teale JD. Octreotide exacerbated fasting hyperglycaemia in a patient with a proinsulinoma: the glucostatic importance of pancreatic glucagon. Clin Endocrinol 1995;43:117–120.[Medline]
33. Opie LH. Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction: relation to myocardial ischemia and infarct size. Am J Cardiol 1975;36:938–953.[CrossRef][Medline]
34. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther 1993;267:744–750.[Abstract/Free Full Text]
35. Kline JA, Raymond RM, Leonova ED, Williams TC, Watts JA. Insulin improves heart function and metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res 1997;34:289–298.[Abstract/Free Full Text]
36. Kline JA, Raymond RM, Shroeder D, Watts JA. The diabetogenic effects of acute verapamil poisoning. Toxicol Appl Pharmacol 1997; 145:357–362.[CrossRef][Medline]
37. Yuan TH, Herns WP, Tomaszewski CA, Ford MD, Kline JA. Insulin improves heart function and metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res 1997;34:289–298.[Abstract/Free Full Text]
38. Yuan TH, Herns WP, Tomaszewski CA, Ford MD, Kline JA. Insulin–glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999;37:463–474.[CrossRef][Medline]
39. Jacobsen D, McMartin KE. Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin Toxicol 1997;35:127–143.[Medline]
40. Van Stee E, Harris A, Horton M, Black KC. The treatment of ethylene glycol toxicosis with pyrazole. J Pharmacol Exp Ther 1975;192:251–259.[Abstract/Free Full Text]
41. McMartin K, Hedstrom K, Tolk B, Ostling-Wentzell H, Blomstrand R. Studies on the metabolic interactions between 4-methylpyrazole and methanol using monkeys as an animal model. Arch Biochem Biophys 1980;199:606–614.[CrossRef][Medline]
42. Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M, Kulig K. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 1999;340:832–838.[Abstract/Free Full Text]
43. Brent J, McMartin K, Phillips S, Aaron C, Kulig K. Fomepizole for the treatment of methanol poisoning. N Engl J Med 2001;344:424–429.[Abstract/Free Full Text]
44. Peterson CD, Collins AJ, Himes JM, Bullock ML, Keane WF. Ethylene glycol poisoning: pharmacokinetics during therapy with ethanol and hemodialysis. N Engl J Med 1981;304:21–23.[Medline]
45. Jacobsen D, Hewlett TP, Webb R, Brown ST, Ordinario AT, McMartin KE. Ethylene glycol intoxication: implications for management. Ann Emerg Med 2000;36:114–125.[CrossRef][Medline]
46. Palatnick W, Redman LW, Sitar DS, Tenenbein M. Methanol half-life during ethanol administration: implications for management of methanol poisoning. Ann Emerg Med 1995;26:202–207.[CrossRef][Medline]
47. Iyaniwura TT. Snake venom constituents: biochemistry and toxicology. Part 1. Vet Hum Toxicol 1991;33:468–474.[Medline]
48. Jurkovich GI, Luterman A, McCullar K, Ramenofsky ML, Curreri PW. Complications of Crotalidae antivenin therapy. J Trauma 1988;28: 1032–1037.[Medline]
49. Kunkel DB, Curry SC, Vance MV, Ryan PJ. Reptile envenomations. J Toxicol Clin Toxicol 1984;21:503–526.
50. Dart RC, Seifert SA, Carroll L. Mixed nonspecific crotalid antivenom ovine Fab for the treatment of crotalid venom poisoning. Ann Emerg Med 1997;30:33–39.[CrossRef][Medline]
51. Dart RC, McNally J. Efficacy, safety and use of snake antivenoms in the United States. Ann Emerg Med 2001;37:181–188.[CrossRef][Medline]
52. Dart RC, Seifert SA, Carroll L, Clark RF, Hall E, Boyer-Hassen LV, Curry SC, Kitchens CS, Garcia RA. Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid venom poisoning. Ann Emerg Med 1997;30:33–39.[CrossRef][Medline]
53. Boyer LV, Seifert SA, Clark RF, McNally JT, Williams SR, Nordt SP, Walter FG, Dart RC. Recurrent and persistent coagulopathy following pit viper envenomation. Arch Intern Med 1999;159:706–710.[Abstract/Free Full Text]
54. Boyer LV, Seifert SA, Cain JS. Recurrence phenomena after immunoglobulin therapy for snake envenomations: 2. Guidelines for clinical management with crotalline Fab antivenom. Ann Emerg Med 2001;37:196–201.[CrossRef][Medline]

This article has been cited by other articles:

				J. A. Kraut and I. Kurtz Toxic Alcohol Ingestions: Clinical Features, Diagnosis, and Management Clin. J. Am. Soc. Nephrol., January 1, 2008; 3(1): 208 - 225. [Abstract] [Full Text] [PDF]

				P. Lada and U. Idrees Toxicity of Oral Agents Used to Treat Diabetes Journal of Pharmacy Practice, June 1, 2005; 18(3): 145 - 156. [Abstract] [PDF]

				K. C. Wilson and J. J. Saukkonen Acute Respiratory Failure from Abused Substances J Intensive Care Med, July 1, 2004; 19(4): 183 - 193. [Abstract] [PDF]

				M. J. Tobin Writing a Review Article for AJRCCM Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 732 - 734. [Full Text] [PDF]

				C. D. N. Cher, A. Armugam, R. Lachumanan, M.-W. Coghlan, and K. Jeyaseelan Pulmonary Inflammation and Edema Induced by Phospholipase A2: GLOBAL GENE ANALYSIS AND EFFECTS ON AQUAPORINS AND Na+/K+-ATPase J. Biol. Chem., August 15, 2003; 278(33): 31352 - 31360. [Abstract] [Full Text] [PDF]

				M. J. Tobin Critical Care Medicine in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 294 - 305. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chu, J. Articles by Hill, N. S. Search for Related Content PubMed PubMed Citation Articles by Chu, J. Articles by Hill, N. S.