CASE REPORT
brodifacoum; rodenticides
Fatal Rodenticide Poisoning With Brodifacoum
From the Division of Critical Care Medicine, Wayne State University
James A Krose, MD Richard W Carlson, MD, PhD
School of Medicine, and Detroit Receiving Hospital, Detroit, Michigan. Receivedfor publication December 3, 1990. Revision received June 7, 1991. Acceptedfor publication July 3, 1991. This case report was presented in part at the Annual Scientific Symposium of the Michigan Chapter of the American College of Physicians in Traverse City, Michigan, September ] 989.
The increased prevalence of rodents resistant to warfarin led to the development of the hydroxycoumarin anticoagulant brodifacoum. A 25year-old man attempted suicide by consuming four boxes of d-CON Mouse-Prufe I1®; each box contains 42 g of bait that is 0.005% brodifacoum. He presented to a hospital nine days later with syncope, hematochezia, gross hematuria, epistaxis, anemia, and a severe coagulopathy. Radiographic studies were consistent with pleural, pericardial, and mediastinal hemorrhages. Vitamin K and fresh frozen plasma were given, and he was later discharged on oral phytonadione (vitamin K1). The patient's coagulopathy recurred, necessitating multiple plasma transfusions and prolonged treatment with oral phytonadione. Fifteen weeks after hospital discharge, he presented again with a history of additional brodifacoum ingestion. Neurologic status was initially normal, but in the emergency department he suddenly became comatose soon after emesis was induced with syrup of ipecac. Computed tomography of the brain revealed a subarachnoid hemorrhage that led to brain death less than 24 hours later. This case demonstrates the severe and prolonged coagulopathy that can result from ingestion of brodifacoum, a compound that has a toxic potency about 200-fold that of warfarin and a half-life as much as 60 times longer. [Kruse JA, Carlson RW: Fatal rodenticide poisoning with brodifacoum. Ann Emerg Med March 1992;21:331-336.]
INTRODUCTION Sweet clover disease was first described in 1924 as a hemorrhagic disorder of cattle following ingestion of spoiled clover silage. In 1939, bishydroxycoumarin was isolated from silage and identified as the toxic agent) -3 Subsequently, warfarin and other coumarin congeners have been used as therapeutic anticoagulants and rodenticides. By interfering with vitamin K metabolism, these compounds inhibit the synthesis of clotting factors II, VII, IX, and X.4-7 In many geographic areas, rats have developed a genetic resistance to the hemorrhagic effects of coumarin anticoagulants. Brodifacoum is a coumarin derivative that is effective I"
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against warfarin-resistant rodents. 8 The mechanism of action is similar to that of warfarin; however, brodifacoum is approximately 200 times as potent and has a markedly longer duration of action. 4 The half-life of brodifacoum in dogs is approximately four months. 9
CASE REPORT A 25-year-old man purchased four boxes of d-CON MousePrufe II® rodenticide with the intention of committing suicide. Each box contains 1.5 oz (42 g) of bait containing 0.005% brodifacoum. He mixed the bait into a cake and ate half of the cake in the evening and the other half on the following morning. During the following nine days, he developed gross hematuria, melena, hematochezia, multiple ecchymoses, epistaxis, abdominal pain, dizziness, and bleeding from comedones. He was taken to a local hospital by his parents after they noted behavioral changes followed by a syncopal episode. At the time of admission, the patient appeared ill but was in no distress. His blood pressure was 110/60 mm Hg;
temperature, 38.3 C; pulse 120; and respirations, 28. He weighed 67 kg. Physical examination revealed evidence of epistaxis, bleeding cutaneous lesions, and melena. Multiple ecchymoses were present on his head, trunk, and extremities. There was lateral deviation of the right eye, the right nasolabial fold was questionably flattened, deep tendon reflexes were diminished on the left, and motor strength in his left lower extremity was slightly weak. The neurologic examination was otherwise normal. Hemoglobin was 7.7 g/dL, and platelet count was 257,000. The prothrombin and partial thromboplastin times were reported as more than 40 and 140 seconds, respectively. Multiple blood cultures were obtained but showed no microbial growth. Chest radiographs revealed a large mass in the superior mediastinum (Figure 1), and decubitus chest radiographs showed free pleural fluid collections bilaterally. Computed tomography (CT) of the chest was performed twice during this admission and also demonstrated the mediastinal mass along with fluid or blood Figure 1.
collections in the pleural and pericardial spaces. Three CT scans of the head were performed and interpreted as highly suspicious for subarachnoid hemorrhage, and there also was a questionable focal hemorrhagic lesion in the left frontoparietal cortex. Esophagogastroduodenoscopy was unremarkable. On psychiatric evaluation, the patient was thought to have an adjustment reaction and depression. Despite treatment with a total of 310 mg vitamin K 1 (phytonadione) and 16 units of fresh frozen plasma, the patient's prothrombin and partial thromboplastin times remained abnormal (Figure 2). The widened superior mediastinum was still present on a chest radiograph one day before discharge. He was discharged with a prescription for 20 5-rag tablets of phytonadione, to be taken as one
tablet twice daily. He had the prescription filled seven days later and took the first phytonadione tablet the following morning. He presented to Detroit Receiving Hospital later that day complaining of right lower extremity pain. On this first admission to Detroit Receiving Hospital, the patient's blood pressure was 94/70 mm Hg; oral temperature, 39.4 C; pulse, 144; and respirations, 20. Physical examination was nm-mal except for moderate tenderness of the right knee. Hemoglobin was 9.4 g/dL; prothrombin time, 83.9 seconds; and partial thromboplastin time, 153.4 seconds. Blood cultures were negative. Chest radiograph was normal (Figure 3), as were CT scans of the head and chest. An initial IV dose of menadiol (vitamin K3) was given and followed later with 50 mg phytonadione IV and • Figure 2. Responses of prothrombin time and partial thromboplastin time to plasma and phytonadione therapy during patient's first and second hospital admissions and during outpatient treatment. © , PTT; of PT;
[] , PT;
, upper normal limit
....... , upper normal limit of PTT;
W, one unit fresh frozen plasma.
Figure 3.
Chest radiograph at initial presentation
Chest radiograph from second admission
demonstrating marked widening of the
showing resolution of mediastinal
superior mediastinum consistent with
hematoma.
hematoma.
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daily 40-mg oral doses of phytonadione. In an attempt to induce the hepatic enzymes that metabolize brodifaeoum, he was also given oral doses of phenobarbital i80 mg/day. A total of I6 units of fresh frozen plasma and three units of packed RBCs were given. The knee pain, thought to be due to hemarthrosis, resolved, and the patient was discharged eight days later with a prothrombin time of 14.8 seconds and a partial thromboplastin time of 34.3 seconds. The patient was given prescriptions for daily doses of phytonadione and phenobarbital, and an appointment was scheduled for three days later at the outpatient transfusion center. Howevel, the patient failed to take either medicine until the morning of his appointment. At that time, his prothrombin and partial thromboplastin times were 28.5 and 55.9 seconds, respectively. His eoagulopathy was partially corrected with fresh frozen plasma during this visit and during a
second outpatient visit. At the time of his third outpatient appointment, 16 days after hospital discharge, his coagulation studies were entirely normal: prothrombin time was 11.8, and partial thromboplastin time was 27.5 seconds. He had no further evidence of bleeding during subsequent outpatient visits and no sequelae from the previous hemorrhagic complications. Approximately three months later, the patient was readmitted to Detroit Receiving Hospital after ingesting five boxes of d-CON Mouse-Prufe II® 20 days before admission. He had melena, epistaxis, and hematemesis during the week before admission. On presentation, his heart rate was ]00, and there was dried blood in the nares, but the remainder of the physical examination and neurologic examination were normal. His serum phenobarbital concentration was 44 ~/mL. The patient was given ipecac and IV menadiol, and arrangements were made for Figure 4.
CT scan of the head from third admission showing fatal subarachnoid hemorrhage.
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admission. He subsequently had severe ipecac-induced retching. Minutes later, while still in the emergency department, he suddenly became deeply comatose. CT of the head was performed immediately and demonstrated subaraehnoid hemorrhage (Figure 4). Twelve units of fresh frozen plasma, three units of packed RBCs, and multiple doses of phytonadione were given; however, he was pronounced brain-dead several hours later. Both kidneys were donated and transplanted suecessfully. A~utopsyfindings included subarachnoid and intracerebral hemorrhages and blood in the gastrointestinal tract.
DISCUSSION Because of the extreme differenees in toxic potency and duration of action, it is of the utmost importance to differentiate brodifaeoum poisoning from that of warfarin. In rats, the acute oral LD5o of brodifacoum is 1/200 that of warfarin, and in dogs the half-life of brodifaeoum may be as long as four months. 9'1° Previously reported human exposures to brodifaeoum have been associated with clinical bleeding for more than six months, n Slow systemic clearance and a large volume of distribution may explain brodifacoum's prolonged effect, whereas its potency may be due to hepatic accumulation, as evidenced
by a high liver-to-serum ratio. 4 Although initial treatment of this patient with vitamin K 1 and plasma transfusions resulted in improvement of clotting times to within the range used in therapeutic anticoagulation, the patient's coagulopathy subsequently rebounded. Clotting tests were not monitored after the first hospitalization. The patient was judged to be a reliable historian by multiple observers, and he denied ingesting additional rodentitide between the first and second hospitalizations. Despite his ability to give a detailed account of the type of rodenticide ingested, the assessments of several physicians were "warfarin poisoning." Prolonged treatment with vitamin K and infusions of fresh frozen plasma, including outpatient transfusion therapy, were necessary to reverse the coagulopathy. The mechanism of action of brodifacoum is similar to that of warfarin. Warfarin, brodifacoum, and related 4-hydroxyeoumarins exert their anticoagulant effects by interfering with vitamin K metabolism. Vitamin K is an obligatory cofaetor in the synthesis of clotting factors II, VII, IX, and X. Its action is to facilitate the earboxylation of glutamyl residues on clotting factor precursors. During this carboxylation reaction, vitamin K~ is converted to an inactive form: vitamin KV2,3epoxide. A reductase
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enzyme then chemically reduces this epoxide form back to the active vitamin K 1. This epoxide reductase-mediated step is inhibited by brodifacoum and other 4-hydroxycoumarin anticoagulants, s,7 It has been demonstrated in animal models that phenobarbital accelerates the metabolism of warfarin and brodifacoum by stimulating hepatic microsomal enzyme activity, a In view of this, phenobarbital was administered to our patient to decrease the half-life of brodifacoum. The effect of this treatment is difficult to assess, particularly because he consumed additional brodifacoum before his final hospitalization. We are aware of only one previously reported death due to brodifacoum ingestion) 2 In that report, the patient also died of a massive intracranial hemorrhage, approximately four weeks after the ingestion. The fatal outcome for these two cases contrasts with those of other reports. Smolinske and colleagues reported 77 pediatric cases of brodifacoum ingestion. 13'14 They found that prothrombin times were prolonged in only seven patients, and these patients had no short-term signs or symptoms of clinical bleeding. In another report, Bennett and associates collected 26 cases of ingestions involving brodifacoum and a related long-acting anticoagulant, diphacinone) s There were no abnormalities in pro-
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thrombin time. Only one patient had clinical evidence of bleeding (epistaxis); however, that patient had a history of frequent nose bleeds preceding the ingestion. The authors concluded that their findings indicated the "benign nature" of these ingestions. All of the cases reported by Smolinske et al and all except one of the cases reported by Bennett et al were pediatric. However, children are not immune from serious effects from these agents. Coagulopathy and severe bleeding occurred in two children, ages 2 and 3, who ingested rodenticides containing bromodialone, a long-acting anticoagulant similar to brodifacoum) 6 All of the cases reported by Smolinske et al and Bennett et al were accidental ingestions and probably involved smaller quantities than our patient intentionally consumed. On the other hand, an abstract by Chen and Deng describes a 20-year-old man who consumed a "mouthful" of rat bait containing the equivalent of i mg brodifacoum) v He developed epistaxis, gingival bleeding, melena, hematuria, and flank pain, and his coagulopathy persisted for 76 days. That case, as well as our case and studies in rats and dogs, demonstrate that one-time ingestions of brodifacoum can cause severe coagulation abnormalities and clinical bleeding. 18 This is in
contrast to warfarin-containing bait, a single ingestion of which is essentially incapable of inducing abnormalities in coagulation. 1aJ9 Extrapo-
ies have seriously questioned both the efficacy and risk-tobenefit ratio of therapeutic gastric emptying for acute poisoning in general. 22'23
lating from the LD5o of rats, Gosselin and associates calculated that it would take approximately 60 lb of warfarin-containing rat bait to induce a similarly toxic onetime dose in human beings. 2° Based on this, others have suggested that neither induced emesis nor gastric lavage is required in the management of single-dose ingestions of warfarin. 3 During his final hospitalization, our patient received ipecac while in the ED. However, gastric emptying would be of no expected benefit if, as according to the history, he had last consumed brodifacoum-containing rat bait nearly three weeks before this presentation. Although ipecac has traditionally been considered standard therapy for alert poisoned patients, this treatment may have played a role in precipitating intracranial hemorrhage by raising intracranial pressure. After receiving ipecac, the patient developed sudden and profound neurologic deterioration immediately after a bout of severe retching. The POISINDEX notes that anticoagulated patients may be at risk for gastrointestinal hemorrhage from ipecac-induced vomiting, but it does not cite a risk of central nervous system bleeding. 21 Recent stud-
Phytonadione has been associated with anaphylactic deaths when given intravenously. Although this has usually been thought to occur only if the agent was infused rapidly, there have been reports of anaphylaxis occurring despite slow infusion of dilute phytonadione solutions. 24-27 These and other authors, as well as the manufacturer, therefore recommend that this form of vitamin K be used intravenously only in acute emergencies where other routes are not feasible and the potential benefits outweigh the risks. 24-26'28"29 Others have further recommended that when IV phytonadione is required, the clinician should be prepared for the possibility of anaphylaxis 3 We believe that our case represented an emergency situation that justified IV administration along with careful monitoring. Intramuscular and subcutaneous injections of phytonadione have not been associated with anaphylaxis; however, the former would be contraindicated in the face of a severe coagulopathy, and the latter, if not contraindicated, might result in slow absorption and a delayed therapeutic effect. When IV vitamin K is indicated for reasons other than to antagonize anticoagu-
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1ant action, such as in the treatment of vitamin K deficiency due to intestinal realabsorption, we recommend that menadiol be used. Unlike phytonadione, IV menadiol has not been associated with life-threatening adverse effects in adults. With this in mind, the policy of our hospital pharmacy is to dispense menadiol when IV "vitamin K" is ordered without indicating a specific form. Menadiol, however, is essentially ineffective in reversing warfarin or brodifacoum-induced anti-
coagulation. 2'3'3°-32 Physician orders for both "vitamin K" and "Synkayvite®'' were initially written for this patient, potentially delaying the onset of anticoagulation reversal. These differences in efficacy and adverse effects underscore the importance of routinely specifying the particular form of vitamin K that is desired rather than simply prescribing "vitamin K." After pronouncement of brain death, our patient's kidneys were harvested and transplanted successfully. Because coumarin-induced anticoagulation is due to interference with clotting factor synthesis in the liver, the anticoagulant effects of brodifacoum would not be expected to carry over to the recipient. However, there is some evidence that coumarin compounds can also cause direct vascular injury and that this effect is also responsible for causing spontaneous homer-
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rhage. 3'2°'33-37 Assuming this capillary damage effect is real, the question may be raised as to whether it might affect viability of the transplanted organs; however, in this case, no problems were encountered with hemostasis during reimplantation, and both grafts continued to function well after 12 months of follow~up.
SUMMARY
rhage. Anticoagulation should be considered a contraindication to ipecac-induced vomiting.
The authors acknowledge Drs Carter Bishop and Mohammed Bazzi, who participated in the clinical management of the patient at Detroit Receiving Hospital, and Dr Myer Roszler for his expert assistance in interpreting the radiographs and CT scans.
This case - - the second
reported case of fatal human poisoning from brodifacoum - - demonstrates three important points. First, it illustrates a basic tenet of clinical toxicology - - that specific identification of the toxic agent can be of critical importance in the management of the poisoned patient. The incorrect assumption that rodenticideinduced coagulopathy was pathognomonic for warfarin poisoning resulted in this patient's second hospitalization with a major bleeding episode. The extended halflife of brodifacoum and related anticoagulants mandates prolonged treatment and monitoring. Second, phytonadione (vitamin K1) must be used to reverse coumarin-induced coagulopathy; menadiol (vitamin K3) should not be used. Finally, by raising intracranial pressure, the induction of vomiting during the patient% third admission may have played a role in precipitating the fatal intracranial hereof-
ANNALS OF EMERGENCY MEDIOINE
REFERENCES 1. Link KP: The anticoagulant from spoiled sweet clever hay. HarveyLect194344;39:182-216. 2. O'Reilly RA: Anticoagulants, antithrombotics, thrombolyt[c drugs, in Gilman AG, Goodman LS, Rail TW, et al (ads): Goodmanand Gillman's The Pharmacolog~ca/Basis of Therapeutics,ed 7. New York, Macmillan, 1985, p 1344q 359. 3. FIomenbaumNE, Goldfrank LR, Howland MA, et el: Rodenticidesand warfarin (coumadin)overdoses, in Goldfrank LR, Flemenbaum NE, Lewin NA, et al (ads): Goldfrank's ToxicologicEmergencies,ed 3. Norwalk, Connecticut, Appleton-CenturyCrofts, 1986, p 697-716. 4. BachmannKA, Sullivan TJ: Dispositional and pharmacodynamiccharacteristics of brodifacoum in warfarin-sensitive rats. Pharmacol1983;27:281-288. 5. Baflow AM, Gay AL, Park BK: Difenacoum (Neosorexa)poisoning. Br Mad J 19821285:541. 6. LeckJB, Park BK: A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K~ metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats. BiochemPharmacol1981;30:123-128. 7. ParkBK, Scott AK, Wilson AC, et al: Plasma disposition of vitamin K1 in relation to anticoagulant poisoning. BrJ Clio Pharmacol1984;18:655-662. 8. Hadler MR, Shadbatt RS: Novel 4hydroxycoumarinanticoagulants active against resistant rats. Nature 19751253:275-277. 9. Lipton RA, Klass EM: Human ingestion of a "supa~arfarin" rodenticide resulting in a prolonged anticoagulant effect. JAMA 19841252:3004-3035. 19. Talon®TechnicalBulletin. Goldsboro,
North Carolina, Agricultural Chemical Division, ICI Americas, Inc. 11. ChangL-L, ChauW-K, He C-H: A case of "superwarfarin" poisoning, ScandJ Haematol1986136:314-315. 12. BasehoreLM, Mowry JM: Death following ingestion of superwarfarin rodenticide: A case report (abstract). Vet Hum Toxicol1987;29:459. 13. Smolinske SC. Scherger DS, Kearns PS, et ah Long-acting anticoagulant rodenticide ingestion in children (abstract). VetHum Toxico11987129:492. 14. Smolinske SC, SchergerDL, Kearns PS, et ah Superwarfarin poisoning in children: A prospective study. Pediatrics 1989;84:490-494. 15. Bennett DL, Caravati EM, Veltri %: Long-acting anticoagulant ingestion: A prospective study (abstract). VetHum Toxice11987129:472-473. 16. Greeff MC, Mashile O, MacDougall LG: "Superwarfarin" (bromadialone)poisoning in two children resulting in prolonged anticoagulation (letter). Lancet198712:1269. 17. ChenTW, Deng JF: A brodifacoum intoxication case of mouthful amount (abstract). Vet Hum Toxice11986;28:488. 18, Fitzgerald KT, Brenstein AC: Comparison of first and second generation anticoagulant rodenticide peisonings: Fourteencanine cases (abstract}. Vet Hum Toxicol 1987;29:476. 19. Godfrey MER, Reid TC, McAIlum HJF: The acute oral toxicity of the anticoagulant bredifacoum to dogs. N Z J ExpAgr 1981;9:147-149. 20. Gasselin RE, Smith RP, Hedge HC: Clinical Toxicologyof CommercialProducts. ad 5. Baltimore, Maryland,Williams & Wilkins, 1984, p ifl-395-gl-397. 21. Smolinske SC, RumackBH: Anticoagulants - - Long acting, in POISINDEX. Denver,Micromedix, 1990, vo166. 22. Kulig K. Bar-OrD, Cantrill SV. et al: Management of acutely poisoned patients without gastric emptying. Ann ErnergMed 1985;14:562-567. 23. Kulig KW: Gastric lavage in acute drug overdose.JAMA 1989;262:1392. 24. de la Ruble J, Grau E, Montserrat I, et al: Anaphylactic shock and vitamin K~. Ann Intern Mad1989;1I0:943. 25. Mattea EJ, Quinn K: Adverse reactions after intravenous phytonadione administration. HaspPharm 1981116:224-235. 26, Physicians'DeskReference,ed 44. Oradell, New Jersey, Medical Economics, 1990, p 1326-1327. 27. Barash P, Kitahata LM, Mandel S: Acute cardiovascularcollapse after intravenous phytenadione.AnesthAnalg CurrRes 1976;55:304-308. •
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28. Havel M, Muller M, GraningerW, et al: Tolerability of a new vitamin K~ preparation for parenteral administration to adults: One case of anaphylactoid reaction. Clin Ther 1987;9:373-379. 29. Lefrere JJ, Girot R: Acute cardiovascular collapse during intravenous vitamin K~ injection (letter). ThrombHaemost 1987;58:790. 30. Jaques LB: Dicoumarol drugs and the problem of haemorrhage.Can Med Assec J 1959;81:848-854. 31. Murdoch DA: Prolongedanticoagulation in cNorphacinono poisoning {letter). Lancet 1983;1:358-356. 32. Physicians"Desk Reference.ed 44. Oradell, New Jersey, Medical Economics, 1990, n 1810-1811. 33. Faraci PA, Deterling RA Jr, Stein AM, et al: Warfarin induced necrosis of the skin. Surg GynecoIObstet1978;146:695-700. 34. Kahn RA, Johnson SA, DeGraff AF: Effects of sodium warfarin on capillary ultrastracture. Am J Pathol 1971;65:149-156. 35. Groth O, Tengstrom B: Haemorrhagic necrosis of the skin during dicoumarol therapy. Acta Dermato-Venereologica 1960;40:104-107. 36. GoodmanLS, Gilman A: The Pharmacological Basis of Therapeutics,ed 2. New York, Macmillan, 1955, p 1514. 37. Innerfield I, Rowley GR: Low dosage proteases, clotting factors, capillary permeability and cellular viability. Life Sci 1970;9 {part II):1359-1367.
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Address for correspondence: James A Kruse, MD, Department of Medicine, Room 5S-10, Detroit Receiving Hospital, 4201 St Antoine, Detroit, Michigan 48201.
ANNALS OF EMERGENCY MEDIClNE 2 1 : 3 MARCH1992
brodifacoum; rodenticides
Fatal Rodenticide Poisoning With Brodifacoum
From the Division of Critical Care Medicine, Wayne State University
James A Krose, MD Richard W Carlson, MD, PhD
School of Medicine, and Detroit Receiving Hospital, Detroit, Michigan. Receivedfor publication December 3, 1990. Revision received June 7, 1991. Acceptedfor publication July 3, 1991. This case report was presented in part at the Annual Scientific Symposium of the Michigan Chapter of the American College of Physicians in Traverse City, Michigan, September ] 989.
The increased prevalence of rodents resistant to warfarin led to the development of the hydroxycoumarin anticoagulant brodifacoum. A 25year-old man attempted suicide by consuming four boxes of d-CON Mouse-Prufe I1®; each box contains 42 g of bait that is 0.005% brodifacoum. He presented to a hospital nine days later with syncope, hematochezia, gross hematuria, epistaxis, anemia, and a severe coagulopathy. Radiographic studies were consistent with pleural, pericardial, and mediastinal hemorrhages. Vitamin K and fresh frozen plasma were given, and he was later discharged on oral phytonadione (vitamin K1). The patient's coagulopathy recurred, necessitating multiple plasma transfusions and prolonged treatment with oral phytonadione. Fifteen weeks after hospital discharge, he presented again with a history of additional brodifacoum ingestion. Neurologic status was initially normal, but in the emergency department he suddenly became comatose soon after emesis was induced with syrup of ipecac. Computed tomography of the brain revealed a subarachnoid hemorrhage that led to brain death less than 24 hours later. This case demonstrates the severe and prolonged coagulopathy that can result from ingestion of brodifacoum, a compound that has a toxic potency about 200-fold that of warfarin and a half-life as much as 60 times longer. [Kruse JA, Carlson RW: Fatal rodenticide poisoning with brodifacoum. Ann Emerg Med March 1992;21:331-336.]
INTRODUCTION Sweet clover disease was first described in 1924 as a hemorrhagic disorder of cattle following ingestion of spoiled clover silage. In 1939, bishydroxycoumarin was isolated from silage and identified as the toxic agent) -3 Subsequently, warfarin and other coumarin congeners have been used as therapeutic anticoagulants and rodenticides. By interfering with vitamin K metabolism, these compounds inhibit the synthesis of clotting factors II, VII, IX, and X.4-7 In many geographic areas, rats have developed a genetic resistance to the hemorrhagic effects of coumarin anticoagulants. Brodifacoum is a coumarin derivative that is effective I"
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against warfarin-resistant rodents. 8 The mechanism of action is similar to that of warfarin; however, brodifacoum is approximately 200 times as potent and has a markedly longer duration of action. 4 The half-life of brodifacoum in dogs is approximately four months. 9
CASE REPORT A 25-year-old man purchased four boxes of d-CON MousePrufe II® rodenticide with the intention of committing suicide. Each box contains 1.5 oz (42 g) of bait containing 0.005% brodifacoum. He mixed the bait into a cake and ate half of the cake in the evening and the other half on the following morning. During the following nine days, he developed gross hematuria, melena, hematochezia, multiple ecchymoses, epistaxis, abdominal pain, dizziness, and bleeding from comedones. He was taken to a local hospital by his parents after they noted behavioral changes followed by a syncopal episode. At the time of admission, the patient appeared ill but was in no distress. His blood pressure was 110/60 mm Hg;
temperature, 38.3 C; pulse 120; and respirations, 28. He weighed 67 kg. Physical examination revealed evidence of epistaxis, bleeding cutaneous lesions, and melena. Multiple ecchymoses were present on his head, trunk, and extremities. There was lateral deviation of the right eye, the right nasolabial fold was questionably flattened, deep tendon reflexes were diminished on the left, and motor strength in his left lower extremity was slightly weak. The neurologic examination was otherwise normal. Hemoglobin was 7.7 g/dL, and platelet count was 257,000. The prothrombin and partial thromboplastin times were reported as more than 40 and 140 seconds, respectively. Multiple blood cultures were obtained but showed no microbial growth. Chest radiographs revealed a large mass in the superior mediastinum (Figure 1), and decubitus chest radiographs showed free pleural fluid collections bilaterally. Computed tomography (CT) of the chest was performed twice during this admission and also demonstrated the mediastinal mass along with fluid or blood Figure 1.
collections in the pleural and pericardial spaces. Three CT scans of the head were performed and interpreted as highly suspicious for subarachnoid hemorrhage, and there also was a questionable focal hemorrhagic lesion in the left frontoparietal cortex. Esophagogastroduodenoscopy was unremarkable. On psychiatric evaluation, the patient was thought to have an adjustment reaction and depression. Despite treatment with a total of 310 mg vitamin K 1 (phytonadione) and 16 units of fresh frozen plasma, the patient's prothrombin and partial thromboplastin times remained abnormal (Figure 2). The widened superior mediastinum was still present on a chest radiograph one day before discharge. He was discharged with a prescription for 20 5-rag tablets of phytonadione, to be taken as one
tablet twice daily. He had the prescription filled seven days later and took the first phytonadione tablet the following morning. He presented to Detroit Receiving Hospital later that day complaining of right lower extremity pain. On this first admission to Detroit Receiving Hospital, the patient's blood pressure was 94/70 mm Hg; oral temperature, 39.4 C; pulse, 144; and respirations, 20. Physical examination was nm-mal except for moderate tenderness of the right knee. Hemoglobin was 9.4 g/dL; prothrombin time, 83.9 seconds; and partial thromboplastin time, 153.4 seconds. Blood cultures were negative. Chest radiograph was normal (Figure 3), as were CT scans of the head and chest. An initial IV dose of menadiol (vitamin K3) was given and followed later with 50 mg phytonadione IV and • Figure 2. Responses of prothrombin time and partial thromboplastin time to plasma and phytonadione therapy during patient's first and second hospital admissions and during outpatient treatment. © , PTT; of PT;
[] , PT;
, upper normal limit
....... , upper normal limit of PTT;
W, one unit fresh frozen plasma.
Figure 3.
Chest radiograph at initial presentation
Chest radiograph from second admission
demonstrating marked widening of the
showing resolution of mediastinal
superior mediastinum consistent with
hematoma.
hematoma.
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daily 40-mg oral doses of phytonadione. In an attempt to induce the hepatic enzymes that metabolize brodifaeoum, he was also given oral doses of phenobarbital i80 mg/day. A total of I6 units of fresh frozen plasma and three units of packed RBCs were given. The knee pain, thought to be due to hemarthrosis, resolved, and the patient was discharged eight days later with a prothrombin time of 14.8 seconds and a partial thromboplastin time of 34.3 seconds. The patient was given prescriptions for daily doses of phytonadione and phenobarbital, and an appointment was scheduled for three days later at the outpatient transfusion center. Howevel, the patient failed to take either medicine until the morning of his appointment. At that time, his prothrombin and partial thromboplastin times were 28.5 and 55.9 seconds, respectively. His eoagulopathy was partially corrected with fresh frozen plasma during this visit and during a
second outpatient visit. At the time of his third outpatient appointment, 16 days after hospital discharge, his coagulation studies were entirely normal: prothrombin time was 11.8, and partial thromboplastin time was 27.5 seconds. He had no further evidence of bleeding during subsequent outpatient visits and no sequelae from the previous hemorrhagic complications. Approximately three months later, the patient was readmitted to Detroit Receiving Hospital after ingesting five boxes of d-CON Mouse-Prufe II® 20 days before admission. He had melena, epistaxis, and hematemesis during the week before admission. On presentation, his heart rate was ]00, and there was dried blood in the nares, but the remainder of the physical examination and neurologic examination were normal. His serum phenobarbital concentration was 44 ~/mL. The patient was given ipecac and IV menadiol, and arrangements were made for Figure 4.
CT scan of the head from third admission showing fatal subarachnoid hemorrhage.
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admission. He subsequently had severe ipecac-induced retching. Minutes later, while still in the emergency department, he suddenly became deeply comatose. CT of the head was performed immediately and demonstrated subaraehnoid hemorrhage (Figure 4). Twelve units of fresh frozen plasma, three units of packed RBCs, and multiple doses of phytonadione were given; however, he was pronounced brain-dead several hours later. Both kidneys were donated and transplanted suecessfully. A~utopsyfindings included subarachnoid and intracerebral hemorrhages and blood in the gastrointestinal tract.
DISCUSSION Because of the extreme differenees in toxic potency and duration of action, it is of the utmost importance to differentiate brodifaeoum poisoning from that of warfarin. In rats, the acute oral LD5o of brodifacoum is 1/200 that of warfarin, and in dogs the half-life of brodifaeoum may be as long as four months. 9'1° Previously reported human exposures to brodifaeoum have been associated with clinical bleeding for more than six months, n Slow systemic clearance and a large volume of distribution may explain brodifacoum's prolonged effect, whereas its potency may be due to hepatic accumulation, as evidenced
by a high liver-to-serum ratio. 4 Although initial treatment of this patient with vitamin K 1 and plasma transfusions resulted in improvement of clotting times to within the range used in therapeutic anticoagulation, the patient's coagulopathy subsequently rebounded. Clotting tests were not monitored after the first hospitalization. The patient was judged to be a reliable historian by multiple observers, and he denied ingesting additional rodentitide between the first and second hospitalizations. Despite his ability to give a detailed account of the type of rodenticide ingested, the assessments of several physicians were "warfarin poisoning." Prolonged treatment with vitamin K and infusions of fresh frozen plasma, including outpatient transfusion therapy, were necessary to reverse the coagulopathy. The mechanism of action of brodifacoum is similar to that of warfarin. Warfarin, brodifacoum, and related 4-hydroxyeoumarins exert their anticoagulant effects by interfering with vitamin K metabolism. Vitamin K is an obligatory cofaetor in the synthesis of clotting factors II, VII, IX, and X. Its action is to facilitate the earboxylation of glutamyl residues on clotting factor precursors. During this carboxylation reaction, vitamin K~ is converted to an inactive form: vitamin KV2,3epoxide. A reductase
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enzyme then chemically reduces this epoxide form back to the active vitamin K 1. This epoxide reductase-mediated step is inhibited by brodifacoum and other 4-hydroxycoumarin anticoagulants, s,7 It has been demonstrated in animal models that phenobarbital accelerates the metabolism of warfarin and brodifacoum by stimulating hepatic microsomal enzyme activity, a In view of this, phenobarbital was administered to our patient to decrease the half-life of brodifacoum. The effect of this treatment is difficult to assess, particularly because he consumed additional brodifacoum before his final hospitalization. We are aware of only one previously reported death due to brodifacoum ingestion) 2 In that report, the patient also died of a massive intracranial hemorrhage, approximately four weeks after the ingestion. The fatal outcome for these two cases contrasts with those of other reports. Smolinske and colleagues reported 77 pediatric cases of brodifacoum ingestion. 13'14 They found that prothrombin times were prolonged in only seven patients, and these patients had no short-term signs or symptoms of clinical bleeding. In another report, Bennett and associates collected 26 cases of ingestions involving brodifacoum and a related long-acting anticoagulant, diphacinone) s There were no abnormalities in pro-
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thrombin time. Only one patient had clinical evidence of bleeding (epistaxis); however, that patient had a history of frequent nose bleeds preceding the ingestion. The authors concluded that their findings indicated the "benign nature" of these ingestions. All of the cases reported by Smolinske et al and all except one of the cases reported by Bennett et al were pediatric. However, children are not immune from serious effects from these agents. Coagulopathy and severe bleeding occurred in two children, ages 2 and 3, who ingested rodenticides containing bromodialone, a long-acting anticoagulant similar to brodifacoum) 6 All of the cases reported by Smolinske et al and Bennett et al were accidental ingestions and probably involved smaller quantities than our patient intentionally consumed. On the other hand, an abstract by Chen and Deng describes a 20-year-old man who consumed a "mouthful" of rat bait containing the equivalent of i mg brodifacoum) v He developed epistaxis, gingival bleeding, melena, hematuria, and flank pain, and his coagulopathy persisted for 76 days. That case, as well as our case and studies in rats and dogs, demonstrate that one-time ingestions of brodifacoum can cause severe coagulation abnormalities and clinical bleeding. 18 This is in
contrast to warfarin-containing bait, a single ingestion of which is essentially incapable of inducing abnormalities in coagulation. 1aJ9 Extrapo-
ies have seriously questioned both the efficacy and risk-tobenefit ratio of therapeutic gastric emptying for acute poisoning in general. 22'23
lating from the LD5o of rats, Gosselin and associates calculated that it would take approximately 60 lb of warfarin-containing rat bait to induce a similarly toxic onetime dose in human beings. 2° Based on this, others have suggested that neither induced emesis nor gastric lavage is required in the management of single-dose ingestions of warfarin. 3 During his final hospitalization, our patient received ipecac while in the ED. However, gastric emptying would be of no expected benefit if, as according to the history, he had last consumed brodifacoum-containing rat bait nearly three weeks before this presentation. Although ipecac has traditionally been considered standard therapy for alert poisoned patients, this treatment may have played a role in precipitating intracranial hemorrhage by raising intracranial pressure. After receiving ipecac, the patient developed sudden and profound neurologic deterioration immediately after a bout of severe retching. The POISINDEX notes that anticoagulated patients may be at risk for gastrointestinal hemorrhage from ipecac-induced vomiting, but it does not cite a risk of central nervous system bleeding. 21 Recent stud-
Phytonadione has been associated with anaphylactic deaths when given intravenously. Although this has usually been thought to occur only if the agent was infused rapidly, there have been reports of anaphylaxis occurring despite slow infusion of dilute phytonadione solutions. 24-27 These and other authors, as well as the manufacturer, therefore recommend that this form of vitamin K be used intravenously only in acute emergencies where other routes are not feasible and the potential benefits outweigh the risks. 24-26'28"29 Others have further recommended that when IV phytonadione is required, the clinician should be prepared for the possibility of anaphylaxis 3 We believe that our case represented an emergency situation that justified IV administration along with careful monitoring. Intramuscular and subcutaneous injections of phytonadione have not been associated with anaphylaxis; however, the former would be contraindicated in the face of a severe coagulopathy, and the latter, if not contraindicated, might result in slow absorption and a delayed therapeutic effect. When IV vitamin K is indicated for reasons other than to antagonize anticoagu-
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1ant action, such as in the treatment of vitamin K deficiency due to intestinal realabsorption, we recommend that menadiol be used. Unlike phytonadione, IV menadiol has not been associated with life-threatening adverse effects in adults. With this in mind, the policy of our hospital pharmacy is to dispense menadiol when IV "vitamin K" is ordered without indicating a specific form. Menadiol, however, is essentially ineffective in reversing warfarin or brodifacoum-induced anti-
coagulation. 2'3'3°-32 Physician orders for both "vitamin K" and "Synkayvite®'' were initially written for this patient, potentially delaying the onset of anticoagulation reversal. These differences in efficacy and adverse effects underscore the importance of routinely specifying the particular form of vitamin K that is desired rather than simply prescribing "vitamin K." After pronouncement of brain death, our patient's kidneys were harvested and transplanted successfully. Because coumarin-induced anticoagulation is due to interference with clotting factor synthesis in the liver, the anticoagulant effects of brodifacoum would not be expected to carry over to the recipient. However, there is some evidence that coumarin compounds can also cause direct vascular injury and that this effect is also responsible for causing spontaneous homer-
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rhage. 3'2°'33-37 Assuming this capillary damage effect is real, the question may be raised as to whether it might affect viability of the transplanted organs; however, in this case, no problems were encountered with hemostasis during reimplantation, and both grafts continued to function well after 12 months of follow~up.
SUMMARY
rhage. Anticoagulation should be considered a contraindication to ipecac-induced vomiting.
The authors acknowledge Drs Carter Bishop and Mohammed Bazzi, who participated in the clinical management of the patient at Detroit Receiving Hospital, and Dr Myer Roszler for his expert assistance in interpreting the radiographs and CT scans.
This case - - the second
reported case of fatal human poisoning from brodifacoum - - demonstrates three important points. First, it illustrates a basic tenet of clinical toxicology - - that specific identification of the toxic agent can be of critical importance in the management of the poisoned patient. The incorrect assumption that rodenticideinduced coagulopathy was pathognomonic for warfarin poisoning resulted in this patient's second hospitalization with a major bleeding episode. The extended halflife of brodifacoum and related anticoagulants mandates prolonged treatment and monitoring. Second, phytonadione (vitamin K1) must be used to reverse coumarin-induced coagulopathy; menadiol (vitamin K3) should not be used. Finally, by raising intracranial pressure, the induction of vomiting during the patient% third admission may have played a role in precipitating the fatal intracranial hereof-
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REFERENCES 1. Link KP: The anticoagulant from spoiled sweet clever hay. HarveyLect194344;39:182-216. 2. O'Reilly RA: Anticoagulants, antithrombotics, thrombolyt[c drugs, in Gilman AG, Goodman LS, Rail TW, et al (ads): Goodmanand Gillman's The Pharmacolog~ca/Basis of Therapeutics,ed 7. New York, Macmillan, 1985, p 1344q 359. 3. FIomenbaumNE, Goldfrank LR, Howland MA, et el: Rodenticidesand warfarin (coumadin)overdoses, in Goldfrank LR, Flemenbaum NE, Lewin NA, et al (ads): Goldfrank's ToxicologicEmergencies,ed 3. Norwalk, Connecticut, Appleton-CenturyCrofts, 1986, p 697-716. 4. BachmannKA, Sullivan TJ: Dispositional and pharmacodynamiccharacteristics of brodifacoum in warfarin-sensitive rats. Pharmacol1983;27:281-288. 5. Baflow AM, Gay AL, Park BK: Difenacoum (Neosorexa)poisoning. Br Mad J 19821285:541. 6. LeckJB, Park BK: A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K~ metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats. BiochemPharmacol1981;30:123-128. 7. ParkBK, Scott AK, Wilson AC, et al: Plasma disposition of vitamin K1 in relation to anticoagulant poisoning. BrJ Clio Pharmacol1984;18:655-662. 8. Hadler MR, Shadbatt RS: Novel 4hydroxycoumarinanticoagulants active against resistant rats. Nature 19751253:275-277. 9. Lipton RA, Klass EM: Human ingestion of a "supa~arfarin" rodenticide resulting in a prolonged anticoagulant effect. JAMA 19841252:3004-3035. 19. Talon®TechnicalBulletin. Goldsboro,
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Address for correspondence: James A Kruse, MD, Department of Medicine, Room 5S-10, Detroit Receiving Hospital, 4201 St Antoine, Detroit, Michigan 48201.
ANNALS OF EMERGENCY MEDIClNE 2 1 : 3 MARCH1992
