Superwarfarin Poisoning FREE

SUPERWARFARINS constitute a class of rodenticides developed in the 1970s to overcome resistance to warfarin in rats.^1- 2 They are popular and readily available in stores and homes. Superwarfarins are long-acting, fat-soluble anticoagulants with a terminal half-life of at least 24.2 days and are 100 times more potent than warfarin.³ Superwarfarins and warfarins concentrate in the liver on ingestion.⁴ There are 3 major groups of superwarfarins: hydroxy coumarin derivatives with a 4-bromo(1-1 biphenyl) side chain; coumatetryls; and indanediones. The most commonly used superwarfarin is brodifacoum, a 4-hydroxy coumarin with a 4-bromo side chain sold as D-Con (Reckitt & Colman, Montvale, NJ.)⁵ Superwarfarins inhibit the carboxylation of vitamin K–dependent factors (II, VII, IX, and X) in the liver. They specifically inhibit the vitamin K 2,3-epoxide reductase enzyme, leading to an increase in vitamin K epoxide,³ the inactive form of vitamin K (Figure 1). Although the events that lead to superwarfarin exposure or poisoning are diverse, the cause is usually straightforward on admission. Sometimes the diagnosis of superwarfarin poisoning can be challenging. Multiple admissions and evaluations^6- 9 are reported for this disorder when it is a manifestation of Munchausen syndrome.

There have been no epidemiological studies of patients with superwarfarin exposure or poisoning. We reviewed the records of 11 patients found to have superwarfarin poisoning over 15 years. We also reviewed the literature on the causes, clinical manifestations, diagnosis, treatment, and prevention of brodifacoum poisoning.

We reviewed all cases (128 charts) at Marshfield Clinic, Marshfield, Wis, with International Statistical Classification of Diseases, 10th Revision (ICD-10)¹⁰ codes 989.4 (toxic effects of other pesticides), including E codes E863.7 (accidental poisoning–rodenticide), E950.6 (suicide-agricultural agent), E962.1 (assault poisoning with solid/liquid), and E980.7 (undetermined poisoning with agricultural agent), and code 286.7 (acquired coagulation factor deficiency) from January 1, 1979, to March 31, 1996.

Exposure was defined as any history of oral intake or inhalation of superwarfarin, or superficial contact with a superwarfarin near the oral mucosa without any biochemical or clinical manifestations of coagulopathy.

Poisoning was defined by exposure to superwarfarin plus clinical and biochemical changes consistent with coagulopathy, including an elevated prothrombin time (PT), an elevated activated partial thromboplastin time (APTT), an increase in the vitamin K epoxide–vitamin K₁ ratio, or depressed levels of vitamin K–dependent coagulation factors (II, VII, IX, and X) with the presence of superwarfarin in the blood. The definitions of exposure and poisoning were established before the epidemiological data were collected.

Eleven cases (7 children, 1 teenager, and 3 adults) satisfied the criteria of superwarfarin exposure or poisoning. Seven patients were male and 4 were female. There were 3 major categories of exposure or poisoning: accidental ingestion (in children), attempted suicide, and deliberate self-poisoning with denial (Munchausen syndrome).

All the children in our study were individuals younger than 6 years who had accidentally ingested superwarfarin. None of the children had documented elevated PTs, clinical signs of coagulopathy, or complications. One child received 5 mg of vitamin K subcutaneously, and 5 children received syrup of ipecac. Test results showed no PT abnormalities in any of the children on follow-up more than 48 hours after treatment. There was no morbidity or mortality reported in this group over many years of follow-up.

The second group, patients who attempted suicide, included 1 teenager and 1 adult. The teenager presented with some bruising and a slightly elevated PT with an international normalized ratio of 1.3. She was sent home and found to be normal on follow-up 3 days later with no clinical signs of coagulopathy. The man who had attempted suicide had an initial PT of 11.7 seconds and no coagulopathy during his 4-day stay. The final outcome of this patient was unknown since he was transferred to another institution on his fourth day at the hospital.

The third group of patients included those with Munchausen syndrome. The first patient was a 44-year-old divorced man who was admitted with multiple ecchymosis and gross hematuria. Laboratory studies yielded the following values: PT, greater than 90 seconds; APTT, greater than 160 seconds; international normalized ratio, 60.8; factor VII, 1%; and factor X, 4%. Mixing studies with the patient's plasma and normal plasma at a ratio of 1:1 corrected the PT to normal. The patient's plasma was negative for warfarin. His vitamin K epoxide level (following high-dose vitamin K₁ therapy) was 50.2 ng/mL (reference range, <0.05 ng/mL) and his phylloquinone level (reduced vitamin K) was 9.5 ng/mL (reference range, 0.1-1.0 ng/mL). The results of his initial screening for superwarfarins were negative. Subsequently, a specific assay for brodifacoum revealed a concentration of 78 ng/mL. After the patient was confronted with this finding and a possible police investigation, he admitted to taking a handful of brodifacoum (Talon). The patient received large doses of parenteral vitamin K₁ in addition to fresh frozen plasma to reverse his coagulopathy as soon as the initial coagulation levels were reported. He was discharged after 11 days in the hospital, requiring 5 months of outpatient follow-up by a home health nurse and 20 weekly doses of subcutaneous vitamin K₁ (410 mg) before the coagulopathy resolved. Although he had been instructed to take oral vitamin K₁, it was discovered that he never had the prescription filled. The patient underwent psychiatric evaluation but refused follow-up visits.

The second patient, a 50-year-old woman, was admitted because of easy bruising and a subungual hematoma. Laboratory studies yielded the following values: PT, 39.6 seconds; APTT, 108.2 seconds; factor VII, 7%; and factor IX, less than 2%. Mixing studies performed as described earlier corrected the PT to normal. The patient's plasma was negative for warfarin; however, she was found to have a brodifacoum level of 310 ng/mL. As a result, she was given large doses of parenteral vitamin K₁ as well as fresh-frozen plasma to reverse her coagulopathy, which resolved after 11 months of outpatient treatment. The treatment included prolonged intake of oral vitamin K and numerous emergency department and clinic visits for fresh-frozen plasma transfusions and parenteral vitamin K₁. The patient was suspected of continuing to ingest brodifacoum, but she refused psychiatric referral.

Superwarfarin exposure or poisoning is a growing problem. Data on exposure or poisoning with long-acting rodenticides from the American Association of Poison Control Centers from 1988 to 1994^11- 17 point to a gradual increase (Figure 2) in cases of superwarfarin exposure and poisoning. In 1995, 13423 individuals were exposed and treated in 5051 facilities that serve a total population of 218.5 million people.¹⁸

Accidental exposure or poisoning usually occurs in children. About 90% of the exposures reported by the American Association of Poison Control Centers in 1995 occurred in individuals younger than 6 years.¹⁸ In our study, 7 of 11 cases of exposure were in children younger than 6 years. Fortunately, there was no notable morbidity or mortality in these patients. When confronted with patients with accidental exposure or ingestion, physicians should follow guidelines recommended by a poison center.⁵

Brodifacoum poisoning in adults is less frequent. Poisoning may be due to suicide attempts,^19- 20 industrial exposure,²¹ psychiatric conditions,²² accidental ingestion,¹⁵ or Munchausen syndrome.⁶ Brodifacoum poisoning is the most common type of superwarfarin poisoning, yet only 24 cases of brodifacoum poisoning have been reported in adults. There have been 11 cases of Munchausen syndrome,^{6- 9,23- 27} 6 attempted suicides,^{19- 20,28- 31} 2 industrial exposures,²¹ 3 cases of unknown cause,^18,32 1 case of accidental ingestion,¹⁵ and 1 case involving a psychiatric disorder.²² Poisoning in the adults and the teenager in our study resulted from 2 suicide attempts and 2 cases of Munchausen syndrome. Thus far, there have been no reports that superwarfarin has been used to commit murder or that the drug has been dispensed erroneously.³³

Clinical manifestations of brodifacoum poisoning include vaginal bleeding,^9,22 epistaxis,^7,27,30,34 hematuria,^{7- 8,19,26- 34} bleeding from the gums,^20,25,31 gastrointestinal bleeding,^8,30- 32 ecchymosis,^6,19,34 spontaneous abortion,²² hemoptysis,^23,25 abdominal pain,²⁰ and intracranial hemorrhage.^18,30,34 Sixteen of the 24 reported cases presented with hematuria. Ecchymosis was present in 6 of the 24 cases. Workup of brodifacoum poisoning is not a problem in cases of acute poisoning but may be challenging in patients with suspected Munchausen syndrome. We advise physicians confronted with cases of brodifacoum poisoning to determine the PT of the patient on initial exposure and at 48 hours.³⁵ Any prolongation in PT indicates that poisoning has occurred. We also suggest that for patients with possible Munchausen syndrome, a mixing study of the patient's plasma with control plasma should be performed. Normalization of the PT and APTT after mixing studies implies the presence of factor deficiency and the absence of an inhibitor. Furthermore, we advise physicians to obtain samples of a few of the vitamin K–dependent factors (II, VII, IX, and X) and factor V, which is produced in the liver but is not vitamin K dependent. Although not usually necessary, one can determine the vitamin K₁ epoxide–reduced vitamin K ratio. A deficiency of vitamin K–related factors plus a very high vitamin K₁ epoxide–reduced vitamin K₁ ratio is consistent with warfarin or superwarfarin poisoning.^36- 37 Vitamin K₁ epoxide is a product of vitamin K metabolism and is the inactive form of vitamin K (Figure 1). The presence of warfarin or superwarfarin in the blood confirms warfarin or superwarfarin exposure or poisoning. Usually none is detected. If Munchausen syndrome is suspected and the patient's blood is negative for warfarin, a specific assay for brodifacoum (Talon) and other superwarfarins should be performed. In our first case, levels of all the vitamin K–dependent factors were low and the factor V level was normal, which is consistent with a lack of vitamin K₁ or inhibition of its activity by warfarin or superwarfarin. After transient resolution, repeated and continuous treatment with large doses of vitamin K₁ was necessary to correct the coagulopathy. The vitamin K₁ epoxide–reduced vitamin K ratio confirmed the presence of a warfarin-type compound while assays for warfarin were being performed. Results of the original screening test for superwarfarin were reportedly negative, but brodifacoum was later detected at a concentration of 78 ng/mL.

The treatment of brodifacoum poisoning in adults is supportive. We believe vitamin K₁ should be intravenously administered to patients with severe coagulopathy. The total amount of vitamin K₁ should be diluted with saline or glucose and infused at a rate not exceeding 5% of the total dose per minute. This treatment can be administered every 6 to 8 hours.³⁸ Intramuscular administration should be reserved for adults with mild cases of poisoning by ingestion, while subcutaneous administration may be used for maintenance therapy. We believe treatment for severe bleeding should include fresh-frozen plasma and red blood cell transfusion as necessary to quickly correct coagulopathy. The role of phenobarbital in the treatment of brodifacoum poisoning has yet to be defined. There are some case reports¹⁹ of its enhancement of hepatic microsomal enzymes. The dose of phenobarbital is 100 to 180 mg/d.⁵

Treatment for superwarfarin poisoning requires long-term outpatient care. Coagulopathy may persist for months, and some patients may die if discharged too early.^29,34 Adequate compliance is crucial to achieving complete reversal of anticoagulation. One of our patients with Munchausen syndrome required continued parenteral therapy because he never filled his prescription for oral vitamin K₁. Although psychiatric evaluation may be indicated, patients with Munchausen syndrome rarely comply with therapy.

Most patients with superwarfarin exposure or poisoning do not have major complications. Of the 79025 cases of exposure or poisoning reported over a period of 8 years,^11- 18 there were 8 reported deaths and only 67 patients (0.08%) with major residual effects (residual disability or disfigurement). However, among 24 patients with brodifacoum poisoning reported in the literature, 6 died (1 committed suicide after being discharged).²⁹ Reported causes of death include sepsis in 1 case,⁹ intracerebral bleeding in 2 cases,^30,34 and events related to the central nervous system in 2 cases.^15,18

Superwarfarin exposure or poisoning is a growing public health problem in the United States affecting those of all ages, but primarily children. The diagnosis of superwarfarin poisoning is usually straightforward in cases of acute poisoning or exposure but may be difficult in patients with Munchausen syndrome. Patients with a coagulopathy consistent with vitamin K₁ deficiency that persists or recurs despite a history of adequate replacement should be evaluated for warfarin or superwarfarin poisoning.

Accepted for publication February 5, 1998.

We wish to thank John W. Suttie, PhD, from the Department of Biochemistry, University of Wisconsin, Madison, for performing the vitamin K ratio tests, and Alice Stargardt for her expertise in the preparation of the manuscript. We also appreciate the advice and care given to the patients with Munchausen syndrome by Dale Sternberg, MS, and Shelly Stanton, MD.

Corresponding author: William R. Friedenberg, MD, Department of Hematology/Oncology, Guthrie Clinic, Guthrie Square, Sayre, PA 18840.