Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) pp-581
2) WBA 8119
3) 3-(3-(4-bromo(1,1-biphenyl)-4-yl)-1,2,3,4-tetrahydro
4) -1-naphthalenyl)-4-hydroxy-2H-1-benzopyran-2-one

1) pp-580
2) WBA 8107
3) 3-(3-1,1-biphenyl-4yl-1,2,3,4-tetrahydro-1-
4) naphthylenyl)-4-hydroxy-2H-1-benzopyran-2-one

1) CAS 104653-34-1

1) LM-637
2) 3-(3-(4-Bromo(1,1-biphenyl)-4-yl)-3-hydroxy-1-
3) phenylpropyl)-4-hydroxy-2H-1-benzopyran-2-one

1) LM-91
2) Chlorphacinone
3) 2(-(p-chlorophenyl)phenylacetyl)-1,3-indandione

1) Dipazin
2) Diphacin
3) Diphenacin
4) Diphenadione
5) Ratindan
6) 2-Diphenylacetyl-1,3-indandione
7) CAS 82-66-6

1) Pival
2) Pivaldione
3) Pivalylindandione
4) 2-pivalyl-1,3-indandione
5) 2-trimethylacetyl-1,3-indandione

1) 2-isovalerylindane-1,3-dione
2) PMP
3) 2-isovaleryl-1,3-indandione

1) Cumatetralyl
2) Endox
3) Endrocid
4) Endrocide
5) Racumin
6) Rodentin
7) 3-(1,2,3,4-Tetrahydro-1-naphthyl)-4-hydroxycoumarin
8) 2H-1-Benzopyran-2-one, 4-hydroxy-3-(1,2,3,4-
9) tetrahydro-1-naphthalenyl)-

1) RATIMUS (TAMOGRAM)
2) BROMADIALONE
3) LONG-ACTING ANTICOAGULANTS
4) BROMODIALONE
5) TOUMARIN
6) OPITOX
7) PID (CAS 82-66-6)
8) BROPRODIFACOUM
9) DIHYDROPENTABORANE
10) PENTABORON UNDECAHYDRIDE

Available Forms Sources

A)

1) INDANDIONES

a) Diphacinone is available as a 0.005% rodent cake, 0.1%, 0.05%, and 0.2% rat and mouse bait and 2% concentrate (Diphacin(R), Promar(R), Ramik(R)).
b) Chlorophacinone is available as a 2.5% concentrate in oil, 0.25% solution, and 0.005% rat and mouse bait (Caid(R), Drat(R), Liphadione(R), Microzul(R), Ramucide(R), Ratomet(R), Raviac(R), Rozol(R), Topitox(R)).
c) Pindone is available as a 0.025, 0.1, 0.2 or 0.5% powder and 0.5%, 1.5% and 2% concentrate (Pival(R), Pivacin(R), Pivalyn(R), Tri-Ban(R)).

2) 4-HYDROXYCOUMARINS

a) Difenacoum is available as a 0.005% grain-based bait (Ratak(R)).
b) Brodifacoum is available as a 0.005% grain-based pellet or loose bait pack (Talon(R), Talon-G(R), Havoc(R)).
c) Bromadiolone is available as a 0.005% grain-based pellet (Bromone(R). Super-Caid(R), Ratimus(R), Maki(R)).
d) Coumatetralyl is available as Endox, Endrocid, Endrocide, Racumin, Racumin 57, and Rodentin (RTECS , 1989; Sax & Lewis, 1989).

3) OTHER

a) Difethialone, a superwarfarin, is derived from 4-hydroxybenzothiopyranones in which the oxygen atom of 4-hydroxy-coumarin is replaced by a sulfur atom. It is available for use in Japan (Kamijo et al, 2011).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Used as a rodenticide.
B) TOXICOLOGY: These agents block the formation of the active form of vitamin K, which in turn inhibits the hepatic production of coagulation factors II, VII, IX, and X. Specifically, they inhibit the subunit 1 of the vitamin K epoxide reductase complex. Primary concern is development of a bleeding diathesis.
C) EPIDEMIOLOGY: This is a common exposure but serious poisoning is rare and generally only occurs after deliberate ingestion. Significant coagulopathy has not been reported after inadvertent exposure in children. Rarely, coagulopathy has been reported in patients smoking marijuana mixed with brodifacoum.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Usually asymptomatic or minimal bleeding issues such as easy bruising.
2) SEVERE TOXICITY: Nearly always results from an intentional ingestion. Patients may develop a severe bleeding diathesis that can last for months despite treatment, which places the patient at higher risk for life-threatening bleeding complications including gastrointestinal bleeding, intracranial bleeding, hematuria, and intraabdominal or retroperitoneal bleeding.

0.2.20)

A) Spontaneous abortion was reported in a 31-year-old woman who ingested 1500 g of Talon. A stillbirth occurred following a suspected brodifacoum ingestion.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most unintentional ingestions (e.g. in children under the age of 6) need no intervention. Asymptomatic low-grade elevation of the INR can be monitored. Significant prolongation of the INR (greater than 2.0) should be treated with vitamin K.

B) MANAGEMENT OF SEVERE TOXICITY

1) If life-threatening bleeding occurs, rapidly reverse coagulopathy with fresh frozen plasma (FFP) or prothrombin complex concentrate. Long-term treatment includes vitamin K, which can be given intravenously or subcutaneously initially, then orally once the patient stabilizes. Long term vitamin K administration (weeks to months) is usually required.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal can be useful if given early after large, deliberate ingestions. If there is dermal or eye exposure, it would be reasonable for simple decontamination with water at home. Inadvertent, exploratory ingestions in young children do not require GI decontamination.
2) HOSPITAL: Activated charcoal may be useful if given early after a large, deliberate ingestion. Neither gastric lavage nor whole bowel irrigation is indicated.

D) AIRWAY MANAGEMENT

1) Respiratory complications are not expected. Endotracheal intubation may be required in patients with intracranial bleeding or in rare patients with severe hemoptysis.

E) ANTIDOTE

1) Give vitamin K1 (phytonadione) in order to reverse coagulopathy, though the effect is delayed compared to giving blood products. In an unstable patient, intravenous (increased risk of anaphylactoid reactions) or subcutaneous dosing may be preferred; switch to oral dosing once patient has stabilized. For patients with severe coagulopathy, an initial dose of 20 to 40 mg vitamin K is reasonable, with further dosing guided by INR monitoring. Long acting anticoagulants have increased stability and longer duration of action than standard medicinal anticoagulants. Initial vitamin K doses for treatment can be as high as 400 mg with 500 to 1000 mg oral doses for daily maintenance. The long acting anticoagulants can cause a persistent coagulopathy for months but also must rule out repeated ingestions/exposure in these patients.

F) TRANSFUSION

1) Administer fresh frozen plasma and/or prothrombin complex concentrate (contains factors II, VII, IX, and X), in addition to vitamin K1, to rapidly reverse coagulopathy in patients with life-threatening bleeding. Monitor INR to determine need for further therapy. Transfusion with packed red blood cells and platelets may also be necessary.

G) COAGULATION FACTOR VII

1) Recombinant activated factor VII 70 to 90 mcg/kg IV has been used along with vitamin K1 to rapidly reverse coagulopathy in several cases.

H) ENHANCED ELIMINATION

1) Hemodialysis is not indicated.

I) PATIENT DISPOSITION

1) HOME CRITERIA: In asymptomatic patients with questionable or unintentional exposure, monitor for easy bruising and bleeding from gums while brushing teeth, otherwise follow up with their personal physician as needed. Patients who inadvertently ingest less than 1 mg of a long-acting anticoagulant rodenticide (LAAR) active ingredient (ie, brodifacoum, bromadiolone, chlorophacinone, difenacoum, and diphacinone) can be observed at home without laboratory monitoring. This amount of active ingredient would include nearly all unintentional ingestions among children less than 6 years of age. However, not all rodenticides are long acting anticoagulants so it is important to identify the specific active ingredient in the commercial product (call the local poison center).
2) OBSERVATION CRITERIA: The delayed onset and prolonged duration of effect make SHORT TERM observation unlikely to be useful. Patients with deliberate overdose or abuse, with chronic ingestion of LAARs, or with symptoms (eg, bleeding, bruising) should be sent to a healthcare facility for evaluation. Patients taking therapeutic anticoagulants who are exposed to any dose of LAAR should have a baseline prothrombin time measured and obtain a repeat measurement 48 to 72 hours after ingestion. Asymptomatic patients inadvertently exposed to 1 mg or more of active ingredient LAAR should be evaluated for coagulopathy 48 to 72 hours after ingestion. Pregnant women with inadvertent exposures to less than 1 mg of LAAR active ingredient should be evaluated by an obstetrician or primary care provider on an outpatient basis. Stable patients with mild toxicity (INR less than 2) are managed as outpatients.
3) ADMISSION CRITERIA: Any patient with active bleeding with a bleeding diathesis should be admitted until the bleeding has stopped and the bleeding diathesis is reversed (unless there is a situation where the patient needs to be maintained on some baseline anticoagulation such as transplanted or artificial heart valve). Depending on the patient's social situation, most patients should be admitted for observation until their bleeding diathesis is improved even if there is no active bleeding.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for any patient with a significantly increased INR, active bleeding or other complications. Any patient with a deliberate ingestion should have a psychiatric evaluation.

J) PITFALLS

1) Not all rodenticides are long acting anticoagulants. Coagulopathy will not start developing until 24 to 48 hours after an acute ingestion. Coagulopathy may be delayed despite treatment due to the long half-life of these substances. Vitamin K1 is most safely given orally as there have been reports of anaphylactoid reactions from IV administration and hematoma formations from IM injections. Unintentional, one-time ingestions rarely require intervention. Consider child abuse/Munchausen’s syndrome in children with coagulopathy.

K) PHARMACOKINETICS

1) There are many different long acting anticoagulants and in overdose they may display differing pharmacokinetics. Brodifacoum, one of the 4-hydroxycoumarin long acting anticoagulants, has a half-life of 24 days and a Vd of 1.0 L/kg. A case of a self-harm ingestion of bromadiolone, another 4-hydroxycoumarin, showed elimination kinetics of a two-compartment model with a rapid, fairly steep decline phase (half-life 3.5 days) followed by a slower termination phase (half-life 24 days). Elimination half-life of chlorophacinone ranged from 5.9 to 11 days in 4 patients.

L) DIFFERENTIAL DIAGNOSIS

1) Bleeding diathesis: DIC, Vitamin K deficiency, rattlesnake envenomation, congenital bleeding disorders (hemophilia, von Willebrand’s disease), or coumadin overdose.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) MILD TO MODERATE TOXICITY: Usually asymptomatic or minimal bleeding issues such as easy bruising.
2) SEVERE TOXICITY: Nearly always results from an intentional ingestion. Patients may develop a severe bleeding diathesis that can last for months despite treatment, which places the patient at higher risk for life-threatening bleeding complications including gastrointestinal bleeding, intracranial bleeding, hematuria, and intraabdominal or retroperitoneal bleeding.

Heent

3.4.5)

A) WITH POISONING/EXPOSURE

1) EPISTAXIS may develop in patients with anticoagulant effects (Laposata et al, 2007; Spiller et al, 2003; Chow et al, 1992; Travis et al, 1993; Kruse & Carlson, 1992).

3.4.6)

A) WITH POISONING/EXPOSURE

1) GINGIVAL BLEEDING: Bleeding from the gingiva may develop in patients with anticoagulant effects (Laposata et al, 2007; Tsutaoka et al, 2003; Hollinger & Pastoor, 1993; Butcher et al, 1992; Travis et al, 1993; Sheen et al, 1994; Kruse & Carlson, 1992; Corke, 1997).

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Chest pain and tachycardia may develop secondary to blood loss (Walker & Beach, 2002; Barnett et al, 1992; Travis et al, 1993; Kruse & Carlson, 1992).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension may develop in patients with substantial blood loss from severe anticoagulant effects (Kruse & Carlson, 1992; Morgan & Tomaszewski, 1995; Corke, 1997).

C) MYOCARDIAL DYSFUNCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 57-year-old woman intentionally ingested 5 boxes of household rodenticide containing difethialone and warfarin (2 boxes were equivalent to 120 g of red-dyed pellets containing 0.0025% (total 3 mg) difethialone and the other 3 contained 360 g of red-dyed pellets containing 0.05% warfarin (total 180 mg) and nitrazepam (total of 280 mg). She was admitted comatose with respiratory acidosis requiring intubation and mechanical ventilation. She was also incontinent of urine and stool (both appeared pink in color suggesting superwarfarin ingestion). On day 2 her INR and aPTT rose to 2.65 and greater than 200 seconds, respectively; a vitamin K infusion was continued. No bleeding developed. However, worsening hypotension was noted and an echocardiogram showed diffuse myocardial hypokinesia with a left ventricular ejection fraction (LVEF) of 34.4%. Cardiac function continued to worsen, with an LVEF of essentially 0 at and an intraaortic balloon pump was inserted. Her LVEF rapidly improved over 24 hours. Laboratory studies were positive for difethialone, warfarin and nitrazepam; no other agents were detected. By day 5, she was successfully extubated with normal mentation. Vitamin K was changed over to oral therapy on day 8. The patient continued to do well and by day 21 had a normal INR and aPTT and was transferred for further psychiatric care (Kamijo et al, 2011).

3.5.3)

A) ANIMAL STUDIES

1) HEART DISORDER

a) Cardiopulmonary injury has been described in laboratory rats, but has not been reported in human overdose.

Respiratory

3.6.2)

A) PULMONARY HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 27-year-old woman developed hemoptysis, hypoxia and respiratory failure secondary to diffuse alveolar hemorrhage and severe coagulopathy from brodifacoum ingestion (Barnett et al, 1992).
b) CASE REPORT: A 15-year-old girl died from massive pulmonary hemorrhage following intentional ingestion of an unknown amount of rodenticide containing brodifacoum. Autopsy showed petechial hemorrhages on her shins, face, trunk, arms, and thighs. Petechial hemorrhages were also distributed on the epicardial surfaces, gastric mucosa, and intestinal mucosa. Microscopic examination of the lung revealed acute alveolar hemorrhage. The concentration of brodifacoum found in the lung tissue was 31 ng/g (Palmer et al, 1999).

B) HEMOTHORAX

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 25-year-old man with bleeding and coagulopathy secondary to brodifacoum ingestion developed a superior mediastinal mass and bilateral pleural fluid collections (Kruse & Carlson, 1992).
b) CASE REPORT: A 26-year-old woman presented with painful swelling of her right leg and menorrhagia 3 weeks after ingesting brodifacoum in a suicidal attempt. On examination, her right calf and thigh were tender and swollen and pedal pulses were slightly diminished. Laboratory results showed a hemoglobin of 9 g/dL with normal peripheral smear, an activated partial thromboplastin time (aPTT) of 166.6 seconds (normal, 21 to 36), a prothrombin time (PT) of greater than 169 seconds (normal, 9.8 to 14), and an INR of greater than 14. Her blood brodifacoum concentration was 71 ng/mL (laboratory reporting limit 5 ng/mL). She was treated with parenteral vitamin K with 6 units of fresh frozen plasma because of the risk of expanding hematoma and impending compartment syndrome. Following supportive care, her condition improved; however, she complained of shortness of breath on day 4. A chest radiograph showed a new right-sided pleural effusion which remained stable in size. She continued to improve following supportive treatment and was discharged home on day 6 on high-dose oral vitamin K and iron (Tahir et al, 2008).

C) HEMOPTYSIS

1) WITH POISONING/EXPOSURE

a) Hemoptysis may develop in patients with coagulopathy (Exner et al, 1992).

Neurologic

3.7.2)

A) INTRACRANIAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Death due to massive hemorrhage, preceded by headache, loss of consciousness, and seizures, has been described after massive brodifacoum ingestion (Basehore & Mowry, 1987; Helmuth et al, 1989; Kruse & Carlson, 1992; Ornstein et al, 1999).
b) CASE REPORT: Bilateral occipital cerebral hemorrhage developed after minor head trauma in a 7-year-old girl secondary to accidental poisoning with brodifacoum. Prothrombin time (PT) and activated partial thromboplastin time (PTT) were elevated at the time of this admission (PT 18.2 seconds, PTT 55 seconds) (Watts et al, 1990).
c) CASE REPORT: A 59-year-old man presented with cervical-dorsal subdural hematoma associated with accidental poisoning with difenacoum (Nighoghossian et al, 1990).
d) CASE REPORT: Ornstein et al (1999) reported a fatal case of a 39-year-old woman who developed severe headache, confusion, and cerebral edema after ingestion of an unknown amount of brodifacoum. Computed tomography scan of the brain showed a diffuse subarachnoid hemorrhage (Ornstein et al, 1999).
e) CASE REPORT: A 40-year-old man presented with severe neck pain, occipital headache, vomiting, and numbness in his left arm following ingestion of an unknown amount of chlorophacinone 20 days prior to presentation. Laboratory data revealed anemia, hematuria, and prolonged prothrombin time and activated partial thromboplastin time. His brain CT scan showed a left cerebellar hematoma with perifocal edema and diffuse brain edema surrounding the fourth ventricle. Despite treatment with mannitol, dexamethasone, fresh frozen plasma (FFP), packed red blood cells (PRBC), and vitamin K1, his condition continued to deteriorate necessitating his transfer to ICU , where he was intubated and mechanically ventilated. Following continued administration of vitamin K1, FFP, PRBC, and platelets, his coagulation normalized by the third day of treatment. Nine days later, the patient was extubated, and seventeen days after that, a repeat brain CT scan showed complete resorption of the hematoma, although his neurological status showed anisocoria and right-side spastic hemiparesis. Physical therapy was initiated and approximately 36 days post ICU-admission, the patient was transferred to a rehabilitation hospital. Neurological examination, one year later, showed complete regression of neurological deficits (Rutovic et al, 2013).

B) COMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 57-year-old woman intentionally ingested 5 boxes of household rodenticide containing difethialone and warfarin (2 boxes were equivalent to 120 g of red-dyed pellets containing 0.0025% (total 3 mg) difethialone and the other 3 contained 360 g of red-dyed pellets containing 0.05% warfarin (total 180 mg) and nitrazepam (total of 280 mg). She was admitted comatose with respiratory acidosis requiring intubation and mechanical ventilation. Her course was complicated by severe myocardial suppression (ie, hypokinesia and a left ventricular ejection fraction of 34.4%). An intraaortic balloon pump was inserted with rapid improvement. By day 5 she was successfully extubated with normal mentation. Laboratory studies were positive for difethialone, warfarin and nitrazepam; no other agents were detected (Kamijo et al, 2011).
b) CASE REPORT: A 29-year-old man was admitted to the emergency department with a Glasgow Coma Score of 3 after ingesting 2 packets of rat poison containing brodifacoum in a suicide attempt. The patient had an intra-abdominal hemorrhage and prolonged circulatory shock but no evidence of an intracerebral bleed on CT scan (Corke, 1997).

3.7.3)

A) ANIMAL STUDIES

1) NEUROPATHY

a) Neurologic toxicity has been described with the indanediones in laboratory rats, however no neurologic symptoms occurred in one massive overdose of chlorophacinone in an adult (Murdoch, 1983).

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Spontaneous emesis may occur (Smolinske et al, 1989).

B) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Gastrointestinal bleeding may develop in patients with coagulopathy (Olmos & Lopez, 2007; Kruse & Carlson, 1992; Sheen et al, 1994).

C) NONTRAUMATIC HEMOPERITONEUM

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Hemoperitoneum without an obvious source developed in a 20-year-old woman with severe coagulopathy from brodifacoum ingestion (Morgan & Tomaszewski, 1995).
b) CASE REPORT: A 26-year-old man developed hypovolemic shock with severe metabolic acidosis secondary to severe intraperitoneal hemorrhage from brodifacoum poisoning (Corke, 1997).
c) CASE REPORT: A 36-year-old woman presented to the emergency department with abdominal pain and hematuria. Physical examination showed abdominal diffuse tenderness. Laboratory analysis revealed an INR of greater than 7, an APTT of 127 seconds, and a thrombin time of 15 seconds. An abdominal CT scan showed a hemoperitoneum and an intravenous urography showed renal pelvis and ureteral hematomas. The patient admitted to intentionally ingesting 850 grams of diphenacoum. Signs and symptoms resolved following a transfusion of fresh frozen plasma and packed red cells and administration of IV Vitamin K (Terneu et al, 2003).
d) CASE REPORT/CHRONIC USE: A 51-year-old woman, who had been ingesting home made capsules containing difenacoum on a daily basis for 2 months, presented to the emergency department with abdominal pain. She had multiple cutaneous hematomas and ecchymoses on her upper and lower extremities. An abdominal CT scan showed a hemoperitoneum and an intramural hematoma of the small intestine. Initially, laboratory analysis revealed an INR greater than 7, an APTT of 115 sec (normal range 26 to 38 sec), and factors II, VII, IX, and X of less than 5% (normal 60% to 150%). She was given fresh frozen plasma and IV vitamin K and, 9 hours later, her INR decreased to 1.4. She was subsequently discharged with oral maintenance therapy of vitamin K, however laboratory data obtained 3 days after discharge revealed an INR of 2.4, indicating that the patient was noncompliant with vitamin K therapy. Although the patient was eventually lost to follow-up, the authors were informed that, 2 years later, the patient had died from rodenticide poisoning (Soubiron et al, 2000).

D) HEMATEMESIS

1) WITH POISONING/EXPOSURE

a) Hematemesis was reported in a 40-year-old woman following suspected ingestion of brodifacoum (Laposata et al, 2007).

Genitourinary

3.10.2)

A) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) Hematuria is a common presenting complaint in adults with coagulopathy from massive ingestion (Hollinger & Pastoor, 1993; Butcher et al, 1992; Sheen et al, 1994; Rauch et al, 1994; Ross et al, 1992; Tecimer & Yam, 1997).
b) CASE REPORT: An 18-year-old man presented to the emergency department with gross hematuria, epistaxis and flank pain 7 days after dermal exposure to a pesticide containing 0.106% diphacinone. Laboratory values showed a PT greater than 40 seconds, a PTT greater than 90, a hemoglobin of 16.2, and platelets of 273. The hematologic values normalized following initiation of vitamin K therapy (Spiller et al, 2003).
c) CASE REPORT: A 52-year-old HIV positive man ingested eight 43 gram boxes of d-CON Mouse-Prufe II (0.005% brodifacoum) and subsequently developed gross hematuria. His six day postingestion prothrombin time (PT) was 79.2 seconds and his activated partial thromboplastin time (aPTT) was 101.3 seconds, with an international normalized ratio (INR) of 38.2. Factor VII levels were less than 1%. The patient received 2 units of fresh frozen plasma. Oral Vitamin K1 therapy was initiated at 150 mg every 6 hours. This regimen was maintained for 46 days of outpatient management. Coagulation studies at day 46 were normalized and there was no further evidence of bleeding (Bruno et al, 2000)
d) CASE REPORT: A 57-year-old man presented to the emergency department with a 2-day history of bilateral loin pain and hematuria following extensive dermal exposure of 250 mL of a concentrated rodenticide, containing 0.25% chlorophacinone, on his torso and arms 9 days prior to presentation. Initial laboratory data revealed a prothrombin time (PT) greater than 200 sec (normal range 11 to 14 sec) and an APTT of 56 sec (normal range 23 to 32 sec). Following administration of fresh frozen plasma and intravenous vitamin K, the patient's PT gradually decreased and he was discharged. However, 2 days later, he again developed hematuria. Laboratory data revealed an INR of greater than 10. He gradually recovered following daily administration of vitamin K. He was discharged on daily oral vitamin K therapy and INR monitoring every other day for a month (Binks & Davies, 2007).

B) URINE COLOR ABNORMAL

1) WITH POISONING/EXPOSURE

a) Urine may be colored pink or blue because of the dye in the rodenticide (Kamijo et al, 2011).

C) FINDING OF VAGINAL BLEEDING

1) WITH POISONING/EXPOSURE

a) Excessive vaginal bleeding may develop in women (Chow et al, 1992; Routh et al, 1991; Barnett et al, 1992).

Hematologic

3.13.2)

A) HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) SIGNS/SYMPTOMS: Hemorrhage is the most common toxic sign and may be manifested by epistaxis, gum bleeding, hemoptysis, hematuria, gastrointestinal bleeding, ecchymoses, bloody or melenotic stools, bruising, and abdominal and flank pain.
b) ONSET OF SIGNS/SYMPTOMS: While the onset of prolonged prothrombin times occurs generally within 48 hours, the first clinical signs of bleeding may be delayed until one to four weeks after ingestion (Burucoa et al, 1989; Ross et al, 1992).

B) BLOOD COAGULATION PATHWAY FINDING

1) WITH POISONING/EXPOSURE

a) The long acting anticoagulants reduce the serum concentrations of the vitamin K defendant clotting factors (II, VII, IX and X), resulting in prolongation of INR, PT and PTT (Chow et al, 1992; Ross et al, 1992). Platelet count, fibrinogen level, and the concentrations of other clotting factors remain unaffected (Babcock et al, 1993). Fibrin split products may be elevated (Routh et al, 1991).
b) ONSET: Prolonged prothrombin time may be evident within 24 hours of ingestion and maximal in 36 to 72 hours. Larger doses produce a more rapid prolongation of PT than smaller doses (Leck & Park, 1981).
c) DURATION: In overdose, PT prolongation, INR elevation, and clinical bleeding have persisted for 45 days to 14 months (Nguyen et al, 2015; La Rosa et al, 1997; Kruse & Carlson, 1992; Lipton & Klass, 1984; Murdoch, 1983; Barlow et al, 1982) . Surreptitious reexposure likely occurred in many of these patients.

1) VALONE/CASE REPORT: A 30-year-old man was found unresponsive after ingesting an unknown amount of valone and Drano(R). His initial PT was 18.1 seconds, peaking at 21.6 seconds before any treatment was initiated. A few hours following initial treatment with fresh frozen plasma and vitamin K, his PT decreased to 13.3 seconds. Thirty-six hours post admission, after receiving 3 additional doses of vitamin K, his PT normalized to 11.9 seconds with a valone concentration of 0.40 mmol/L (compared with 0.96 mmol/L on admission) (Burkhart et al, 2000). It is noted that, compared to the anticoagulation effects following 4-hydroxycoumarin ingestions, valone-induced anticoagulation appears to be relatively short-lived.
2) BRODIFACOUM/CASE REPORT: A 17-year-old boy presented with mucosal and dermal bleeding. Laboratory analysis indicated a prolonged prothrombin time (PT) and an elevated Factor II induced in vitamin K absence (PIVKA-II) antigen. He was treated with 2 units of fresh frozen plasma (FFP) and intravenous and oral vitamin K, and was discharged. Two months later, the patient presented to the emergency department with syncope thought to be secondary to heart block resulting from verapamil intoxication. Laboratory data demonstrated a prolonged PT and activated partial thromboplastin times (APTT). Further investigation revealed that the patient had been smoking marijuana intentionally combined with a rodenticide containing brodifacoum. The patient was treated with intravenous and oral vitamin K and was discharged with continued vitamin K treatments for 3 months until he was lost to follow-up. Fourteen months after original presentation, the patient experienced bilateral flank pain with hematuria and oral and nasal mucosa bleeding. Although the patient denied exposure to brodifacoum, his PT and APTT were extremely prolonged. Again he was treated with oral and intravenous vitamin K and 4 units of FFP, and was discharged. The patient eventually described the method used to smoke marijuana mixed with brodifacoum that he had learned from friends. He denied any oral or parenteral exposure to brodifacoum (La Rosa et al, 1997).

d) CASE REPORT: A 22-year-old man developed severe coagulopathy after daily ingestion, over a period of 3 months (total ingestion of more than 6 boxes), of a rodenticide containing brodifacoum to purportedly potentiate the euphoric effects of illicit drugs. The patient presented to the emergency department with epistaxis, hematemesis, hematuria, and abdominal pain. Laboratory studies revealed a hematocrit of 28% and a PT and PTT of greater than 116 seconds and 143 seconds, respectively. Liver function tests were normal. Following receipt of several units of fresh frozen plasma and packed red blood cells over the next several days, the patient's laboratory values gradually normalized (Spahr et al, 2007).
e) CASE REPORT: A 46-year-old woman presented with gastric and pulmonary hemorrhage and severe coagulopathy after ingesting an unknown amount of rodenticide containing brodifacoum over a period of 2 days approximately 1 week prior to presentation. Initial laboratory data indicated a prothrombin time and activated partial thromboplastin time of greater than 110 seconds each. High-performance liquid chromatographic analysis of the patient's serum, performed 5 days post-presentation, quantitatively determined the presence of brodifacoum, with a serum brodifacoum concentration of 1302 ng/mL. The patient gradually recovered with vitamin K therapy (Olmos & Lopez, 2007).
f) CASE REPORT: A 41-year-old woman intentionally ingested 2.4 g of doxylamine and 20 mL of a rodenticide, later identified to contain brodifacoum. She initially had an episode of torsade de pointes and was successfully resuscitated. Laboratory data revealed an INR that fluctuated between 1.1 and 7.5 and a factor VII level from 2% to 92%, requiring high doses of vitamin K therapy over the course of 9 months (285 days), at daily doses ranging from 5 to 300 mg. Brodifacoum was detected in blood samples, via liquid chromatography-mass spectrophotometry, 193 days after ingestion (Nguyen et al, 2015).

C) VITAMIN K DEFICIENCY

1) WITH POISONING/EXPOSURE

a) The normal ratio of vitamin K epoxide to vitamin K1 is 0.1 to 0.2 . A vitamin K epoxide/vitamin K ratio of 2.7 was used to confirm a suspicion of rodenticide ingestion in a 62-year-old man who then admitted to brodifacoum overdose (Ross et al, 1992).

Dermatologic

3.14.2)

A) PURPURA

1) WITH POISONING/EXPOSURE

a) Multiple ecchymoses and hematomas may be evident on physical examination (Exner et al, 1992; Babcock et al, 1993; Chow et al, 1992; Rauch et al, 1994; Palmer et al, 1999).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Severe tissue hypoxia during periods of profound hypotension with muscle ischemia has resulted in rhabdomyolysis with increased serum CPK and myoglobinuria following anticoagulant poisoning (Corke, 1997).

Reproductive

3.20.1)

A) Spontaneous abortion was reported in a 31-year-old woman who ingested 1500 g of Talon. A stillbirth occurred following a suspected brodifacoum ingestion.

3.20.3)

A) ABORTION

1) Spontaneous abortion was reported in a 31-year-old woman who ingested 1500 g of Talon(R) (containing 75 mg of brodifacoum) five weeks earlier (Lipton & Klass, 1984).

B) STILLBIRTH

1) CASE REPORT: A 21-year-old woman, who was 37 weeks pregnant, presented with a 1-week history of gross hematuria. An obstetric ultrasound indicated a live fetus with intracranial hemorrhage. Laboratory data of the patient revealed coagulopathy with prolonged prothrombin and activated partial thromboplastin times and significantly decreased coagulation factors II, VII, IX, and X. With administration of IV prothrombin complex, fresh plasma, and IM vitamin K therapy, the patient's coagulation parameters improved; however, the fetal heart rate disappeared and the infant was delivered stillborn. Autopsy of the neonate revealed hemorrhage of the brain and lungs and multi-organ autolysis. Toxicological testing of the patient's blood, umbilical cord blood, amniotic fluid, and placenta demonstrated high levels of brodifacoum (1310 ng/mL, 652 ng/mL, 328 ng/mL, and 1033 ng/mL, respectively). After further interview with the patient, inadvertent ingestion of rat poison containing brodifacoum may have occurred approximately 4 days prior to the onset of hematuria. The patient completely recovered with continued vitamin K therapy over a period of several months post-presentation (Yan et al, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Laboratory monitoring is not needed if it is a recent, asymptomatic, unintentional exposure.
B) For symptomatic patients or those with deliberate ingestions, obtain an INR (note: INR may be normal for 24 to 48 hours after a single acute ingestion). Obtain a CBC in patients with evidence of bleeding or coagulopathy, type and cross match for patients with significant bleeding.
C) In patients with severe bleeding and/or significant coagulopathy frequent determination of INR and CBC may be necessary to guide administration of blood products and vitamin K1.
D) Specific assays do exist for some long acting anticoagulants such as brodifacoum and may be useful to identify occult ingestions but they are only available from specialty laboratories and are not helpful in guiding clinical management.
E) In patients taking therapeutic anticoagulants who are exposed to any dose of long-acting anticoagulant rodenticide (LAAR), obtain a baseline prothrombin time measurement and a repeat measurement 48 to 72 hours after ingestion.

4.1.2)

A) COAGULATION STUDIES

1) International normalized ratio or prothrombin times may be normal 24 hours postingestion, and become prolonged at 48 hours or later, therefore a 48 hour INR has been recommended (Smolinske et al, 1989; Caravati et al, 2007). Retrospective studies suggest that a single 48 hour INR may be sufficient after accidental ingestions of 1 mg or greater of long acting anticoagulant rodenticide active ingredient in asymptomatic children (Morrissey & Robertson, 1994; Brands et al, 1995).
2) Any prolongation of PT or elevation of INR when compared to normal controls indicates toxicity. In patients with significant coagulopathy or clinical evidence of abnormal bleeding, follow INR or PT, PTT every 6 to 12 hours during therapy until stable.
3) Normalization of the PT after mixing the patient's plasma with normal plasma suggests a clotting factor deficiency (Chow et al, 1992; Hollinger & Pastoor, 1993; Babcock et al, 1993).

B) CLOTTING FACTOR ASSAY

1) Determination of blood clotting factors II, VII, IX, and X may be helpful in guiding therapy in symptomatic patients. Since clotting factors may be abnormal with a normal INR or PT, they are a more sensitive measure of toxicity and may be more useful in guiding vitamin K1 therapy (Hoffman et al, 1988).
2) Assays of clotting factors may also identify surreptitious poisoning more rapidly. Clotting factor assays generally can be obtained within a day, while serum concentrations of long acting anticoagulants are generally not available for up to a week (Miller et al, 2006).

C) BLOOD/SERUM CHEMISTRY

1) The normal ratio of vitamin K epoxide to vitamin K1 is 0.1 to 0.2.
2) A 7-year-old girl with suspected brodifacoum poisoning had a ratio of vitamin K1 epoxide to vitamin K1 of 20:1 (Watts et al, 1990). Subsequent analysis of the patient's serum by HPLC technique found 280 ng brodifacoum/mL.
3) A vitamin K epoxide/vitamin K ratio of 2.7 was used to confirm a suspicion of rodenticide ingestion in a 62-year-old man who then admitted to brodifacoum overdose (Ross et al, 1992).

D) HEMATOLOGIC

1) Follow serial hemoglobin and hematocrit in patients with significant coagulopathy or clinical evidence of bleeding.

E) BRODIFACOUM CONCENTRATION

1) Serial blood brodifacoum levels have been proposed as an additional adjunct in determining length of vitamin K1 therapy (Bruno et al, 2000). Validation studies of the clinical reliability of such monitoring techniques have not yet been published and its routine use in patient care cannot be advised.

4.1.4)

A) OTHER

1) FECAL

a) STOOL GUAIC: check for the presence of blood in the stools in symptomatic patients or in patients with an elevated INR or prolonged PT.

2) OTHER

a) Most of these products contain a water-soluble dye (usually blue or green). However, evidence of dye in the mouth was not predictive of which children developed a prolonged PT in a prospective study of 110 accidental pediatric ingestions (Smolinske et al, 1989).

Methods

A)

Medtox Scientific Inc
St Paul, MN
Telephone:  800-832-3244

1) Brodifacoum serum levels can be analyzed using a high performance liquid chromatographic (HPLC) method with either UV or fluorescent detection (Murphy & Gerkin, 1989). Veterinary samples only (NOT human samples) can be analyzed by this laboratory:

Minnesota Veterinary Diagnostic Laboratory
    1943 Carter Avenue
    College of Veterinary Medicine
    University of Minnesota
    St Paul, MN  55108
    Telephone:  612-625-8787

2) The following laboratories will perform brodifacoum assays on human specimens:

National Medical Services
Willow Grove, PA
Telephone: 800-522-6671

3) In one study, liquid chromatography-mass spectrometry was used to quantify bromadiolone in whole blood and plasma. Limits of detection and quantification were 0.005 mg/L and 0.01 mg/L, respectively (Vindenes et al, 2008).
4) Wallace et al (1990) describe a method of analyzing brodifacoum in human plasma using HPLC. Assay sensitivity is reported to be 0.05 mcg/mL (S/N ratio 3) with no interfering peaks observed (Wallace et al, 1990).
5) An HPLC method, described by Guan et al (1999), was conducted that could simultaneously determine 5 anticoagulant rodenticides, including warfarin, coumatetralyl, diphacinone, chlorophacinone, and bromadiolone, in whole blood. For all of the rodenticides, the detection limit was 0.05 mcg/mL of whole blood (Guan et al, 1999).
6) An HPLC with fluorescence detection was used for quantitation of brodifacoum in the tissues and fluids of a 15-year-old girl who died following intentional ingestion of a rodenticide containing 0.005% brodifacoum. The limits of detection, using this method, were 5 ng/mL and 5 ng/g for fluids and tissues, respectively (Palmer et al, 1999).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any patient with active bleeding with a bleeding diathesis should be admitted until the bleeding has stopped and the bleeding diathesis is reversed (unless there is a situation where the patient needs to be maintained on some baseline anticoagulation such as transplanted or artificial heart valve). Depending on the patient's social situation, most patients should be admitted for observation until their bleeding diathesis is improved even if there is no active bleeding.
B) Coagulopathy commonly persists for 6 weeks or longer in patients who ingest large amounts in suicidal attempts. Premature discharge of such patients at 3 to 4 weeks postingestion prior to full normalization of factor levels has resulted in fatality in 3 cases (Basehore & Mowry, 1987; Helmuth et al, 1989; Kruse & Carlson, 1992).
C) Frequent outpatient monitoring should be done on patients discharged on oral vitamin K1 to ensure compliance and adequacy of treatment. Factor assays should be normal prior to discontinuation of vitamin K1.

6.3.1.2) HOME CRITERIA/ORAL

A) In asymptomatic patients with questionable or unintentional exposure, monitor for easy bruising and bleeding from gums while brushing teeth, but otherwise follow up with their personal physician as needed.
B) Patients who inadvertently ingest less than 1 mg of a long-acting anticoagulant rodenticide (LAAR) active ingredient (ie, brodifacoum, bromadiolone, chlorophacinone, difenacoum, and diphacinone) can be observed at home without laboratory monitoring. This amount of active ingredient would include nearly all unintentional ingestions among children less than 6 years of age. However, not all rodenticides are long acting anticoagulants so it is important to identify the specific active ingredient in the commercial product (call the local poison center) (Caravati et al, 2007).
C) Children with a history of a single, acute, unintentional ingestion of less than 1 mg of active ingredient (e.g. less than 20 g or 2/3 oz. net weight of a 0.005% product) can be observed at home without decontamination but with telephone follow-up. Outpatient evaluation of the INR or prothrombin time should be performed in patients with clinical evidence of bleeding (Ingels et al, 2002; Shepherd et al, 2002). Larger or unknown ingestions should prompt consideration of activated charcoal administration, along with clinical and laboratory evaluation (Smolinske et al, 1989; Ingels et al, 2002; Caravati et al, 2007).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for any patient with a significantly increased INR, active bleeding or other complications. Any patient with a deliberate ingestion should have a psychiatric evaluation.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) The delayed onset and prolonged duration of effect make SHORT TERM observation unlikely to be useful. Patients with deliberate overdose or abuse, with chronic ingestion of long-acting anticoagulant rodenticides (LAARs), or with symptoms (eg, bleeding, bruising) should be sent to a healthcare facility for evaluation. Patients taking therapeutic anticoagulants who are exposed to any dose of LAAR should have a baseline prothrombin time measured and obtain a repeat measurement 48 to 72 hours after ingestion. Asymptomatic patients inadvertently exposed to 1 mg or more of active ingredient LAAR should be evaluated for coagulopathy 48 to 72 hours after ingestion. Pregnant women with inadvertent exposures to less than 1 mg of LAAR active ingredient should be evaluated by an obstetrician or primary care provider on an outpatient basis (Caravati et al, 2007). Stable patients with mild toxicity (INR less than 2) are managed as outpatients and patients with more severe coagulopathy or bleeding are admitted.

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) SUMMARY

1) Children with exploratory ingestions of less than a box of bait or less than 1 mg of active ingredient (e.g., less than 20 g or 2/3 oz. net weight of a 0.005% product) rarely develop clinical or laboratory evidence of coagulopathy. Gastrointestinal decontamination is generally not required in these cases (Ingels et al, 2002; Caravati et al, 2007).

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY

1) Children with exploratory ingestions of less than a box of bait or less than 1 mg of active ingredient (e.g. less than 20 g or 2/3 oz. net weight of a 0.005% product) rarely develop clinical or laboratory evidence of coagulopathy. Gastrointestinal decontamination is generally not required in these cases(Ingels et al, 2002; Caravati et al, 2007). Activated charcoal should be considered for large or deliberate ingestions.

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) GASTRIC LAVAGE/NOT RECOMMENDED

1) Not recommended as it may induce bleeding in adults with significant coagulopathy and is not necessary in children after unintentional ingestion.

6.5.3)

A) MONITORING OF PATIENT

1) Children with exploratory ingestions of less than a box of bait or less than 1 mg of active ingredient (e.g. less than 20 g or 2/3 oz. net weight of a 0.005% product) rarely develop clinical or laboratory evidence of coagulopathy (Ingels et al, 2002; Caravati et al, 2007). They do not require routine laboratory monitoring.
2) Monitor INR or PT after large or deliberate ingestions. An INR or PT obtained prior to 48 hours post-ingestion may not be predictive of subsequent coagulopathy. A 48 to 72 hour INR/PT is therefore recommended (Smolinske et al, 1989). If any prolongation is observed, repeat INR or PT every 6 to 12 hours to assess efficacy of therapy.
3) PATIENT CURRENTLY ON THERAPEUTIC ANTICOAGULATION: Get INR or PT immediately. If patient is anticoagulated for prosthetic valve or other procedure requiring absolute anticoagulation, do not give vitamin K unless anticoagulation is excessive. Only a small intravenous dose (1 to 5 mg) titrated to return INR to THERAPEUTIC (not normal) should be utilized. Substitution of heparin as an anticoagulant may be necessary until INR is therapeutic.
4) In patients taking therapeutic anticoagulants who are exposed to any dose of long-acting anticoagulant rodenticide (LAAR), obtain a baseline prothrombin time measurement and a repeat measurement 48 to 72 hours after ingestion (Caravati et al, 2007).
5) Follow hematocrit closely, at least a reading every four hours until it is stable.
6) All stools and vomitus should be Hematest for occult blood.

B) PHYTONADIONE

1) VITAMIN K 1 (phytonadione, AquaMEPHYTON(R), Mephyton(R)): is a specific antidote and should be administered to any patient with a prolonged INR/PT. Menadione (Vitamin K 3, Synkayvite(R)) SHOULD NOT be used.

a) ORAL VITAMIN K INDICATIONS - Oral phytonadione may be indicated in small ingestions or when the amount is uncertain, but presumed to be small. Administer 15 to 25 mg in adults and 5 to 10 mg in children.
b) ORAL DOSE - Absorption is inconsistent. Large daily maintenance doses (100 to 125 mg/day) were required for prolonged therapy in severe overdose (75 mg of brodifacoum) (1.5 to 8 months) (Lipton & Klass, 1984). 20 to 100 mg/day was adequate to prevent bleeding in 4 adult cases where less amounts were ingested (2.15 to 10 mg) (Jones et al, 1984; Chong et al, 1986; Hoffman et al, 1988; Ross et al, 1992), and in two young children with chronic Bromadine poisoning (Greeff et al, 1987).

1) Prolonged coagulopathy in a 23-year-old man, who intentionally ingested 4 boxes of rodenticide containing brodifacoum, required treatment with high-dose oral vitamin K1 therapy (300 to 600 mg/day) for 5 months. Compliance may be questionable in patients who require long-term therapy with large doses of vitamin K1 (Tsutaoka et al, 2003).

c) INTRAVENOUS INJECTION

1) INTRAVENOUS VITAMIN K INDICATIONS: Intravenous phytonadione is preferable in SEVERE cases where rapid correction is required.
2) DOSE: Adults: A minimum of 10 mg intravenously diluted in saline or glucose at a rate not exceeding 5 percent of the total dose per minute. In maximally anticoagulated individuals, repeat doses at six to eight hour intervals may be required. Initial intravenous doses of up to 400 mg have been required (Hoffman et al, 1988; Vogel et al, 1988; Burucoa et al, 1989) in actively hemorrhaging patients.
3) ADVERSE EFFECTS: Rapid intravenous infusion may produce flushing, cyanosis, dizziness, hypotension, and bronchoconstriction.

d) SUBCUTANEOUS INJECTION: May be used for initial reversal in patients with coagulopathy without life threatening bleeding. Maintenance doses of 50 to 100 mg/day were required in an adult who ingested 10 mg of brodifacoum (Hoffman et al, 1988).
e) INTRAMUSCULAR INJECTION/CASE REPORT: A 21-year-old woman, 37 weeks pregnant, presented with a 1-week history of gross hematuria following inadvertent ingestion of rat poison containing brodifacoum approximately 4 days prior to symptom onset. At the time of presentation, an obstetric ultrasound indicated a live fetus with intracranial hemorrhage. Laboratory data of the patient revealed coagulopathy with prolonged prothrombin and activated partial thromboplastin times and significantly decreased coagulations factors II, VII, IX, and X. The patient was given an initial vitamin K dose of 10 mg IM twice daily, followed by a maintenance dose of 40 mg IM three times daily, as well as IV prothrombin complex and fresh plasma, resulting in improvement in her coagulation parameters, although the neonate was delivered stillborn, with an autopsy revealing hemorrhage of the brain and lungs, and multi-organ autolysis. With continued vitamin K therapy over a period of several months post-presentation, the patient made a complete recovery (Yan et al, 2013).
f) MENADIONE/MENADIOL - (Vitamin K 3) requires metabolism by the liver to Vitamin K 1. The ability of the liver to utilize menadione in the face of generalized hemorrhagic disease is doubtful. Menadione was ineffective as maintenance therapy in one human overdose (Murdoch, 1983), and as initial parenteral therapy in an acute overdose (Kruse & Carlson, 1992).

2) DURATION OF THERAPY

a) Monitoring of serial blood brodifacoum levels has been suggested to determine the duration of oral vitamin K1 therapy in severe cases of brodifacoum poisoning (Bruno et al, 2000). Using the kinetic modeling proposed by Bruno et al, no brodifacoum-associated coagulopathy was noted when levels were below 4-10 ng/mL, and this vitamin K1 therapy could be safely discontinued. However, this clinical observation in a single case has not yet been validated; its clinical utility requires further study.

C) COAGULATION FACTOR VII

1) CASE SERIES - Four patients with severe coagulopathy from long acting anticoagulant poisoning (INR >7, factor VII activity 0.04 International units or less, [normal 0.7 to 1.2], clinical bleeding) were treated with recombinant activated factor VII. The doses used ranged from 70 to 90 micrograms/kilogram intravenously and intravenous vitamin K 20 to 40 mg was administered at the same time. Clinical bleeding stopped within 20 minutes and laboratory evidence of coagulopathy (PT, INR, APTT and factor VII clotting activity) normalized within 15 minutes of factor VII administration(Zupancic-Salck et al, 2005). Factor VII administration appears to be rapidly effective in reversing long acting anticoagulant induced bleeding and coagulopathy; however, it is quite expensive.

D) COAGULATION FACTOR IX

1) CASE REPORT: A 52-year-old man, who presented with an expanding hematoma of the neck region and bleeding of the oral mucosa after intentional ingestion of brodifacoum, was treated with Bebulin(R) VH Immuno (factor IX complex), 2000 units intravenously, and vitamin K. Initially, his laboratory values showed a PT greater than 100 seconds, an INR greater than 98.5, and an aPTT of 111.3 seconds. Following treatment with Bebulin(R) VH Immuno and vitamin K, the patient's PT was less than 12 seconds, and he was subsequently discharged on oral maintenance therapy with vitamin K (Eng & Ramstack, 2001).

E) TRANSFUSION

1) There is not a specific therapeutic maneuver other than restoration of prothrombin level to normal if toxicity occurs. Administer fresh frozen plasma and/or factor concentrates in addition to packed red blood cells and vitamin K in patients with active bleeding.

F) PHENOBARBITAL

1) Phenobarbital, 100 to 180 mg/day has been administered to adults in an attempt to induce liver microsomal enzymes and hasten metabolism of brodifacoum, but its efficacy has not been proven and it is not routinely recommended (Jones et al, 1984; Lipton & Klass, 1984; Kruse & Carlson, 1992).
2) Administration of phenobarbital to an adult poisoned with chlorophacinone resulted in a decrease in the apparent elimination half-life from 22.8 days to 5.9 days (Burucoa et al, 1989).
3) CASE REPORT: A 33-year-old man ingested 1875 mg of chlorophacinone and, other than a prothrombin index of more than 96% 8 hours post-ingestion and a decrease in the vitamin K-dependent clotting factors three days post-ingestion, there were no other toxic effects noted. The patient was treated with IV Vitamin K1, in doses ranging from 50 to 120 mg/day for 17 days, and phenobarbital in doses of 200 mg/day for the first 8 days and then 100 mg/day until day 16. He was discharged 17 days post-admission. (Lagrange et al, 1999). The authors speculated that the higher dose of phenobarbital (200 mg/day) shortened the terminal elimination half-life of chlorophacinone in this patient (3.27 days in this patient compared with 6.5 to 22.8 days in previous case reports) .
4) In rats pretreated with phenobarbital, hypoprothrombinemia was only partially antagonized (Bachmann & Sullivan, 1983).

G) TELEPHONE CONSULTATION

1) NATIONAL PESTICIDE TELECOMMUNICATIONS NETWORK:

a) The National Pesticide Information Center (NPIC) is a cooperative effort of Oregon State University and the US EPA. NPIC provides consultation to poison centers and other health care professionals for the management of pesticide poisoning. Calls regarding emergency cases requiring immediate medical response will be transferred to the Oregon Poison Center.

1) NPIC contact information: phone: 1-800-858-7378. email: npic@ace.orst.edu Hours: 8 AM to 12 PM Pacific time Monday through Friday, excluding holidays.

Abstracts

Case Reports

A)

1) DIFENACOUM: Acute ingestion of 25 mg (equivalent to 500 g of bait) on one occasion and 90 mg on another resulted in a bleeding diathesis lasting 47 and 42 days, respectively, in a 17-year-old girl (Barlow et al, 1982).
2) BRODIFACOUM: Ingestion of 30 bait packets (equivalent to 75 mg) resulted in generalized ecchymosis and spontaneous abortion in a 31-year-old woman. Control of prothrombin time was inadequate with 25 mg of vitamin K and 125 mg per day was required to partially correct the PT to 15 to 19 seconds. Daily plasma infusions were required for 12 days (Lipton & Klass, 1984).
3) BRODIFACOUM: Ingestion of 20 mL of a 0.005% solution (1 mg of brodifacoum) resulted in a bleeding diathesis lasting 76 days in a 20-year-old man. He received a total of 1120 mg of vitamin K (Chen & Deng, 1986).
4) BRODIFACOUM: Ingestion of 200 grams of a 0.005% bait (equivalent to 10 mg of brodifacoum or 0.17 mg/kg) was reported in a 30-year-old man. Hematuria and fatigue were noted 4 days postingestion. Examination 8 days postingestion revealed ecchymoses, stool occult blood, hemoglobin 9.8 g/dL, hematocrit 27%, and PT and APTT greater than 100 seconds. Subcutaneous vitamin K in doses of up to 100 mg/day were required. Coagulopathy was present for at least 43 days postingestion (Hoffman et al, 1988).
5) BRODIFACOUM: A 7-year-old girl developed a bilateral occipital hemorrhagic cerebral infarct following minor head trauma secondary to prolonged clotting times (PT 18.2 seconds, PTT 55 seconds) associated with brodifacoum poisoning (Watts et al, 1990). The duration of the initial coagulopathy was 13 months.

a) Brodifacoum was identified in 2 samples of serum sent to different laboratories. Radioimmunoassay technique identified 15 ng/mL and HPLC technique found 280 ng/mL.
b) Several pellets of rat poison were subsequently found in the ceiling over the kitchen and removed.
c) Seven months after coagulation times had returned to normal this child presented again with prolonged clotting times and a brodifacoum concentration of 170 ng/mL. Coagulopathy had resolved 3 weeks after phenobarbital 2 mg/kg/day was added to treatment to hasten superwarfarin degradation.
d) The suspected source of poisoning was rat feces, which were found in the home and found to contain brodifacoum. A social service investigation found no evidence of intentional poisoning.

6) BRODIFACOUM: A 52-year-old man had an onset of unexplained epistaxis 3 months prior to admission for recurrent bleeding into the left calf after a bicycle fall. Brodifacoum was identified in the serum using HPLC. He presumably had acutely ingested a rodenticide a few weeks prior to the onset of epistaxis. Despite demonstration of the continued need for vitamin K therapy, he discontinued follow-up after 82 days of treatment (Swigar et al, 1990).
7) BRODIFACOUM: A 25-year-old woman was evaluated for hemoptysis and gingival bleeding; warfarin assays were negative. She later admitted chronic ingestion of brodifacoum when her prothrombin time appeared at 78 seconds (normal 11.5 to 13.5 seconds). Eight months after her last brodifacoum ingestion, she still required daily doses of vitamin K to maintain a normal prothrombin time (Exner et al, 1992).
8) BRODIFACOUM: On admission a 62-year-old man showed gross hematuria, which had begun 3 days preadmission. Laboratory studies indicated prolonged acquired coagulopathy. Test values for prothrombin time (PT) and partial thromboplastin time (PTT) were 53.4 and 83.2 seconds, respectively. The patient was given phytonadione 10 mg per day IV for several days and fresh frozen plasma with subsequent dosing of phytonadione 60 mg/day PO, which maintained normal PT and PTT ranges. A 13-fold greater than normal ratio for epoxide to vitamin K1 heightened suspicions of vitamin K antagonist ingestion. Though previously denying it the patient later admitted taking a small container (43 grams) of d-Con Mouse-prufe II rodenticide (0.005% brodifacoum), equivalent to 2.15 mg of brodifacoum and a bottle of antifreeze (methanol) after an alcohol binge (ingestion estimated at 4 weeks prior to admission). The patient continued on decreasing doses of phytonadione for 10 weeks, after which PT and PTT measurements continued normal without additional therapy (Ross et al, 1992).
9) BRODIFACOUM: A 25-year-old man intentionally ingested 4 boxes of d-Con Mouse-Prufe II (42 grams per box, 0.005% brodifacoum) equivalent to 8.4 milligrams brodifacoum. When he presented 9 days later, his symptoms included gross hematuria, melena, hematochezia, multiple ecchymoses, epistaxis, abdominal pain, dizziness, and bleeding from comedones. The prothrombin (PT) and partial thromboplastin (PTT) rates were 40 and 140 seconds, respectively. After 310 mg phytonadione and 16 units of fresh frozen plasma, he was discharged on phytonadione 5 mg twice daily. Seven days later he again was hospitalized; his PT and PTT were 83.9 and 153.4 seconds (patient denied ingesting more rodenticide); he received menadiol IV, 50 mg phytonadione IV, 40 mg oral phytonadione daily, 180 mg phenobarbital per day, 16 units of fresh frozen plasma, and 3 units of packed RBC. At discharge 8 days later PT and PTT were 14.8 and 34.8 seconds. He made visits to the Outpatient Transfusion Center where he received more frozen plasma, and 16 days post discharge had PT and PTT of 11.8 and 27.5. Three months later he presented to the emergency department having experienced melena, epistaxis, and hematemesis following ingestion of 5 boxes of d-Con Mouse-Prufe II, equivalent to 10.5 mg of brodifacoum, 20 days earlier. He received menadiol IV and ipecac, which produced retching. Minutes later he became comatose and was pronounced brain-dead several hours later despite multiple doses of frozen plasma, packed RBC's and phytonadione. Autopsy findings showed subarachnoid and intracerebral hemorrhages and blood in the GI tract (Kruse & Carlson, 1992).
10) BRODIFACOUM: A 29-year old man was admitted to the emergency department with Glasgow Coma Score 3 after ingesting 2 packets of "Mortein Rat Kill" containing brodifacoum in a suicide attempt. The patient had an elevated APTT and PT (both greater than 150 seconds) and a severe metabolic acidosis (pH 6.65, base excess -30 mmol/L). CT scans revealed a large intraabdominal hemorrhage but no evidence of intracranial bleeding. During laparotomy, the patient was noted to have a massive mesenteric hematoma with free intraperitoneal blood.

a) The patient developed rhabdomyolysis (with serum CK peaking on day 2 at 15,600 U/L) and acute renal failure. The patient recovered after supportive therapy, multiple blood and plasma transfusions, and vitamin K therapy. He was discharged 5 weeks after initial presentation on vitamin K 100 mg/day (Corke, 1997).

11) BRODIFACOUM: A 52-year-old HIV positive man ingested eight 43 gram boxes of d-CON Mouse-Prufe II (0.005% brodifacoum) and subsequently developed gross hematuria. His six day postingestion PT was 79.2 seconds and his aPTT was 101.3 seconds, with an international normalized ratio (INR) of 38.2. Factor VII levels were less than 1%. The patient received 2 units of fresh frozen plasma. Oral Vitamin K1 therapy was initiated at 150 mg every 6 hours. This regimen was maintained for 46 days of outpatient management. Coagulation studies at day 46 were normalized and there was no further evidence of bleeding (Bruno et al, 2000)
12) CHLOROPHACINONE: Ingestion of 625 mg (250 mL of 0.25% concentrate) in a 37-year-old woman resulted in urethral hemorrhage and prolonged PT for 59 days (Murdoch, 1983).
13) CHLOROPHACINONE: An 18-year-old woman ingested 50 grams of a 0.2% bait (total chlorphacinone 100 mg or 1.6 mg/kg). Three days later she presented asymptomatic with a prothrombin time of 79 seconds. She was inadvertently given 160 mg of intravenous vitamin K1, followed by 10 mg/day orally. The coagulopathy rapidly corrected and no bleeding was noted at any time. Vitamin K therapy was required for 7 weeks, despite demonstration of negligible plasma chlorophacinone levels after 41 days (Vogel et al, 1988).
14) CHLOROPHACINONE: A 20-year-old woman ingested 250 mg of chlorophacinone. Seven days postingestion the onset of hematuria was noted, along with hypoprothrombinemia. Administration of FFP and 100 mg of vitamin K1 IV returned the PT to normal within 24 hours. She continued to receive oral vitamin K1 50 mg/day for 49 days postingestion. Serum chlorophacinone levels were 6.3 mcg/mL on day 12 and 1.2 mcg/mL on day 27, with a half-life of 6.5 days (Burucoa et al, 1989).
15) CHLOROPHACINONE: A 60-year-old woman ingested an unknown amount of chorophacinone, and presented with hematuria, metrorrhagia, gum bleeding, and ecchymosis. Intravenous vitamin K1 400 mg and FFP were administered, and the PT normalized within 24 hours. Phenobarbital 100 mg/day was given from day 6 to 24 after admission, along with oral vitamin K1 50 mg/day. The apparent half-life of chlorophacinone was 22.8 days prior to initiation of phenobarbital therapy and 5.9 days during therapy (Burucoa et al, 1989).
16) CHLOROPHACINONE: A 23-year-old man ingested an unknown amount of chlorophacinone, and presented with abdominal pain, hematuria, and buccal hemorrhage. Administration of FFP and vitamin K1 150 mg IV returned the PT to 13 seconds. He continued to receive vitamin K1 50 mg/day for 74 days after onset of symptoms. He was readmitted 102 days after onset of symptoms with similar symptoms, due to a second exposure. The serum chlorophacinone level was 15.2 mcg/mL during the first admission and 13.3 mcg/mL during the second admission. The half-lives were 11 and 9.2 days, respectively (Burucoa et al, 1989).
17) BROMODIALONE: Presumed chronic ingestion of bromodialone pellets by two children, aged 2 and 3 years, resulted in coagulopathy, with hematoma in one and hemarthrosis in the other. Both children required oral vitamin K therapy for at least 3 months (Greeff et al, 1987).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) DIPHACINONE - 20 to 30 milligrams initially followed by 2 to 4 milligrams/day have been used therapeutically as an anticoagulant. The onset of action was 24 hours resulting in a full effect within 48 to 72 hours. Single doses of 4 milligrams produced a prolongation in PT within 14 hours which normalized by the third day. A smaller increase occurred with a 2 milligram dose. Twenty milligrams produced definite hypoprothrombinemia in 14 hours, which was marked at 48 hours and persisted for 6 to 10 days (Hayes, 1982). Hypoprothrombinemia may persist for 20 days after cessation of therapy.

Minimum Lethal Exposure

A)

1) BRODIFACOUM

a) An adult patient who was reported to chronically ingest brodifacoum presented with epistaxis, hematuria, and ecchymosis, with an initial PT of 60 seconds. Three weeks after stabilization and discharge on oral vitamin K therapy, the patient was found in status epilepticus with intracranial hemorrhage and expired (Basehore & Mowry, 1987).
b) A 35-year-old man who ingested an unknown amount of brodifacoum died of massive intracranial hemorrhage approximately 3 to 4 weeks postingestion, after failing to comply with outpatient vitamin K supplementation (Helmuth et al, 1989).
c) A death associated with brodifacoum ingestion was reported in a 29-year-old woman. Her course was complicated by a systemic reaction to the vitamin K preparation and subsequent deterioration associated with sepsis, septic shock, and a diffuse hemorrhagic diatheses (Routh et al, 1991).
d) Ingestion of 8.5 mg on one occasion and 10.5 mg three months later resulted in death secondary to subarachnoid hemorrhage in a 25-year-old man (Kruse & Carlson, 1992).

Maximum Tolerated Exposure

A)

1) In a prospective study of 545 children younger than 6 years with unintentional ingestion of less than one box of bait, 463 patients received follow up by phone contact (222), 48 to 96 hour INR (62) or both (179). No child had clinically significant coagulopathy (Ingels et al, 2002).

a) Two patients had an INR of 1.5 or greater without symptoms, 2 had single nose bleeds with normal INRs, one had blood streaked stool and normal INR.

2) The overall incidence of abnormal prothrombin times was 7.2% in one study of 110 cases (Smolinske et al, 1989) and 0% in another study of 88 cases (Sullivan et al, 1989). In the latter study, 56% of the patients did not have PTs obtained later than 24 hours postingestion, thus some prolonged PTs may not have been detected. Aggressive decontamination may also have prevented toxicity.

B)

1) Asymptomatic patients inadvertently exposed to 1 mg or more of active ingredient long-acting anticoagulant rodenticides should be evaluated for coagulopathy 48 to 72 hours after ingestion (Caravati et al, 2007).

C)

1) BRODIFACOUM

a) ADULT

1) Case reports of brodifacoum ingestion are summarized:

AGE (years)	AMOUNT (mg)	AMOUNT (mg/kg)	DURATION OF PT INCREASE	REFERENCE
17	7.5	0.12	51 days	Jones, 1984
20	10	0.14	6 months	Chong, 1986
30	10	0.17	43 days	Hoffman, 1988
31	75	1.1	8 months	Lipton, 1984
20	1	0.014	76 days	Chen, 1986
62	2.15	0.03	10 weeks	Ross, 1992

2) CASE REPORT: A 41-year-old woman intentionally ingested 2.4 g of doxylamine and 20 mL of a rodenticide, later identified to contain brodifacoum. She initially had an episode of torsade de pointes and was successfully resuscitated. Laboratory data revealed an INR that fluctuated between 1.1 and 7.5 and a factor VII level from 2% to 92%, requiring high doses of vitamin K therapy over the course of 9 months (285 days), at daily doses ranging from 5 to 300 mg. Brodifacoum was detected in blood samples, via liquid chromatography-mass spectrophotometry, 193 days after ingestion (Nguyen et al, 2015).

b) PEDIATRIC

1) An abnormal PT ratio (1.2 to 1.44) was observed in 7 of 77 children with a history of accidental ingestion of brodifacoum. Amounts ingested ranged from a mouthful to a full 1.5 ounce bait package. Spontaneous emesis, abdominal pain, and transient heme positive stools were the only effects noted (Smolinske et al, 1989).
2) In a retrospective review of 10,762 cases of single acute unintentional brodifacoum ingestions in children less than 7 years old, no deaths or major adverse effects were reported. Minor effects occurred in 308 cases (2.86%) and moderate effects occurred in 54 cases (0.50%); PT elevations were reported in 39 cases (0.36%) and bleeding was reported in 16 cases (0.15%). Approximately 50% of the children received gastrointestinal decontamination, but no effect was observed on clinical outcome (Shepherd et al, 2002).
3) In a prospective, poison center based study of 550 unintentional acute exposures in patients younger than 6 years of age, no deaths or adverse effects were reported (Ingels et al, 2002).

c) ANIMAL DATA

1) RABBITS: administered 1 mg/kg were still anticoagulated six weeks later.

a) The rate of prothrombin complex degradation was 2 to 3 times slower with low doses in animals (0.1 mg/kg) than with high doses (1 mg/kg) (Leck & Park, 1981).

2) RATS: The minimum amount required to produce anticoagulant effects in rats, 0.15 mg/kg, is equivalent to 30 g of 0.005 percent bait in a child weighing 10 kg.
3) RATS: 0.1 mg/kg produced no anticoagulation within 24 hours; 0.15 mg/kg produced inconsistent effects; 0.2 mg/kg decreased prothrombin complex (PCA) to 7 percent of normal; 0.33 mg/kg decreased PCA to 4% of normal (Bachmann & Sullivan, 1983).

2) DIFENACOUM

a) HUMAN: Acute ingestion of 25 mg and 90 mg resulted in anticoagulation lasting 42 to 47 days in a teenager (Barlow et al, 1982).
b) CASE REPORT: A 36-year-old woman developed a hemoperitoneum and multiple hematomas in the renal pelvis and ureters after intentionally ingesting 850 g of difenacoum. Her INR was greater than 7, and her thrombin time was 15 seconds. She recovered following administration of IV Vitamin K (Terneu et al, 2003).
c) ANIMAL: In rabbits, 18 hours after administration of a dose 100 times less than warfarin (0.85 mg/kg), prothrombin time was 11% versus 50% of normal for difenacoum and warfarin, respectively (Park et al, 1979).

3) DIFETHIALONE

a) CASE REPORT: A 57-year-old woman intentionally ingested 5 boxes of household rodenticide containing difethialone and warfarin (2 boxes were equivalent to 120 g of red-dyed pellets containing 0.0025% (total 3 mg) difethialone and the other 3 contained 360 g of red-dyed pellets containing 0.05% warfarin (total 180 mg) and nitrazepam (total of 280 mg). She was admitted comatose with respiratory acidosis requiring intubation and mechanical ventilation. On day 2 her INR and aPTT rose to 2.65 and greater than 200 seconds, respectively. Urine and stool appeared pink in color suggesting superwarfarin ingestion, but no active bleeding developed. She was treated with vitamin K. However, worsening hypotension was noted and an echocardiogram showed diffuse myocardial hypokinesia with a left ventricular ejection fraction of 34.4%. Cardiac function continued to worsen and an intraaortic balloon pump was inserted with rapid improvement over 24 hours. Laboratory studies were positive for difethialone, warfarin and nitrazepam; no other agents were detected. By day 5, she was successfully extubated with normal mentation. The patient continued to do well and by day 21 was transferred for further psychiatric care (Kamijo et al, 2011).

4) CHLOROPHACINONE

a) Acute ingestion of 625 mg in a 37-year-old resulted in anticoagulation lasting 59 days (Muedoch, 1983).
b) Acute ingestion of 100 mg (1.6 mg/kg) in an 18-year-old woman resulted in asymptomatic anticoagulation lasting 7 weeks (Vogel et al, 1988).
c) Ingestion of 250 mg resulted in anticoagulation lasting 49 days in a 20-year-old woman (Burucoa et al, 1989).
d) CASE REPORT: A 33-year-old man ingested 1875 mg of chlorophacinone and, other than a prothrombin index of more than 96% 8 hours postingestion and a decrease in the vitamin K-dependent clotting factors three days postingestion, there were no other toxic effects noted. The patient was treated with IV vitamin K1 and phenobarbital therapy, and was discharged 17 days after admission (Lagrange et al, 1999).

5) 2-ISOVALERYL-1,3-INDANDIONE

a) The minimum oral dose that depressed plasma prothrombin was 5 to 7.5 milligrams/kilogram in rabbits. Onset was within 24 hours and maximal at 48 to 72 hours. Following larger doses (150 mg/kg) onset was within 5.5 hours (Kabat et al, 1944).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) BRODIFACOUM

1) Plasma concentration of brodifacoum was 0.63 micrograms/milliliter in a 36-year-old man (Wallace et al, 1990).

a) Hematological parameters at the time of this brodifacoum concentration were hemoglobin 12 grams/deciliter (normal 13 to 18), prothrombin ratio greater than 10 (normal 0.85 to 1.15), and activated partial thromboplastin time 46 seconds (normal 20 to 30).
b) Treatment up to this time included 1 unit whole blood, 4 units fresh frozen plasma, 3 units packed cells, 10 milligrams vitamin K subcutaneously, and 10 milligrams vitamin K intravenously over the course of the first 4 days of admission.

2) Brodifacoum (786 nanograms/milliliter) was detected in plasma of a 29-year-old woman who presented with gingival bleeding. Her condition deteriorated and she subsequently died secondary to septic complications and diffuse hemorrhagic diatheses. Her postmortem brodifacoum concentration in plasma was 117 nanograms/milliliter. Liver and kidney samples contained 4-bromobenzoic acid concentrations corresponding to 56.5 and 59.2 nanograms brodifacoum per gram of tissue, respectively (Routh et al, 1991).
3) The combination of calf and thigh hematoma with hemothorax, and impending compartment syndrome were observed in a woman who had a brodifacoum blood concentration of 71 ng/mL (laboratory reporting limit 5 ng/mL) 3 weeks after ingesting an unknown amount of brodifacoum in a suicide attempt. Following supportive care, she gradually improved and was discharged home on day 6 on high-dose oral vitamin K and iron (Tahir et al, 2008).
4) Serum levels measured in a dog who died were 50 nanograms/milliliter. Levels measured in a human poisoning were 97.5 nanograms/milliliter (Felice & Murphy, 1989).
5) A serum brodifacoum level of 710 nanograms/milliliter was associated with a PT of 85.2 seconds, PTT of 70 seconds, hematuria and heme positive stools in a 37-year-old man (Tecimer & Yam, 1997).
6) A 39-year-old woman died due to intracranial bleeding after a presumed intentional ingestion of an unknown amount of brodifacoum. Serum brodifacoum levels were approximately 160 ng/mL near the time of death (Ornstein et al, 1999).
7) The following tissue and fluid brodifacoum concentrations were found at autopsy of a 15-year-old girl who died from massive pulmonary ingestion after intentionally ingesting a rodenticide containing 0.005% brodifacoum (Palmer et al, 1999):

1) Liver - 50 ng/g
2) Spleen - 34 ng/g
3) Lung - 31 ng/g
4) Fixed liver - 820 ng/g
5) Heart blood - 2240 ng/mL
6) Femoral blood - 3919 ng/mL
7) Bile - 4276 ng/mL

b) BROMADIOLONE

1) A 27-year-old woman developed easy bruising, epistaxis, menorrhagia and a PT of 35.6 with a serum bromadiolone level of 40 nanograms/milliliter (Chow et al, 1992).
2) Bromadiolone (concentrations of 0.011 to 0.75 mg/L) was detected in 13 of 16 blood samples obtained from a 62-year-old woman with repeated exposure to bromadiolone. The mean plasma/blood ratio was approximately 1.7 +/- 0.6 (Vindenes et al, 2008).

c) CHLOROPHACINONE

1) In a series of 4 adult poisonings (in 3 patients) where multiple plasma levels were obtained, the risk of bleeding was minimal when the plasma level was below 1 microgram/milliliter. The levels at presentation with clinical bleeding were 6.3, 12.9, 13.3, and 15.2 micrograms/milliliter in these cases (Burucoa et al, 1989).

d) DIFENACOUM

1) A 34-year-old man developed hematuria and a PT of greater than 90 seconds after ingesting a packet of difenacoum-containing rodenticide a day for one month (Butcher et al, 1992). Plasma concentration of difenacoum was 0.6 micrograms/milliliter.

Toxicity Information

7.7.1)

A) BROMADIOLONE

Pharmacology Toxicology

Toxicologic Mechanism

A)

Physicochemical

Animal Toxicology

Clinical Effects

11.1.3)

A) Accidental ingestion of long acting anticoagulant rodenticides in 4 dogs resulted in more severe clinical signs, length of hospitalization, and duration of vitamin K therapy than ingestion of warfarin rodenticides in 10 dogs (Fitzgerald & Bronstein, 1987).
B) Clinical effects seen in dogs include anorexia, mouth bleeding, bloody stools, decreased activity, pale mucous membranes, swollen limbs, hematuria, lower abdominal edema, and labored breathing (FDRL, 1987).

1) Signs are various depending on the location of hemorrhages. Pulmonary signs include cough, abnormal alveolar sounds, and breathlessness. Abdominal pain and lethargy are common. Physical evidence of bleeding such as hematuria, epistaxis, and bruising may be seen. Mucous membranes are sometimes pale or even white. An unusual presentation is rear leg weakness or lameness and pain.

C) Clinical signs reported in 9 confirmed cases of second-generation anticoagulant rodenticide poisoning in dogs include: lethargy, dyspnea, hematuria, altered gait, and ventral hematomas. Gross postmortem findings included: hemoperitoneum, hemothorax, hemopericardium, suffusive subendocardial hemorrhage, free blood in the lumen of the intestine, atelectasis with free blood in the tracheal bifurcation, petechiations on the serosal surface of the lungs and a hemorrhagic urinary bladder mucosa (DuVall et al, 1989).
D) In a retrospective case study of rodenticide poisoning in 21 dogs, common signs of toxicity were dyspnea (57%), lethargy (48%), coughing/hemoptysis (30%), pallor (26%), epistaxis (17%), and hematochezia (13%). In 83% of cases, the dog was anemic with packed cell volume ranging from 7% to 35% (median 25%). Activated clotting time (ACT), one-stage prothrombin time (OSPT), and activated partial thromboplastin time (APTT) were increased in all dogs. Survival rate after supportive care, blood transfusions, and/or vitamin K was 83% (Sheafor & Couto, 1999).
E) Prolonged coagulopathy was reported in two dogs following ingestion of brodifacoum, requiring up to 8 weeks of vitamin K therapy (Hall, 1990).
F) Pericardial effusion resulting in cardiac tamponade occurred in a dog who ingested brodifacoum. The dog recovered following pericardiocentesis and administration of vitamin K (Petrus & Henik, 1999).
G) SITE OF HEMORRHAGE - Clinical signs of animals poisoned with anticoagulant rodenticides depend on the site of hemorrhage. External (melena, epistaxis, hematemesis, hematuria, gingival bleeding, or prolonged bleeding from trauma) or internal (peritoneal &/or pleural cavities, fascial or mediastinal planes, etc) hemorrhage may occur. Depression, lethargy, weakness, pallor and/or dyspnea may be observed (Mount, 1988).
H) ONSET - Animals absorbing toxic doses of anticoagulant rodenticides are generally asymptomatic until depletion of active clotting factors which occurs 1 to 3 days post ingestion. At this time, depression, vomiting, anorexia, diarrhea, hemorrhage, melena, weakness and dyspnea are commonly observed. Less commonly, generalized pain, fever, lameness or acute death are observed (Dorman, 1990).
I) DIFFERENTIAL DIAGNOSIS may include DIC or autoimmune disease (primary), trauma, reaction to coccidiostats or sulfa drugs, and hepatic insufficiency.

11.1.6)

A) The clinical sign reported in one confirmed case of brodifacoum toxicosis in a cat was lethargy (DuVall et al, 1989).

11.1.13)

A) OTHER

1) DIFFERENTIAL DIAGNOSIS - Two main toxicities cause similar clinical syndromes: sweet clover poisoning and ingestion of long-acting anticoagulant rodenticide baits. Assess history for both.

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
6) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

2) ACTIVATED CHARCOAL - Administer activated charcoal, 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
3) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

11.2.5)

A) DOGS/CATS

1) Treatment consists of support and antidotal Vitamin K1. Length of antidotal treatment depends upon the half-life of the agent. First-generation agents, including warfarin and fumarin, require one week of treatment. Inandione compounds and second-generation agents, including pindone, chlorophacinone, diphacinone, valdone, bromadiolone, and brodifacoum require 2 to 4 weeks of treatment. Brodifacoum has an especially long half-life and four weeks of Vitamin K treatment are recommended.
2) All Vitamin K1 treatment periods should be followed 3 to 5 days after last treatment with a prothrombin time. If PT is normal, the administered treatment is usually adequate. If PT is elevated, Vitamin K treatment must be continued for another 1 to 2 weeks and PT checked again after last treatment.
3) LABORATORY - The most useful initial measurement is the prothrombin time because it measures clotting factor VII, which has the shortest half-life of the affected factors. This should be assessed upon presentation and again after 24 hours of treatment. Activated partial thromboplastin time and activated coagulation time will also be abnormal after a period of time. Other useful parameters to monitor are the packed cell volume (take one initially, another after 24 hours) and platelet count (one initially, repeat every 24 hours if abnormal).
4) Significant increases in circulation clotting factor activity are not observed for 6 to 12 hours following vitamin K1 therapy. Animals with mild clinical signs and packed cell volumes > 30 may be treated with vitamin K1 (3 to 5 mg/kg), cage rest, and supportive care. Oral dosing is the preferred method of administering vitamin K1 (Dorman, 1990).
5) Dogs receiving 20 or 100 mg bromadiolone/kg body weight were successfully treated with daily doses of 5 mg vitamin K1/kg body weight for 1 to 2 weeks (Lorgue et al, 1985).
6) VITAMIN K -

a) Dose is 3 to 5 milligrams/kilogram body weight/day for dogs and cats, usually divided into two doses given every 12 hours. An initial loading dose of 5 milligrams/kilogram is given in multiple sites subcutaneously.

1) Traditionally, Vitamin K1 is administered in the veterinary hospital subcutaneously during the first day or two of treatment. Thereafter, oral formulations may be administered at home.

b) ADVERSE EFFECTS - Extreme overdose (approximately 20 to 25 milligrams/kilogram) may result in hemolytic anemia. Vitamin K1, NOT K3, should be administered subcutaneously or orally. Oral administration may cause mild localized reaction such as wheals. Intravenous administration is not recommended due to possible massive anaphylaxis.
c) SERUM LEVEL CRITERIA - In one canine and one feline case of brodifacoum poisoning, vitamin K1 therapy was discontinued when serum brodifacoum concentrations fell below 0.5 ng/mL without clinical ill effects (DuVall et al, 1989).

7) VITAMIN K1 EPOXIDE/VITAMIN K1 RATIO -

a) Dogs experimentally dosed with 0.8 mg/kg diphenadione per day for three days were protected from coagulopathic effects by either 2.5 or 5 mg vitamin K1/kg body weight administered orally for 21 days. Inhibition of vitamin K1 epoxide reductase was followed by determining the ratio of vitamin K1 epoxide to vitamin K1. Ratios less than 0.2 were observed in control dogs given 5 mg/kg vitamin K1 subcutaneously, while ratios greater than 0.5 were observed in animals exposed to diphenadione when samples were drawn 8 hours following vitamin K1 treatment.
b) The ratio of vitamin K1 epoxide to vitamin K1 may prove to be both a valuable indicator of the presence of vitamin K1 epoxide reductase inhibitors in cases of unknown coagulopathies as well as a monitor of the length of therapy in cases of long-acting anticoagulant rodenticide toxicosis (Mount & Kass, 1989).

B) ACUTE OVERDOSE

1) MAINTAIN VITAL FUNCTIONS - Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
2) TRANSFUSION - Vitamin K1 has no direct effect on coagulation, and clinically significant synthesis of new clotting factors commonly requires at least 6 to 12 hours. Thus, emergency needs for circulating clotting factors can only be met via a transfusion.

a) Animals with markedly reduced PCV's or signs of severe hypovolemic shock often require fresh plasma (9 mL/kg body weight) or whole blood (20 to 25 mL/kg body weight) (Mount et al, 1986; (Osweiler et al, 1985).
b) In animals with a packed cell volume <25, whole blood or plasma transfusion is indicated. Animals in hypovolemic shock may require fluid therapy (Mount, 1988).
c) Administer Vitamin K1 as above.

3) Treat other conditions, such as pleural effusion, hypothermia, etc, as necessary.

C) LATE CRISIS - Despite proper Vitamin K1 treatment, poor clinical response may be seen within the first 12 to 24 hours. This late crisis is usually due to secondary platelet-consuming abnormalities such as DIC or immune-mediated phenomena. Check the platelet count.

1) DIC is not treated with heparin, but rather with replacement of clotting factors from fresh plasma/whole blood transfusion.

D) Table 1: Toxicity and Therapy of Anticoagulant Rodenticides Note: The length of therapy values in this table are based on dogs experimentally dosed with an LD50 amount of the respective rodenticide. Individual animal variations may occur (Mount et al, 1986; Murphy & Gerken, 1989).

Chemical Name	Bait Conc (ppm)	Acute PO LD50			Vitamin K1 Dose/ Duration (mg/kg)
		Cmpd (mg/kg)		Bait(a) (oz/lb)
		Dog	Cat	Dog
Unknown:
Fumarin	250	?	?	?	1 x 4-6d (b)
Pindone	250	5-75	?	0.3	1 x 4-6d
Valone	250	?	?	?	1 x 4-6d
Long Acting:
Diphacinone	50	0.9-8	15	0.3	2.5/5 x 3-4 wk(d)
Chloro-	50	?	?	?	2.5-5 x 3-4 wk(d)
Brodifacoum	50	0.2-4	>25(c)	0.06	2.5/5 x 2-3 wk(d)
Bromadiolone	50	11-15	25(c)	3.5	2.5/5 x ?
Key:
(a) ounces of finished bait per pound of body weight required to achieve the lowest LD50 value reported in the dog.
(b) animals should be closely observed/re-examined at the end of therapy
(c) limited data
(d) re-examination following therapy is stronglyrecommended
(?) no data available
Reference: Murphy & Gerkin DF (1989)

Range Of Toxicity

11.3.2)

A) DOGS

1) CASE REPORTS

a) BROMADIOLONE - One female beagle dog developed hypoprothrombinemia after an oral dose of 0.5 mg/kg. PT prolongation was maximal at 3 days postingestion in this dog. Other dogs given 2 to 19.8 mg/kg had maximal prolongation at 4 to 5 days postingestion (FDRL, 1987).

2) In dogs, the acute poisoning LD50 from anticoagulant rodenticides is as follows (Sheafor & Couto, 1999a):

1) Brodifacoum - 0.25 to 3.5 mg/kg
2) Diphacinone - 0.88 to 7.5 mg/kg

B) CATS

1) In cats, the acute poisoning LD50 from anticoagulant rodenticides is as follows (Sheafor & Couto, 1999a):

1) Brodifacoum - 25 mg/kg
2) Diphacinone - 15 mg/kg

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
6) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

2) ACTIVATED CHARCOAL - Administer activated charcoal, 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
3) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

Kinetics

11.5.1)

A) LACK OF INFORMATION

1) There was no specific information on absorption at the time of this review.

11.5.2)

A) SPECIFIC TOXIN

1) Serum concentrations of 1 to 9 ng/mL have been reported in field cases of canine cases of brodifacoum toxicosis. Hepatic brodifacoum concentrations in cases at necropsy ranged from 1.2 to 12.7 ppm. In one case where serum and liver were examined a 1000-fold greater concentration in the liver was observed. Hepatic diphacinone concentrations in canine cases at necropsy ranged from 0.11 to 0.21 ppm. Hepatic bromadiolone concentrations in canine cases at necropsy ranged from 0.04 to 0.16 ppm (DuVall et al, 1989).
2) Dogs receiving approximately 1.1 mg/kg brodifacoum had hepatic concentrations ranging from 80 to 400 ng/g, 5 to 11 days post exposure (Ray et al, 1989).

11.5.4)

A) SPECIFIC TOXIN

1) BRODIFACOUM - 120 days in dogs (Lipton & Klass, 1984); at least 156 hours in rats; however, serum levels were not determined for a long enough period to enable precise half-life calculation (Bachmann & Sullivan, 1983).

References

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