Vitamin K-induced cardiovascular collapse

ELSEVIER

Case Conference Series Editors:

A. Joseph Layon, MD, Michael E. Mahla, MD, Jerome H. Mode& MD

Vitamin K-Induced Cardiovascular Collapse Kenneth A. Songy, Jr, MD,* A. Joseph Layon, MDT Departments of Medicine,

of Anesthesiology, Gainesville, FL.

Surgery, and Medicine, University of Florida College

Comments by Jan S. Moreb, MD:

A patient underwent a partial right hqbatic lobectomy for adenocarcinoma oj the colon metastatic to the liver. He was admitted to the surgical intensive care unit in stable condition. Six hours after surgery, the patient experienced sudden and severe hypotension, bradycardia, and asystole. Diffential diagnoses included acute myocardial infarction, hemorrhage jkom the surgical site, and pulmonary embolism. However, these complications were ruled out. We believe that an allergic reaction to vitamin K caused the acute &compensation in this patient. Indications for administering vitamin K and its potential side effects are discussed. 0 1997 by Elsevier Science Inc. Keywords: untoward drug reaction, vitamin cardiopulmonary arrest, hypotension.

K,

*Resident in Anesthesiology i-Professor of Anesthesiology,

Surgery, and Medicine

&4ssociate Professor of Medicine Address correspondence to: ATTN: Editorial Office, Department of Anesthesiology, University of Florida College of Medicine, Box 100254, Gainesville, FL 32610-0254, USA. Case Conference presentations are selected and edited at the Department of Anesthesiology, University of Florida College of Medicine. Received and accepted for publication

April 22, 1997.

Journal of Clinical Anesthesia 9:514-519, 1997 0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

The Case The Patient A 62-year-old white man was admitted to the general surgery service at Shands Hospital at the University of Florida with the diagnosis of adenocarcinoma of the colon metastatic to the liver. Two years earlier, the patient had been diagnosed with adenocarcinoma of the sigmoid colon and had undergone a left hemicolectomy. After that procedure, he was asymptomatic until right flank pain developed. During diagnostic evaluation for this problem, an abdominal ultrasound was performed, which revealed nephrolithiasis involving the right kidney and a 4 cm lesion on the right lobe of the liver. A needle biopsy of the liver confirmed the diagnosis of metastatic, moderately differentiated adenocarcinoma, likely from the colon. A bone scan and computerized tomographic examinations of the chest, abdomen, and pelvis did not demonstrate further spread of the disease. Approximately 4 weeks before this admission, the patient was started on a regimen of leucovorin and 5-fluorouracil therapy in an attempt to shrink the neoplasm. The patient’s medical history was notable for hypertension, a 4year history of insulin-dependent diabetes mellitus, and a 40 pack-year history of tobacco use. He reported no allergies. He had no history of myocardial infarction (MI), angina, or orthopnea; a preoperative exercise tolerance test, performed because of his cardiac risk factors, was negative for electrocardiographic (EGG) changes sug0952-8180/97/$17.00 PII SO952-8180(97)00112-8

Vitamin K-Induced cardiovascular collapse: Song et al.

gesting ischemia. Physical examination on atdmission revealed an elderly man in no distress. Vital signs included blood pressure (BP) of 138/88 mmHg, heart rate (HR) 82 beats per min (BPM), and temperature 36°C. The patient was 180.3 cm tall and weighed 97 kg. His lungs were clear to auscultation bilaterally, with no evidence of rales. Cardiac examination revealed a regular rhythm without murmur, gallop, or rub. His abdomen was soft, with no tenderness or distension, and had normal bowel sounds. Neurologic examination showed no focal deficit. Preoperative laboratory studies showed a hematocrit (Hct) of 40%, a prothrombin time (PT) of 12.6 seconds (INR l.l), and a partial thromboplastin time (PTT) of 24 s,econds (normal 22 to 34 seconds). The admitting diagnosis was adenocarcinoma of the colon metastatic to the liver. The patient was admitted to determine if the disease was in fact confined to the liver, and if so, if a surgical cure was possible. He was scheduled for elective exploratory laparotomy with possible liver resection. Ofxratiue

and Intensive Care Unit Course

On the morning of the operation, the patient was taken to the preoperative holding area where monitors (ECG, noninvasive blood pressure monitor, and pulse oximeter) were placed and an Ls-L, epidural catheter was inserted without difficulty. He was then taken to the operating room (OR), where monitors were placed again, and general anesthesia was induced with thiopental sodium. 400 mg and fentanyl 100 yg; succinylcholine 100 mg was used for muscle relaxation. Anesthesia was maintained with isoflurane in oxygen and air, with intermittent boluses of lidocaine 2% with epinephrine through the epidural catheter. Muscle relaxation was maintained with pancuronium. After induction and endotracheal intubation, a 20-gauge arterial catheter was placed in the left radial artery and a 7.5 French double-lumen catheter in the right internal .jugular vein. Temperature was monitored with an esophageal temperature probe. A partial (segments 6 and 7) right hepatic lobectomy was performed. Total fluid administered during the operation was isotonic crystalloid solution 2,600 ml; hydroxyethylstarch 500 ml; and 3% sodium chloride 250 ml. Blood loss was estimated at 375 ml. A,t the end of surgery, muscle relaxation was reversed, and the patient’s trachea was extubated in the OR before transport to the surgical intensive care unit (ICU). The patient was stable on admission to the ICU. Admission vital signs included BP of 130 to 158 mmHg systolic (SBP) and 76 to 88 mmHg diastolic (DBP), sinus tachycardia of 110 to 120 BPM, and respiratory rate of 16 to 18 breaths/min. Tachycardia continued despite two boluses of 0.9% saline 500 ml intravenously (IV). Therefore, propranolo10.5 mg IV was administered, which decreased HR to 100 to 105 bpm. For the next 20 minutes, the patient’s vital signs remained essentially unchanged except for a slight decrease in HR. Repeat laboratory studies showed a Hct of 31%, platelet count of 181,00O/mm”, PT of 14.2 seconds (INR = 1.4), and a PTT of 23 seconds. Six hours after operation, the patient experienced sudden and severe hypotension followed 2 minutes later

by bradycardia and then asystole. Output from the Jackson-Pratt drains had been 110 ml since surgery. Cardiopulmonary resuscitation (CPR) was initiated at that time, and epinephrine 1 mg IV was administered. The patient’s trachea was orally intubated with ease, and manual ventilation with 100% oxygen was begun. Arterial blood gas tensions, electrolyte concentrations, and Hct were measured. SBP increased to 60 mmHg, and HR returned after approximately 2 minutes of CPR. A second dose of epinephrine 1 mg was administered and CPR was discontinued. After 15 minutes, the patient was once again awake, deficit. Vital signs at responsive, and without neurologic this time included SBP of 90 to 100 mmHg and HR ranging from 90 to 115 bpm. Arterial blood gas analysis from a sample taken within 15 minutes after termination of CPR revealed that pH was 7.20, partial pressure of carbon dioxide (PaCO,) was 53 mmHg, partial pressure of oxygen (PaO,) was 98 mmHg, and hemoglobin was 10 g/dl. An ECG after resuscitation revealed sinus rhythm with a HR of 95 bpm with no ST- or T-wave changes compared with the preoperative EGG. Electrolyte concentrations were within the normal range. Over the next 30 minutes, infusions of both dopamine and epinephrine were started and titrated to keep SBP greater than 90 mmHg. At this time, increased output from the Jackson-Pratt drains was noted. Total output over 20 minutes was approximately 600 ml of bright red blood. Two units of packed red blood cells (PRBCs) were promptly administered, and the patient was taken to the OR for surgical re-exploration of the abdomen. During the second operation, the resected edges of the patient’s liver were noted to be free from bleeding, although there was evidence of subhepatic clot, with approximately 2 to 3 units of clotted blood in the right upper quadrant. Four units of fresh frozen plasma and 1 unit of PRBCs were administered. Dopamine 2 p,g/kg/min was continued. Vital signs stabilized, and the patient was returned to the surgical ICU with his trachea still intubated. Initial BP on return to the ICU was 175/90 mmHg, and the dopamine infusion was rapidly weaned and discontinued. Heart rate continued to range from 100 to 115 bpm. The patient’s Hct was 34%, PT was 16.5 seconds (INR = 1.9), and PTT was 27 seconds. For the next 2 hours, the patient remained stable during mechanical ventilation. Then, the patient’s BP began to decrease rapidly once again but this time was associated with an increase in HR to 150 bpm and a decrease in arterial oxygen saturation to 60%. Quick assessment revealed markedly decreased breath sounds bilaterally with slight expiratory wheezing. The patient was manually ventilated with 100% oxygen, and epinephrine 1 mg IV was administered, with rapid restoration of BP and oxygen saturation. At the same time, a diffuse, patchy, macular rash was noted on the upper torso and all four extremities. All IV infusions were discontinued, including a IO-mg infusion of vitamin K diluted in crystalloid 100 mL that had been ongoing for the previous 30 minutes (total drug administered 5 mg) Because of the rash, diphenhydramine 50 mg and famotidine 20 mg were administered IV. Within 5 minutes, the patient’s vital signs had once again stabilized. J. Clin. Anesth., vol. 9, September 1997

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Mechanical ventilation was slowly discontinued overnight, and the patient’s trachea was extubated the next morning. He remained stable for the remainder of his intensive care, and he was transferred to the surgical ward on postoperative day 2. The remainder of the patient’s hospitalization was uneventful, and he was discharged from the hospital on postoperative day 3 in stable condition.

Case Conference During the patient’s initial acute decompensation in the ICU, our differential diagnosis included acute MI, hemorrhage from the surgical site, and pulmonary embolism. We focused on treating and attempting to confirm or disprove these medical conditions. Once the surgical drainage output began to increase, the patient was taken back to the OR for surgical exploration and correction of bleeding. Later that evening, when the patient again decompensated, expiratory wheezing and the macular rash prompted us to consider anaphylaxis, a possibility that had not been on our initial differential diagnosis. The vitamin K infusion was discontinued and medical treatment for anaphylaxis was initiated. Review of the medical record showed that the patient’s initial decompensation had also been preceded by administration of vitamin K (10 mg IV over 10 minutes). The patient received no further doses of vitamin K, and the remainder of his postoperative recovery was uneventful. This case illustrates that vitamin K, which frequently is used for both medical and surgical patients, is not entirely benign. Vitamin Kwas discovered by Henrick Dam in 1935 while he was investigating the effect of a cholesterol-free diet on baby chickens.r He found that hemorrhagic disease resulted from a nutritional deficiency of a fat-soluble compound that he labeled vitamin K (“IY stood for koagule&g, which is Danish for coagulation). Vitamin K currently can be categorized into three groups as follows*: K,, or phytonadione, which is found in green leafy vegetables, is considered the main source for humans; K,, or menaquinone, which is manufactured by bacteria; and Ks, or menadione, which is a synthetic form. We administered to our patient AquaMEPHYTON (Merck & Co., Inc., West Point, PA), which is an aqueous colloidal solution of phytonadione and several inactive ingredients. Vitamin K serves as a necessary cofactor in the gammacarboxylation for Factors II, VII, IX, and X, and for proteins C and S3 It is the carboxylation of specific glutamic acid residues of hepatically-synthesized precursors that enable the clotting factors both to bind calcium ions and, in turn, to be bound to a phospholipid surface, both processes being necessary for clot formation. With vitamin K deficiency, clotting factors in the blood do not contain carboxylated glutamic acid residues, which results in a deficiency of the clotting system that prolongs PT.

Indications for Vitamin K Vitamin K was initially used to prevent hypoprothrombinemia, which is caused by a simple deficiency of vitamin K due to such problems as malabsorption, and hemor516

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rhagic disease of the newborn.4 The form of vitamin K used for this therapy was menadione and its water-soluble salts. However, menadione is ineffective for treating or reversing the anticoagulant state induced by the oral anticoagulant drugs such as Coumadin (warfarin), whereas phytonadione is highly effective. Therefore, phytonadione is now the generally preferred form for medical uses. A list of current indications for phytonadione consists of prophylaxis and therapy for hemorrhagic disease of the newborn and hypoprothrombinemia caused by5 oral anticoagulant drugs; limited absorption of vitamin K because of such problems as obstructive jaundice, ulcerative colitis, celiac disease, and intestinal obstruction; and liver disease (vitamin K is more effective with biliary obstruction than hepatocellular disease) .‘j AquaMEPHYTON, the commercial preparation of phytonadione in fluid that we used for our patient, is approved for IV, intramuscular (IM), or subcutaneous administration. The IV route, however, is associated with significant side effects and should be used only in emergencies and be infused at a rate not greater than 1 mg/min.5 IV use of the drug is recommended for emergencies only because absorption by the IM route can be erratic and unreliable.4a’ PT should be noticeably improved approximately 2 hours after IV administration, and normal after 12 to 36 hours.’

Side Effects Although adverse reactions to IV administration of vitamin K were observed early after its introduction to the U.S. market in 1960, it was not until 1963 that the extent of the risk came to light when five cases of serious side effects, including one death, were reported in conjunction with IV use of a vitamin K preparation containing propylene glycol as an emulsifying agent (Konakion). Reactions have included facial flushing, altered sensations of taste, diaphoresis, chest pain, dyspnea, cyanosis, respiratory and cardiac arrest, and, as discovered in 1963, even death.6x7 There have been no reports in the literature of such adverse reactions associated with IM or subcutaneous administration. To avoid adverse reactions with IV administration, some have recommended diluting the drug and infusing it at no greater than 5 mg/min.6,g However, even with these precautions, severe reactions, including another death, have been reported between 1916 and the present (Table associated 1). lo-l3 Since the initial report of complications with IV vitamin K, the severe reactions and cardiovascular collapse were often assumed to be secondary to an anaphylactic or anaphylactoid response. It was never clear whether these reactions were caused by the vitamin K itself or by one of the various emulsifiers used in the IV preparation. In two cases, however, cardiovascular collapse followed vitamin K administration in which an anaphylactic effect was unlikely (Tab& 1) .10,12The authors of one of these reports concluded that reactions can occur from hypersensitization to vitamin K preparations and that, perhaps, this response is caused by new antigen formation

Vitamin K-Induced cardiovascular collapse: Songy et al. Table

1.

Year Reported

Cases of Adverse

Effects from Vitamin

Diagnosis

K Preparations Treatment/Outcome/ Comments

Regimen/Dose

Effect Severe hypotension, pulmonary artery measurements indicated acute peripheral vasodilation Patient felt “sick,” cardiac arrest

1976l’

Cirrhosis, squamous cell carcinoma of vocal cord

100 mg over 10 min

1982”

Esophageal ulceration, transient ischemic attacks (T&s), prolonged prothrombin time (PT)

7 mg over 5 to 10 min

1982ll

Acute bronchitis with bronchospasm, TIAs, hematuria Cirrhosis, esophageal varices, prolonged PT

5 mg at 1 mg/min

10 mg IV for 6 days; 10 mg IV over 1 min 3 times a day

During 2nd regimen, 3 min after dose, “anaphylactoid reaction”: facial flushing, hypotension, wheezing, stridor, unconsciousness

Mitral valve replacement; total abdominal hysterectomy (TAJFI), unilateral salpingooophorectomy; TIA Colon cancer

10 mg in 100 ml dextrose over 20 min; 9 days later, 30 mg at 0.66 mg/min 10 mg in 100 ml crystalloid over 30 min-twice given on the same day

During 2nd regimen, facial flushing, hypotension, cyanosis, loss of consciousness First dose: severe hypotension, bradycardia, asystole Second dose: hypotension, increased heart rate, wheezing, rash on torso and all four limbs

19871”

198913

1996 (this report)

between vitamin K (as a hapten) and the emulsifying compounds.‘2 In our case, vitamin K was used to aid with postoperative hemostasis following hepatic lobectomy. 1The medication was given IV, diluted in 100 ml of crystalloid solution, and administered at a rate equal to or slowfer than the recommended 1 mg/min. Despite these precautions, severe hypotension and bradycardia developed, and the patient became unconscious, requiring CPR and mechanical ventilatory support. Due to the recent surgical procedure and the increased output from the surgical drains, the possibility of an adverse drug reaction was not consid-

ered at that time. Following the second dose of vitamin K, however, the appearance of the rash and expiratory wheezing strongly suggested that an anaphylactic or anaphylactoid reaction was responsible for the cardiovascular collapse. All infusions were immediately discontinued, and the patient’s condition quickly stabilized. This case emphasizes that IV administration of a vitamin K preparation can be dangerous, and that if vitamin K is indicated, alternative routes of administration should be used whenever possible. Because our patient was not bleeding in the immediate postoperative period, the IM or

Difficulty breathing, hypotension, cardiac

arrest

Subsequent intravenous (IV) and intramuscular (IM) doses of vitamin K had no effect Cardiopulmonary resuscitation (CPR), epmephrine, and sodium bicarbonate; uneventful recovery Resuscitation unsuccessful; on autopsy, no suggestion of anaphylaxis Corticosteroids, calcium, and fluid bolus; patient recovered after 10 min Intradermal allergy test positive to vitamin K preparations but not to their individual components IV fluid administration; patient recovered uneventfully First dose: CPR and epinephrine Second dose: 100% 0, and epinephrine; diphenhydramine, 50 mg, and famotidine, 20 mg Patient recovered uneventfully

subcutaneous route might have been effective. This case also demonstrates that, whenever signs of cardiovascular collapse develop acutely, anaphylactic or anaphylactoid drug reaction should always be included in the differential diagnosis. Comment Dr. Moreb: This case, presented by Drs. Songy and Layon, illustrates the complication of allergic reaction and cardiovascular collapse due to IV administration of vitamin K. Although this is a rare complication, it can be lethal, and usually can be avoided. Several questions related to this case should be discussed: Was there an indication for vitamin K treatment? If so, which dose was appropriate? Which route of administration should have been used? This patient had none of the indications for vitamin K treatment. He did not have underlying liver disease and did not have a history implying vitamin K deficiency, such as malnutrition and debilitation due to metastatic disease. On the contrary, his liver metastasis was found during diagnostic evaluation for right nephrolithiasis; his weight was 97 kg. J. Clin. Anesth., vol. 9, September 1997

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I conclude that the vitamin K was given after hepatectomy for an elevated PT. Indeed, hepatectomy is associated with a high frequency of postoperative bleeding, especially when performed for hepatocellular carcinoma,i4 which is a diagnosis frequently associated with underlying chronic liver disease and dysfibrinogenemia. i5-18 Still, most of the bleeding after hepatectomy is related to the surgical procedure rather than to clotting deficiency, and careful attention to surgical technique has been reported to reduce the bleeding incidence significantly.14,1g Patients who have a poor food intake after surgery, or who are receiving antibiotics or parenteral nutrition may develop hemorrhagic manifestations due to vitamin K deficiency, but only after two weeks.20-22 These patients should receive a supplement of vitamin K 1 mg once per week, which may be increased to 10 mg weekly if necessary for the purpose of maintaining normal PT.‘3 This patient was treated with vitamin K 10 mg twice on the day of the surgery, which seems to be excessive, even with a prolonged PT. et al. 24 found that clinical coagulopathy, Chakraverty which is defined as bleeding unexplained by local or surgical factors, was identified in 13.6% of 235 patients whom they studied. On the other hand, laboratory evidence of coagulopathy was more common with a PT ratio (PTR) of 1.5 or greater, found in 66% of patients, and platelets less than 10 X log/L, found in 38% of patients. Both factors were predictive of excessive bleeding and poor outcome. It is interesting, however, that vitamin K deficiency was diagnosed prospectively in only one patient, while in a retrospective analysis of plasma from 45 of the above patients with prolonged PT using Echis time (ET), vitamin K deficiency was found in 20%. This implies that in an intensive care patient with prolonged PT, vitamin K treatment will be cost-effective in eliminating the need for fresh frozen plasma transfusions. These findings are in agreement with another report that reviewed the acquired coagulation disorders in emergency and intensive care situations.*’ In general, vitamin K deficiency can be suspected in every patient who is given parenteral nutrition, taking antibiotics, and has liver disease and a prolonged PT. 25 Again, this patient did not fall into any of these categories. A small dose of vitamin K (1 to 2) mg usually shortens the PT within 6 to 8 hours, even in patients being treated with vitamin K antagonists such as warfarin. A larger dose (5 to 10 mg) will neutralize the activity of warfarin completely. 26 Although the standard dose that has been used and recommended for the treatment of coagulopathy is 10 mg daily, this dose is excessive for prophylactic use. Also, while IV vitamin K is recommended for patients subcutaneous administration can with coagulopathy, achieve the same effect, especially when used prophylactically. The use of IV vitamin K should be considered for patients who are in shock or who have bleeding that is z6,2’ If vitamin K has to be given IV, then life-threatening. it should be given slowly in an infusion over a minimum of 30 minutes. Patients who are predisposed to vitamin K 518

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deficiency, especially due to restricted or poor nutrition, can be treated with oral or subcutaneous vitamin K prophylactically in advance of their scheduled elective surgery. The recommended dose is 10 mg daily for 3 days before surgery. In summary, the main lesson to remember from this case report is that IV vitamin K can lead to a lifethreatening complication and, therefore, should be used conservatively. When determining the dose and route of administration of vitamin K, physicians should differentiate between prophylactic use and use in a life-threatening coagulopathy due to vitamin K deficiency.

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Vitamin K-Induced cardiovascular collapse: Song)! et al. 21. Pineo GF, Gallus AS, Hirsh J: Unexpected vitamin Kdeficiency of hospitalized patients. Can Nled AssocJ 1973;109:880-3. 22. Alperin JB: Coagulopathy caused by vitamin K. deficiency in critically ill, hospitalized patients. JAM4 1987;258:1916-9. 23. Olson RE: Vitamin K. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 2d ed. Philadelphia: J.B. Lippincott Co., 1987:846-60. 24. Chakraverty R, Davidson S, Peggs K, Stross P, Garrard C, Little-

wood TJ: The incidence and cause of coagulopathies in an intensive care population, Br J Haamatol 1996;93:460-3. 25. Staudinger T, Locker GJ, Frass M: Management of acquired coagulation disorders in emergency and intensive-care medicine. Semin Thromb Hemost 1996;22:93-104. 26. Brigden ML: When bleeding complicates oral anticoagulant therapy. How to anticipate, investigate, and treat. Poslgrad Med 1995;98:153-65. 27. Hirsh J: Use of war-farm (coumarin). HeatiLk Stroke 1993;2:209-16.

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