Warfarin in the ED

Clinical Aspects of Vitamin K Toxicity

Learning Objectives: After reading this article, the physician should be able to:

1. Identify the type of reactions to vitamin K.
2. Describe the incidence of reactions to vitamin K.
3. Discuss options that will minimize the potential for serious adverse reactions.

Release Date: May 2007

Warfarin is ubiquitous, its clinical indications myriad, and its complications vast. The reversal of anticoagulation is controversial and largely unstudied in the ED for anticoagulated patients presenting with spontaneous intracranial hemorrhage. Surprisingly little data exist about interventions to rapidly obtain a normalized INR in critical patients, such as those with intracranial bleeding. Although it would seem that rapidly reversing an elevated INR in ICH would be beneficial, there is minimal evidence that emergency and aggressive intervention alter the outcome to any great extent. Prognosis is always dismal when the anticoagulated patient bleeds into the brain.

TABLE: SUMMARY: REACTIONS IN PATIENTS RECEIVING VITAMIN K

Figure: Vitamin K by the IV route has been implicated in serious systemic reactions and rarely fatalities. The oral use is universally safe, and should be used when possible. If the IV route is mandated, use a dilute solution (such as 5–10 mg in 100 ml), begin with a slow rate, and be on the lookout for systemic reactions. The best remedy for a systemic reaction, likely an idiosyncratic reaction, is unknown, but general supportive measures seem to work well.

Three approaches are generally considered to normalize an elevated INR secondary to warfarin therapy: fresh frozen plasma (FFP), administration of vitamin K, and administration of a variety of coagulation factors that are deficient in patients treated with warfarin, such as prothrombin complex concentrate (PCC) and Factor VII (rFVIIa). When rapid action is required, FFP or PCC (or possibly rFVIIa?), along with vitamin K, are possible approaches.

This month, I discuss the occasional hypersensitivity reactions associated with parenteral administration of vitamin K₁. Oral vitamin K supplementation is relatively innocuous, and is universally considered safe. Systemic reactions to parenteral (SC, IM, or IV) vitamin K are certainly few and far between, but they are well publicized, so physicians must be aware of the possible consequences.

Anaphylactic Shock and Vitamin K

Rubia J, et al

Ann Intern Med 1989;110(11):943

This is a single case report purporting to document an anaphylactoid (wrongly termed “anaphylactic”) reaction secondary to intravenous vitamin K₁ (phytonadione). Isolated case reports have documented similar reactions associated with the rapid intravenous infusion of the undiluted drug. The unusual spin on this report is that the reaction developed during the slow infusion of a dilute vitamin K solution. But the scenario is even more confusing than that.

A 41-year-old woman received without complications 10 mg of IV vitamin K₁, dissolved in 100 ml of a dextrose solution during a previous admission five years earlier. On a subsequent admission, she received 10 mg of IV vitamin K in 100 ml of D5W over 20 minutes prior to surgery. This also was tolerated without consequence, and oral anticoagulation therapy was initiated after surgery.

Nine days after surgery, her treating physicians attempted to reverse Coumadin-induced coagulopathy by another administration of IV vitamin K. On this occasion, she received 30 mg in 100 ml of a 5% dextrose solution infused over 45 minutes. The reason for this massive dose was not given. Within two minutes of beginning the infusion, the patient developed a facial flush, abdominal pain, hypotension, cyanosis, hyperthermia, and tachycardia, and then lost consciousness. The vitamin K₁ infusion was stopped, and intravenous fluids were rapidly administered. No other therapy was required, and the patient's condition stabilized.

The authors cite four other reports of similar reactions secondary to intravenous vitamin K₁. Previous reactions had usually occurred after rapid bolus infusion of undiluted drug. The previous formulation used castor oil as an additive and stabilizer. This additive was thought to be involved in the systemic reaction. Therefore, the slow infusion of vitamin K₁ in a dilute infusion was recommended, and that caveat was followed in this case.

The authors conclude that vitamin K₁ preparations should be given by the intravenous route only in acute emergencies and suggest that it should be avoided altogether in patients previously treated with the drug. Ostensibly this is because previous administration would sensitize the patient. This is theoretical only, however, and not supported by science. Certainly this admonition is not supported by this report. Careful medical observation during drug infusion to detect or reverse anaphylaxis during vitamin K₁ administration was suggested.

Comment: This letter to the editor is frequently cited in all reviews that discuss toxicity due to parenteral vitamin K₁. Interestingly, it is assumed that this was straightforward anaphylactic shock. I disagree, and think the case was significantly overstated. The reaction appeared to be non-life-threatening in nature, short-lived, and did not require antihistamines or epinephrine. One would be hard pressed to eschew IV vitamin K₁ based on this anecdotal report. Certainly this does not describe an immediate hypersensitivity or a classic IgE-mediated reaction. Exactly what it was is puzzling. The hypotension and hyperthermia would suggest a simple pyrogen reaction. Prohibiting subsequent vitamin K in any patient just because of a previous, possibly sensitizing dose is certainly an invalid conclusion. In fact, there are numerous reports where vitamin K has been well tolerated after a previous reaction, typical for idiosyncratic reactions.

The medical literature, however, seems to accept the concept of the serious danger of IV vitamin K as gospel, and the PDR contains a boxed warning about the possible lethal effects. No doubt some patients will experience an idiosyncratic response to vitamin K and/or its additives, and a cautious approach is prudent. Most patients requiring IV vitamin K will have multiple medical problems that can cloud the issue. Serious or even life-threatening Coumadin-induced bleeding is certainly more common than lethal reactions to vitamin K. Sometimes you just have to take some calculated risks. The medical literature does contain other case reports with similar cautions. The literature fails to provide true scientific investigation or a sophisticated analysis of these reactions.

Box: Boxed warning in 1999 Physician's Desk Reference (Medical Economics Co.) for AquaMEPHYTON, or Vitamin K₁ (Merck & Co., Inc). This warning has been in the PDR for many years, and it is based on anecdotal and somewhat exaggerated case reports. While IV vitamin K and possibly SC and IM use likely can cause an idiosyncratic reaction, usually hypotension, true anaphylaxis has not been documented. As with any medication, it is prudent to be cautious, and oral vitamin K has become the therapy of choice under most circumstances. Fresh frozen plasma is another alternative to parenteral vitamin K. The major disadvantage of large doses of parenteral vitamin K is that subsequent anticoagulation becomes problematic.

Probably the most scientific documentation of vitamin K-induced pathology appeared in 1982 by Rich et al. (Post Grad Med 1982;72[5]:304.) This report describes two cases of cardiac arrest temporally related to IV vitamin K, one that proved fatal. Both patients were quite ill with multiple medical problems, but the timing reasonably implicates vitamin K as the culprit. It's difficult to prove or to disprove a direct association of parenteral vitamin K and subsequent death, but it is a recurring theme and one that should garner your attention. (See Arch Intern Med 1995;155:2127.)

AquaMEPHYTON is the vitamin K₁ preparation usually used for IV administration. Although other forms of vitamin K are available (vitamin K₃ and K₄), vitamin K₁ is the superior product and the only preparation used to reverse warfarin-induced coagulopathy. Vitamin K may be administered orally, subcutaneously, intramuscularly, or intravenously. Because of the possibility of hypersensitivity reactions, the oral route is preferred whenever possible. The intramuscular route can cause bleeding in anticoagulated patients, and absorption is erratic. This preparation no longer contains castor oil as a solubilizer, but even the newer preparations have been reported to cause idiosyncratic reactions. (Clin Ther 1987;9[4]:379.) Current IV formulations contain benzyl alcohol, a possible cause of systemic reactions. The IV preparation actually can be administered orally.

TABLE: CLINICAL MANAGEMENT OF AN ELEVATED INR

Emergency physicians most likely would be familiar with vitamin K₁ as a treatment for bleeding secondary to excessive Coumadin. A significantly elevated INR has prompted many clinicians to administer vitamin K₁ as a prophylactic approach to prevent bleeding. In the absence of bleeding or other caveats, merely finding an elevated INR, often at very high levels, is not as much of an emergency as some physicians presume. When I was a resident, finding a high PT on routine testing was considered a big deal. The standard rationale for vitamin K in this scenario was to prevent spontaneous bleeding from over-anticoagulation before it began, ostensibly because intracerebral or retroperitoneal hemorrhage could be spontaneous and fatal.

When patients presented with bleeding (usually hematuria) secondary to an elevated INR, almost all clinicians reflexively administered very large doses of vitamin K₁. The 30 mg IV dose described in the article is certainly bizarre, and that patient would be nearly impossible to anticoagulate for weeks. The obvious downside of vitamin K in patients with DVT, mechanical heart valves, or atrial fibrillation is that they are at risk for embolic phenomena. Over the years a more conservative approach, especially to asymptomatic excessive anticoagulation, has been promulgated.

The current clinical approach to various scenarios associated with an elevated INR is outlined in the table. Intravenous vitamin K₁ has been recommended only for serious bleeding secondary to Coumadin toxicity. When it is given, doses in the 5 mg to 10 mg range are recommended, but in seriously compromised patients, most would first give FFP or PCP, followed by vitamin K. If intravenous vitamin K₁ is given, it is always recommended to be diluted and given at a slow rate (less than 1 mg/min) because of the danger of systemic reactions. Anecdotal reports suggest, however, that even slow infusion of the dilute solution, or even SC/IM doses, will not guarantee total safety. I could find no problems related to oral use.

The clinical approach to an elevated INR and bleeding disorders secondary to vitamin K₁ deficiency has come under scrutiny, and a much more conservative approach is now the mainstream consensus. Emergency physicians would be hard pressed to ever document the need for a large dose (more than 10 mg) of IV vitamin K₁. The reflex vitamin K reversal of all Coumadin-induced coagulopathy has been called into question, and, in fact, it is not required nor suggested as standard of care. When intravenous vitamin K₁ is indicated, it should be given with the knowledge that there is a slight but certainly a real chance for a potentially serious reaction, regardless of dose or administration technique. As with other medications given on a daily basis without a second thought, such as thiamine and naloxone, a proper observation and monitoring period should be routine following parenteral administration of vitamin K₁.

I could find no guidelines on the treatment of vitamin K₁-induced reactions. Moreover, I could not find a colleague who had personally witnessed such a reaction. If any reader has personal experience, an email would be appreciated. It is impossible to ascertain the physiology of the reaction, and it seems to be idiosyncratic, usually producing alarming but poorly defined systemic reactions. Hypotension, fever, and flushing seem to predominate. It is not a true IgE-mediated event, and apparently it can occur with the first dose. This is a classic anaphylactic or idiosyncratic reaction.

It is also unclear whether standard anaphylactic therapy would be helpful or would reverse the condition. I think it is reasonable to administer IV fluids and antihistamines and possibly epinephrine in severe or resistant cases if the extremely rare vitamin K₁ reaction is encountered. Most current recommendations include the caution that IV vitamin K₁ be administered “only in an emergency.” This is hardly a firm guideline because the definition of an emergency is certainly open to debate.

Most clinicians will never encounter a reaction to IV vitamin K₁, but the seasoned clinician will be informed and cautious. I have given this vitamin many times in 10 mg IV bolus doses, and I have never seen even a hint of a reaction. Having further researched the topic, however, I have become more conservative (aka paranoid). This means using oral vitamin K and FFP more frequently, always using a diluted solution given slowly, and telling the nurse to stay in the room for the first few minutes when the infusion is begun. I would be interested in hearing from any readers who have encountered an adverse reaction from intravenous vitamin K₁. Any reaction to oral vitamin K probably represents a case report.

Acute Cardiovascular Collapse after Intravenous Phytonadione

Barash P, et al Anesth Analg 1976;55(2):304

This article seems to document cardiovascular collapse after IV vitamin K. On careful reading, however, this is a confusing case, and the facts may not substantiate the conclusions. A 43-year-old man with cancer of the pharynx underwent uneventful surgery for a laryngectomy. Because of some bleeding postoperatively, he was given 10 mg of phytonadione, infused intravenously over 10 minutes.

Five minutes following the infusion, the blood pressure and pulmonary artery pressure dropped precipitously. The patient was treated with vasopressors and IV fluids, and a relationship to the vitamin K was suspected. Curiously, within the next two days, he was again administered vitamin K on two separate occasions following this incident without complications. Doses included 25 mg IM and 10 mg IV in a dilute solution run over one hour.

The authors agreed that this is not firm evidence for anaphylaxis, nor is there a proven cause-and-effect relationship, but they are convinced that this case illustrates previously described reactions. Certainly this was not a classic allergic reaction because the patient received subsequent injections without adverse effects. It is postulated that severe hypotension due to vasodilation was the culprit. The additives (fat emulsions, now removed) in the vitamin K were possibly contributory.

Comment: This is another anecdotal report frequently quoted as evidence for severe reactions related to parenteral vitamin K. I do not think unsubstantiated reports should be published; they tend to cloud the issues and are fodder for frivolous litigation. The authors state that as of the writing of this report (1976) no fatalities had been reported with the parenteral use of vitamin K analogues. Fatalities have, however, been reported to the FDA. Although this patient did not suffer any significant consequences, he appeared to experience significant vasodilation and hypotension that was temporally related to the vitamin K infusion. “Cardiovascular collapse” in the title is a tad misleading. I would not underplay the potential of vitamin K to produce real pathology, but when other commonly quoted articles are studied in detail, I have found that some authors have drawn similar misleading conclusions. (See Hosp Pharm 1981;16:224.)

Finally, as a further depressing observation on the shortcomings and inaccuracies of the medical literature, it is instructive to note that the current edition of a major toxicology textbook states that “death secondary to anaphylactoid reactions” has resulted from parenteral vitamin K. The author of this quote cites the articles I have reviewed, and clearly these reports do not document a fatal outcome. The message is clear, however. Parenteral vitamin K is not without risk, albeit it extremely small, but why take the chance if better alternatives are available?

The Up-to-Date computer-based reference, generally quite current and well written, continues to promulgate the cautions about vitamin K even in 2007. The reference source's latest reference is 2001. (J Thromb Thrombolysis 2001;11[2]:175.) This reference is a nifty compilation of the medical literature and FDA data on this subject, and is summarized in the table. I was impressed by the number of cases reported to the FDA that have not been highlighted in the medical literature. The FDA data suggest that this is a real phenomenon, albeit rare.

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