Abstract
Parenteral vitamin K1 (phytonadione) is used for anticoagulant reversal, and a boxed warning exists with intravenous and intramuscular administration due to the possibility of severe reactions, including fatalities. These reactions resemble hypersensitivity or anaphylaxis, including anaphylactoid reaction, and have led to shock and cardiac and/or respiratory arrest. The objective of this review is to summarize the available literature detailing the anaphylactic/anaphylactoid reactions with parenteral vitamin K1 in order to better characterize the reaction and provide a more in-depth understanding of its importance. A comprehensive literature search of MEDLINE (1946 to June 2016) and EMBASE (1947 to June 2016) was conducted using the terms vitamin K1, phytonadione, phytomenadione, vitamin K group, anaphylaxis, polyoxyethylated castor oil, and cremophor. A total of 2 retrospective surveillance studies, 2 retrospective cohort studies, and 17 case reports were identified for inclusion and assessment. Based on a review of the literature, use of parenteral vitamin K1 may result in severe hypotension, bradycardia or tachycardia, dyspnea, bronchospasm, cardiac arrest, and death. These reactions are most consistent with a nonimmune-mediated anaphylactoid mechanism. It appears that intravenous administration is more frequently associated with these reactions and occurs at an incidence of 3 per 10 000 doses of intravenous vitamin K1. The solubilizer may also increase the risk of adverse reactions, which occurred in patients with and without previous exposure to vitamin K1. Although there are known factors that increase the risk of an adverse drug event occurring, reactions have been reported despite all precautions being properly followed.
Background
Vitamin K is a fat-soluble vitamin that acts as a cofactor in hepatic synthesis of coagulation factors II, VII, IX, and X and proteins C and S in humans. It is also involved in the carboxylation of plasma proteins that facilitate coagulation factor binding to platelets. 1 Vitamin K1, also known as phylloquinone, phytonadione, or phytomenadione, is the naturally occurring plant form of vitamin K and the main dietary source of vitamin K for humans. 2 Vitamin K1 is practically insoluble in water, somewhat soluble in alcohol, and fully soluble in fatty oils, vegetable oils, dehydrated alcohol, chloroform, ether, and benzene. 3
In the United States, vitamin K1 is commercially available as phytonadione, a synthetic derivative identical to naturally occurring vitamin K1.1,4,5 Phytonadione formulations currently approved by the US Food and Drug Administration (FDA) include an oral tablet and an injectable emulsion that can be administered via the intravenous (IV), intramuscular (IM), or subcutaneous (SQ) route. 4,5 Due to its poor water solubility, injectable phytonadione requires formulation with an emulsifying agent such as polyoxyethylated fatty acid derivatives, polysorbate-80, or mixed micelles (MM). 2 Additionally, injectable phytonadione is formulated with benzyl alcohol, which serves as a preservative. 4
The FDA-approved indications for vitamin K1 include anticoagulant-induced prothrombin deficiency (anticoagulant reversal), prothrombin deficiency secondary to other drug therapy or factors causing limited absorption or synthesis of vitamin K, and prophylaxis and treatment of hemorrhagic disease of the newborn. 4,5 The recommended dose and route of administration vary for the different indications, and the recommendations for anticoagulant reversal differ between the package insert and published guidelines (Table 1). Although the package insert advocates avoidance of IV administration due to safety concerns, 4,5 multiple guidelines state a preference for IV administration in urgent situations requiring parenteral vitamin K1. 6 –8 This recommendation is based on literature indicating that SQ and IM administration may be less efficacious due to erratic and unpredictable absorption. 9
Vitamin K1 Dosing Recommendations.
Abbreviations: ACCP, American College of Chest Physicians; BCSH, British Committee for Standards in Haematology; IM, intramuscular; INR, international normalized ratio; IV, intravenous; SQ, subcutaneous.
aRarely up to 50 mg.
bMay require higher dose if mother is anticoagulated.
The prescribing information for vitamin K1 emulsion notes that injection site pain, transient flushing, taste disturbance, and cutaneous reactions have been reported. Rare instances of dizziness, rapid and weak pulse, sweating, hypotension, dyspnea, and cyanosis are also addressed. 4,5 Benzyl alcohol has been associated with toxicity in newborns, termed “gasping syndrome,” characterized by metabolic acidosis, encephalopathy, intracranial hemorrhage, and respiratory depression with gasping. 3,4 Vitamin K1 has a boxed warning about the possibility of severe reactions, including fatalities, with IV and IM administration. These reactions resemble hypersensitivity or anaphylaxis, including anaphylactoid reaction, and have led to shock and cardiac and/or respiratory arrest. 4,5,10 –13 Unfortunately, they are not well understood or characterized. It has been suggested that the reaction occurs as a result of vitamin K1 itself and/or as a result of the polyoxyethylated fatty acid vehicle. Although adequate dilution, appropriate dosing, and slow administration have been thought to minimize these reactions, reactions have still been reported despite those precautions. 4,5,10 –12
Although the presentation of anaphylactic and anaphylactoid reactions is very similar, the mechanism is very different. Anaphylactic reactions are immediate hypersensitivity type I reactions; these immune-mediated reactions occur as a result of the production of drug-specific immunoglobulin E (IgE) antibodies after a period of sensitization. Anaphylactic reactions are exemplified by the occurrence of anaphylaxis with symptoms of urticaria, laryngeal edema, wheezing, and cardiorespiratory collapse. After the initial period of sensitization, these reactions occur within minutes of the repeat exposure. Anaphylactoid reactions, also known as pseudoallergic reactions, mimic anaphylactic reactions in presentation but do not require sensitization and are not mediated by the presence of IgE antibodies. These reactions are thought to occur via nonimmune degranulation of mast cells and basophils, leading to direct release of mediators and the classic end-organ effects they exert. It is also possible that the nonimmune release of anaphylatoxins through complement pathway activation could contribute. Similar to anaphylactic reactions, anaphylactoid reactions are often immediate and severe, but they may occur with the first exposure to the offending agent as they do not require sensitization. 14
As previously discussed, vitamin K1 is highly lipid soluble and requires formulation as an aqueous colloidal dispersion to keep it in solution. Polyoxyethylated fatty acid derivatives are commonly used for this purpose, most frequently polyoxyethylated castor oil (PEO-CO), also known as polyoxyl castor oil or cremophor. The PEO-CO is a nonionic solubilizer and emulsifier made by reacting ethylene oxide with castor oil. It is used as a solubilizer or diluent for several drugs including paclitaxel, teniposide, cyclosporine, clotrimazole, miconazole, and fat-soluble vitamins including phytonadione. Anaphylactoid reactions have been reported after IV administration with PEO-CO when used as a solubilizer for cyclosporine, paclitaxel, and teniposide, and cardiorespiratory arrest has been reported after IV miconazole. 10,11
A better comprehension of the mechanism, common presentation, risk factors, and outcomes of these reactions enables better informed decisions of when and how to use parenteral vitamin K1 safely. The objective of this review is to summarize the available literature detailing the anaphylactic/anaphylactoid reactions with parenteral vitamin K1 in order to better characterize the reaction and provide a more in-depth understanding of its importance.
Data Sources
A comprehensive search of MEDLINE (1946 to June 2016) and EMBASE (1947 to June 2016) was conducted using the terms vitamin K1, phytonadione, phytomenadione, vitamin K group, anaphylaxis, PEO-CO, and cremophor. The search was limited to English-language primary literature, including clinical studies and case reports in humans, that evaluated serious reactions to parenteral vitamin K1. Additional literature was identified through a manual bibliographic review of references identified in the initial search. A total of 2 retrospective surveillance studies, 2 retrospective cohort studies, and 17 case reports were identified for inclusion. 15 –35
Literature Review
Retrospective Surveillance Studies
Fiore et al 15 reviewed all adverse drug reactions (ADRs) to vitamin K1 reported in the US FDA Spontaneous Reporting System Adverse Reaction database between August 1968 and September 1997. Their objective was to summarize the known data on anaphylactoid reactions with vitamin K1. An anaphylactoid reaction was defined as any ADR coded as anaphylaxis, allergic reaction, apnea, dyspnea, death, heart arrest, hypotension, shock, or vasodilation. A total of 2236 ADRs in 1019 patients secondary to vitamin K1 were identified in the FDA database. Among the 192 patients with an ADR secondary to IV vitamin K1, 132 (69%) patients experienced anaphylactoid reactions; death resulted in 24 (18%) of these patients. When broken down by dose of IV vitamin K1 administered, no dose-dependent patterns were noted in terms of presentation or outcomes, and life-threatening reactions including death occurred within all dose ranges. Among the 217 patients with an ADR secondary to a non-IV administration of vitamin K1, 38 (18%) patients experienced anaphylactoid reactions (5 oral, 10 SQ, and 23 IM) and only 1 death resulted (oral). 15
The ADRs associated with 2 vitamin K1 formulations were analyzed by Pereira and Williams 16 based on data from worldwide postmarketing surveillance from the manufacturer’s (Roche) International Drug Safety Department, the World Health Organization Collaborating Centre for International Drug Monitoring, spontaneous reports, and clinical trial data during the period January 1, 1974 to June 30, 1995. Two vitamin K1 formulations were evaluated—vitamin K1 solubilized in PEO-CO (PEO-CO) and vitamin K1 solubilized in MM. During this time frame, PEO-CO accounted for 95% of the combined sales figures (1290 million patients exposed to PEO-CO vs 68 million patients exposed to MM), because MM was not commercially available until 1994. During the last 12 months of the surveillance period, while MM was commercially available, another analysis was conducted to provide a more even comparison, given that PEO-CO accounted for just 62% of the sales figures (21 million patients exposed to PEO-CO vs 13 million patients exposed to MM). For all analyses, an ADR was defined as any untoward change in health status. The ADR was further delineated as probably or possibly related to vitamin K1 exposure. An anaphylactoid reaction was considered when the patient had a reaction shortly after exposure with symptoms from 2 or more of 4 systems (cardiovascular, respiratory, skin/conjunctiva, and gastrointestinal), or when the reporting authority described the reaction as an anaphylactoid reaction. A total of 404 ADRs in 286 patients were included in the review, 120 of which were considered serious. The majority of these ADRs were associated with PEO-CO: 387 (96%) of the total ADRs and 117 (98%) of the serious ADRs. Among the 387 ADRs associated with PEO-CO, route of administration was known in 301; of these, 273 (91%) occurred with parenteral administration and 28 (9%) occurred with oral administration. Overall, 105 of the ADRs were categorized as possible or probable anaphylactoid reactions, 102 (97%) of which were associated with PEO-CO (85 probable and 17 possible). Fatalities resulted in 20 (7.0%) of 286 patients with ADRs; all had received PEO-CO. Seven fatalities were possibly or probably caused by PEO-CO, all as a result of an anaphylactoid reaction (6 probable and 1 possible). Among the 85 anaphylactoid reactions probably associated with PEO-CO, 6 (7.1%) were fatal. During the last 12 months of the surveillance period, 14 serious ADRs were reported among an estimated 21 million patients treated with PEO-CO, while no serious ADRs were reported among an estimated 13 million patients treated with MM. 16
Retrospective Cohort Studies
Shields et al 17 conducted a retrospective cohort study of inpatients who received IV vitamin K1 before a diagnostic or surgical procedure between September 1994 and March 1996. Their primary objectives were to determine the efficacy and safety of IV vitamin K1; safety was evaluated through the assessment of ADRs occurring after IV vitamin K1 administration. An ADR to IV vitamin K1 was defined as facial flushing, fever, diaphoresis, rise in blood pressure, cyanosis, chest tightness, or cardiovascular collapse during or immediately after administration. A total of 105 patients were included in the analysis, with a mean age of 69.6 years (range: 33-92 years) and a mean weight of 75.2 kg (range: 36.4-134.8 kg). The initial dose of IV vitamin K1 given was 0.5 or 1 mg in 85 (81%) patients; 72% of patients received a single dose. Two (1.9%) patients experienced an ADR; both during infusion of an initial 0.5 mg dose. The reactions were similar between the 2 and were characterized by dyspnea and chest tightness, resolving within 15 minutes after stopping the infusion. 17
Riegert-Johnson and Volcheck 18 conducted a retrospective review of IV vitamin K1 administered at a large academic medical center between March 1995 and December 2000. Their objective was to determine the incidence of anaphylaxis after IV vitamin K1. Anaphylaxis was identified as a clinical scenario consistent with shock or edema or symptoms indicative of mediator release in combination with additional symptoms from one of the following organ systems—oral/gastrointestinal, respiratory, or cardiovascular. During the study period, a total of 6572 doses of IV vitamin K1 were administered to 2938 patients. Most doses were 10 mg (51.2%), followed by 1 mg (32.3%), 0.5 mg (16.0%), and 20 mg (0.5%). Two patients experienced anaphylaxis with IV vitamin K1, indicating an incidence of 3 per 10 000 doses (95% confidence interval: 0.04-11 per 10 000 doses). These patient cases will be discussed in more detail with the case reports. 18
Case Reports
Seventeen adult patients ranging from 28 to 89 years of age were represented in the case reports (Table 2). The majority of patients experienced reactions with IV administration, although 2 cases of IM 19,27 and 1 case of SQ 22 administration were also represented. Reported doses administered ranged from 0.5 to 100 mg, with only 3 patients receiving doses above those recommended in the prescribing information and guidelines (>10 mg). 4 –8 Three reactions resulted in death, 20,21,30 whereas 1 reaction resulted in fetal death. 27 Among 12 reactions to IV administration reporting infusion rate, 9 occurred despite an infusion rate equal to or slower than the 1 mg per minute recommended in the package insert. 18,21,23,24,26,30,31 Of these, 3 also met the suggestions of the American College of Chest Physicians (ACCP) guidelines with total infusion times of at least 20 minutes. 18,26 Of the 10 reactions detailing previous vitamin K1 exposure, 6 had previously received some form of vitamin K1. 25,26,29,30,32 Two cases reported on patients with prior reactions to other medications formulated with PEO-CO. 19,22 Five cases described rechallenge of the patient with vitamin K1 22,23,25,31,32 , 2 of which resulted in recurrence of the reaction. 23,25
Case Reports of Severe Reactions With Parenteral Vitamin K1.
Abbreviations: BP, blood pressure (mm Hg); D5W, dextrose 5% solution; F, female; HR, heart rate (beats per minute); IM, intramuscular; IV, intravenous; M, male; MM, mixed micelles; NS, normal saline solution; PAP, pulmonary artery pressure (mm Hg); PEO-CO, polyoxyethylated castor oil; QD, daily; RR, respiratory rate (breaths per minute); SQ, subcutaneous; TID, 3 times daily; TPN, total parenteral nutrition.
Three pediatric patients ranging from newborn to 9 years of age were represented in the case reports (Table 2). The newborn case described IM administration, 33 whereas the other 2 cases described IV administration. 34,35 The presentation was similar to that seen with adult patients, as was the time frame for the onset of reaction. Both reports of IV administration were given at a rate more rapid than 1 mg per minute. One patient had previous exposure to vitamin K1. 35
Discussion
Severe reactions to parenteral vitamin K1 may result in severe hypotension, bradycardia or tachycardia, dyspnea, bronchospasm, cardiac arrest, and death. Reported reactions have occurred during or within 20 minutes after administration. Intravenously administered vitamin K1 appears to be more likely to cause these reactions than other routes of administration; however, reactions have also been seen with IM, SQ, and oral administration. Although these reactions are not very common, with an estimated incidence of 3 per 10 000 doses, those occurring with IV administration have been associated with death in as much as 18% of reactions. 15,18 Although the prescribing information for vitamin K1 strongly recommends SQ as the preferred parenteral route of administration, the more recently updated British Committee for Standards in Haematology and ACCP guidelines recommend against both SQ and IM administration due to unpredictable and erratic absorption. 4 –8
Among patients with route of administration documented, 91% of the reactions reported by Pereira and Williams occurred with parenteral administration. 16 Fiore et al reported that 69% of reactions with IV administration were anaphylactoid, as compared to just 18% of reactions with non-IV route of administration. 15 Although IV administration appears to be associated with the highest risk of severe reactions, Fiore et al reported ADRs and anaphylactoid reactions with oral, SQ, and IM administration as well, suggesting that any route of administration may put the patient at risk. 15
It has been suggested that adverse reactions are more likely with higher doses, inadequate dilution, and rapid infusion of vitamin K1. The ACCP guidelines advocate the use of the lowest effective dose (ie, 5-10 mg), dilution in at least 50 mL of fluid, and infusing over a minimum of 20 minutes. 6 The vitamin K1 prescribing information recommends a dose of 2.5 to 10 mg or up to 25 mg, dilution in 0.9% sodium chloride, 5% dextrose or 5% dextrose and sodium chloride, and slow infusion with a maximum rate of 1 mg per minute. 4,5
Although higher doses of vitamin K1 may be associated with an increased risk of reaction, reactions have been reported at doses as low as 0.5 to 1 mg. 17,18,21,33 Both ADRs reported by Shields et al occurred with a 0.5 mg dose, suggesting that avoidance of higher doses is not completely protective against these reactions. 17 Similarly, Riegert-Johnson and Volcheck reported anaphylactic reactions in 2 patients, both of which occurred with 0.5 mg doses. 18 Fiore et al reported that 21 patients with anaphylactoid reactions and 4 fatalities were reported with IV vitamin K1 administered at doses below 5 mg. They further assessed the relationship to dose and noted no trends. 15
Reactions have been reported in cases where the vitamin K1 was adequately diluted, 18,23,24,26 and with infusions as slow as 0.5 mg over 1 hour. 18 Riegert-Johnson and Volcheck utilized a standard dosing protocol for IV vitamin K1, which specified dilution in 50 mL fluid and slow infusion over 1 hour. These specifications meet those recommended in the prescribing information and guidelines, but reactions occurred despite the use of those protective mechanisms. 18 Although it is reasonable to dilute IV vitamin K1 and administer as a slow infusion, this will not ensure that such reactions are avoided.
Pereira and Williams observed that vitamin K1 formulated with PEO-CO was associated with more reactions than the MM formulation, suggesting that the solubilizer rather than vitamin K1 itself may be the causative agent. 16 This notion is also supported by case reports describing patients with previous reactions to medications containing PEO-CO. 18,19 An animal study by Mi et al noted severe reactions with IV vitamin K1 during initial administration and rechallenge, but no reactions occurred in the absence of a solubilizer. 36 The PEO-CO has also been associated with anaphylactoid reactions when injected intravenously as a component of other medications. 11 It is important to be mindful of the fact that anaphylactoid reactions still occurred in patients receiving the MM formulation, suggesting that the reaction cannot be entirely attributed to the solubilizer. 16,29 It is possible that both the solubilizer and vitamin K1 itself have the ability to induce reactions.
The exact mechanism and nature of these reactions has been debated over the years, with suggestions of an immune-mediated anaphylactic reaction as well as a nonimmune-mediated anaphylactoid reaction. 10,11 Many cases of these reactions have been reported in patients receiving vitamin K1 for the first time, 18,24,28,30,31 which is not consistent with immune-mediated anaphylaxis as sensitization is required for development of drug-specific IgE antibodies. 14 The reaction in the newborn also does not support an immune-mediated mechanism, given that the immune system is not fully developed until 6 months of life. 33 The animal study by Mi et al reported anaphylaxis-like symptoms with IV vitamin K1, associated with increased histamine but no effect on IgE, also supporting a nonimmune-mediated anaphylactoid reaction. 36 However, some case reports support an immune-mediated anaphylactic reaction. It is possible that reactions due to PEO-CO and those due to vitamin K1 itself occur via different mechanisms, which could explain why varying characteristics have been reported.
One of the early case reports describes an instance of cardiovascular collapse induced by IV vitamin K1 associated with a drop in pulmonary artery pressure and systemic arterial pressure. The authors suggest that acute peripheral vasodilation appeared to be primarily responsible and that therapy for hypotension following IV vitamin K1 should be directed at correcting the peripheral vasodilation. 31 Since that report, several in vivo and in vitro studies have been conducted to better elucidate the mechanism behind the cardiovascular effects of vitamin K1. 37 –39 Barnette et al found that IV vitamin K1-induced hemodynamic changes were consistent with dilation of the arterial system and possibly the venous system through a humoral inflammatory or allergic response. 37 In contrast, Tirapelli et al determined that the dose-dependent decrease in mean arterial pressure seen with IV vitamin K1 most likely involves activation of the nitric oxide pathway and vasodilator release. 38 Drolet et al reported that IV vitamin K1 exerted a direct effect of on cardiac action potential through blocking major ionic currents, warranting caution in patients sensitive to small changes in action potential (eg, QT interval prolongation [QT] prolongation). 39 These studies help to provide a better comprehension of the mechanism behind the cardiovascular effects seen with IV vitamin K1, which allows for better characterizing patients at high risk as well as determining how to treat these patients.
There are inherent limitations to the information presented, as the studies and case reports presented are all retrospective in nature. The studies differ considerably in methodology and are heterogeneous, making comparisons difficult. The noninterventional, retrospective nature of the studies included introduces the potential for confounding, and the studies are not able to conclude an absolute cause and effect relationship. Reporting bias is another limitation, given the fact that spontaneous reporting does not include the denominator, omits cases, and tends to favor more severe reactions. It is possible that there was some duplication of reported cases; FDA reports and/or patients from studies may have also been published as case reports. Some reports lacked complete information regarding concomitant disease states and medications, severity of illness, and allergies, which could contribute to reactions. Patients receiving vitamin K are often very sick, so it is difficult to determine whether other factors may play a role. Additionally, the MM formulation of vitamin K1 is not commercially available in the United States, making it difficult to apply some of the information universally.
Ideally, a study prospectively comparing the parenteral routes of vitamin K administration is needed to better differentiate the safety of each route. But, this is unlikely due to the large number patients needed and the resources that would be necessary to support such an investigation. Thus, with the absence of prospective data, the outcomes associated with parenteral vitamin K1 identified through retrospective studies and case reports gain additional importance and clinical utility.
Conclusion
Vitamin K1 may induce severe reactions including death when administered via the parenteral route, especially when given intravenously. These reactions are most consistent with an anaphylactoid mechanism. The majority of reactions have occurred in patients receiving vitamin K1 solubilized with PEO-CO, suggesting that the solubilizer may contribute in many of these reactions. The fact that reactions have been reported in patients receiving formulations free of PEO-CO indicates that vitamin K1 itself may also be responsible in some reactions. These reactions may be more likely to occur when vitamin K1 is administered at higher doses, inadequately diluted, or quickly administered, but reactions have been reported despite all precautions being properly followed.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.