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Life-threatening intraoperative anaphylaxis to gelatin in Floseal during pediatric spinal surgery
Clinical Communications Life-threatening intraoperative anaphylaxis to gelatin in Floseal during pediatric spinal surgery Niti S. Agarwal, MD, Collette Spalding, MD, and Mervat Nassef, MD Clinical Implications
This case highlights the importance of using a broad differential when determining the cause for intraoperative anaphylaxis and suggests that Floseal should only be given to patients with a negative history of allergies to gelatin and bovine protein.
TO THE EDITOR: Identifying the cause of intraoperative anaphylaxis is a difficult task for the allergist/immunologist given the large number of potential culprits. The incidence of intraoperative anaphylaxis is reported to occur between 1 in 4000 to 1 in 25,000 cases, with the majority being attributed to muscle relaxants.1 Gelatin in colloids has been implicated in approximately 0.34% of perioperative anaphylaxis cases.2 Gelatin is a protein derived from collagen and is used in numerous items, including meats, yogurts, jellies, juices, and vaccines.3 The most severe reports of allergic reactions to gelatin are with parenteral colloid usage or with vaccines. Nevertheless, severe anaphylaxis to gelatin in newer topical hemostatic agents, for example, thrombin soaked Gelfoam (Pfizer Inc., New York, NY), has also been reported.4-6 These agents have become widespread in reducing bleeding in surgery. Floseal (Floseal Hemostatic Matrix; Baxter Healthcare Corp, Hayward, Calif) combines gelatin granules with pooled human thrombin. The gelatin is extracted from bovine corium, and the collagen is gelatinized and stabilized with glutaraldehyde.7 We present a case of severe intraoperative anaphylaxis to the gelatin component in Floseal in a boy with unknown bovine allergy. Our patient was a 9-year-old boy with a medical history significant for glaucoma, conductive hearing loss, and hemivertebrae, with a clinical diagnosis suggestive of Marden Walker syndrome. He has mild persistent asthma and is atopic with multiple allergies. He developed hives and coughing immediately after eating salmon and tuna on separate occasions. He also developed nasal congestion with dust mite exposure, and latex exposure caused hives. He presented to the allergy/immunology service after intraoperative anaphylaxis during removal of segmental spinal instrumentation for worsening kyphosis. Anesthesia was induced with propofol, fentanyl, and rocuronium, and the patient was continued on rocuronium and remifentanil infusions. One hour later, he was given tobramycin and cefazolin, and surgery commenced. Sixty minutes into the procedure, Floseal was injected into the screw holes. Within minutes, the patient became tachycardic with an increase from baseline of 80 beats/min to 105 beats/ min, and hypotensive, with mean arterial pressure dropping from 75 mmHg to 45 mmHg. The patient was placed supine, given a 0.5 mg/kg (10 mcg) intravenous bolus of epinephrine 4 times, followed by intravenous atropine twice, subcutaneous terbutaline,
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and inhaled albuterol via a metered-dose inhaler. Despite these interventions, the patient became pulseless and required chest compressions for 1 minute before regaining pulses. He then was started on epinephrine and vasopressin infusions. He received 2 mg/kg of methylprednisolone and 2 mg/min/kg of phenylephrine, in addition to receiving a total of 30 mL/kg of normal saline solution and 20 mL/kg of lactated Ringer solution (Figure 1). After stabilization in the operating room, the patient was transferred to the intensive care unit, sedated, and intubated on pressor support. It was determined that, during a spinal operation 8 years prior, the patient had an episode of less-severe anaphylaxis. Although the cause of the reaction was unclear at that time, Floseal had been administered. He also had an episode of anaphylaxis after measles, mumps, and rubella, varicella, diphtheria, and polio vaccines were administered together, with the first two known to contain gelatin. Furthermore, he developed a facial rash minutes after eating beef and has been avoiding the food for years. Results of our patient’s physical examination was notable for an edematous face with no rash or angioedema of the lips, tongue, or extremities. Results of a postoperative workup revealed an elevated tryptase level of 72.4 ng/mL (reference range, 0.4-10.9 ng/mL), which was drawn approximately 1 hour after anaphylaxis. ImmunoCAP (Viracor-IBT Laboratories Inc., Lee’s Summit, Mo) testing showed an increased IgE level to bovine gelatin, at 1.61 kU/L (reference value, <0.35 kU/L) and an increased IgE level to bovine protein at 0.45 kU/L (reference value, <0.35 kU/L). The patient was advised to avoid all gelatincontaining medications, vaccines, and products. At his 6-month follow-up, the patient was retested, and his baseline tryptase level normalized to 2 ng/mL. Latex IgE and porcine IgE tests were negative, although bovine IgE value remained low positive (0.38 kU/L).
DISCUSSION Gelatin allergy has been well described in type 1 hypersensitivity reactions to vaccines, but only a few case reports have been published about anaphylaxis associated with hemostatic agents.4-6 Patients who are atopic, asthmatic, and allergic are more likely to develop hypersensitivity than individuals who are not allergic. Our patient’s atopy and past exposure to beef and gelatin most likely resulted in his underappreciated clinical allergy.4 Gelatin in Floseal is derived from bovine sources, and there is high cross reactivity between mammalian gelatin antigens; however, there is no cross reactivity with fish gelatin.8 Thus, both bovine and porcine antigelatin antibodies can contribute to the severity of the reaction. Our patient tested positive only for bovine gelatin and bovine protein through ImmunoCAP testing. Skin testing to Floseal was not performed because it has not been studied in detail, and its negative predictive value is unknown, with questionable penetration through the skin.4 Our patient received cefazolin in a subsequent procedure, with no reactions. Latex-induced anaphylaxis also is improbable because the operating room is a latex-free environment. Given our evaluation, we believe that the elevated tryptase level after intraoperative anaphylaxis was due to Floseal. The package insert for Floseal states not to use Floseal in patients with “known allergies to materials of bovine origin,” but no mention of explicit
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FIGURE 1. A graph of the intraoperative time course of events during spinal surgery in our 9-year-old patient. The black squares indicate the heart rate at a given point in time, and the gray shading represents the variation between the systolic and diastolic blood pressures during these same time points.
caution is made with regard to a gelatin allergy. Tolerance of ingested gelatin may not rule out gelatin allergy because digested gelatin may not be as allergenic as injected gelatin. All patients who are to receive gelatin-containing products, including Floseal, should be questioned thoroughly regarding a previous reaction to gelatin-containing foods or medications. A broad differential is essential when determining the cause of intraoperative anaphylaxis. When past reactions to gelatincontaining products are reported by patients, gelatin allergy should be considered and diagnostic testing recommended. If the patient is identified as having a gelatin allergy, then other gelatinbased topical hemostatic agents should be avoided, including Surgiflo (Surgiflo Hemostatic Matrix; Ethicon Inc, Sommerville, NJ), Spongostan (Absorbable Hemostatic Gelatin Sponge; Ethicon), and thrombin-soaked Gelfoam. Safe alternatives include fibrin sealants, which use human fibrinogen, and thrombin, such as Evicel (Evicel Fibrin Sealant; Ethicon) and Tissucol (Tissucol Duo; Baxter Healthcare Corp, Berlin, Germany). Cellulose-based products and synthetic adhesives, for example, Omnex (Omnex Surgical Sealant; Ethicon), also are safe options.9 Department of Pediatric Allergy and Immunology, Columbia University Medical Center, New York, NY No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication April 8, 2014; revised May 15, 2014; accepted for publication May 19, 2014. Available online July 03, 2014.
Corresponding author: Niti Agarwal, MD, Department of Pediatric Allergy and Immunology, Columbia University Medical Center, 622 West 168th St, PH 8 East 101, New York, NY 10032. E-mail: [email protected]. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.05.010 REFERENCES 1. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:477-480.el1-42. 2. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg 2003;97:1381-95. 3. Mullins RJ, James H, Platts-Mills TAE, Commins S. The relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose. J Allergy Clin Immunol 2012;129:1223-1232.e.1. 4. Spencer HT, Hsu JT, McDonald DR, Karlin LI. Intraoperative anaphylaxis to gelatin in topical hemostatic agents during anterior spinal fusion: a case report. Spine J 2012;12:e1-6. 5. Luhmann SJ, Sucato DJ, Bacharier L, Ellis A, Woerz C. Intraoperative anaphylaxis secondary to intraosseous gelatin administration. J Pediatr Orthop 2013;33:e58-60. 6. Khoriaty E, McClain C, Permaul P, Smith ER, Rachid R. Intraoperative anaphylaxis induced by the gelatin component of thrombin-soaked Gelfoam in a pediatric patient. Ann Allergy Asthma Immunol 2012;108:209-10. 7. Oz MC, Rondinone JF, Shargill NS. Floseal matrix: new generation topical hemostatic sealant. J Card Surg 2003;18:486-93. 8. Sakaguchi M, Hori H, Ebihara T, Irie S, Yanagida M, Inouye S. Reactivity of the immunoglobulin E in bovine gelatin-sensitive children to gelatins from various animals. Immunology 1999;96:286-90. 9. Emilia M, Santleri L, Francesca B, Bottero L, Stfanini P, Giuseppe F, et al. Topical hemostatic agents in surgical practice. Transfus Apher Sci 2011;45: 305-11.
This case highlights the importance of using a broad differential when determining the cause for intraoperative anaphylaxis and suggests that Floseal should only be given to patients with a negative history of allergies to gelatin and bovine protein.
TO THE EDITOR: Identifying the cause of intraoperative anaphylaxis is a difficult task for the allergist/immunologist given the large number of potential culprits. The incidence of intraoperative anaphylaxis is reported to occur between 1 in 4000 to 1 in 25,000 cases, with the majority being attributed to muscle relaxants.1 Gelatin in colloids has been implicated in approximately 0.34% of perioperative anaphylaxis cases.2 Gelatin is a protein derived from collagen and is used in numerous items, including meats, yogurts, jellies, juices, and vaccines.3 The most severe reports of allergic reactions to gelatin are with parenteral colloid usage or with vaccines. Nevertheless, severe anaphylaxis to gelatin in newer topical hemostatic agents, for example, thrombin soaked Gelfoam (Pfizer Inc., New York, NY), has also been reported.4-6 These agents have become widespread in reducing bleeding in surgery. Floseal (Floseal Hemostatic Matrix; Baxter Healthcare Corp, Hayward, Calif) combines gelatin granules with pooled human thrombin. The gelatin is extracted from bovine corium, and the collagen is gelatinized and stabilized with glutaraldehyde.7 We present a case of severe intraoperative anaphylaxis to the gelatin component in Floseal in a boy with unknown bovine allergy. Our patient was a 9-year-old boy with a medical history significant for glaucoma, conductive hearing loss, and hemivertebrae, with a clinical diagnosis suggestive of Marden Walker syndrome. He has mild persistent asthma and is atopic with multiple allergies. He developed hives and coughing immediately after eating salmon and tuna on separate occasions. He also developed nasal congestion with dust mite exposure, and latex exposure caused hives. He presented to the allergy/immunology service after intraoperative anaphylaxis during removal of segmental spinal instrumentation for worsening kyphosis. Anesthesia was induced with propofol, fentanyl, and rocuronium, and the patient was continued on rocuronium and remifentanil infusions. One hour later, he was given tobramycin and cefazolin, and surgery commenced. Sixty minutes into the procedure, Floseal was injected into the screw holes. Within minutes, the patient became tachycardic with an increase from baseline of 80 beats/min to 105 beats/ min, and hypotensive, with mean arterial pressure dropping from 75 mmHg to 45 mmHg. The patient was placed supine, given a 0.5 mg/kg (10 mcg) intravenous bolus of epinephrine 4 times, followed by intravenous atropine twice, subcutaneous terbutaline,
110
and inhaled albuterol via a metered-dose inhaler. Despite these interventions, the patient became pulseless and required chest compressions for 1 minute before regaining pulses. He then was started on epinephrine and vasopressin infusions. He received 2 mg/kg of methylprednisolone and 2 mg/min/kg of phenylephrine, in addition to receiving a total of 30 mL/kg of normal saline solution and 20 mL/kg of lactated Ringer solution (Figure 1). After stabilization in the operating room, the patient was transferred to the intensive care unit, sedated, and intubated on pressor support. It was determined that, during a spinal operation 8 years prior, the patient had an episode of less-severe anaphylaxis. Although the cause of the reaction was unclear at that time, Floseal had been administered. He also had an episode of anaphylaxis after measles, mumps, and rubella, varicella, diphtheria, and polio vaccines were administered together, with the first two known to contain gelatin. Furthermore, he developed a facial rash minutes after eating beef and has been avoiding the food for years. Results of our patient’s physical examination was notable for an edematous face with no rash or angioedema of the lips, tongue, or extremities. Results of a postoperative workup revealed an elevated tryptase level of 72.4 ng/mL (reference range, 0.4-10.9 ng/mL), which was drawn approximately 1 hour after anaphylaxis. ImmunoCAP (Viracor-IBT Laboratories Inc., Lee’s Summit, Mo) testing showed an increased IgE level to bovine gelatin, at 1.61 kU/L (reference value, <0.35 kU/L) and an increased IgE level to bovine protein at 0.45 kU/L (reference value, <0.35 kU/L). The patient was advised to avoid all gelatincontaining medications, vaccines, and products. At his 6-month follow-up, the patient was retested, and his baseline tryptase level normalized to 2 ng/mL. Latex IgE and porcine IgE tests were negative, although bovine IgE value remained low positive (0.38 kU/L).
DISCUSSION Gelatin allergy has been well described in type 1 hypersensitivity reactions to vaccines, but only a few case reports have been published about anaphylaxis associated with hemostatic agents.4-6 Patients who are atopic, asthmatic, and allergic are more likely to develop hypersensitivity than individuals who are not allergic. Our patient’s atopy and past exposure to beef and gelatin most likely resulted in his underappreciated clinical allergy.4 Gelatin in Floseal is derived from bovine sources, and there is high cross reactivity between mammalian gelatin antigens; however, there is no cross reactivity with fish gelatin.8 Thus, both bovine and porcine antigelatin antibodies can contribute to the severity of the reaction. Our patient tested positive only for bovine gelatin and bovine protein through ImmunoCAP testing. Skin testing to Floseal was not performed because it has not been studied in detail, and its negative predictive value is unknown, with questionable penetration through the skin.4 Our patient received cefazolin in a subsequent procedure, with no reactions. Latex-induced anaphylaxis also is improbable because the operating room is a latex-free environment. Given our evaluation, we believe that the elevated tryptase level after intraoperative anaphylaxis was due to Floseal. The package insert for Floseal states not to use Floseal in patients with “known allergies to materials of bovine origin,” but no mention of explicit
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J ALLERGY CLIN IMMUNOL PRACT VOLUME 3, NUMBER 1
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FIGURE 1. A graph of the intraoperative time course of events during spinal surgery in our 9-year-old patient. The black squares indicate the heart rate at a given point in time, and the gray shading represents the variation between the systolic and diastolic blood pressures during these same time points.
caution is made with regard to a gelatin allergy. Tolerance of ingested gelatin may not rule out gelatin allergy because digested gelatin may not be as allergenic as injected gelatin. All patients who are to receive gelatin-containing products, including Floseal, should be questioned thoroughly regarding a previous reaction to gelatin-containing foods or medications. A broad differential is essential when determining the cause of intraoperative anaphylaxis. When past reactions to gelatincontaining products are reported by patients, gelatin allergy should be considered and diagnostic testing recommended. If the patient is identified as having a gelatin allergy, then other gelatinbased topical hemostatic agents should be avoided, including Surgiflo (Surgiflo Hemostatic Matrix; Ethicon Inc, Sommerville, NJ), Spongostan (Absorbable Hemostatic Gelatin Sponge; Ethicon), and thrombin-soaked Gelfoam. Safe alternatives include fibrin sealants, which use human fibrinogen, and thrombin, such as Evicel (Evicel Fibrin Sealant; Ethicon) and Tissucol (Tissucol Duo; Baxter Healthcare Corp, Berlin, Germany). Cellulose-based products and synthetic adhesives, for example, Omnex (Omnex Surgical Sealant; Ethicon), also are safe options.9 Department of Pediatric Allergy and Immunology, Columbia University Medical Center, New York, NY No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication April 8, 2014; revised May 15, 2014; accepted for publication May 19, 2014. Available online July 03, 2014.
Corresponding author: Niti Agarwal, MD, Department of Pediatric Allergy and Immunology, Columbia University Medical Center, 622 West 168th St, PH 8 East 101, New York, NY 10032. E-mail: [email protected]. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.05.010 REFERENCES 1. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:477-480.el1-42. 2. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg 2003;97:1381-95. 3. Mullins RJ, James H, Platts-Mills TAE, Commins S. The relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose. J Allergy Clin Immunol 2012;129:1223-1232.e.1. 4. Spencer HT, Hsu JT, McDonald DR, Karlin LI. Intraoperative anaphylaxis to gelatin in topical hemostatic agents during anterior spinal fusion: a case report. Spine J 2012;12:e1-6. 5. Luhmann SJ, Sucato DJ, Bacharier L, Ellis A, Woerz C. Intraoperative anaphylaxis secondary to intraosseous gelatin administration. J Pediatr Orthop 2013;33:e58-60. 6. Khoriaty E, McClain C, Permaul P, Smith ER, Rachid R. Intraoperative anaphylaxis induced by the gelatin component of thrombin-soaked Gelfoam in a pediatric patient. Ann Allergy Asthma Immunol 2012;108:209-10. 7. Oz MC, Rondinone JF, Shargill NS. Floseal matrix: new generation topical hemostatic sealant. J Card Surg 2003;18:486-93. 8. Sakaguchi M, Hori H, Ebihara T, Irie S, Yanagida M, Inouye S. Reactivity of the immunoglobulin E in bovine gelatin-sensitive children to gelatins from various animals. Immunology 1999;96:286-90. 9. Emilia M, Santleri L, Francesca B, Bottero L, Stfanini P, Giuseppe F, et al. Topical hemostatic agents in surgical practice. Transfus Apher Sci 2011;45: 305-11.