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A153 Post-tonsillectomy hemorrhage associated with nutraceutical use #397 Brianna K. Crawley, MD; Aaron R. Morrison, M.D.; Garth T. Olson, MD; David Garcia, M.D.; Mark L. Beauchamp, M.D. Departments of Internal Medicine (Division of Hematology-Oncology) & Surgery (Division of Otolaryngology) University of New Mexico School of Medicine, Albuquerque, NM. ABSTRACT REPORT OF A CASE Objective: to report a case of serious post-operative bleeding, the first in the otolaryngologic literature, associated with the use of forskolin, and to review its activity. A 25-year-old man was referred to otolaryngology as he had experienced 6-9 episodes of non-streptococcal pharyngitis each year for the preceding four years. There was no evidence of sleep-disordered breathing or tonsillar asymmetry. His other medical problems included asthma and hypospadias for which he had undergone multiple surgeries, the most recent of which preceded his presentation by six months. He denied any history of unusual bleeding after his prior surgeries and no family history of bleeding was elicited by any of his care providers. The patient underwent outpatient tonsillectomy without complication. On the evening of his third postoperative day, the patient was awakened from sleep coughing up small amounts of bright red blood. The patient was brought to the emergency room where he was confirmed to have stable vital signs and the presence of bright red blood in the left tonsillar fossa. He denied non-compliance with diet and activity instructions, and denied postoperative usage of NSAIDs. He was taken to the operating room where electrocautery was utilized to control his hemorrhage. Upon induction of anesthesia and placement of the mouth gag, his bleeding appeared to increase in the left tonsillar fossa. After several areas of bleeding had been controlled on the left, brisk new bleeding was noted in the right tonsillar fossa, which was subsequently controlled. Following the procedure, the patient was extubated and awakened without incident, but it was noted upon transfer to his gurney that he was wearing a drug-delivery patch on his right thigh (Image 1). The patch was determined to be a Nexagen USA product distributed over the counter, called Jen Fe Next. This is a transdermal patch containing forskolin, chromium poly-nicotinate, epicathechin, black pepper, and guarana. The patch was removed and the patient was admitted for 24-hour observation and subsequently discharged home. On his second post-operative day four, the patient again began to bleed orally. He bled several times throughout the day before returning to the ED and shortly thereafter, was taken to the operating room. Initially blood emanated from the right superior and mid tonsillar fossa before diffuse bleeding was elicited from the left tonsillar fossa, as well. Hemostasis was achieved with cautery and the patient was awakened, recovered, and discharged home . Laboratory results obtained throughout the post-operative period demonstrated that liver function tests and blood chemistries were entirely within normal limits. The prothrombin and activated partial thromboplastin times were normal. The patient’s hematocrit remained stable at 40% and his platelet count rose from 289 to 333 x 103/μl. The patient returned for follow-up two days after his surgery and he had experienced no further bleeding. Study design: This is the report of a case and associated literature concerning the hematologic activity of forskolin. Methods: A 25-year-old otherwise healthy, non-coagulopathic male underwent tonsillectomy for chronic tonsillitis, suffering two atypical posttonsillectomy hemorrhages requiring operative control. Subsequent examination revealed that the patient had been wearing the transdermal Jen Fe Next patch on his right lower extremity. Investigation into the constituents of this energy-enhancing patch revealed the presence of black and white pepper, chromium, guarana, and forskolin. Results: Forskolin, a diterpine derived from the Indian plant, Coleus forskohlii, activates cell membrane adenylate cyclase which, in turn converts cAMP to ATP. Its role in the cAMP signaling cascade effects many changes in the body, from increasing cardiac contractility to influencing differentiation of mesenchymal cells. It also inhibits platelet activation, an action that may be potentiated by other platelet inhibitors and anticoagulation agents. Conclusions: Forskolin is marketed without regulation as a weight-loss agent and energy-enhancer. It should be discontinued prior to undergoing surgery, for at least two weeks. This report serves as reminder that all forms of “nutraceuticals”, herbal supplements, and over-the-counter “alternative” medications should be completely reviewed with a patient during preoperative evaluation. Courtesy PubChem Common name forskolin Molecular formula C22H34O7 Molecular weight 410.50 g/mol IUPAC name [(3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-ethenyl-6,10,10btrihydroxy-3,4a,7,7,10a-pentamethyl- 1-oxo-5,6,6a,8,9,10hexahydro-2H-benzo[f]chromen-5-yl] acetate Synonyms Colforsin, Coleonol, colforsina, colforsine, colforsinum, Boforsin, Colforsine [French], Colforsinum [Latin], Colforsina [Spanish] CONCLUSIONS INTRODUCTION Post-tonsillectomy hemorrhage is the most significant, potentially lifethreatening, complication of tonsillectomy. Investigators have sought predictors in order to anticipate which of the 500,000 patients who undergo tonsillectomy each year in the United States possess a risk for this serious complication. Post-operative hemorrhages are classified as primary, generally defined as occurring within 24 hours of the initial surgery, or secondary, usually occurring between postoperative days 5-10(2). Primary hemorrhages are principally attributed to surgical technique and tissue trauma during the procedure, whereas secondary hemorrhages are ascribed to other factors, including age and gender of the patient, season, intraoperative injection and topical application of vasoconstrictors. Medications with known antithrombotic properties (e.g., warfarin, heparin, low molecular weight heparin) are routinely discontinued prior to surgery in an effort to minimize bleeding risk. Here we describe a case of atypical secondary posttonsillectomy hemorrhages attributed to the use of transdermal forskolin, a nutraceutical product marketed for weight loss. This case highlights the necessity for surgeons, anesthesiologists and hematologists to inquire about the use of herbal or “alternative” substances that might affect the coagulant potential of the blood prior to invasive procedures. • This is the first report in the literature of a healthy patient requiring operative control on two occasions for uncomplicated tonsillectomy while using forskolin. The reported incidence of post-tonsillectomy hemorrhage varies from below 2 to 20%; 4.5% in Blakeley's meta-analysis(1). • Screening laboratory tests can be normal both in patients with bleeding disorders as well as in patients taking antithrombotic agents(4) and are poor predictors of post-tonsillectomy hemorrhage(5). • Forskolin causes vasodilatation and a transient decrease in systolic blood pressure while increasing heart rate and contractility. It's antithrombogenic effect is due to direct stimulation of adenylate cyclase which converts ATP to cAMP, inhibiting platelet activation in whole blood(7). Its activity is potentiated by other platelet inhibitors(8), and cyclooxygenase inhibitors which are often used for post-operative pain control. • Forskolin is marketed as a “safe” alternative to most other weight loss drugs because a 2005 randomized, doubleblind, placebo-controlled study funded by the manufacturer indicated that Jen Fe Next has a negligible effect on heart rate, blood pressure, and respiratory rate(6). A month’s supply is sold for $69.95. The product packaging does not incorporate any warning concerning increased risks of bleeding or the necessity of disclosing the usage of this patch to a physician prior to surgery . • Many herbal supplements and over-the-counter “alternative” medications have been associated with perioperative bleeding(9). • The American Society of Anesthesiologists recommends stopping all herbal medications two weeks prior to any operation(10). References 1 Blakley BW. Post-tonsillectomy bleeding: how much is too much? Otolaryngol Head Neck Surg. United States, 2009, 288-90. 2 Windfuhr JP, Chen YS. Post-tonsillectomy and -adenoidectomy hemorrhage in nonselected patients. Ann Otol Rhinol Laryngol. 2003; 112: 63-70. 3 Collison PJ, Mettler B. Factors associated with post-tonsillectomy hemorrhage. Ear Nose Throat J. 2000; 79: 640-2, 4, 6 passim. 4 Windfuhr JP, Chen YS, Remmert S. Unidentified coagulation disorders in post-tonsillectomy hemorrhage. Ear Nose Throat J. 2004; 83: 28, 30, 2 passim. 5 Zagolski O. [Post-tonsillectomy haemorrhage--do coagulation tests and coagulopathy history have predictive value?]. Acta Otorrinolaringol Esp. Spain: 2009 Elsevier Espana, S.L, 2010, 287-92. 6 Clinical Study Summary, Jen Fe Next Patch. NexagenUSA , LLC, 2006. 7 Christenson JT, Thulesius O, Nazzal MM. The effect of forskolin on blood flow, platelet metabolism, aggregation and ATP release. Vasa. 1995; 24: 56-61. 8 Srivastava KC. Evidence for the mechanism by which garlic inhibits platelet aggregation. Prostaglandins Leukot Med. 1986; 22: 313-21. 9 Javed F, Golagani A, Sharp H. Potential effects of herbal medicines and nutritional supplements on coagulation in ENT practice. J Laryngol Otol. 2008 Feb;122(2): 116-9. 10 Hodges PJ, Kam PC. The peri-operative implications of herbal medicines. Anaesthesia. England, 2002, 889-99.