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Perioperative anesthesia clinical considerations of alternative medicines Alan D. Kaye, MD, PhDa,b,*, Ian Kucera, MD, PharmDa,b, Raj Sabar, MDa a

Department of Anesthesiology, Texas Tech Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA b Department of Pharmacology, Texas Tech Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA

Alternative medical systems Alternative medicine is a form of medical treatment used as a substitute for conventional medicine. For example, alternative therapy can be used in the form of a special diet or herbal concoction to treat cancer instead of conventional therapeutic modalities (eg, surgery, radiation therapy, or chemotherapy). This form of medicine may be based on elaborate systems of theory and clinical practice. Examples of alternative medical systems used in Western cultures include homeopathic and naturopathic medicines. Eastern cultures have a long tradition of practice of alternative medicine, which includes traditional Chinese medicine and Ayurveda, a science of herbs unique to the Indian sub-continent for over 5000 years. Naturopathic medicine Naturopathic medicine is an alternative medical system in which practitioners work with ‘‘natural healing forces’’ within the body, with a goal of helping the body heal from disease and attain better health. The practice of Naturopathy may include massage, dietary modifications, exercise, acupuncture, minor surgery, and various other interventions. Homeopathic medicine is based on the theory of ‘‘like cures like’’ meaning that small, diluted quantities of medicinal substances are

The authors have no actual or potential conflict of interest in relation to this article or continuing medical education activity. * Corresponding author. Departments of Anesthesiology and Pharmacology, Texas Tech Health Sciences Center, 3601 4th Street, Lubbock, Texas 79430. E-mail address: [email protected] (A.D. Kaye). 0889-8537/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8537(03)00113-5

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given to cure symptoms, these substances, when given at higher concentrations, would actually reproduce those symptoms; whereas, Ayurvedic system of medicine, relies on diet, herbs, and emphasizes the use of body, mind, and spirit in disease prevention and treatment. Aromatherapy Aromatherapy involves the use of essential oils (extracts or essences) from flowers, herbs, and trees to promote health and well-being. The chiropractic system focuses on the relationship between bodily structures (primarily the spine) and function, and how that interaction affects the preservation and maintenance of health. Chiropractors use manipulation of the spine as an integral treatment tool. Massage therapy involves manipulation of muscle and connective tissue to enhance function, increase muscle relaxation, and promote general well being. [1] Herbal therapy or dietary supplements An area that has seen a large increase in usage in the United States is dietary supplements and herbal remedies. According to Dietary Supplement Health and Education Act (DSHEA) of 1994, dietary supplements are defined as ‘‘a product (other than tobacco) taken by mouth that contains a ‘‘dietary ingredient’’ intended to supplement the diet.’’ Dietary supplements typically include vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, and metabolites. Dietary supplements are marketed as extracts, concentrates, tablets, capsules, gelcaps, liquids, and powders. Under DSHEA, dietary supplements are considered foods, not drugs. The earliest recorded evidence of the use of plants by humans as therapeutic agents, dates back to the Neanderthal period. Ancient middle-eastern civilizations have a rich history of use of herbal therapy, also known as nutraceuticals. In the 16th century, herbal gardens were created and carefully nurtured to grow medicinal plants for medical schools [2]. In the United States, the history of herbal medicine use dates back to the early colonial days when health care was largely provided in the home. The 19th century witnessed the advancement of scientific methods of practice of conventional medicine and the demise of the practice of herbology [2]. During the 1960, nutraceutical popularity reemerged and in 1992, this increasing popularity of herbal products led to the establishment of the Office of Alternative Medicines by the National Institutes of Health in Bethesda, Maryland. The contribution of botanicals cannot be overlooked because 30% of all modern conventional therapeutic agents are derived from plants [3]. There are more than 20,000 nutraceuticals available in the United States health care market [4]. Many patients do not consider herbal compounds to be medications and do not convey use of these agents at the time of surgery [5]. According to one estimate, approximately 20% of the adult United States population take nutraceutical agents along with prescription drugs and this market

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has grown to a multi-billion dollar industry [6,7]. In 1997, at least 42% of adult Americans used at least some form of nonconventional therapies including herbal products [7]. A majority of patients with chronic ailments including diabetes mellitus, malignancy, arthritic conditions, and AIDS attempt to cure their respective disease states with self-prescribed alternative therapies such as herbal medicines [2]. The prevalence of herbal use is further encouraged by the relaxed policy of the Food and Drug Administration regarding these compounds. Because nutraceuticals are included in the ‘‘supplement’’ category, there is no existing protocol for standardization of these products. However, insurance plans and managed care organizations are initiating physician generated referral (ie, physician directed) with reimbursement for many of these compounds. [2] Over the past 2 decades, the United States health market has been flooded with over-the-counter ‘‘alternative medicines’’. Although many of these products are neither recommended nor prescribed by health care providers, an increasing number of people are taking these products on a daily basis. Anesthesiologists are also involved in the care of these patients. Because these drugs carry a potential to cause bleeding problems or to contribute to unexpected responses to anesthetic agents, the authors review here commonly used herbs from the perspective of the anesthesiologist. A recent survey of 163 health food retail stores in the United States revealed that top 10 selling herbs were, echinacea (Echinacea purpurea, Echinacea pallida, and Angustifolia), garlic, goldenseal (Hydrastis canadenis), ginseng (Asian Panax ginseng and American Panax quinquefolius), gingko (Gingko biloba), saw palmetto (Serenoa repens), aloe (Aloe species), ma huang (Ephedra sinica), Siberian ginseng (Eleutherococcus senticosus), and cranberry (Vaccinium macrocarpon) [8]. However current trends suggest that St. John’s wort (Hypericum perforatum), valerian (Valeriana officinalis), and feverfew (Tanacetum parthenium) are likely to earn a spot among the 10 most commonly used herbs [2]. In a recent survey of 752 patients scheduled for elective surgery conducted within the Department of Anesthesiology at Texas Tech University in Lubbock, 32% were

Box 1. Herbal remedies that decrease platelet aggregation Bilberry Bromelain Don quoi Feverfew Fish oil Flax seed oil Garlic Ginger Ginkgo biloba Grape seed extract

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Box 2. Herbs that inhibit clotting Chamomile Dandelion root Dong quoi Horse chestnut actively using at least one nutraceutical agent and 70% of these patients did not tell their anesthesiologist during routine preoperative assessment [5]. Many of these agents have the potential to decrease platelet aggregation (Box 1) and inhibit clotting (Box 2). Additionally, some herbs have central activity that may potentiate the CNS depressant effects of anesthesia (Box 3). The following paragraphs provide more specific information regarding some of the more commonly used herbal remedies.

Echinacea The Echinacea are members of the daisy family and grow widely throughout North America. There are nine species of echinacea, and the medicinal preparations are primarily derived from three of these—Echinacea pallida (pale purple coneflower), Echinacea purpurea (purple coneflower), and Echinacea angustifolia (narrow leaved coneflower). [9– 11]. The alkylamide and polysaccharide constituents of echinacea possess significant in vitro and in vivo immunostimulation properties because of enhanced phagocytosis and nonspecific T-cell stimulation [12]. The most common side effect of this herb is an unpleasant taste sensation [13]. Prolonged use of echinacea (> 2 months) can cause tachyphylaxis, albeit through an unknown mechanism [14]. Relevance to anesthesia includes a possibility of anaphylaxis even with a single dose of this herb [9]. Further, this herb carries the risk for hepatotoxicity, if used along with other anesthetic or nonanesthetic hepatotoxic agents (eg, anabolic steroids, amiodarone, methotrexate, and ketoconazole) [15]. Flavinoids from E. purpurea can inhibit the hepatic cytochrome P-450 3A4 and sulfotransferase [16,17]. The use of echinacea is contraindicated in systemic and autoimmune disorders. Box 3. Herbs that potentiate central nervous system depression of anesthesia Hops Kava kava Passion flower

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Anesthesia implications The immunostimulatory effects of echinacea may antagonize the immunosuppressive actions of corticosteroids and cyclosporine. Because the herb can cause inhibition of the hepatic microsomal enzymes, its concomitant use with drugs, such as phenytoin, rifampin, phenobarbital, which are metabolized by the hepatic microsomal enzymes, should be avoided because echinacea can precipitate toxicity of these drugs.

Garlic (Allium sativum) Garlic has been used for therapeutic purposes for centuries. The most active ingredient of garlic is allicin, which contains sulfur and when combined with breakdown products, gives garlic its characteristic smell. Crushing the garlic clove activates the enzyme allinase that converts alliin to allicin. [9] Recent studies have targeted its vasodilatory and hypocholesterolemic activities [20 – 24]. Garlic derivatives are frequently used for antiplatelet, antioxidant, and fibrinolytic effects [18 – 20]. Evidence supporting the use of garlic for hypertension is less substantial, with a few clinical trials showing modest decreases in systolic and diastolic blood pressure with garlic supplements [9]. Decreased platelet aggregation has been reported with the use of garlic in conjunction with its use for hyperlipidemia [21 – 24]. There is a reported case of spontaneous spinal or epidural hematoma in a 87-year-old man, with associated platelet dysfunction related to excessive garlic ingestion. [25] In this regard, garlic-induced decreased platelet aggregation has been described in the literature [26]. Anesthesia implications The clinical anesthesiologist should be aware that garlic may augment the effects of warfarin, heparin, nonsteriodal anti-inflammatory drugs (NSAIDs), and aspirin, and may result in an abnormal bleeding time, which can lead to an increased risk for intra-operative or postoperative bleeding [26].

Ginger (Zingiber offcinale) Ginger has been described as an effective therapy for nausea, vomiting, motion sickness, and vertigo. Anti-vertigo effects of ginger have been observed in a study with no study subject experiencing nausea, when compared with placebo with caloric stimulation of the vestibular system [27]. Ginger has been shown to exert a superior anti-motion sickness response as compared with dimenhydrinate. These studies concluded that ginger exerts a gastric mechanism unlike dimenhydrinate, which has a central nervous system mechanism [28]. Ginger has been found to be effective in controlling symptoms in hyperemesis gravidarum [29]. However,

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results from two recent clinical trials, revealed that ginger was ineffective in reducing the incidence of nausea and vomiting in patients undergoing gynecologic laparoscopic surgery [30,31]. Ginger is a potent inhibitor of thromboxane synthetase enzyme, which can prolong bleeding time [32]. Anesthesia implications Use of ginger may alter bleeding time; therefore, its use should be avoided in patients on anticoagulants like warfarin and heparin or drugs such as NSAIDs and aspirin.

Gingko biloba The use of gingko biloba is on the rise in the United States. In the year 1997, it was one of the best selling herbs on the United States market, with sales exceeding 240 million dollars [33]. The most important components of gingko are flavinoids, terpenoids, and organic acids. Metabolic pathways vary with different compounds. [9] Four preparations of gingko have been used in clinical trials so far, namely tebonin, tanakan, rokan, and kaveri. The extract from the first three forms have been named EGB761. This herb is used as an antioxidant and a circulatory stimulant. Gingko is also used for the treatment of intermittent claudication, tinnitus, vertigo, memory enhancement, and sexual dysfunction [7]. A large placebo-controlled, doubleblind, randomized trial of an extract of gingko (EGB761) was conducted to study its effectiveness in patients with dementia and it was concluded that gingko extract was capable of stabilizing and modestly improving patient’s cognitive performance and social functioning [34]. Gingko biloba has been shown to potentially improve the symptoms of intermittent claudication [35,36]. Study subjects using gingko biloba have experienced reduction of pain in their lower extremities with an improved claudication distance. The herb has a potential to inhibit plateletactivating-factor, modulate nitric oxide, and possesses a significant anti-inflammatory effect [35 – 40]. Gingko biloba is considered to be safe with few side effects limited to mild gastrointestinal upset and headache. However, a few disturbing case reports have been mentioned in the literature. Gingko biloba-induced spontaneous hyphema (bleeding from iris the anterior chamber of the eye), subarachnoid hemorrhage, and spontaneous bilateral subdural hematomas have been described [41 – 44]. Of additional concern is the gingko toxin in both the gingko leaf and seed, which is considered to be potentially neurotoxic [45]. Anesthesia implication Concomitant use of gingko biloba with aspirin, or any NSAIDs and anticoagulants such as warfarin and heparin, is not recommended because gingko may increase the potential for bleeding in these patients. It would also be

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appropriate to avoid its concomitant use with anticonvulsant drugs (eg, carbamazapine, phenytoin, and phenobarbital) because gingko may decrease the effectiveness of these agents [15]. In addition, it has been recommended that gingko should be avoided in patients taking tricyclic antidepressant agents, because it might potentiate the seizure threshold-lowering action of these drugs [15].

St. John’s wort (Hypericum perforatum) St. John’s wort is approved in Germany for the treatment of anxiety, depression, and sleep related disorders. In 1993, more than 2.7 million prescriptions for this herb were written in Germany, and in 1994, over 66 million daily doses were taken, making this herb the 7th most popular medicine in Germany [46]. St. John’s wort is also commonly known as hardhay, amber, goatweed, klamath weed, and tipton weed. Active compounds include, naphthadihydrodianthrones, particularly hypericin and pseudohypericin; flavinoids including quercitin, rutin, and hyperin [7]. The mechanism of action of this herb is controversial. Hypericum extract inhibits isoforms of monoamine oxidase in vitro, but this has not been observed in in vivo [47]. In-vitro studies have shown inhibition of GABA receptors by hypericum, which suggest that GABA inhibition might be the mode of its antidepressant action [48,49]. However, additional in-vivo studies are required to confirm hypericum’s mechanism of action and clinical effectiveness [50,51]. Side effects described include dry mouth, dizziness, fatigue, constipation, and nausea. The most prominent adverse effect, attributed to its hypericin component, is photosensitivity [52]. There have been no reports of any adverse effects on cardiac conduction although if used concomitantly with a selective serotonin reuptake inhibitor (SSRI) it can cause serotonergic syndrome, which is characterized by tremors, hypertonicity, myoclonus, autonomi dysfunction, hallucinosis, hyperthermia, and even death [9,53]. Anesthesia implications The clinical anesthesiologist should preoperatively review additional medications or herbs that the patient may be taking. For example, concomitant use of St. John’s wort is not recommended with photosensitization drugs (eg, piroxicam, tetracycline, and so forth), monoamine oxidase inhibitors, b-sympathomimetic amines (eg, ma huang, pseudoephedrine hydrochloride), or SSRIs. There is no data regarding the multitude of potential anesthetic-St. John’s Wort interactions.

Panax ginseng There is a variation in the components of this herb. Depending on its geographic origin, ginseng can be classified as American ginseng (Panax quinquefolius grows in the United States), Chinese ginseng, or Korean ginseng.

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However Siberian ginseng, also known as Eleutherococcus senticosus, belongs to a different genus [7]. Active compound in panax ginseng is Ginsenoside. In the ancient times, the herb was used as an aphrodisiac, anti-aging, and energyenhancing tonic. It is also used by modern day athletes, to boost their ‘‘energy levels’’ and is frequently used as an antioxidant [54 –56]. The herb has been labeled as adaptogenic, augmenting adrenal steroidogenesis by way of a central mechanism [57]. Ginseng’s immunomodulatory effects have also been described. Studies have shown that ginseng possess some hypoglycemic properties [58,59]. These hypoglycemic effects have been attributed to ginsenoside Rb2 and panaxans I, J, K, and L components of the herb [60 – 64]. Adverse effects associated with the use of ginseng include hypertension, insomnia, headache, vomiting, and epistaxis [65,66]. Stevens-Johnson syndrome, abnormal vaginal bleeding, mastalgia, and diffuse breast nodularity have been described with the use of this herb [67 –70]. Ginseng should be avoided in pregnancy, in children, lactating women, and in patients with cardiovascular disease [7,15]. One known fatality associated with ginseng laced with ma huang has been described [71]. Ginseng has been reported to have significantly decreased international normalized ratios (INR) suggesting clinically relevant coagulation modulation albeit in an isolated case [72]. Finally, a recent study suggested that Ginseng may exert some antiplatelet activity [73]. Anesthesia implications Ginseng should be avoided with patients on anticoagulant medications such as warfarin, heparin, NSAIDs and aspirin. Because ginseng can cause hypertension, the clinical anesthesiologist should be focused on clinical consequences of longterm use of this agent. Long-standing hypertension can cause end organ damage, volume depletion, and autonomic instability. Further, because many anesthetic agents can cause generalized vasodilatory effects, hemodynamic variability can be seen including profound intraoperative hypotension. Concomitant use of ginseng with monoamine oxidase inhibitors (eg, phenelzine sulfate), should be avoided because manic episodes have been reported with routine use of ginseng [74,75]. Because of its potential to exert hypoglycemic effects, ginseng should be used cautiously in diabetic patients on insulin or oral hypoglycemic medications. It would therefore follow that the anesthesiologist would need to have appropriate evaluation of blood glucose levels perioperatively for applicable patients.

Kava kava (Piper methysticum) Kava-kava is commonly used for treatment of anxiety disorders. For centuries, this herb has been used by Pacific islanders, as a part of their ceremonial rituals. This herb grows in Polynesia, Melanesia, and Micronesia [76]. It has been used in Germany to treat gonorrhea and the Hawaiians used it for treating certain skin diseases [77]. Kava kava can cause visual alterations, characteristic ichthyosiform

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dermapathy, and hallucinations [2,78]. Antinociceptive effects produced by kava kava may be similar to local anesthetic responses and seems to be mediated through a non-opiate dependent pathway [79,80]. Noradrenaline inhibition may contribute to the psychotropic effects of kava kava [81]. Anesthesia implications Ethanol can increase the hypnotic effects of kava kava [82]. It should be avoided in patients with endogenous depression, and can potentiate the effect of barbiturates and benzodiazepines and can cause excessive sedation [83,84].

Feverfew (Tanacetum parthenium) The word feverfew is derived from the latin word, febrifugia, meaning ‘‘fever reducer.’’ This herb is commonly used for migraine headaches although the literature is contradictory regarding its effectiveness [85,86]. There is a considerable lack of standardization in the quantity of the active ingredient, parthenolide in most of the feverfew preparations, which increases the difficulty to conduct clinical trials on this herb [87]. Feverfew inhibits serotonin release from aggregating platelets possibly related to inhibition of the release of arachidonic acid by way of a phosholipase-linked mechanism [87 – 89]. The herb has been found to reduce 86% to 88% of prostaglandin production without inhibition of the cyclooxygenase enzyme [90]. Feverfew can cause apthous ulcers, gastrointestinal irritability, and rebound headache with an abrupt stoppage of the herb. Feverfew is not recommended for children, pregnant patients, or nursing mothers [91]. Post feverfew syndrome is characterized by nervousness, headaches, insomnia, arthralgias, joint stiffness, and fatigue [92]. Anesthesia implications Because feverfew can inhibit platelet activity, it is reasonable to avoid the concomitant use of this herb in patients taking medications such as, heparin, warfarin, NSAIDs, aspirin, and vitamin E [93,94]. Tannin-containing herbs like feverfew, can interact with iron preparations, thereby reducing the bioavailability of such preparations [15].

Ma huang (Ephedra sinica) Ma Huang is traditionally used for the treatment of common cold, flu, various allergic symptoms, bronchitis, low blood pressure, fever, asthma, arthritis and fluid retention. The herb was listed in Shen Neng’s classic text on medicinals as 1 of the 365 herbs, as early as the 1st century AD [95]. Ma huang acts as a sympathomimetic agent, and possesses positive ionotropic and chronotropic

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responses. The herb also has bacteriostatic and antitussive actions. It is a cardiovascular stimulant (acts as an a- or b-adrenergic agonistic agent) and is a potent bronchodilator [96]. Because it increases metabolic rate, ma huang features prominently in various over-the-counter weight loss preparations. Adverse effects of this herb include hypertension, tachycardia, cardiomyopathy, cardiac dysarrhythmias, myocardial infarction, CVA, seizures, psychosis, or death. Numerous fatalities have been associated with the use of this herb and these deaths have been attributed to a lack of standardization in its formulation [97,98]. The Bureau of Food and Drug Safety of the Texas Department of Health has reported eight deaths, during a 21-month period between 1993 and 1995, associated with ephedrine-containing compounds. Seven of these deaths were secondary to myocardial infarction or cerebrovascular accident [7]. Anesthesia implications The use of ephedrine containing over the counter products is highly relevant to the perioperative period. The possibility of hypertension causing myocardial ischemia or stroke needs to be considered. Ephedra can potentially interact with volatile general anesthetic agents (eg, halothane, isoflurane, and desflurane) and cardiac glycosides (eg, digitalis) to cause cardiac dysarrhythmias. Patients taking ephedra, for prolonged periods of time can deplete peripheral catecholamine stores. Thus, under general anesthesia, these patients can potentially have profound intraoperative hypotension, which can be controlled with a direct vasoconstrictor (eg, phenylephrine) instead of ephedrine. Use of ephedra with phenelzine or other monoamine oxidase inhibitors may result in insomnia, headache, and tremulousness. Concomitant use with oxytocin, has been shown to cause hypertension [99].

Summary The presence of nutraceutical agents in the United States health care system dictates the need for a general understanding of these agents by all physicians and health care providers. Increasing trend toward reimbursement of herbal medicines by the insurance companies and managed care organizations have further encouraged their use. Because herbs are listed under the ‘‘supplement’’ category by the Food and Drug Administration, the Dietary Supplement and Health Education Act establishes no protocol for standardization of the products labeled as ‘‘supplements’’ thereby increasing the risk for adverse effects associated with the use of these products. Moreover, there is little motivation for the manufacturers to conduct randomized, placebo-controlled, double-blinded safety and efficacy trials on these drugs. Reports indicate that within the last 2 decades, more than 100 herbogenic deaths have occurred [100]. Many serious complications have been reported, including renal failure and need for renal or hepatic transplantation after taking nutraceuticals [101 – 107].

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The anesthesiologists should have a detailed knowledge and understanding of the potential risks and purported benefits of herbal medicines and should thoroughly inquire about patient’s use of herbal products [108 –111]. In addition, the education of each patient regarding the serious, potential drug-herb interactions should be a routine component of preoperative assessment. The American Society of Anesthesiologists (ASA), suggests that all herbal medications should be discontinued 2 to 3 weeks before an elective surgical procedure. If the patient is not sure of the contents of the herbal medicine, he or she should be urged to bring the container so that the anesthesiologist can review the contents of the herb or preparation. Although this idea holds some promise in the elective-care settings, anesthetic care in emergency settings should be based on a thorough drug-intake history from the patient or a relative, if possible. Unfortunately, the anesthesia literature has not addressed this new group of health supplements, despite many of these drugs having the potential to cause serious health problems and drug-herb interactions. There is a need to conduct additional scientific clinical trials to study the anesthetic responses to commonly used nutraceutical agents.

Acknowledgments The authors thank Mrs. Wanda Rodriguez for her expert secretarial skills in the preparation of this manuscript.

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