Anesthetic Implications of Complementary and Alternative Therapies

Key Points

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Herbal medication use has increased dramatically in the overall population and particularly in preoperative patients.
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Patients might not volunteer information unless they are queried specifically about herbal medication use.
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Although many commonly used herbs have side effects that affect drug metabolism, bleeding, and neuronal function, they are not subject to regulations on purity, safety, and efficacy.
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Knowledge of specific interactions and metabolism of herbs can provide practical guidelines to facilitate perioperative management.
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Other complementary therapies, including acupuncture and music therapy, have become increasingly popular and have shown positive results for certain pain conditions, albeit high-quality data are still lacking.
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Dietary supplements may influence gut microbiota, a consortium of diverse microorganisms residing in the gastrointestinal tract, which represents a new research frontier in perioperative medicine.

Acknowledgment

The editors and publisher would like to thank Drs. Chong-Zhi Wang, Chun-Su Yuan, and Jonathan Moss for contributing a chapter on this topic in the prior edition of this work. It has served as the foundation for the current chapter.

Complementary and alternative medicine (CAM) has implications for physicians in general, but has particular importance for the perioperative period because of specific complications associated with certain therapies. Complementary medicine is defined as the addition of nonconventional therapies to accepted treatments; alternative medicine describes the use of nonconventional therapies in lieu of accepted treatments. They have become an important part of contemporary health care. The more popular term of “integrative health or integrative medicine” is used when complementary approaches are incorporated into mainstream health care.

According to a 2012 U.S. National Health Interview Survey (NHIS), 33.2% of adults and 11.6% of children (4-17 years of age) have used CAM. Visits to CAM practitioners exceed those to American primary care physicians, and CAM is even more widely used in Europe, where herbal medicines are prescribed more frequently than conventional drugs are. Furthermore, patients undergoing surgery appear to use CAM more than the general population does. Aside from the widespread use of CAM, perioperative physicians have a special interest in CAM therapies for several reasons. First, several commonly used herbal medications exhibit direct effects on the cardiovascular and coagulation systems. Second, some CAMs can interfere with conventional medications that are commonly given in the postoperative period. Finally, the therapeutic potential of CAM in the perioperative period is increasingly being described in the literature for reducing postoperative nausea, vomiting, and pain.

Despite the public enthusiasm for CAM, scientific knowledge in this area is still incomplete and often confusing for practitioners and patients. One recent study confirmed poor knowledge of this subject among physicians. Recommendations for clinicians are often based on small clinical trials, case reports, animal studies, predictions derived from known pharmacology, and expert opinion. Research is essential because CAM therapies are often widely adopted by the public before adequate data are available to support their safety and efficacy. In 1991, Congress established the Office of Alternative Medicine, which is now known as the National Center for Complementary and Integrative Health. It operates within the National Institutes of Health.

Based on the 2012 NHIS study, the most commonly used CAMs were natural products, deep breathing exercises, meditation, chiropractic or osteopathic manipulation, massage, and yoga. Interestingly, a 2017 NHIS survey noted increases in the use of yoga and meditation by both adults and children ( https://nccih.nih.gov/research/statistics/NHIS , Accessed 11/13/2018/tg). CAM practices can be classified into three general categories ( Box 33.1 ). This chapter is not intended as a comprehensive review of CAM. Specific therapies relevant to anesthesia are discussed, with a focus primarily on herbal medicines. Nonherbal dietary supplements, acupuncture, and music are also considered because they are relevant to perioperative care.

BOX 33.1

Three Major Categories of Complementary and Alternative Medicine

Modified from the National Center for Complementary and Integrative Health. https://nccih.nih.gov/health/integrative-health. Accessed April 11, 2018.

1.
Natural products: this group includes a variety of products, such as herbs (also known as botanicals),vitamins and minerals, and probiotics. They are widely marketed, readily available to consumers, and often sold as dietary supplements.
2.
Mind-body practices: yoga, chiropractic and osteopathic manipulation, meditation, and massage therapy are among the most popular mind and body practices used by adults. Other mind and body practices include acupuncture, relaxation techniques (such as breathing exercises, guided imagery, and progressive muscle relaxation), tai chi, qi gong, and hypnotherapy.
3.
Others: traditional healers, Ayurvedic medicine, traditional Chinese medicine, homeopathy, naturopathy, and functional medicine.

Herbal Medicines

Preoperative use of herbal medicines has been associated with adverse perioperative events. Surveys estimate that 22% to 32% of patients undergoing surgery use herbal medications. In a recent retrospective review, 23% of surgery patients indicated the use of natural products, and older patients preferred dietary supplements.

Herbal medicines can affect the perioperative period through several classic mechanisms: direct effects (i.e., intrinsic pharmacologic effects), pharmacodynamic interactions (i.e., alteration of the action of conventional drugs at effector sites), and pharmacokinetic interactions (e.g., alteration of the absorption, distribution, metabolism, and elimination of conventional drugs). Because approximately 50% of herbal medicine users take multiple herbs concomitantly and 25% of herbal medicine users take prescription drugs, adverse effects are difficult to predict and attribute.

Herbal medicines are associated with unique problems not usually found with conventional drugs. Many of the issues complicating the understanding of herbal medications derive from the fact that they are classified as dietary supplements under the Dietary Supplement Health and Education Act of 1994. As such, the introduction of herbal medications does not require animal studies, clinical trials, or postmarketing surveillance. Under current law, the burden is shifted to the U.S. Food and Drug Administration (FDA) to prove products unsafe before they can be withdrawn from the market, such as the withdrawal of intranasal Zicam (cold medicine) after more than 130 reports of persistent anosmia. Commercial herbal medicine preparations can have unpredictable pharmacologic effects resulting from inaccurate labeling, misidentified plants, adulterants, variations in natural potency, and unstandardized processing methods.

Two of the major problems confronting herbal medicine research involve quality control and added adulterants. In a recent clinical trial to treat human H1N1 influenza, an herbal formulation containing 12 different Chinese herbal medicines including licorice (genus Glycyrrhiza ) was used. Some of the other botanicals in the formula were not accurately identified. There are three Glycyrrhiza species on the market that may show a twofold difference when the three species are compared.

Labeled active ingredients can vary tenfold in different commercial preparations. In June 2007, the FDA issued regulations for current good manufacturing practices (GMPs) for dietary supplements. This rule requires that proper controls be in place so that dietary supplements are processed in a consistent manner and meet quality standards. Especially emphasized are the identity, purity, strength, and composition of the products. Dietary products adhering to GMPs undoubtedly reduce the potential risk in the use of herbal medicines. Because this rule is somewhat similar to that for prescription drug GMPs, many supplement manufacturers believe that it is not practical for botanicals.

Beyond quality control is the inclusion of biologically active pharmacologic adulterants in herbal medications and supplements. There are clinical consequences when quality control is lacking or herbal preparations are adulterated, as found in a weight-loss remedy study that revealed one manufacturer’s incorrect substitution of an herb for another when the carcinogen aristolochic acid led to an outbreak of nephropathy and urothelial carcinoma. In another event, more than 14 million capsules of asexual enhancement supplement were recalled because the compound on the label did not actually exist and the supplement did contain an analogue of sildenafil, which has not been tested in humans. In light of these events, in August 2016, the FDA proposed a new guidance to evaluate the safety of supplements based on their history of use, formulation, proposed daily dose, and recommended duration of use. Although the guidance represents only a fraction of what is necessary for a new drug application, it requires some testing for tolerability in animals, but not in humans, when products are marketed for consumption at doses substantively greater than those historically ingested. Any ingredient formulated or prepared in a novel manner is considered a new ingredient.

In this section, we discuss the preoperative assessment and management of patients who use herbal medicines and examine 11 herbal medicines that have the greatest effect on perioperative patient care: Echinacea , ephedra, garlic, ginger, Ginkgo biloba , ginseng, green tea, kava, saw palmetto, St. John’s wort, and valerian ( Table 33.1 ).

TABLE 33.1

Clinically Important Effects, Perioperative Concerns, and Recommendations for Perioperative Discontinuation of 11 Commonly Used Herbal Medicines

Herbs (Common Names)	Pharmacologic Effects	Perioperative Concerns	Discontinue Before Surgery
Echinacea (purple coneflower root)	Activation of cell-mediated immunity	Allergic reactions	No data
		Decreases effectiveness of immunosuppressants
		Potential for immunosuppression with long-term use
Ephedra (ma huang)	Increases heart rate and blood pressure through direct and indirect sympathomimetic effects	Risk of myocardial ischemia and stroke from tachycardia and hypertension	24 h
		Ventricular arrhythmias with halothane
		Long-term use depletes endogenous catecholamines and may cause intraoperative hemodynamic instability
		Life-threatening interaction with MAO inhibitors
Garlic (ajo)	Inhibits platelet aggregation (may be irreversible)	May increase risk of bleeding, especially when combined with other medications that inhibit platelet aggregation	7 days
	Increases fibrinolysis
	Equivocal antihypertensive activity
Ginger	Antiemetic Antiplatelet aggregation	May increase risk of bleeding	No data
Ginkgo (duck-foot tree, maidenhair tree, silver apricot)	Inhibits platelet-activating factor	May increase risk of bleeding, especially when combined with other medications that inhibit platelet aggregation	36 h
Ginseng (American ginseng, Asian ginseng, Chinese ginseng, Korean ginseng)	Lowers blood glucose	Hypoglycemia	7 days
	Inhibits platelet aggregation (may be irreversible)	May increase risk of bleeding
	Inhibits platelet aggregation (may be irreversible)	May decrease anticoagulant effect of warfarin
	Increased PT/PTT in animals	May decrease anticoagulant effect of warfarin
Green tea	Inhibits platelet aggregation Inhibits thromboxane A2 formation	May increase risk of bleeding May decrease anticoagulant effect of warfarin	7 days
Kava (awa, intoxicating pepper, kawa)	Sedation	May increase sedative effect of anesthetics	24 h
Kava (awa, intoxicating pepper, kawa)	Anxiolysis	Increase in anesthetic requirements with long-term use unstudied	24 h
Saw palmetto (dwarf palm, Sabal )	Inhibits 5α-reductase	May increase risk of bleeding	No data
Saw palmetto (dwarf palm, Sabal )	Inhibits cyclooxygenase	May increase risk of bleeding	No data
St. John’s wort (amber, goat weed, hardhay, hypericum, Klamath weed)	Inhibits neurotransmitter reuptake	Induction of cytochrome P450 enzymes; affects cyclosporine, warfarin, steroids, and protease inhibitors; may affect benzodiazepines, calcium channel blockers, and many other drugs	5 days
	MAO inhibition unlikely
		Decreased serum digoxin levels
		Delayed emergence
Valerian (all heal, garden heliotrope, vandal root)	Sedation	May increase sedative effect of anesthetics	No data
		Benzodiazepine-like acute withdrawal
		May increase anesthetic requirements with long-term use

MAO, Monoamine oxidase; PT, prothrombin time; PTT, partial thromboplastin time.

Preoperative Assessment and Management

Preoperative assessment should address the use of herbal medicines (see Table 33.1 ). One study found that 90% of anesthesia providers do not routinely ask about herbal medicine use. Moreover, more than 70% of patients are not forthcoming about their herbal medicine use during routine preoperative assessment. When a positive history of herbal medicine use is elicited, one in five patients is unable to properly identify the preparation being taken. Asking patients to bring their herbal medicines and other dietary supplements with them at the time of the preoperative evaluation would be helpful. A positive history of herbal medicine use should alert one to the presence of undiagnosed disorders causing symptoms leading to self-medication. Patients who use herbal medicines may be more likely to avoid conventional diagnosis and therapy.

In general, herbal medicines should be discontinued preoperatively. Patients who require nonelective surgery are not evaluated until the day of surgery or are noncompliant with instructions to discontinue herbal medications preoperatively. In this situation, anesthesia can usually proceed safely at the discretion of the anesthesia provider, who should be familiar with commonly used herbal medicines. For example, recent use of herbal medicines that inhibit platelet function (e.g., garlic, ginseng, G. biloba ) may warrant specific strategies for procedures with substantial intraoperative blood loss (e.g., platelet transfusion) and those that alter the risk-benefit ratio of using certain anesthetic techniques (e.g., neuraxial blockade).

Preoperative discontinuation of all herbal medicines might not eliminate complications related to their use. Withdrawal of some of the herbal medicines can increase morbidity and mortality after surgery similar to regular medications. The danger of abstinence after long-term use may be similar with herbal medicines such as valerian, which can produce acute withdrawal after long-term use.

Although the American Society of Anesthesiologists has no official standard or guideline for the preoperative use of herbal medications, public and professional educational information released by this organization suggests that herbals be discontinued at least 2 weeks before surgery. Our review of the literature favors a more targeted approach. When pharmacokinetic data for the active constituents in an herbal medication are available, the timeframe for preoperative discontinuation can be tailored. Some herbal medications are eliminated quickly and may be discontinued near the time of surgery. For other herbal medicines, 2 weeks is recommended.

Evidence-based estimates of herbal safety in the perioperative period are limited. One study of 601 patients who used traditional Chinese herbal medications suggested an infrequent rate of potential serious complications. Clinicians should be familiar with commonly used herbal medications to recognize and treat any complications that might arise. Table 33.1 summarizes the clinically important effects, perioperative concerns, and recommendations for preoperative discontinuation of the 11 herbal medications that account for 30% of the dietary supplements sold in the United States. The type of surgery and potential perioperative course should be considered in these clinical recommendations.

Echinacea

Three species of Echinacea , a member of the daisy family, are used for the prophylaxis and treatment of viral (decreasing the incidence and duration of the common cold), bacterial, and fungal infections, particularly those of upper respiratory origin, although its efficacy in fungal infections is doubtful. The biological activity of Echinacea could be immunostimulatory, immunosuppressive, or antiinflammatory. Although studies have not specifically addressed interactions between Echinacea and immunosuppressive drugs, experts generally warn against the concomitant use of Echinacea and these drugs because of the probability of diminished effectiveness. In contrast to its immunostimulatory effects with short-term use, long-term use of more than 8 weeks is accompanied by the potential for immunosuppression and a theoretically increased risk for postsurgical poor wound healing and opportunistic infections. A recent phytochemical study identified a potential immunosuppressant compound from Echinacea —cynarine.

Information about Echinacea’s pharmacokinetics is still limited. Echinacea significantly reduced plasma concentrations of S-warfarin, but did not significantly affect warfarin pharmacodynamics and platelet aggregation in healthy subjects. However, this herb should be discontinued as far in advance of surgery as possible when compromises in hepatic function or blood flow are anticipated. In the absence of definitive information, patients with preexisting liver dysfunction should be cautious in using Echinacea .

Ephedra

Ephedra, known as ma huang in Chinese medicine, is a shrub native to central Asia. It is used to promote weight loss, increase energy, and treat respiratory conditions such as asthma and bronchitis. Ephedra contains alkaloids, including ephedrine, pseudoephedrine, norephedrine, methylephedrine, and norpseudoephedrine. Commercial preparations can be standardized to a fixed ephedrine content. Publicity about adverse reactions to this herb prompted the FDA to bar its sale in 2004, but ephedra is still widely available via the Internet.

Ephedra causes dose-dependent increases in arterial blood pressure and heart rate. Ephedrine, the predominant active compound, is a noncatecholamine sympathomimetic that exhibits α ₁ , β ₁ , and β ₂ activity indirectly by releasing endogenous norepinephrine (noradrenaline). These sympathomimetic effects have been associated with more than 1070 reported adverse events, including fatal cardiac and central nervous system complications. Vasoconstriction and, in some cases, vasospasm of coronary and cerebral arteries can cause myocardial infarction and thrombotic stroke. Ephedra can also affect cardiovascular function by causing hypersensitivity myocarditis, characterized by cardiomyopathy with myocardial lymphocyte and eosinophil infiltration. Long-term use results in tachyphylaxis from depletion of endogenous catecholamine stores and can contribute to perioperative hemodynamic instability. In these situations, direct-acting sympathomimetics may be preferred as first-line therapy for intraoperative hypotension and bradycardia. Concomitant use of ephedra and monoamine oxidase inhibitors can result in life-threatening hyperpyrexia, hypertension, and coma. Finally, continuous ephedra is a rare cause of radiolucent kidney stones. Recently, there was a case report describing acute angle-closure glaucoma caused by ephedra.

The pharmacokinetics of ephedrine have been studied in humans. Ephedrine has an elimination half-life of 5.2 hours, with 70% to 80% of the compound excreted unchanged in urine. Based on the pharmacokinetic data and the known cardiovascular risks associated with ephedra, including myocardial infarction, stroke, and cardiovascular collapse from catecholamine depletion, this herb should be discontinued at least 24 hours before surgery.

Garlic

Garlic is one of the most extensively researched medicinal plants. It has the potential to modify the risk for atherosclerosis by reducing arterial blood pressure, thrombus formation, and serum lipid and cholesterol concentrations. These effects are primarily attributed to its sulfur-containing compounds, particularly allicin and its transformation products. Commercial garlic preparations can be standardized to a fixed alliin and allicin content.

Garlic inhibits platelet aggregation in vivo in a concentration-dependent fashion. The effect of one of its constituents, ajoene, is irreversible and can enhance the effect of other platelet inhibitors such as prostacyclin, forskolin, indomethacin, and dipyridamole. Although the effects are not consistently demonstrated in volunteers, there is one case described in an 80 year old who had a spontaneous epidural hematoma develop that was attributed to continuous garlic use. Garlic has interacted with warfarin, resulting in an increased international normalized ratio (INR).

In addition to bleeding concerns, garlic can decrease systemic and pulmonary vascular resistance in laboratory animals, but this effect is marginal in humans. Although there are insufficient pharmacokinetic data on garlic’s constituents, the potential for irreversible inhibition of platelet function may warrant discontinuation of garlic at least 7 days before surgery, especially if postoperative bleeding is a particular concern or other anticoagulants are given. Additionally, garlic’s pharmacokinetics should be considered when a risk-benefit analysis is made for neuraxial techniques.

Ginger

Ginger ( Zingiber officinale ) is a popular spice with a long history of use in Chinese, Indian, Arabic, and Greco-Roman herbal medicines. Ginger has a wide range of reported health benefits for those with arthritis, rheumatism, sprains, muscular aches, pains, sore throats, cramps, constipation, indigestion, nausea, vomiting, hypertension, dementia, fever, infectious diseases, and helminthiasis. Ginger contains up to 3% volatile oil, mostly monoterpenoids and sesquiterpenoids. Gingerols are representative compounds in ginger.

Ginger is an antiemetic and has been used to treat motion sickness and to prevent nausea after laparoscopy. The number of postoperative antiemetic medications was significantly reduced after aromatherapy with essential oil of ginger. In another recent trial, ginger supplementation reduced the severity of acute chemotherapy-induced nausea in adult cancer patients and compared favorably to conventional antiemetics.

In an in vitro study, gingerols and related analogues inhibited arachidonic acid–induced human platelet serotonin release and aggregation, with a potency similar to that of aspirin. In another in vitro study, the antiplatelet effects of 20 ginger constituents were evaluated. Five constituents showed antiplatelet activities at relatively low concentrations. One of the ginger compounds (8-paradol) was the most potent cyclooxygenase-1 inhibitor and antiplatelet aggregation drug. In a case report, a ginger-phenprocoumon combination resulted in an increased INR and epistaxis. Although the sample size was relatively small, the platelet inhibition potential of ginger has been suggested in a pilot clinical study. This result may warrant the discontinuation of ginger at least 2 weeks before surgery,

Ginkgo

Ginkgo is derived from the leaf of G. biloba and has been used for cognitive disorders, peripheral vascular disease, age-related macular degeneration, vertigo, tinnitus, erectile dysfunction, and altitude sickness. Studies have suggested that ginkgo can stabilize or improve cognitive performance in patients with Alzheimer disease and multiinfarct dementia, but not in healthy geriatric patients. The compounds that might be responsible for its pharmacologic effects are the terpenoids and flavonoids. The two ginkgo extracts used in clinical trials are standardized to ginkgo-flavone glycosides and terpenoids.

Ginkgo alters vasoregulation, acts as an antioxidant, modulates neurotransmitter and receptor activity, and inhibits platelet-activating factor. Of these effects, inhibition of platelet-activating factor is of primary concern for the perioperative period. Although bleeding complications have not occurred in clinical trials, four cases of spontaneous intracranial bleeding, one case of spontaneous hyphema, and one case of postoperative bleeding after laparoscopic cholecystectomy have been described when ginkgo was being taken.

Terpene trilactones are highly bioavailable when administered orally. The elimination half-lives of the terpene trilactones after oral administration are between 3 and 10 hours. For ginkgolide B, a dosage of 40 mg twice daily resulted in a higher area under the curve, and a longer half-life and residence time, than after a single 80-mg dose. A once daily dose of 80 mg guaranteed a larger maximum concentration peak (T _max ) that was reached 2 to 3 hours after administration. The pharmacokinetics of terpene trilactones in three different ginkgo preparations in human plasma indicate that ginkgo should be discontinued at least 2 weeks before surgery to avoid bleeding.

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