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April 2001; Volume 3; 26-30
By Carol L. Norred, CRNA, MHS
The pharmaceutical plethora administered during an anesthetic combined with preoperative use of herbs increases the potential for interactions. Botanical products may exacerbate cardiovascular, neuromuscular, or sedative effects of anesthetics, or may result in increased surgical bleeding.1,2 To allow for clearance of botanical medicines, the American Society of Anesthesiologists (ASA) recommends the discontinuation of herbs at least two weeks prior to surgery.3
Use of Herbs by Surgical Patients
Herb consumption is common among surgical patients. A 1999 survey at the University of Colorado found 51% of surgical patients took preoperative alternative supplements (herbs, vitamins, dietary supplements, or homeopathics; range one to 22 medicines per patient). Almost one-fourth of patients consumed herbs.1 In 2000, a follow-up survey found 73% of patients consumed up to 44 alternative medicines per patient preoperatively. Thirty-seven percent of surgical patients took 62 different types of herbs; 20% of patients combined up to 13 herbs in the two weeks prior to surgery.2 Another survey of presurgical patients at Harvard found that 22% of presurgical patients took herbs.4 In a Texas study, 32% of presurgical patients reported herb use. This anonymous study also found that 70% of those surveyed who consumed botanical medicines reported that they did not disclose use during anesthetic interview.5
Anesthesiologists worry that ginger (Zingiber officinale), ginseng (Panax ginseng), feverfew (Tanacetum parthenium), ginkgo (Ginkgo biloba), and garlic (Allium sativum) may cause an "increased risk of intra-operative instability" due to inhibition of coagulation.5 However, of these herbs, excessive operative bleeding has been associated only with garlic and possibly ginkgo. The preoperative use of dietary garlic has been associated with increased surgical blood loss during transurethral resection of the prostate6 and augmentation mammaplasty.7 Garlic inhibits platelet aggregation, reduces thromboxane, increases fibrinolytic activity, and increases streptokinase-activated plasminogen activator.8,9
Ginkgo has been associated with spontaneous and increased bleeding when combined with anticoagulants and would be expected to increase the risk of operative hemorrhage. Ginkgo inhibits platelet-activating factor, decreases fibrinogen levels, and decreases plasma viscosity, possibly due to flavonoids and ginkgolide B.10
Spontaneous bilateral subdural hematomas occurred in a healthy female taking ginkgo.11 The combination of ginkgo with aspirin has been associated with ocular hyphema,12 and intracerebral hemorrhage resulted from combining warfarin with ginkgo for two months.13 A mastectomy patient who preoperatively consumed ginkgo, eleuthero or Siberian ginseng (Eleutherococcus senticosus), bilberry (Vaccinium myrtillus), the Chinese herb huang qi (Astragalus membranaceous), and vitamin E as well as quinine sulfate and sertraline hydrochloride (Zoloft®) had acute excessive postoperative bleeding requiring emergency surgical re-exploration.14 Ginkgo may be implicated, but the concurrent use of multiple herbs and drugs makes it impossible to determine causality. Reports of herb-drug interactions often lack laboratory analysis of the purported botanicals.15 Another case report described postoperative bleeding after the consumption of ginkgo prior to surgery; the frequency and dose of herb, and information on concomitant anesthetics, preoperative pharmaceuticals, coagulation studies, or surgical trauma were not noted. The preoperative hemoglobin dropped from 16.5 to 5.4 g/dl postoperatively.16
Ginger, ginseng, feverfew, and many other plants contain anticoagulant components; however, these herbal constituents may have limited clinical significance. Ginger, for example, inhibits platelet aggregation in vitro, acting as a potent inhibitor of arachidonic acid, epinephrine, adenosine diphosphate (ADP), and collagen. However, a placebo-controlled study in which eight males ingested 2 g of ginger showed that although thromboxane synthetase and prostaglandin synthetase were reduced in a dose-dependent manner, no differences were found in bleeding time, platelet counts, or platelet function between the placebo and control groups.17
Ginseng also has uncertain effects upon coagulation. In vitro, ginsenoside Rg2 inhibits aggregation, ginsenoside Ro inhibits the conversion of fibrinogen to fibrin,18 and ginsenoside Rg3 inhibits platelet-activating factor.19 While a case report implicated ginseng in lowering international normalized ratio in a patient on warfarin,20 an in vivo study of rats revealed no pharmacodynamic or pharmacokinetic interactions of single-dose or steady-state ginseng upon warfarin.21
Parthenolide in feverfew inhibits platelet aggregation by decreasing the release of serotonin and affects the protein kinase pathway.22 Of 10 patients who took the herb long-term (3.5-8 years), ADP and thrombin-stimulated platelet aggregation were no different from four controls. Serotonin-induced aggregation, however, was reduced.23 A 27-year-old woman who self-prescribed feverfew for migraine headaches for six months prior to the procedure had orthopedic surgery cancelled after laboratory analysis revealed a prothrombin time of 15.3 (norm 11.0-13 seconds) and partial thromboplastin time of 28.4 (norm 21-30 seconds). No other information on this case was provided.24
Sedative herbs may interact with anesthetic barbiturates, hypnotics, benzodiazepines, or narcotics.1,2 A patient who chronically took large amounts of valerian (Valeriana officinalis) had high-output cardiac failure and delirium with emergence from general anesthesia. The patient’s signs and symptoms improved upon administration of benzodiazepines.25 In animals, valerian causes CNS depression and has muscle relaxant effects;26 additionally, it has affinity for benzodiazepine receptors in vivo.27
The recent finding that St. John’s wort (Hypericum perforatum) inhibits the binding of naloxone to µ-, d, and k-opioid receptors28 has raised the theoretical concern that the herb may cause excessive sedation when combined with narcotics; however, no such cases have been reported so far.
Intra-operatively, anesthetics can trigger hypotension due to vasodilation and hypovolemia. Hypertension and cardiac arrhythmias may result from sympathetic stimulation during intubation and surgery. Anesthesiologists have expressed apprehension about the potential of monoamine oxidase inhibitor (MAOI) activity of St. John’s wort. 29 In vitro studies have been mixed.30,31 However, more recent investigation of the affinity of hypericin for 30 neurotransmitter reuptake sites found only weak MAOI activity that was considered inconsequential.32
A 23-year-old healthy female who consumed St. John’s wort for six months preoperatively had cardiovascular collapse under general anesthesia. After induction, the patient developed hypotension of 60/20 that for 10 minutes was unresponsive to copious IV fluid resuscitation and large doses of ephedrine and neosynephrine. Her blood pressure increased to 110/80 after administration of epinephrine. The patient had taken no other preoperative medications, received normal anesthetic doses of induction agents, and had no problems with previous anesthesia using a similar type and dose of anesthetics. The authors of this report theorized that adrenergic sensitization from St. John’s wort may have precipitated her unresponsiveness to vasopressors. 33
Ephedra could interact with the cardiovascular effects of volatile anesthetic agents. The herb ephedra or ma huang (Ephedra sinica) is the botanical precursor of ephedrine, a drug routinely used as an anesthetic vasopressor. Obviously, the preoperative use of the herb ephedra could be problematic.1,2
Problems with ephedra are not merely theoretical. A study of 12 healthy normotensive adults who ingested four capsules of ephedra at hours 8 and 17 reported variable effects upon blood pressure; heart rates increased significantly for six of the participants.34 A study of 10 patients who ingested four capsules of ephedra with an average ephedrine content of 19.4 mg/four capsules found similar pharmacokinetics to 25 mg PO ephedrine.35 One hundred forty adverse events related to ephedra products were submitted to the FDA. A review found that 33% were definitely associated with ephedra use while 33% were possibly or probably related. Forty-seven percent of adverse events involved cardiovascular effects including hypertension, palpitations, tachycardia, stroke, or seizures.36
Additionally, the chronic use of licorice (Glycyrrhiza glabra) may cause hypokalemia, pseudoaldosteronism, hypertension, or arrhythmias.37,38 Hypokalemia can potentiate anesthetic muscle relaxants and cause adverse cardiovascular effects.1,2,39,40 Most "licorice" in the United States is flavored with anise (Pimpinella anisum) rather than licorice.
Interactions Affecting Drug Metabolism
Medications metabolized by hepatic cytochrome P450 CYP 1A1, 1A2, or 3A4 may increase drug metabolism and lower serum levels.41 St. John’s wort interacts with many drugs and potently induces CYP3A4 and the P-glycoprotein drug transporter.42 Furthermore, goldenseal (Hydrastis canadensis), cat’s claw (Uncaria tomentosa, U. guianensis), echinacea (Echinacea species), wild cherry (Prunus serotina), chamomile (Matricaria recutita), and licorice inhibit CYP3A4 in vitro, although the clinical significance is undetermined.43 Chronic consumption of the illicit herb marijuana (Cannabis sativa) greatly increases anesthetic requirements due to extensive hepatic drug metabolism.44
Several herbs may be therapeutic for surgical patients. A systematic review of ginger administered orally prior to induction of anesthesia found the herb effective and safe for prophylaxis of postoperative nausea and vomiting.45 Milk thistle (Silybum marianum) has hepatoprotective effects in animals and may have potential in preventing liver damage from hepatotoxic drugs such as excessive alcohol, phenothiazines, or buteryphenones, or toxic doses of acetaminophen.46 Cardiopulmonary bypass patients administered Egb 761, a standardized ginkgo extract, had significant reductions in oxidative stress measures of free radicals; no differences in clinical outcomes were noted in the treatment vs. control group.47
Consumption of herbs by surgical patients may increase the risk of botanical-drug interactions. Patients should be advised to discontinue herbs two weeks preoperatively. The drugs administered during general anesthesia act synergistically to produce amnestic, analgesic, hypnotic, and paralytic effects while minimizing adverse effects. The interaction of anesthetics is unique to each patient; individuals vary in absorption, distribution, and clearance of drugs.40 Each anesthetic induction is an n-of-1 experiment in fast-acting polypharmacy.
However, many surgical patients may take herbs regardless of recommendations and may not inform surgeons or anesthesiologists, especially if bias against herbs is perceived. Therefore, health care providers must strive for neutrality when asking patients about the use of herbs and dietary supplements, and provide unbiased advice about known and potential risks as well as benefits of herbs.
The paucity of extant research on botanical-anesthetic drug interactions and herbs for surgical patients makes it difficult to discern the true risks from herbs consumed prior to anesthesia.48 The frequent consumption of herbs by surgical patients and relative dearth of case reports of adverse effects could indicate that serious risk may be uncommon. Until further research and better education of anesthesia practitioners is achieved, it is prudent to follow the ASA recommendations to discontinue herbs preoperatively to minimize the potential risks of botanical-anesthetic drug interactions.
Ms. Norred is a Certified Registered Nurse Anesthetist; Clinical Instructor, School of Medicine in the Department of Anesthesiology; and doctoral student in the School of Nursing, University of Colorado Health Sciences Center in Denver.
Institutional predoctoral training is provided through a National Research Service Award funded by the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute (HL T32 07085).
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