© Springer International Publishing AG 2018Ehab Farag, Maged Argalious, John E. Tetzlaff and Deepak Sharma (eds.)Basic Sciences in Anesthesiadoi.org/10.1007/978-3-319-62067-1_25
Department of General Anesthesiology, Cleveland Clinic, Cleveland, OH, USA
Kenneth C. CummingsIII
25.4.1 Classes of Anti-emetic Drugs
25.4.2 Consensus Guidelines
25.5.1 Prokinetic Agents
25.5.4 Anticholinergic Drugs
25.8.2 Beta Adrenergic Antagonists
25.8.3 Alpha-2 Adrenergic Agonists
25.8.5 Lipid-Lowering Medications
25.8.6 Psychoactive Medications
25.9.1 Beta Adrenergic Antagonists
25.9.2 Alpha-2 Adrenergic Agonists
25.10 Questions and Answers
KeywordsPremedicationAnesthesiaPreoperative careAntibiotic prophylaxisRespiratory aspirationAdrenergic beta-antagonistsAspirinAntiemetics
Premedication is often used to reduce discomfort, allay anxiety, or in an attempt to reduce perioperative risk.
A simple score predicts the risk of postoperative nausea and vomiting (PONV). Female gender, use of perioperative opioids, nonsmoking status, and a history of PONV or motion sickness each yield 20% additive risk.
Multiple antiemetic options are available. Each treatment reduces the risk of PONV by 20–25%.
Droperidol in larger doses causes QTc prolongation and is associated with torsades de pointes. The first generation 5-HT3 antagonists also cause QTc prolongation but do not carry the same warning label as droperidol.
The American Society of Anesthesiologists preoperative fasting guidelines do not recommend any routine prophylaxis against pulmonary aspiration of gastric contents. Antacids, acid-suppression agents, and prokinetic drugs are useful in patients considered to be at risk for aspiration.
Chronic corticosteroid therapy can cause suppression of the hypothalamic-pituitary-adrenal axis. In patients with this condition, surgical stress may produce an adrenal crisis. Supplemental hydrocortisone can prevent this complication.
Surgical antibiotic prophylaxis is given to reduce the microbial burden of the surgical wound. In most cases, skin flora are the causative organisms in surgical site infections.
Most medications are continued through the perioperative period. Caution must be exercised, however, due to the potential for serious drug interactions. Recent clinical trial evidence does not support starting beta blockers, alpha-2 agonists, or aspirin in an attempt to reduce the risk of perioperative cardiac events. Patients taking beta blockers or alpha-2 agonists, however, should continue them through the perioperative period.
Premedication refers to the administration of drugs to a patient prior to anesthesia and surgery. These drugs are related to the anesthetic and surgical plans but are not directly part of the anesthetic regimen. Premedication is often used to decrease anxiety, lower the likelihood of postoperative nausea and vomiting (PONV), and reduce the risk of complications such as pulmonary aspiration, adrenal insufficiency, and myocardial ischemia. Surgical antibiotic prophylaxis can also be considered premedication.
Opioid analgesics are not typically administered as a premedicant unless the patient is experiencing pain in the preoperative setting or is on a chronic opioid regimen. Respiratory depression from opioid use is the primary risk in this setting, as most preoperative units do not have close patient monitoring. Consequently, opioids should be used cautiously in patients with obstructive sleep apnea (OSA). Patients with increased intracranial pressure also may not tolerate the respiratory depressant effect of opioids due to increased cerebral blood flow from the resulting hypercarbia.
Non-opioid analgesics such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) specific inhibitors, and anticonvulsants such as pregabalin and gabapentin are often used preoperatively for their analgesic and opioid-sparing effects both intra- and postoperatively. The preoperative use of NSAIDs is limited by concerns about surgical bleeding due to inhibition of platelet thromboxane A2 synthesis, although COX-2 inhibitors do not share this property.
Preoperative anxiety is common and can be severe. Non-pharmacologic methods of anxiolysis (eg, preoperative visit with an anesthesiologist) can be very helpful, but judicious use of anxiolytic drugs can improve patient satisfaction, decrease the physiologic consequences of excess anxiety, and improve patient compliance with necessary preoperative procedures.
Benzodiazepines are effective anxiolytic and sedative drugs, as evidenced by their widespread use in the general population. Benzodiazepines facilitate activation of the GABAA receptor, inhibiting neuronal depolarization by increasing chloride conductance. Preoperatively, these drugs are useful because of minimal respiratory depression and hemodynamic effects when used as the sole agent. Caution is still warranted, however, in patients with obstructive sleep apnea as they have increased sensitivity to benzodiazepines. A specific benzodiazepine antagonist (flumazenil) provides a means to rapidly rescue patients from oversedation, although not without the risk of provoking withdrawal and/or seizures in patients physically dependent on benzodiazepines or ethanol.
With a clinical effective duration of less than 2 h (intravenous dosing) and an elimination half-life of 2–7 h, midazolam is the benzodiazepine of choice for perioperative use. In adults, intravenous midazolam 1–2 mg typically provides anxiolysis and a variable degree of anterograde amnesia. Intravenous lorazepam is another reasonable choice. Alternatively, oral midazolam liquid (0.5–0.75 mg/kg) is useful for pediatric patients and does not appear to prolong emergence in moderate-length procedures.
Although study quality varies, orally administered melatonin has been shown in meta-analysis to produce sedation and anxiolysis roughly equivalent to benzodiazepines.
25.3.3 Clonidine and Dexmedetomidine
These centrally acting alpha-2 adrenergic agonists also have sedative and anxiolytic properties that can be useful in the perioperative period. Their use as premedication may be limited by hemodynamic effects (hypotension, bradycardia) and prolonged duration of action.
Ketamine is an anesthetic drug that is thought to act primarily via inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors in the central nervous system (CNS), although it interacts with multiple other receptor pathways. It has profound analgesic and amnestic properties when used at anesthetic doses, but is often associated with negative psychological effects (dysphoria, hallucinations) at higher doses. These effects may be reduced by the concurrent administration of benzodiazepines.
Ketamine is often used for premedication in pediatric patients when a deeper level of sedation and analgesia is needed, such as in children with developmental delay or when uncomfortable procedures must be performed. Ketamine produces significant salivation and is often given in combination with an anticholinergic agent such as glycopyrrolate or atropine.
25.4 Antiemetics/Postoperative Nausea and Vomiting
Postoperative nausea and vomiting is a significant problem in perioperative care. Using a simple risk stratification tool, it is possible to easily predict the likelihood of PONV given 4 risk factors :
History of PONV or motion sickness
Planned postoperative use of opioids
When 0 factors are present, the risk of PONV is 10%. One, 2, 3, and 4 risk factors yield PONV risks of approximately 20%, 40%, 60%, and 80%, respectively. Conversely, it has been demonstrated that each prophylactic intervention reduces the risk by approximately 20–25% .
25.4.1 Classes of Anti-emetic Drugs
Scopolamine is a muscarinic anticholinergic drug that readily crosses the blood-brain barrier. In the CNS, it suppresses the emetic response to vestibular stimulation, one of the mechanisms of PONV. Typically, it is administered transcutaneously via a patch applied several hours prior to surgery. The patch formulation reaches peak effectiveness in 4 h and delivers approximately 1 mg of scopolamine over 72 h.
Dose-limiting side effects include dry mouth, mydriasis (leading to blurred vision), decreased gastrointestinal motility, urinary retention, and sedation/amnesia. Blockade of muscarinic receptors in the stomach delays gastric emptying and may increase gastric volume. Concern exists about administering anticholinergic drugs to patients with open-angle glaucoma due to the possibility of creating acute angle-closure glaucoma—an ophthalmologic emergency. Caution should also be used in elderly patients, as they are at increased risk for delirium from centrally acting anticholinergic drugs.
Histamine H1 Antagonists
Diphenhydramine and promethazine both have antihistamine effects and are thought to act via blockade of H1 histamine receptors in the chemoreceptor trigger zone (CTZ). They both also exert anticholinergic effects similar to scopolamine, producing sedative and anti-emetic effects. Diphenhydramine has also been shown to decrease the nausea associated with opioid administration.
Dopaminergic D2 Antagonists
Several classes of drugs exert common antagonist effects at D2 receptors in the chemoreceptor trigger zone (CTZ). These include the phenothiazines, the butryophenones (haloperidol and droperidol), and metoclopramide. This antagonism reduces both the sensation of nausea and actual vomiting. Metoclopramide’s effect may largely lie outside the CNS, however, as it exerts a prokinetic cholinergic effect on the gastrointestinal tract.
Caution should be used when choosing these drugs. They should not be used in patients with Parkinson’s disease, restless legs syndrome, or other movement disorders as they can interfere with drug therapy and prompt exacerbations of these conditions. Extrapyramidal effects (dystonia, akathisia) can limit these drugs’ usefulness and may be very troublesome to patients. Other effects include sedation and orthostatic hypotension. Prolonged use of metoclopramide (3 months or longer) has been associated with tardive dyskinesia. Its short-term perioperative use, however, does not appear to carry this risk.
Much attention has been devoted to the effect of droperidol (and, to a lesser extent, haloperidol) on the QTc interval. Droperidol (along with many other drugs) inhibits the delayed inward rectifier (IKr) potassium current in cardiac myocytes, thus prolonging the QTc interval and rendering the myocardium more vulnerable to arrhythmias. Due to reports of torsades de pointes (TdP) in patients receiving larger doses of droperidol (such as for neuroleptanalgesia), the U.S. Food and Drug Administration (FDA) requires a “black box” warning on droperidol, including the requirement for cardiac monitoring for 4 h after drug administration. There has been much debate about the validity of this warning in light of the low doses of droperidol used for PONV prophylaxis (commonly less than 1.25 mg), its proven efficacy, and clinical evidence that supports droperidol’s safety in low doses .
Corticosteroids (usually dexamethasone) are commonly used for PONV prophylaxis. Dexamethasone (typically 4–8 mg intravenous [IV]) has been demonstrated to reduce the risk of PONV as well as decrease postoperative pain. Dexamethasone’s mechanism of action is not clear. It is presumed that it exerts anti-inflammatory effects in the CNS and peripherally to reduce inflammatory cytokine production.
A single perioperative dose of dexamethasone is generally well tolerated. Reported adverse effects include hyperglycemia, mood effects, headache, and edema. Hyperglycemia is unlikely in patients with normal glucose metabolism, however. The risk-benefit balance appears to support the perioperative use of dexamethasone, as no convincing evidence of increased risk of surgical site infection exists.
The most commonly used drugs in this category include dolasetron, granisetron, and ondansetron. They bind to and inhibit activation of serotonergic receptors in the gastrointestinal tract, the solitary tract nucleus, and the CTZ. They are significantly more effective in preventing vomiting than nausea. No differences in efficacy or toxicity among the 3 drugs have been demonstrated at clinically used doses (dolasetron 12.5 mg, granisetron 0.35–3 mg, and ondansetron 4 mg). Contrary to many other prophylactic drugs, these agents are usually administered at the end of surgery. The second generation 5-HT3 antagonist palonosetron (usual dose 0.075 mg), however, is administered at the start of surgery due to its much longer half-life (40 h). Palonosetron also appears to be more effective in preventing PONV than the first-generation drugs.
The 5-HT3 antagonists are generally well tolerated. The most common side effect is mild headache (15–20%) followed by dizziness (10%). QTc prolongation also occurs with the first-generation drugs but not palonosetron. There have been case reports of TdP in patients receiving first-generation 5-HT3 antagonists. These drugs do not carry the black box warning that droperidol has, but the FDA does recommend cardiac monitoring for patients with electrolyte abnormalities or patients who are receiving other QTc-prolonging medications. These medications should also be used very cautiously (if at all) in patients taking class III antiarrhythmics such as dofetilide due to the risk of TdP.
Substance P is a neuropeptide with a wide distribution in the CNS. It is found in particularly high concentrations in neurons innervating the solitary tract nucleus and CTZ. Acting through neurokinin type 1 (NK1) receptors, it affects many functions including regulation of nausea and vomiting. The NK1 receptor antagonist aprepitant was originally demonstrated to reduce delayed chemotherapy-induced nausea and vomiting. It has also been demonstrated to be an effective and long-lasting prophylactic antiemetic (40 mg PO 3 h prior to surgery) but, due to its slow onset and oral administration, it is not an effective rescue medication. Common side effects of aprepitant include fatigue, abdominal pain, and diarrhea.
Caution is warranted with aprepitant because it is a moderate inhibitor of CYP3A4. Dexamethasone is a substrate of this enzyme and many clinical trials used reduced doses of dexamethasone in combination with aprepitant. Other subtrates of CYP3A4 include macrolide antibiotics, many chemotherapeutic agents, opioids (including fentanyl), benzodiazepines (including midazolam), calcium channel blockers, statins, warfarin, and oral contraceptives. This long list of drug interactions, combined with high acquisition cost, has dampened enthusiasm for aprepitant’s perioperative use.
In addition to its effects on anxiety, prophylactic midazolam (50 mcg/kg IV with induction of anesthesia) has also been shown to reduce the incidence of PONV compared to placebo.
25.4.2 Consensus Guidelines
The Society for Ambulatory Anesthesia has published guidelines outlining a strategy for managing PONV . After clinical assessment, patients are assigned as low-, medium-, or high-risk for PONV. Low-risk patients do not require prophylaxis. Medium-risk patients should receive 1 or 2 interventions. High-risk patients, however, should receive at least 2 interventions with consideration to a multimodal approach including regional anesthesia, avoidance of inhalational anesthetics, and other strategies.