Ketorolac is a parenteral nonsteroidal antiinflammatory drug (NSAID) that provides analgesia by inhibiting prostaglandin synthesis. A peripherally acting drug, it has become a popular alternative to opioids for postoperative analgesia because of its minimal central nervous system side effects.
Ketorolac is indicated for the short-term (<5 days) management of pain, and appears to be particularly useful in the immediate postoperative period. A standard dose of ketorolac provides analgesia equivalent to 6 to 12 mg of morphine administered by the same route. Its time to onset is also similar to morphine, but ketorolac has a longer duration of action (6–8 h).
Ketorolac does not cause respiratory depression, sedation, or nausea and vomiting. In fact, ketorolac does not cross the blood–brain barrier to any significant degree. Numerous studies have shown that oral and parenteral NSAIDs have an opioid-sparing effect. They may be most beneficial in patients at increased risk for postoperative respiratory depression or emesis.
As with other NSAIDs, ketorolac inhibits platelet aggregation and prolongs bleeding time. It and other NSAIDs should therefore be used with caution in patients at risk for postoperative hemorrhage. Long-term administration may lead to renal toxicity (eg, papillary necrosis) or GI tract ulceration with bleeding and perforation. Because ketorolac depends on kidney elimination, it should not be given to patients with kidney disease. Ketorolac is contraindicated in patients allergic to aspirin or NSAIDs. Patients with asthma have an increased incidence of aspirin sensitivity (approximately 10%), particularly if they also have a history of nasal polyps (approximately 20%).
Ketorolac has been approved for administration as either a 60 mg intramuscular or 30 mg intravenous loading dose; a maintenance dose of 15 to 30 mg every 6 h is recommended. Elderly patients clear ketorolac more slowly and should receive reduced doses.
Aspirin decreases the protein binding of ketorolac, increasing the amount of active unbound drug. Ketorolac does not affect minimum alveolar concentration of inhalation anesthetic agents, and its administration does not alter the hemodynamics of anesthetized patients. It decreases the postoperative requirement for opioid analgesics.
Other NSAID Adjuvant Drugs
Other NSAID agents are used perioperatively. Ketorolac and other NSAIDs inhibit cyclooxygenase (COX) isoenzymes. COX-1 maintains gastric mucosa and stimulates platelet aggregation. COX-2 is expressed during inflammation. Diclofenac and ibuprofen are now available for intravenous administration. Whereas ketorolac, diclofenac, and ibuprofen are nonselective COX inhibitors, other agents such as celecoxib are specific for COX-2. COX-2 inhibitors spare both the gastric mucosa and platelet function. However, their use is associated with an increased risk of hypertension, stroke, and cardiovascular events. Indeed, the FDA warns that all non-aspirin nonsteroidal antiinflammatory drugs increase the risk of myocardial infarction or stroke.
Intravenous acetaminophen (Ofirmev) is available for perioperative use in the United States. Acetaminophen is a centrally acting analgesic with likely central COX inhibition and with weak peripheral COX effects. Its exact mechanism of action remains controversial; nevertheless it does not cause gastric irritation and clotting abnormalities. A maximal adult (>50 kg weight) dose of 1 g is infused to a maximum total dose of 4 g/d. Patients weighing 50 kg or less should receive a maximal dose of 15 mg/kg and a maximal total dose of 75 mg/kg/d. Hepatoxicity is a known risk of overdosage, and the drug should be used with caution in patients with hepatic disease or undergoing hepatic surgery. Oral and rectal acetaminophen are as effective as the intravenous form and orders of magnitude less expensive.
Clonidine is an imidazoline derivative with predominantly α2-adrenergic agonist activity. It is highly lipid soluble and readily penetrates the blood–brain barrier and the placenta. Studies indicate that binding of clonidine to receptors is highest in the rostral ventrolateral medulla in the brainstem (the final common pathway for sympathetic outflow), where it activates inhibitory neurons. The overall effect is to decrease sympathetic activity, enhance parasympathetic tone, and reduce circulating catecholamines. There is also evidence that some of clonidine’s antihypertensive action may occur via binding to a nonadrenergic (imidazoline) receptor. In contrast, its analgesic effects, particularly in the spinal cord, are mediated entirely via pre- and possibly postsynaptic α2-adrenergic receptors that block nociceptive transmission. Clonidine also has local anesthetic effects when applied to peripheral nerves and is frequently added to local anesthetic solutions to increase duration of action.
Clonidine is a commonly used antihypertensive agent that reduces sympathetic tone, decreasing systemic vascular resistance, heart rate, and blood pressure. In anesthesia, clonidine is used as an adjunct for epidural, caudal, and peripheral nerve block anesthesia and analgesia. It is often used in the management of patients with chronic neuropathic pain to increase the efficacy of epidural opioid infusions. When given epidurally, the analgesic effect of clonidine is segmental, being localized to the level at which it is injected or infused. When added to local anesthetics of intermediate duration (eg, mepivacaine or lidocaine) administered for epidural or peripheral nerve block, clonidine will markedly prolong both the anesthetic and analgesic effects.
Unlabeled/investigational uses of clonidine include serving as an adjunct in premedication, control of withdrawal syndromes (nicotine, opioids, alcohol, and vasomotor symptoms of menopause), and treatment of glaucoma as well as various psychiatric disorders.
Sedation, dizziness, bradycardia, and dry mouth are common side effects. Less commonly, orthostatic hypotension, nausea, and diarrhea may be observed. Abrupt discontinuation of clonidine following long-term administration (>1 month) can produce a withdrawal phenomenon characterized by rebound hypertension, agitation, and sympathetic overactivity.
Epidural clonidine is usually started at 30 mcg/h in a mixture with an opioid or a local anesthetic. Oral clonidine is readily absorbed, has a 30 to 60 min onset, and lasts 6 to 12 h. In the initial treatment of hypertension, 0.1 mg can be given two times a day and adjusted until the blood pressure is controlled. The maintenance dose typically ranges from 0.1 to 0.3 mg twice daily. Transdermal preparations of clonidine can also be used for maintenance therapy. They are available as 0.1, 0.2, and 0.3 mg/d patches that are replaced every 7 days. Clonidine is metabolized by the liver and excreted by the kidney. Dosages should be reduced for patients with kidney disease.
Clonidine enhances and prolongs sensory and motor blockade from local anesthetics. Additive effects with hypnotic agents, general anesthetics, and sedatives can potentiate sedation, hypotension, and bradycardia. The drug should be used cautiously, if at all, in patients who take β-adrenergic blockers and in those with significant cardiac conduction system abnormalities. Lastly, clonidine can mask the symptoms of hypoglycemia in diabetic patients.
Dexmedetomidine is a parenteral selective α2 agonist with sedative properties. It appears to be more selective for the α2 receptor than clonidine. At higher doses, it loses its selectivity and also stimulates α1-adrenergic receptors.
Dexmedetomidine causes dose-dependent sedation, anxiolysis, some analgesia, and blunting of the sympathetic response to surgery and to other stress. Most importantly, it has an opioid-sparing effect and does not significantly depress respiratory drive; excessive sedation, however, may cause airway obstruction. The drug can be used for short-term (<24 h), intravenous sedation of mechanically ventilated patients. Discontinuation after more prolonged use can potentially cause a withdrawal phenomenon similar to that of clonidine. It is also used for intraoperative sedation and as an adjunct to general anesthetics.
The principal side effects are bradycardia, heart block, and hypotension. It may also cause nausea.
The recommended initial loading dose is 1 mcg/kg intravenously over 10 min with a maintenance infusion rate of 0.2 to 0.7 mcg/kg/h. Dexmedetomidine has a rapid onset and terminal half-life of 2 h. The drug is metabolized in the liver and its metabolites are eliminated in the urine. Dosage should be reduced in patients with liver or kidney disease.
Caution should be used when dexmedetomidine is administered with vasodilators, cardiac depressants, and drugs that decrease heart rate. Reduced requirements of hypnotics/anesthetic agents should prevent excessive hypotension.
Gabapentin was initially employed as an anticonvulsant. Gabapentin and pregabalin act by blocking voltage-gated calcium channels, resulting in diminished release of glutamate. Various studies have demonstrated that both drugs may reduce perioperative opioid consumption when included in multimodal pain management. Gabapentin may be given to adults as a 600 mg preemptive dose prior to surgery and continued postoperatively (1200 mg/d in divided doses). These agents are also commonly used for management of chronic (particularly neuropathic) pain syndromes.
Capsaicin is a TRPV1-receptor agonist. It depletes substance P and inhibits pain signal transmission. Infiltration of capsaicin in surgical wounds reduces opioid consumption and improves perioperative analgesia.
Doxapram is a peripheral and central nervous system stimulant. Selective activation of carotid chemoreceptors by low doses of doxapram stimulates hypoxic drive, producing an increase in tidal volume and a slight increase in respiratory rate. At larger doses, respiratory centers in the medulla are stimulated.
Doxapram is not a specific reversal agent and should not replace standard supportive therapy (ie, mechanical ventilation). Drug-induced respiratory and central nervous system depression, including that seen immediately postoperatively, can be temporarily overcome. Doxapram will not reverse paralysis caused by muscle relaxants and will not alleviate airway obstruction.
Stimulation of the central nervous system leads to a variety of possible side effects: changes in mental status (confusion, dizziness, seizures), cardiac abnormalities (tachycardia, dysrhythmias, hypertension), and pulmonary dysfunction (wheezing, tachypnea). Vomiting and laryngospasm are of particular concern to the anesthesiologist in the postoperative period. Doxapram should not be used in patients with a history of epilepsy, cerebrovascular disease, acute head injury, coronary artery disease, hypertension, or bronchial asthma.
Bolus intravenous administration (0.5–1 mg/kg) results in transient increases in minute ventilation (the onset of action is 1 min; the duration of action is 5–12 min). Continuous intravenous infusions (1–3 mg/min) provide longer-lasting effects (the maximum dose is 4 mg/kg).
The sympathetic stimulation produced by doxapram may exaggerate the cardiovascular effects of monoamine oxidase inhibitors or adrenergic agents.
Naloxone is a competitive opioid receptor antagonist. Its affinity for opioid μ receptors appears to be much greater than for opioid κ or δ receptors Naloxone has no significant agonist activity.
Naloxone reverses the agonist activity associated with endogenous (enkephalins, endorphins) or exogenous opioid compounds. A dramatic example is the reversal of unconsciousness that occurs in a patient with opioid overdose who has received naloxone. Thus, naloxone is widely available for first responders and relatives of those who abuse opioids. Perioperative respiratory depression caused by opioids is rapidly antagonized (1–2 min). Some degree of opioid analgesia can often be spared if the dose of naloxone is limited to the minimum required to maintain adequate ventilation (40–80 mcg intravenously in adults, repeated as needed). Small doses of intravenous naloxone reverse the side effects of spinal or epidural opioids without necessarily reversing the analgesia.
Abrupt, complete reversal of opioid analgesia can result in a surge of sympathetic stimulation (tachycardia, ventricular irritability, hypertension, pulmonary edema) caused by severe, acute pain, and an acute withdrawal syndrome in patients who are opioid-dependent.
In postoperative patients experiencing respiratory depression from excessive opioid administration, intravenous naloxone (0.4 mg/mL vial diluted in 9 mL saline to 0.04 mg/mL) can be titrated in increments of 0.5 to 1 mcg/kg every 3 to 5 min until adequate ventilation and alertness are achieved. Doses in excess of 200 mcg are rarely needed. The brief duration of action of intravenous naloxone (30–45 min) is due to rapid redistribution from the central nervous system. A more prolonged effect will be necessary to prevent the recurrence of respiratory depression from longer-acting opioids. Therefore, intramuscular naloxone (twice the required intravenous dose) or a continuous naloxone infusion is recommended. Naloxone may precipitate symptoms of withdrawal in infants of opioid-exposed mothers.
The effect of naloxone on nonopioid anesthetic agents such as nitrous oxide or clonidine is insignificant.
Naltrexone is also a pure opioid antagonist with a high affinity for the μ receptor, but with a significantly longer half-life than naloxone. Naltrexone is used orally for maintenance treatment of addiction. Chapter 48 reviews the use of the peripherally acting opioid receptor antagonists alvimopan and methylnaltrexone in the management and prevention of postoperative ileus as an element of enhanced perioperative recovery.
Flumazenil, an imidazobenzodiazepine, is a specific and competitive antagonist of benzodiazepines at benzodiazepine receptors.
Flumazenil is useful in the reversal of benzodiazepine sedation and the treatment of benzodiazepine overdose. Although it promptly (onset <1 min) reverses the hypnotic effects of benzodiazepines, amnesia has proved to be less reliably prevented. Some evidence of respiratory depression may linger despite an alert and awake appearance. Specifically, tidal volume and minute ventilation return to normal, but the slope of the carbon dioxide response curve remains depressed. Effects in elderly patients appear to be particularly difficult to reverse fully, and these patients are more prone to relapse of sedation.
Side Effects & Drug Interactions
Rapid administration of flumazenil may cause anxiety reactions in previously sedated patients and symptoms of withdrawal in those on long-term benzodiazepine therapy. Flumazenil reversal has been associated with increases in intracranial pressure in patients with head injuries and abnormal intracranial compliance. Flumazenil may induce seizure activity if benzodiazepines have been given as anticonvulsants or in conjunction with an overdose of tricyclic antidepressants. Flumazenil reversal following a midazolam–ketamine anesthetic technique may increase the incidence of emergence dysphoria and hallucinations. Nausea and vomiting are not uncommon following administration of flumazenil. The reversal effect of flumazenil is based on its strong antagonist affinity for benzodiazepine receptors. Flumazenil does not affect the minimum alveolar concentration of inhalation anesthetics.
Gradual titration of flumazenil is usually accomplished by intravenous administration of 0.2 mg/min until reaching the desired degree of reversal. The usual total dose is 0.6 to 1.0 mg. Because of flumazenil’s rapid hepatic clearance, repeat doses may be required after 1 to 2 h to avoid re-sedation and premature recovery room or outpatient discharge. Liver failure prolongs the clearance of flumazenil and benzodiazepines.
CASE DISCUSSION Management of Patients at Risk for Aspiration Pneumonia
A 58-year-old man is scheduled for elective laparoscopic cholecystectomy. His past history reveals a persistent problem with heartburn and passive regurgitation of gastric contents into the pharynx. He has been told by his internist that these symptoms are due to a hiatal hernia. Why would a history of hiatal hernia concern the anesthesiologist?
Perioperative aspiration of gastric contents (Mendelson syndrome) is a potentially fatal complication of anesthesia. Hiatal hernia is commonly associated with symptomatic GERD, which is considered a predisposing factor for aspiration. Mild or occasional heartburn may not significantly increase the risk of aspiration. In contrast, symptoms related to passive reflux of gastric fluid, such as acid taste or sensation of refluxing liquid into the mouth, should alert the clinician to a high risk of pulmonary aspiration. Paroxysms of coughing or wheezing, particularly at night or when the patient is flat, may be indicative of chronic aspiration. Aspiration can occur on induction, during maintenance, or upon emergence from anesthesia. Which patients are predisposed to aspiration?
Patients with altered airway reflexes (eg, drug intoxication, general anesthesia, encephalopathy, neuromuscular disease) or abnormal pharyngeal or esophageal anatomy (eg, large hiatal hernia, Zenker diverticulum, scleroderma, pregnancy, obesity, history of esophagectomy) are prone to pulmonary aspiration. Does aspiration consistently result in aspiration pneumonia?
Not necessarily. The seriousness of the lung damage depends on the volume and composition of the aspirate. Traditionally, patients are considered to be at risk if their gastric volume is greater than 25 mL (0.4 mL/kg) and their gastric pH is less than 2.5. Some investigators believe that controlling acidity is more important than volume and that the criteria should be revised to a pH less than 3.5 with a volume greater than 50 mL.
Patients who have eaten immediately prior to emergency surgery are obviously at risk. Traditionally, “NPO after midnight” implied a preoperative fast of at least 6 h. Current opinion allows clear liquids until 2 h before induction of anesthesia. According to the American Society of Anesthesiologists (ASA) guideline, breast milk is permitted up to 4 h before anesthesia. Infant formula, nonhuman milk and a light meal are permitted up to 6 h before induction. Patients consuming a heavy meal including meat, fats, and fried foods should fast for 8 h. Certain patient populations are particularly likely to have large volumes of acidic gastric fluid: patients with an acute abdomen or peptic ulcer disease, children, the elderly, diabetic patients, pregnant women, and obese patients. Furthermore, pain, anxiety, or opioids may delay gastric emptying. Note that pregnancy and obesity place patients in double jeopardy by increasing the chance of aspiration (increased intraabdominal pressure and distortion of the lower esophageal sphincter) and the risk of aspiration pneumonia (increased acidity and volume of gastric contents). Aspiration is more common in patients undergoing esophageal, upper abdominal, or emergency laparoscopic surgery. Which drugs lower the risk of aspiration pneumonia?
H2-Receptor antagonists decrease gastric acid secretion. Although they will not affect gastric contents already in the stomach, they will inhibit further acid production. Both gastric pH and volume are affected. In addition, the long duration of action of ranitidine and famotidine may provide protection in the recovery room.
Metoclopramide shortens gastric emptying time and increases lower esophageal sphincter tone. It does not affect gastric pH, and it cannot clear large volumes of food in a few hours. Nonetheless, metoclopramide with ranitidine is a good combination for most at-risk patients. Antacids usually raise gastric fluid pH, but, at the same time, they increase gastric volume. Although antacid administration technically removes a patient from the at-risk category, aspiration of a substantial volume of particulate matter will lead to serious physiological damage. For this reason, clear antacids (eg, sodium citrate) are employed. In contrast to H2 antagonists, antacids are immediately effective and alter the acidity of existing gastric contents. Thus, they are useful in emergency situations and in patients who have recently eaten.
Anticholinergic drugs, particularly glycopyrrolate, decrease gastric secretions if large doses are administered; however, lower esophageal sphincter tone is reduced. Overall, anticholinergic drugs do not reliably reduce the risk of aspiration pneumonia and can reverse the protective effects of metoclopramide. Proton pump inhibitors are generally as effective as H2 antagonists.
The ASA guideline recommends that prophylaxis against gastric content aspiration be undertaken only in at-risk patients. What anesthetic techniques are used in full-stomach patients?
If the full stomach is due to recent food intake and the surgical procedure is elective, the operation should be postponed. If the risk factor is not reversible (eg, large hiatal hernia) or the case is emergent, proper anesthetic technique can minimize the risk of aspiration pneumonia. Regional anesthesia with minimal sedation should be considered in patients at increased risk for aspiration pneumonia. If local anesthetic techniques are impractical, the patient’s airway must be protected. Delivering anesthesia by mask or laryngeal mask airway is contraindicated. As in every anesthetic case, the availability of suction must be confirmed before induction. A rapid-sequence induction (or, depending upon airway examination, an awake intubation) is indicated. How does a rapid-sequence induction differ from a routine induction?
What are the relative contraindications to rapid-sequence inductions?
The patient is always preoxygenated prior to induction. Patients with lung disease require 3 to 5 min of preoxygenation.
A wide assortment of blades, video laryngoscopes, intubation bougies, and endotracheal tubes are prepared in advance and immediately available.
An assistant may apply firm pressure over the cricoid cartilage prior to induction (Sellick maneuver). Because the cricoid cartilage forms an uninterrupted and incompressible ring, pressure over it is transmitted to underlying tissue. The esophagus is collapsed, and passively regurgitated gastric fluid cannot reach the hypopharynx. Excessive cricoid pressure (beyond what can be tolerated by a conscious person) applied during active regurgitation has been associated with rupture of the posterior wall of the esophagus. The effectiveness of Sellick maneuver has been questioned.
A propofol induction dose is given as a bolus. Obviously, this dose must be modified if there is any indication that the patient’s cardiovascular system is unstable. Other rapid-acting induction agents can be substituted (eg, etomidate, ketamine).
Succinylcholine (1.5 mg/kg) or rocuronium (0.9–1.2 mg/kg) is administered immediately following the induction dose, even if the patient has not yet lost consciousness.
The patient is not artificially ventilated, to avoid filling the stomach with gas and thereby increasing the risk of emesis. Once spontaneous efforts have ceased or muscle response to nerve stimulation has disappeared, the patient is rapidly intubated. Cricoid pressure is maintained until the endotracheal tube cuff is inflated and tube position is confirmed. A modification of the classic rapid-sequence induction allows gentle ventilation as long as cricoid pressure is maintained.
If the intubation proves difficult, cricoid pressure is maintained and the patient is gently ventilated with oxygen until another intubation attempt can be performed. If intubation is still unsuccessful, spontaneous ventilation should be allowed to return and an awake intubation performed. Sugammadex can be administered to reverse rocuronium-induced muscle relaxation.
After surgery, the patient should remain intubated until airway reflexes and consciousness have returned.
Rapid-sequence inductions are often associated with increases in intracranial pressure, arterial blood pressure, and heart rate. Describe the pathophysiology and clinical findings associated with aspiration pneumonia.
The pathophysiological changes depend on the composition of the aspirate. Acid solutions cause atelectasis, alveolar edema, and loss of surfactant. Particulate aspirate will also result in small-airway obstruction and alveolar necrosis. Granulomas may form around food or antacid particles. The earliest physiological change following aspiration is intrapulmonary shunting, resulting in hypoxia. Other changes may include pulmonary edema, pulmonary hypertension, and hypercapnia.
Wheezing, rhonchi, tachycardia, and tachypnea are common physical findings. Decreased lung compliance can make ventilation difficult. Hypotension signals significant fluid shifts into the alveoli and is associated with massive lung injury. Chest roentgenography may not demonstrate diffuse bilateral infiltrates for several hours after the event. Arterial blood gases reveal hypoxemia, hypercapnia, and respiratory acidosis. What is the treatment for aspiration pneumonia?
As soon as regurgitation is suspected, the patient should be placed in a head-down position so that gastric contents drain out of the mouth instead of into the trachea. The pharynx and, if possible, the trachea should be thoroughly suctioned. The mainstay of therapy in patients who subsequently become hypoxic is positive-pressure ventilation. Intubation and the institution of positive end-expiratory pressure, or noninvasive ventilation, may be required. Bronchoscopy and pulmonary lavage are usually indicated when particulate aspiration has occurred. Use of corticosteroids is generally not recommended, and antibiotics are administered depending upon culture results.