Anesthesia Drugs

Anesthesia Drugs

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
Abstract
The obstetrician-gynecologist is often solely responsible for analgesia/sedation and regional blocks during office-based and outpatient procedures. The American Society of Anesthesiologists guidelines for the provision of analgesia/sedation for nonanesthesiologists provide helpful recommendations to maximize patient safety during office-based and outpatient procedures. This article provides a review of the fundamentals of sedation/analgesia, monitored anesthesia care, and local anesthetics.
Key words: Sedation/analgesia, Monitored anesthesia care, Lipid rescue, Local anesthetic toxicity, Maximum dose recommendations
• Other Sections▼
o Abstract
o Sedation/Analgesia and MAC
o Regional Blocks and Topical Anesthesia
o Conclusion

Analgesic techniques for obstetric and gynecologic patients include local infiltration and regional blocks with or without sedation, parenteral agents and neuraxial blockade during labor, and general anesthesia for more extensive surgeries and, occasionally, for cesarean deliveries. Although the American College of Obstetricians and Gynecologists (ACOG) and the American Society of Anesthesiologists (ASA) have established goals to ensure prompt provision of anesthetic services in all hospitals providing obstetric care, ensuring such services remains a challenge, particularly in smaller hospitals or in rural locations.1 As a result, anesthesia expertise may not be available for routine labor management and, rarely, during emergency cesarean deliveries. In addition, the obstetrician-gynecologist (ob-gyn) is often solely or primarily responsible (in conjunction with nursing staff) for analgesia and sedation during office-based or outpatient procedures. This article provides a review of the fundamentals of sedation/analgesia, monitored anesthesia care (MAC), and local anesthetics.
Sedation/Analgesia and MAC
Sedation/analgesia and MAC, as distinguished by the depth of sedation attained and the level of expertise of the individual administering and monitoring the sedation, are the anesthetic techniques of choice, alone or in combination with regional blocks, for a number of outpatient and office-based obstetric and gynecologic procedures. As such, a review of ASA recommendations for the provision of sedation/analgesia by nonanesthesiologists, as well as a summary of the mechanisms, physiologic effects, dosing regimens, and peculiar characteristics of the anesthetic drugs most commonly used during intravenous (IV) sedation and MAC procedures, is in order.
In 2002, the ASA updated its recommendations for various aspects of sedation/analgesia, including preprocedure patient evaluation, monitoring, training of personnel involved, and recovery care.2 In addition to defining the various levels of sedation/analgesia (Table 1), the guideline task force underscores that the provider must be prepared to rescue patients in the event of drug-induced respiratory depression, airway obstruction, and/or cardiovascular collapse. Beyond preoperative evaluation with strict attention to airway concerns (Table 2), coexisting diseases, and nil per os status (Table 3), such preparedness involves vigilant monitoring of the patient’s response to verbal and painful stimuli, detection of hypoxia with pulse oximetry, observation and auscultation of ventilatory function with or without exhaled carbon dioxide detectors, blood pressure measurements at regular intervals, and electrocar-diographic monitoring, if indicated by the level of sedation or the patient’s cardiovascular risk factors. Supplemental oxygen, per face mask or nasal cannula, should also be provided, particularly at deeper levels of sedation. Another integral aspect of preparedness is availability of emergency airway and resuscitation equipment, as well as personnel trained in cardiopulmonary resuscitation (CPR). Often a chin-lift maneuver and/or stimulation, placement of an oral or nasal airway, or ventilation using positive pressure by face mask suffices if the patient develops airway obstruction or loses respiratory drive temporarily. However, more advanced airway protection and CPR are critically important skills, as is working knowledge of the drugs commonly administered.
Propofol
Propofol, a substituted isopropyl-phenol that increases inhibitory γ-aminobutyric acid activity, is a commonly used IV sedative-hypnotic that features a rapid onset, swift redistribution, and a relatively benign side-effect profile. Although it provides no clinically significant analgesia, propofol has antiemetic, antipruritic, and anticonvulsant properties, and effectively temporizes emergence delirium.3
Propofol produces rapid and profound decreases in consciousness that can culminate rapidly in a state of general anesthesia. At doses of 1.5 to 2.5 mg/kg IV, it induces unconsciousness within roughly 30 seconds. Doses vary dramatically, but conscious sedation can be achieved with 25 to 100 μg/kg/min. Alternatively, small intermittent boluses, titrated to effect, or administration of 0.7 mg/kg with 3-minute lockout periods are effective regimens for IV conscious sedation.4 Recovery from propofol should occur within minutes, and is generally marked by a sense of well-being.
At sedative doses of propofol, the provider should anticipate decreases in systemic blood pressure and dose-related depression of ventilation, with little to no decrease in heart rate. However, bradycardia and asystole, refractory to anticholinergics and possibly associated with decreased sympathetic activity, have been reported with propofol.5 Dose-dependent depression of ventilation, exacerbated by concomitant administration of benzodiazepines or opioids, occurs with both sedative and induction doses of propofol. As a result, supplemental oxygen should always be used during its administration. Further, clinicians well versed not only in propofol administration, but also in emergency equipment and rescue procedures should be prepared to intervene.
Propofol is a water-insoluble drug that is suspended in soybean oil and egg lecithin to create an aqueous solution. The preparation burns on injection, supports bacterial growth, and, rarely, can cause anaphylactic reactions in patients with multiple drug and/or food sensitivities.6 Selection of larger veins, prior administration of IV lidocaine, and slow administration with a generous crystalloid infusion may serve to minimize the undesirable burning sensation commonly experienced upon injection of propofol. It is recommended that unused propofol from an open vial be discarded within 6 hours.
Midazolam
Midazolam, a water-soluble benzodiazepine, is commonly used in combination with other agents for its anxiolytic, amnestic, and hypnotic properties during conscious sedation/MAC and during procedures under local or regional blocks. In contrast to diazepam, midazolam has a steep dose-response curve that necessitates careful titration to avoid oversedation, boasts a short elimination half-life of roughly 1 to 4 hours, has clinically inactive metabolites, and is painless upon injection.7 Further, it decreases analgesic requirements and diminishes agitation without cardiovascular depression. However, significant respiratory depression, particularly when used in combination with opioids, and postoperative psychomotor and cognitive impairment warrant caution during its administration. Marked variability in dose-response among patients, with the elderly particularly sensitive, is also common with midazolam. Flumazenil, a benzodiazepine antagonist, reverses midazolam’s sedative and amnestic effects, but its short duration (45–90 minutes) leads to concerns for resedation (Table 4). With regard to the obstetric population, midazolam crosses the placenta, enters fetal circulation, and may contribute to neonatal depression. A disadvantage with midazolam premedication for cesarean delivery is the potential for maternal amnesia.
Midazolam 2 mg IV administered prior to propofol sedation has proven to decrease intraoperative anxiety, recall, and discomfort without prolonging recovery from propofol.8 Patients who take benzodiazepines on a regular basis may require a higher initial dose and more frequent redosing vis-à-vis the benzodiazepine-naive patient, although the potential for respiratory impairment must be considered. Midazolam in combination with opioids leads to a marked synergistic effect that clinically decreases the dose of each required for hypnosis and analgesia and also increases the likelihood of life-threatening complications, such as hypoxemia and apnea.9 Midazolam’s duration of sedation is roughly 15 to 80 minutes, although time to complete recovery may be significantly longer.10
Fentanyl
Fentanyl, an opioid, is a common component of conscious sedation/MAC on account of its profound, short-lived analgesia and its synergistic reduction in sedative dose requirements. Compared with morphine, fentanyl is highly lipid soluble and boasts a more rapid onset, a roughly 100-fold greater potency, and a shorter duration of action. Unlike morphine, fentanyl is not associated with histamine release and, alone, seldom produces hypotension.
Low doses of fentanyl (1–2 μg/kg IV) exert a peak effect within 5 minutes and provide effective analgesia for roughly 30 minutes. Fentanyl may be redosed in 25- to 50-μg increments during conscious sedation procedures, keeping in mind that the effect-site equilibration time may be prolonged and that the concomitant administration of sedatives reduces analgesic requirements. Although fentanyl swiftly redistributes to inactive tissues, prolonged infusions or frequent redosing may lead to saturation of inactive sites and significant prolongation of action, including adverse effects.
Analgesic doses of fentanyl only minimally impact the cardiovascular system. However, bradycardia, which can result in decreases in blood pressure and cardiac output, is more common at higher doses and with concomitant administration of sedatives, such as benzodiazepines. Fentanyl causes dose-related respiratory depression, which is also more pronounced when administered in combination with sedatives. Naloxone is a pure opioid antagonist that reverses the effects of fentanyl and other opioids. Titrated in 0.04 mg IV increments every 2 to 3 minutes, naloxone can effectively reverse pruritus, nausea, respiratory depression, and other adverse opioid effects without altering analgesia. However, naloxone should be used with caution, as it may acutely reverse analgesia, precipitate withdrawal syndrome, and cause hypertension, pulmonary edema, and arrhythmias. Renarcotization may occur, requiring redosing every 30 minutes.
Remifentanil
Remifentanil, another opioid, can provide an appropriate analgesic complement to local, regional, and MAC cases due to its rapid onset and reliably rapid offset. Specifically, its effect-site equilibration time is 1 to 1.5 minutes, facilitating titration to patient comfort. Further, unlike other opioids used in clinical practice today, remifentanil is metabolized primarily by nonspecific esterases, ensuring rapid offset and minimal to no accumulation during prolonged infusions. This predictable onset and clearance reduces the risk of respiratory depression and renders remifentanil well suited for outpatient procedures. However, administration by experienced providers and vigilant monitoring of remifentanil’s inherent, potent respiratory depressant effect is paramount.11 Concomitant administration of other agents, such as midazolam, may lead to a synergistic respiratory depressant effect.
During conscious sedation and MAC, remifentanil is often administered in conjunction with propofol or midazolam via continuous infusion, at doses ranging from 0.05 to 0.25 μg/kg/min. A single slow bolus of 1 μg/kg over 30 to 60 seconds prior to a specific, short-lived stimulus, such as a regional block, has been shown to be effective, albeit not without risk of respiratory depression.12 Because the analgesic effect of remifentanil is short lived at 6 to 10 minutes, it alone is not appropriate for procedures in which postoperative pain is expected.
Ketamine
A phencyclidine derivative with inhibitory activity at the N-methyl D-aspartate receptors, among several other target receptors, ketamine is frequently used for pediatric and adult sedation, as an analgesic complement to neuraxial and general anesthesia, as an induction and maintenance agent, and for postoperative pain relief. For sedation/analgesia purposes, ketamine provides profound analgesia, albeit for somatic more than visceral pain, and amnesia without depressing ventilatory function. It also stimulates release of endogenous catecholamines and increases sympathetic nervous system outflow, thereby increasing heart rate, arterial blood pressure, and cardiac output, as well as myocardial oxygen demand. However, in patients with imminent cardiovascular collapse and limited catecholamine reserves, ketamine may cause direct myocardial depression. Although ketamine generally preserves respiratory function and causes marked bronchodilation, it stimulates copious secretions and may predispose patients to laryngospasm.
Ketamine causes a dissociative, cataleptic-like state, marked by lack of communication and a nystagmic gaze, which may make it difficult to discern depth of sedation and which may contribute to profound emergence delirium. Vigilance and preparedness to rescue a patient from cardiorespiratory collapse is therefore required during ketamine sedation, particularly in the presence of other sedatives. Finally, ketamine causes an increase in cerebral blood flow and, at least theoretically, intraocular pressure, so caution must be used when selecting the appropriate patient population for ketamine sedation.
Ketamine is available in a racemic form, although the S (+) isomer, with fewer untoward effects and far greater potency, is commonly used outside the United States. Intense analgesia at subanesthetic doses of 0.2 to 0.5 mg/kg IV occurs within 1 minute of administration and lasts approximately 20 to 60 minutes. Infusions of 10 to 100 μg/kg/min or intermittent boluses of one-third to one-half of the initial dose, titrated to effect, are effective maintenance regimens.
Dexmedetomidine
Dexmedetomidine, a highly specific α2-agonist, has gained popularity as an adjuvant to general anesthesia, a sedative for awake intubations and similar conscious sedation procedures, the sole anesthetic agent for certain surgical procedures, and as a postoperative sedative in intensive care units. An agent with anxiolytic, sedative, hypnotic, and analgesic properties, dexmedetomidine shows particular promise also for its limited impact on the respiratory system and for its stable and predictable hemodynamic effects, namely a reduction in both heart rate and blood pressure. The initial hemodynamic response to the loading dose, however, is often marked by a transient increase in blood pressure. The decrease in heart rate that ensues may be marked, requiring swift dose adjustment and/or anticholinergic treatment. Vigilance to patient monitoring must be maintained also to avoid airway obstruction related to a deeper-than-anticipated level of sedation. Atipamezole, a selective α2-adrenoceptor antagonist, rapidly reverses the sedative and cardiovascular effects of dexmedetomidine, although it is not routinely readily available.
Dexmedetomidine is generally administered via a loading dose of 0.5 to 1 μg/kg IV over 10 to 20 minutes, followed by an infusion of 0.2 to 0.7 μg/kg/h. It is available in 2-mL vials containing 100 μg/mL and requires careful dilution prior to administration.
Regional Blocks and Topical Anesthesia
Several obstetric and gynecologic procedures are currently performed under regional nerve block or with topical local infiltration, including cervical cerclage, dilatation and evacuation, and perineal infiltration, among others. As such, an intimate understanding of the mechanism, pharmacology, dosing, and toxicity of local anesthetics is indispensable for the patient provider.
Local anesthetics in use today fall into 2 broad categories, esters and amides (Table 5). Esters, which include cocaine, procaine, chloroprocaine, and tetracaine, among others, are metabolized by the enzyme pseudocholinesterase (aka, plasma cholinesterase), whereas amides, including lidocaine, mepivacaine, bupivacaine, prilocaine, and ropivacaine undergo hepatic metabolism. Levobupivacaine, the less cardiotoxic S-enantiomer of bupivacaine, has been withdrawn from the US market. Amides and their metabolites linger longer than esters, whereas clinically relevant esters are predictably and rapidly metabolized, except in the rare case of pseudocholinesterase deficiency.
Local anesthetics are often categorized by onset, potency, and duration. Onset is determined primarily by pKa, whereas potency is related to lipid solubility and duration is associated with protein binding. The addition of sodium bicarbonate in a ratio 1 mL to 10 mL of local anesthetic, which effectively increases the pH of the local anesthetic to approximate its pKa, speeds onset by roughly 3 to 5 minutes.13 With regard to potency of commonly used local anesthetics, lidocaine, mepivacaine, and chloroprocaine are considered intermediate in potency; ropivacaine and bupivacaine are highly potent.14 Chloroprocaine is of short duration; lidocaine and mepivacaine are moderate in duration; and bupivacaine has a long duration of action.
Toxicity of local anesthetics ranges from the rare allergic reaction to central nervous system (CNS) derangements and cardiotoxicity. Allergic reactions to esters can be traced to the metabolite para-aminobenzoic acid, whereas allergic reactions to amides may be due to the preservatives present in multiuse vials that are structurally similar to para-aminobenzoic acid. These rare reactions manifest as rash, urticaria, laryngeal edema, and, in extreme cases, bronchospasm and hypotension, and must be distinguished from tachycardia and hemodynamic changes associated with inadvertent intravascular injection of epinephrine-containing local anesthetics. Cross-sensitivity between esters and amides does not occur in the absence of a common metabolite or preservative, namely para-aminobenzoic acid.
Systemic toxicity from local anesthetics results from excessive plasma concentration in the blood, most often due to inadvertent intravascular injection during a nerve block. Less often, systemic absorption from the injection site culminates in toxicity. Site of injection, including vascularity of the area, dose injected, properties of local anesthetic administered, and the presence or absence of epinephrine affect the degree of systemic absorption. In descending order, the areas of highest plasma concentration from absorption include intercostal, caudal, paracervical, epidural, brachial plexus, and sciatic/femoral. The addition of epinephrine in a concentration of 5 μg/mL (1:200,000) serves to diminish this systemic absorption via vasoconstriction and has the additional benefits of decreasing blood loss and prolonging the duration of action of local anesthetics. However, it is not recommended in patients with uncontrolled hypertension, arrhythmias, or cardiovascular disease, for parturients with suspected uteroplacental insufficiency, or for administration in highly vascular areas where high systemic absorption is likely.
With regard to epinephrine, 1:200,000 means 1 g per 200,000 mL; as there are 1,000,000 μg in 1 g, 1:200,000 is equivalent to 5 μg/mL.15 Also note that epinephrine comes in different packages of 1:1000 (ie, 1 mg/mL) and 1:10,000 (ie, 0.1 mg/mL). Alternatively, it is available premixed with local anesthetic, usually in the 5 μg/mL concentration. Similarly, packaging and concentrations vary among local anesthetics. Care must be taken to review the concentration before administration and to confirm concentration in milligrams per milliliter. For example, 2% lidocaine contains 20 mg/mL, and 1.5% lidocaine contains 15 mg/mL.
Early signs of systemic toxicity range from lightheadedness, dizziness, circumoral numbness, tinnitus, slurred speech, and restlessness. Over-activity of the CNS, as manifested by twitches, tremors, and, often, tonicclonic seizures, marks the more advanced stages of neurotoxicity. Global CNS depression, culminating in unconsciousness and respiratory arrest, ultimately develops. Acidosis, hypercarbia, and hypoxia both predispose to and exacerbate CNS toxicity. Although the cardiovascular system is more resistant to local anesthetic toxicity than the CNS, at high plasma concentrations profound hypotension, dysrhythmias, and conduction blockade of the cardiac sodium channels occur. Bupivacaine, with its high lipid solubility, is particularly worrisome with regard to cardiotoxicity, reflecting its high affinity for and its slow dissociation from cardiac sodium channels, among other protein receptors. In addition, bupivacaine-induced cardiotoxicity appears highly refractory to resuscitation efforts. However, cardiotoxicity is not limited to bupivacaine, as demonstrated by case reports of adverse cardiac events with the administration of etidocaine and, rarely, mepivacaine, lidocaine, and ropivacaine, among others. Pregnancy,16 the concomitant administration of epinephrine and phenylephrine, coexisting cardiac disease, and tachycardia may lower the threshold for bupivacaine-induced cardiotoxicity. Treatment of CNS and cardiotoxicity requires immediate attention to airway, oxygenation, and ventilation and early commencement of cardiopulmonary resuscitation, as well as the timely administration of a benzodiazepine, such as midazolam, or thiopental, a barbiturate, for seizure control.
Over the past decade, a series of case reports have demonstrated the successful treatment of refractory local anesthetic-induced toxicity with IV lipid emulsion.17 Although the timing, dose, and exact mechanism are not yet agreed upon, multiple case reports have demonstrated that the administration of a loading dose of a 20% lipid emulsion (1-1.5 mg/kg IV), followed by a 0.25 mL/kg/min infusion, may serve to bind the excess lipid-soluble local anesthetics in the bloodstream. Standard therapy and cardiopulmonary resuscitation are to be continued throughout.
Although systemic reactions to local anesthetics cannot be avoided completely, several recommendations may aid in the reduction of the incidence of adverse outcomes. Limiting the total dose of local anesthetic administered, frequent negative aspirations for intravascular injection, divided dosing, and an epinephrine test dose may serve to minimize complications.18 With regard to maximum total dose, current recommendations are not evidence based, and the practitioner must take into account the site of injection, the presence or absence of epinephrine, and patient-specific factors that may influence the pharmacokinetics of the local anesthetic, including pregnancy, age, and coexisting disease.19 Although current recommendations vary from country to country and among manufacturers, broadly accepted maximum doses, applicable to systemic absorption, may serve to complement clinical acumen .
Conclusion
The gynecologist/obstetrician is often solely or primarily responsible (in conjunction with nursing staff) for analgesia/sedation and regional blocks during office-based and outpatient procedures. ASA guidelines for the provision of analgesia/sedation for nonanesthesiologists, reviewed in this article, provide helpful recommendations to maximize patient safety during office-based and outpatient procedures. A working knowledge of the drugs commonly used, including hypnotics, sedatives, analgesics, and local anesthetics, and preparedness to rescue a patient in the event of apnea, cardiovascular collapse, or local anesthetic-induced toxicity, are additional indispensable tools.