Anesthesia and Analgesia in the Neonate
Sally H. Vitali
Anthony J. Camerota
John H. Arnold
Despite the widespread use of potent analgesic agents in adult patients and older children, it is remarkable that, until recently, systemic analgesia and sedation were rarely administered to neonates. An analysis of neonatal anesthetic practice published in 1985 revealed that only 23% of preterm infants undergoing patent ductus arteriosus ligation received adequate intraoperative anesthesia (1). In a retrospective survey of opioid use in a single institution, only 14% of 933 neonates received opioid analgesia after a variety of surgical procedures (2). However, in a 1995 questionnaire, all neonates received either systemic opioids and/or regional anesthesia for major surgery (3). Although appreciation and management of operative and postoperative pain in neonates has improved, use of analgesia for nonoperative painful procedures remains limited. Despite evidence that premedication reduces the pain and physiologic instability associated with awake direct laryngoscopy and endotracheal intubation in neonates, surveys in the United States, Canada, and Great Britain indicate that premedication is rare even in nonemergent intubations in neonatal intensive care units (4,5,6,7). Circumcision is another known source of neonatal pain that can be reduced with premedication, but a 1998 survey of residency programs teaching circumcision training practices indicated that 26% of programs teaching circumcision provided no training in anesthesia and analgesia for the procedure (8). A recent consensus statement by the American Academy of Pediatrics and Canadian Pediatric Society recognizes the recent improvement in neonatal pain assessment and management but concludes that “prevention and treatment of unnecessary pain attributable to anticipated noxious stimuli remain limited” (9).
Although adequate anesthesia and analgesia were not given to neonates in the past because of the belief that they could not feel pain, there is overwhelming evidence that pain perception and physiologic responses to stress occur in neonates of all gestational ages (10). It is broadly accepted that anesthesia and analgesia in the neonatal population have important clinical and physiologic consequences and may have long-term psychologic impact. Control of the stress response in the perioperative period may improve the outcome of infants after cardiac surgery (11,12). Appropriate analgesia and sedation are proven means of reducing catabolism associated with surgery and recovery from surgery, illness, and injury (13). Human and animal studies have found compelling evidence that early pain and stress affect nociception and behavioral responses to pain later in life, but the conflicting results of these studies leave the nature and mechanism of these long-term effects largely unexplained (14,15). Given that critically ill preterm neonates have been reported to experience as many as 488 painful procedures during their stay in neonatal intensive care units, pain and its management may have profound implications for the health of these children (16).
As these data are assimilated and accepted, there is often a discrepancy between the growing understanding of neonatal pain and actual clinical practice. A survey of British pediatric anesthetists found that only 5% routinely prescribed systemic opioids to neonates postoperatively, although 80% of the respondents believed that neonates feel pain (17). There are probably several reasons for the lag in changing clinical practice to match current knowledge, but a crucial element may be the lack of standard guidelines for the use of drugs, doses, and schedules that can be applied to various clinical situations by the practitioner at the bedside. The International Evidence-Based Group for Neonatal Pain summarized the current evidence for a set of standard guidelines in 2001; the impact of these guidelines on clinical practice remains to be studied (18).
This chapter reviews the rapidly developing field of neonatal anesthesia and analgesia, summarizes the relevant pharmacokinetic and pharmacodynamic data, and highlights practical considerations for the most commonly used agents.
PAIN PERCEPTION
In addition to the ethic arguments for preventing needless human suffering, the risks and benefits of using anesthesia and analgesia to prevent pain and stress must be physiologically evaluated. Pivotal aspects of this physiologic rationale are based on one question: Does the neonate feel pain?
Components of the pain system may be traced from sensory receptors in the skin to sensory areas in the cerebral cortex and used as a framework to study its development (4). The density of nociceptive nerve endings in newborn skin, labeling of specific proteins (e.g., GAP-43) produced by axonal growth cones, reflex activity and receptive fields of primary afferent neurons, and development of synapses between primary afferents and interneurons in the dorsal horn of the spinal cord indicate the anatomic and functional maturity of the peripheral pain system during fetal life (19,20). Cellular and subcellular organization in the dorsal horn, with maturation of primary afferent terminations, occur during later in gestation and postnatally (21,22). In the dorsal horn, various neurotransmitter and neuromodulatory substances associated with pain (e.g., substance P, somatostatin, calcitonin gene-related peptide, vasoactive intestinal peptide, met-enkephalin, glutamate) appear during early gestation (23).
Lack of myelination in neonatal nerves or central nerve tracts is offset completely by the shorter interneuronal and neuromuscular distances traveled by the impulses. Quantitative neuroanatomic data show that nociceptive nerve tracts in the spinal cord and central nervous system undergo complete myelination during the second and third trimesters of gestation (10). Subcortical foci associated with nociception are characterized by a high density of opioid receptors during the middle of gestation, with a differential reduction in binding capacities during the third trimester (24). Development of the fetal neocortex begins at 8 weeks of gestation; by 20 weeks, each cortex has a full complement of 109 neurons. Arborization of dendritic processes in the cortical neurons is followed by synaptogenesis with incoming thalamocortical fibers by 24 to 26 weeks of gestation. Functional maturity of the cerebral cortex is suggested by fetal and neonatal electroencephalographic patterns, cortical somatosensory-evoked potentials, studies of regional cerebral metabolism, early behavioral development, and the specific behavioral responses of neonates to painful stimuli (10,25).
Endorphinergic cells in the anterior pituitary are responsive to corticotrophin-releasing factor stimulationin vitro and show increased β-endorphin production during fetal and neonatal life. Endogenous opioids and other hormones (e.g., catecholamines, steroid hormones, glucagon, growth hormone) are secreted by the human fetus in response to stress, leading to catabolism and other complications (12,26). Significant changes in cardiovascular parameters, transcutaneous partial pressure of oxygen, and palmar sweating have been observed in neonates undergoing painful clinical procedures. These physiologic changes are closely associated with behavioral responses of newborns to pain. Neonatal behavioral responses are characterized by simple motor responses, precise changes in facial expression associated with pain, highly specific patterns of crying activity, and a variety of complex behavioral changes. These neonatal responses suggest integrated emotional and behavioral changes correlated with pain, and they are retained in memory long enough to modify subsequent behavior patterns (10).
The surgical stress responses of neonates can be inhibited by potent anesthesia, as demonstrated by randomized trials of halothane anesthesia in term neonates, fentanyl anesthesia in preterm neonates, and sufentanil anesthesia in neonates undergoing cardiac surgery (12,27,28). These results imply that the nociceptive stimuli during surgery are at least partially responsible for the marked stress responses of neonates and are prevented by the provision of adequate anesthesia. In these trials, the reduction in surgical stress responses was associated with significant improvements in clinical outcome, supporting the use of potent anesthetic agents for newborns undergoing surgery. In contrast, a recent randomized, double-blind study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion in infants less than 6 months old undergoing cardiac surgery found that these anesthetic regimens did not blunt the metabolic and hormonal responses to surgical stress, yet no adverse postoperative outcomes were observed. These findings indicate that improvements in clinical outcome observed in previous trials may have been related to factors other than reduction in surgical stress (29).
In recent years, the concept of blunting the pain response in neonates to improve physiologic parameters has been extended from the operating room to the intensive care unit. High-dose narcotic anesthesia for the first postoperative night after complex cardiac surgery reduces mortality (6,30,31). Using narcotics during painful procedures, such as tracheal suctioning, has been shown to reduce concomitant hypoxemia (32). Fentanyl infusions have been shown to decrease plasma stress hormone levels in preterm infants (33). A multicenter pilot study of 67 premature infants randomized to midazolam (0.2 mg/kg loading dose followed by 0.02 to 0.06 mg/kg/hour infusion), morphine (0.1 mg/kg loading dose followed by 0.01 to 0.03 mg/kg/hour infusion), or 10% dextrose for up to 14 days of mechanic ventilation showed improvement in pain scores and neurologic outcome in the morphine-treated infants, but a much larger trial will be required before this practice can be universally recommended (34).
ANESTHESIA
Anesthesia is classically defined as a drug-induced state that includes analgesia, amnesia, and muscle relaxation.
The provision of anesthesia to infants undergoing surgical procedures has gone through a remarkable transition coincident with the development of new intravenous agents and more sophisticated monitoring techniques. As recently as 1985, there was considerable debate about whether neonates feel pain, and sophisticated researchers advocated the use of minimal anesthesia in neonates undergoing surgical procedures, citing the dangers of anesthetic administration to this population (35,36,37). Beginning with the landmark paper of Robinson and Gregory (38), practitioners of neonatal and pediatric anesthesia have proclaimed the importance of providing adequate anesthesia, particularly to ill preterm infants (38,39). In modern anesthetic practice, adequate anesthetic depth and control of the neonatal stress response can be achieved without undue risk to the infant.
The provision of anesthesia to infants undergoing surgical procedures has gone through a remarkable transition coincident with the development of new intravenous agents and more sophisticated monitoring techniques. As recently as 1985, there was considerable debate about whether neonates feel pain, and sophisticated researchers advocated the use of minimal anesthesia in neonates undergoing surgical procedures, citing the dangers of anesthetic administration to this population (35,36,37). Beginning with the landmark paper of Robinson and Gregory (38), practitioners of neonatal and pediatric anesthesia have proclaimed the importance of providing adequate anesthesia, particularly to ill preterm infants (38,39). In modern anesthetic practice, adequate anesthetic depth and control of the neonatal stress response can be achieved without undue risk to the infant.
The appropriate anesthetic technique is dictated by the preoperative condition of the patient, planned surgical procedure, and skills of the anesthetist. The encounter between the anesthesiologist and neonate usually occurs in the setting of a surgical emergency, and a general anesthetic with control of the airway is most often the technique of choice. General anesthesia is provided using a combination of inhaled and intravenous agents and muscle relaxants. The inhaled agents include an inorganic gas (e.g., nitrous oxide) and volatile liquids (e.g., halothane, enflurane, isoflurane, sevoflurane, and desflurane). Delivery of potent inhaled agents by means of the respiratory system offers a reliable route of administration and excretion with the ability to rapidly alter anesthetic concentrations in the central nervous system.
Inhaled Anesthetics
Each of the inhaled anesthetic agents has unique effects on the cardiovascular, respiratory, and central nervous systems, which are not exhaustively reviewed here (Table 57-1). The volatile anesthetics produce dose-dependent decreases in mean arterial blood pressure, particularly in premature infants, due to direct myocardial depression, and decreases in systemic vascular resistance due to exaggerated depression of the baroreceptor reflex (40,41,42). Nitrous oxide produces minimal alterations in myocardial performance or systemic vascular resistance, due in part to direct stimulation of the sympathetic nervous system (43). However, if combined with a potent volatile agent or opioids, nitrous oxide significantly depresses myocardial contractility (44). If ventilation is carefully controlled, nitrous oxide has insignificant effects on pulmonary vascular resistance (45).
TABLE 57-1 SYSTEMIC EFFECTS OF INHALED ANTHESTHETICS | ||||||||||||||||||||||||||||||||||||||||
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All inhaled agents increase the respiratory rate, reduce tidal volume and functional residual capacity, decrease the ventilatory responses to hypoxemia and hypercapnia, and decrease bronchial smooth muscle reactivity. These agents produce a dose-dependent increase in cerebral blood flow despite simultaneous depression of cerebral metabolic oxygen requirement. At high concentrations, isoflurane and desflurane induce an isoelectric electroencephalographic pattern; this property is not shared by the other inhaled anesthetic agents.
Although halothane is most frequently associated with perioperative hepatic dysfunction, other inhaled agents and intravenous anesthetics may result in hepatic necrosis (46). True halothane-induced hepatitis is a rare event, occurring in approximately 1 of 30,000 patients. It is seen most commonly after repeated administration and is probably mediated by an immune mechanism involving an intermediate oxidative metabolite (47,48). The inhaled agents produce dose-related decreases in renal blood flow and urine output due to effects on cardiac output and systemic vascular resistance. Fluoride-induced nephrotoxicity is a potential complication of prolonged exposure to the fluorinated hydrocarbons (e.g., enflurane, isoflurane), although it is of practical concern only during prolonged administration of enflurane and sevoflurane (49,50).
Two newer inhaled anesthetics, sevoflurane and desflurane, are gaining popularity due to their low lipid solubility (51). This property allows for rapid induction of anesthesia as well as a short recovery time. Sevoflurane has the advantage of providing a smooth, less irritating induction of anesthesia that rivals that of halothane, with less risk of hepatitis and fewer hemodynamic effects (52,53). The drawbacks are the biotransformation of sevoflurane into potentially toxic Compound A (2-fluoromethoxy-1,1,3, 3,3-pentafluoro-1-propene) and the accumulation of fluoride ions (54,55). As in adults, inhaled sevoflurane has been shown to prolong the QTc interval in infants, an
effect that lasts at least 60 minutes into the postoperative period (56). Desflurane does not undergo biodegradation in vivo or in vitro, but its irritating effects on the airway prevent its role as an induction agent (57,58).
effect that lasts at least 60 minutes into the postoperative period (56). Desflurane does not undergo biodegradation in vivo or in vitro, but its irritating effects on the airway prevent its role as an induction agent (57,58).
Opioid Anesthesia
Morphine and the synthetic opioids have been a consistent adjunct to the volatile agents throughout the history of anesthesia. High-dose opioids have become the preferred anesthetic technique for cardiac surgical procedures in adults and children (59,60). The virtues of opioids include minimal effects on myocardial performance, ablation of pulmonary vascular responses to nociceptive stimuli, and preservation of hypoxic pulmonary vasoconstriction (61,62,63).
Because of their wide margin of safety in ill infants with congenital heart disease, opioid anesthesia is often effective in ill preterm infants with cardiopulmonary instability undergoing surgical stress. Fentanyl, sufentanil, and remifentanil are the most popular agents due to their negligible effect on cardiovascular function, but if combined with other anesthetic agents, these opioids may be associated with significant hemodynamic instability. Morphine anesthesia may increase plasma histamine concentrations and decrease vascular resistance, and it is not recommended as a primary anesthetic for ill neonates (64).
The elimination half-lives of most opioids are variable but significantly prolonged in the neonate (Table 57-2) and may be further prolonged by any compromise of hepatic blood flow (65,66,67,68,69,70). The exception to this rule is the synthetic opioid remifentanil; a recent study in children showed that clearance was as much as twice as rapid in infants from birth to 2 years than in older children, and half-life was similar in all age groups studied (71). Premature infants have an even more prolonged morphine clearance than term newborns that shortens with postconceptual age (72). Prolonged postoperative respiratory depression may occur if these important pharmacokinetic variables are ignored in the perioperative period.
Regional, Neuraxial, and Local Anesthesia
Regional anesthetic techniques have become increasingly popular in the pediatric and neonatal populations (73). General anesthesia may be associated with an increased incidence of postoperative apnea in the preterm infant (74). This may be a particularly difficult issue in the day-surgery setting, where former preterm neonates commonly present for minor surgical procedures (e.g., circumcision, herniorrhaphy). It is in this population that regional or local anesthetic techniques may be particularly advantageous. The use of spinal anesthesia for herniorrhaphy decreases the need for postoperative mechanic ventilation in former preterm infants matched for gestational age at birth and incidence of bronchopulmonary dysplasia (75). Epidural anesthesia has been shown to reduce the need for postoperative ventilation after both esophageal atresia repair and Nissen fundoplication (76,77).
TABLE 57-2 ELIMINATION HALF-LIVES OF OPIOIDS | |||||||||||||||||||||||||||||||||||
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Spinal anesthesia consists of injection of an anesthetic agent into the subarachnoid space. The technique is easy to perform and safe (78,79). The most frequent local anesthetic agents are hyperbaric lidocaine, tetracaine, and bupivacaine. Side effects of spinal anesthesia, such as dural puncture headaches and hemodynamic compromise, are common in adults but surprisingly uncommon in infants or children (78,80).
Epidural anesthesia consists of a single injection or repeated injections through an epidural catheter of an anesthetic agent into the potential space between the dura mater and ligamentum flavum. The advantage epidural has over spinal anesthesia is the potential for long-term, continuous, or intermittent administration of anesthetics. Although the epidural space can be approached at any level, for most infants, a lumbar or caudal epidural blockade is used. Caudally inserted epidural catheters can also be advanced to the thoracic region and dilute local anesthetic solutions applied for thoracic-level anesthesia in infants, but radiographic confirmation of tip placement has been shown to be important for safety (81). Caudal epidural blockade with bupivacaine is used most frequently for postoperative pain relief after lower abdominal and lower extremity procedures. Compared with older children and adults, infants and toddlers require higher doses of local anesthetic and demonstrate a shorter duration of effect. Combining local anesthetics with an epidural opioid (fentanyl, hydromorphone), clonidine, or ketamine prolongs the duration of analgesia (82). Several case reports have suggested that epidural clonidine may contribute to postoperative apnea in the former preterm infant (83,84,85). Caudal anesthesia has been sufficient as
the sole anesthetic technique for lower abdominal procedures (86). Caudal epidural blockade may be used in combination with general anesthesia in infants during abdominal procedures. Complications rarely result from improper placement of the needle and injection of the anesthetic agent into a vein, the dura, the subarachnoid space, or sacral marrow.
the sole anesthetic technique for lower abdominal procedures (86). Caudal epidural blockade may be used in combination with general anesthesia in infants during abdominal procedures. Complications rarely result from improper placement of the needle and injection of the anesthetic agent into a vein, the dura, the subarachnoid space, or sacral marrow.
Local anesthetics may be used to block peripheral nerves in infants undergoing limited surgical procedures (e.g., orchiopexy, herniorrhaphy, circumcision). These techniques are simple to perform, have limited complications, and significantly decrease the need for postoperative analgesia (87,88,89).
Local anesthetic toxicity is manifested by effects on the cardiovascular system (e.g., myocardial depression, arrhythmias) and central nervous system (e.g., delirium, seizures) (90,91). In premature infants, the subtle behavioral changes that precede cardiovascular collapse and generalized seizures may be difficult to recognize. The reduced protein binding and prolonged elimination of local anesthetics in this population make the neonate susceptible to toxic effects at lower doses, decreasing the therapeutic index. Careful attention to total administered dose (particularly with field blocks) and monitoring of cardiovascular parameters during the administration of any local anesthetic are essential.
The topical anesthetic EMLA, a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, has shown efficacy in neonatal circumcisions (92,93), but two randomized, controlled trials have shown that dorsal penile nerve block is more effective than EMLA (94,95). EMLA is not effective in reducing pain with heel sticks, perhaps owing to the incidental vasoconstriction associated with EMLA which may require more vigorous squeezing to obtain a blood sample (96). Oral sucrose has been shown to be more effective than EMLA as analgesia for neonatal venipuncture in two randomized, controlled trials (97,98). Although methemoglobinemia is a potential side effect of EMLA, it appears to be safe even in preterm infants (99,100). A newer topical agent, amethocaine, in a 4% gel, avoids the possibility of methemoglobinemia, and its vasodilatory effects on the skin may facilitate blood sampling (101).
Propofol
Propofol, as a loading dose of 2 to 4 mg/kg, acts as a complete anesthetic with a short recovery period, similar to or even briefer than the lipid-soluble pentothal. A continuous infusion of 50 to 100 mg/kg/minute maintains anesthesia and may, when discontinued, have a shorter recovery time than that of inhalation agents. However, prolonged infusions lead to lipid deposition and persistent anesthetic effects of propofol, even with discontinuation. A recent study of propofol infusions in neonates, infants, and children showed that most newborns and children have similar propofol pharmacokinetics as adults, but that elimination is prolonged in children after cardiac surgery and in low-birth-weight infants (102). Postoperative emesis and analgesic requirements may be reduced with propofol versus pentothal-halothane. Pain at the infusion site has limited the enthusiasm for propofol. Pain can be alleviated by adding 0.2 mg/kg of lidocaine for every 3 mg/kg of propofol. The incidence of hypotension with propofol is comparable to similar agents.
Prolonged propofol infusion (3 to 5 days) has been linked to metabolic acidosis, heart failure, and death in critically ill children. Associated with these have been lipemic serum and fatty infiltration of the liver (103). Propofol may be used during the course of some anesthetics, but a recent, unpublished clinical trial showed a significantly increased mortality in children sedated with propofol, and as a result, its use for sedation of children younger than 16 years is contraindicated (104).
ANALGESIA
Opioids
The provision of adequate analgesia for painful diseases and procedures should be of utmost concern to the neonatologist (105). Despite widespread misgivings about their potential side effects, systemic therapy with opioid analgesics remains the mainstay of treatment for severe pain in neonates. The administration of opioids produces profound analgesia and sedation through specific activity on μ1,δ, and other opioid receptors in the brain and spinal cord (106).
The dosage and mode of administration of opioids should be carefully titrated to avoid undertreatment of pain or oversedation (Fig. 57-1). Continuous intravenous infusion of opioids provides an effective alternative to intermittent intravenous doses, with constant blood levels and minimal fluctuations in analgesia. Nearly all opioids have prolonged half-lives in neonates (Table 57-2), and continuous infusions can result in a slow accumulation of the drug over time, with high blood levels that may not be considered or detected immediately. In addition, morphine has an active metabolite that can accumulate in renal insufficiency, compounding the narcotic effect. Despite this disadvantage, continuous intravenous infusion is ideal for providing a constant level of analgesia if appropriate precautions are observed.
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