Anesthesia and Analgesia in the Neonate
Sally H. Vitali
Despite the widespread use of potent analgesic agents in adult patients and older children, it is remarkable that, until the 1990s, systemic analgesia and sedation were not routinely 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). However, in a 1995 questionnaire, all neonates received either systemic opioids or regional anesthesia for major surgery (2). Although appreciation and management of operative and postoperative pain in neonates are now routine, use of analgesia for nonoperative painful procedures in neonates remains varied. Despite evidence that premedication reduces the pain and physiologic instability associated with awake direct laryngoscopy and endotracheal intubation in neonates and national and international consensus statements recommending premedication for all elective intubations, a 2006 survey of US neonatal fellowship program directors found that only 43.6% routinely provided sedative premedications for intubation (3). Similarly, the French EPIPAIN study reported that only 41.6% of elective intubations were premedicated (4). In contrast, the use of premedication for circumcision improved dramatically from the 1990s to 2000s. In surveys of family practice, pediatric, and obstetric residency programs, the percent reporting that they routinely teach analgesic premedication rose from 74% in 1998 to 97% in 2006 (5). A recent consensus statement by the American Academy of Pediatrics (AAP) and Canadian Pediatric Society notes that although effective pain relief is now usually provided for neonates during and after a major surgical procedure, pain-reducing therapies are often underused for the numerous minor procedures that are a part of routine medical and nursing care for neonates (6).
Pain perception and physiologic responses to pain and stress occur in fetuses and neonates of all gestational ages. In addition to their vital role in reducing suffering, anesthesia and analgesia in the neonatal population have important short- and long-term clinical, physiologic, psychological, and neurodevelopmental consequences. In the short term, anesthesia and analgesia control the stress response in the perioperative period and may improve the outcome of infants after surgery (7,8,9). Appropriate analgesia and sedation are proven means of reducing catabolism associated with surgery and recovery from surgery, illness, and injury. Human and animal studies have found compelling evidence that early pain and stress affect nociception and behavioral responses to pain later in life (10). Given that critically ill preterm neonates have been reported to experience an average of 11.4 painful procedures per day during their stay in neonatal intensive care units (NICUs), pain and its management may have profound implications for the health of these children (11).
As neonatal pain management has become more of a defined objective in the NICU, more than 40 scoring systems have been validated to attempt to quantify the magnitude of responses to pain in infants and drive the use of pharmacologic and nonpharmacologic pain control methods (12). One strategy that has had the most direct and quantifiable success in reducing the amount of pain in neonates is the reduction in the number of painful procedures performed (11). More recently, the choice of anesthetics and analgesics in neonates has been complicated by a growing body of animal data revealing the neurotoxicity of nearly all of the medications used for these purposes. Interpretation of these data and its translatability to the human is difficult, and effective nonneurotoxic alternatives for pain control and sedation are lacking.
In this chapter, the rapidly developing field of neonatal anesthesia and analgesia is reviewed, the relevant pharmacokinetic and pharmacodynamic data are summarized, and practical considerations for the most commonly used agents are highlighted.
▪ PAIN PERCEPTION
At the foundation of our understanding of the neonatal pain experience and efforts to control, is evidence that nociceptive pathways are present and functional even in preterm newborns.
In general, nociceptive pathways develop structure and function during gestation; their activity and function mature after birth as their organization and transcriptional program continue to develop. The density of nociceptive nerve endings in newborn skin, labeling of specific proteins (e.g., GAP43) 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 (13,14). Cellular and subcellular organization in the dorsal horn, with maturation of primary afferent terminations, occurs during later in gestation and postnatally (15,16). In the dorsal horn, various neurotransmitter and neuromodulatory substances associated with pain (e.g., substance P, somatostatin, calcitonin gene-related peptide, vasoactive intestinal peptide, metenkephalin, glutamate) appear during early gestation (17).
Myelination of the nociceptive nerve tracts in the spinal cord and central nervous system is completed during the second and third trimesters of gestation. Lack of myelination in some neonatal nerves or central nerve tracts is offset completely by the shorter interneuronal and neuromuscular distances traveled by the impulses. Development of the fetal neocortex begins at 8 weeks of gestation, and the full complement of neurons is present by 20 weeks. Dendritic processes in the cortical neurons arborize and then synapse with incoming thalamocortical fibers by 24 to 26 weeks of gestation (18). 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 (19).
Endorphinergic cells in the anterior pituitary are responsive to corticotrophin-releasing factor stimulation in 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 (12,20). 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 patterns form the basis for the pain scoring systems that have been developed, validated, and employed in the care of the term and preterm newborn.
Long-Term Effects of Neonatal Pain and Its Treatment
The developing nervous system of the neonate is vulnerable to insults that modulate neurodevelopment. These insults include not only the repeated stressors and pain necessitated by resuscitation and life support in the NICU but the medications used to blunt the infant’s responses to these stressors and painful interventions. Many studies in preterm infants and animal models have provided evidence that repeated painful interventions in the neonatal period contribute to hyperalgesia that is more profound and long-lasting than seen in nonneonates (21). Poorer developmental outcomes have been associated with increased exposure to procedural pain in both human preterm infants and animal neonates (22).
More recently, at least 50 studies in a number of different immature animal models have documented the neurotoxic effect of nearly every anesthetic or analgesic agent used in neonates (23). Many outcome studies of preterm and term infants who have undergone major surgery (and therefore major anesthesia) in the neonatal period provide some evidence that neurodevelopmental outcomes are adversely impacted by early anesthesia, but these data are confounded by many other complicating factors in these infants including the surgery itself and the multiple painful stressors in the NICU. A large analysis of very-low-birth-weight infants who underwent major surgery, compared with similar gestational age infants who did not undergo major surgery, found a 50% increased risk of death or neurodevelopmental impairment at 18 to 22 months’ corrected gestational age, but the question of how much of this difference is attributable to general anesthesia remains (24). Though the ability to translate this animal data to human neonates is questionable, it has reframed a number of research goals and fueled a desire to find less neurotoxic drugs and better treatment strategies for infants.
▪ 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 (25). Beginning with the landmark paper of Robinson and Gregory (26), practitioners of neonatal and pediatric anesthesia have proclaimed the importance of providing adequate anesthesia, particularly to ill preterm infants. In modern anesthetic practice, adequate anesthetic depth and control of the neonatal stress response can be achieved without undue acute 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 often 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 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 (8,27,28). 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 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).
Inhaled Anesthetics
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. Each of the inhaled anesthetic agents has unique effects on the cardiovascular, respiratory, and central nervous systems, which are not exhaustively reviewed here (Table 53.1). 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 (30,31). Nitrous oxide produces minimal alterations in myocardial performance or systemic vascular resistance, due in part to direct stimulation of the sympathetic nervous system. However, if combined with a potent volatile agent or opioids, nitrous oxide significantly depresses myocardial contractility (32).
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 (33). 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, although it is of practical concern only during prolonged administration of enflurane and sevoflurane (34).
Two newer inhaled anesthetics, sevoflurane and desflurane, are gaining popularity due to their low lipid solubility. This property
allows for rapid induction of anesthesia as well as a short recovery time (35). 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 (36). 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 (37). 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 (38).
allows for rapid induction of anesthesia as well as a short recovery time (35). 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 (36). 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 (37). 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 (38).
TABLE 53.1 Systemic Effects of Inhaled Anesthetics | |||||||||||||||||||||||||||||||||||||||||||||
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Opioid Anesthesia
Morphine and the synthetic opioids have been a consistent adjunct to the volatile agents throughout the history of anesthesia. Highdose opioids have become the preferred anesthetic technique for cardiac surgical procedures in adults and children. The virtues of opioids include minimal effects on myocardial performance, ablation of pulmonary vascular responses to nociceptive stimuli, and preservation of hypoxic pulmonary vasoconstriction (39,40).
Because of their wide margin of safety in ill infants with congenital heart disease, opioid anesthesia is often the anesthesiologist’s choice in 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.
The elimination half-lives of most opioids are variable but significantly prolonged in the neonate (Table 53.2) and may be further prolonged by any compromise of hepatic blood flow. 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 (41). Premature infants have a more prolonged morphine clearance than term newborns that shortens with postconceptual age (42). Prolonged postoperative respiratory depression may occur if these important pharmacokinetic variables are ignored in the perioperative period.
The prescription of opiates for their sedative properties has been extended from the operating room to intubated babies in the NICU. Whether infants should be routinely sedated with narcotics while intubated and mechanically ventilated has been investigated in a meta-analysis of 1,505 infants. Although pain scores were significantly improved with opiate use for this purpose, duration of mechanical ventilation, mortality, and short-term and long-term developmental outcomes were not improved. They concluded that opiates should not be used routinely for mechanical ventilation in neonates but selectively when supported by clinical judgment (43). This clinical judgment is assisted by frequent, regular pain scoring of neonates, which is the standard of practice in modern NICUs. More information about the use of opiates for pain management can be found in the “Analgesia” section below.
TABLE 53.2 Elimination Half-lives of Opioids | |||||||||||||||||||||||||||||||
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Regional, Neuraxial, and Local Anesthesia
Regional anesthetic techniques have become increasingly popular in the pediatric and neonatal populations for a number of reasons. General anesthesia may be associated with an increased incidence of postoperative apnea in the preterm infant (44). 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), and in this population, regional or local anesthetic techniques may be particularly advantageous. The use of spinal anesthesia for herniorrhaphy decreased the need for postoperative mechanical ventilation in former preterm infants matched for gestational age at birth and incidence of bronchopulmonary dysplasia (45). Epidural anesthesia has been shown to reduce the need for postoperative ventilation after both esophageal atresia repair and Nissen fundoplication (46,47). Beyond the opioid and mechanical ventilation-sparing effects of regional anesthesia, it may help reduce the use of general anesthetics that have been associated with neurodevelopmental injury in animal models (48).
Spinal anesthesia consists of injection of an anesthetic agent into the subarachnoid space. The technique is easy to perform and safe, especially under ultrasound guidance. The most frequent local anesthetic agents are racemic bupivacaine, levobupivacaine, and ropivacaine. Side effects of spinal anesthesia, such as dural puncture headaches and hemodynamic compromise, are common in adults but surprisingly uncommon in infants or children (49,50).
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. The most commonly used long-term anesthetic agents are bupivacaine and chloroprocaine, the latter of which has a shorter half-life (51). Although the epidural space can be approached at any level, for most infants, a lumbar or caudal epidural blockade is used. Epidural catheter placement can be challenging in neonates, but the improvement in ultrasound guidance has helped facilitate easier and safer placement (52). Though rare, case reports of spinal hematomas serve as a reminder that complications of epidural analgesia can be serious (53). Caudally inserted epidural catheters can also be advanced to the thoracic region and dilute local anesthetic solutions infused for thoracic-level anesthesia in infants, but radiographic confirmation of tip placement prior to infusion has been shown to be important for safety (54). A thoracic epidural or surgically placed paravertebral catheter with local anesthetic infusion was found to reduce postoperative ventilator requirement and time to first stool and full enteral feeds, when compared with opiate analgesia in a population of infants undergoing thoracotomy for resection of congenital lung malformations (55). 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 (56). However, several case reports have suggested that epidural clonidine may contribute to postoperative apnea in the former preterm infant (57,58). Caudal anesthesia has been sufficient as the sole anesthetic technique for lower abdominal procedures but is often used in combination with general anesthesia in infants undergoing abdominal procedures. Rarely, complications result from improper placement of the needle and injection of the anesthetic agent into a vein, the dura, the subarachnoid space, or the 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. Catheters may be left behind to provide continuous infusion of local anesthetic in hopes of extending the duration of the nerve block and provide postoperative analgesia, though care must be taken to not exceed maximum recommended dosing (59).
postoperative analgesia. Catheters may be left behind to provide continuous infusion of local anesthetic in hopes of extending the duration of the nerve block and provide postoperative analgesia, though care must be taken to not exceed maximum recommended dosing (59).
Local anesthetic toxicity is manifested by effects on the cardiovascular system (e.g., myocardial depression, arrhythmias) and central nervous system (e.g., delirium, seizures). 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.
A eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, the topical anesthetic known as EMLA, has shown efficacy in neonatal circumcisions, but two randomized controlled trials have shown that dorsal penile nerve block is more effective than EMLA (60,61). EMLA is not effective in reducing pain with heel sticks, perhaps owing to the incidental vasoconstriction associated with EMLA which may result in the need for more vigorous squeezing to obtain a blood sample (62). Oral sucrose has been shown to be more effective than EMLA as analgesia for neonatal venipuncture in two randomized controlled trials (63,64), and a recent trial found that the addition of EMLA to an oral sucrose regimen increased effectiveness of pain control with venipuncture in preterm infants (65). Although methemoglobinemia is a potential side effect of EMLA, it appears to be safe even in preterm infants.
Propofol
Propofol, in a loading dose of 2 to 4 mg/kg, acts as a complete anesthetic, with a short recovery period similar to or even shorter than the recovery period for the lipid-soluble pentothal. A continuous infusion of 50 to 100 mg/kg/min 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. Studies of propofol boluses and infusions have determined that most newborns and children have similar propofol pharmacokinetics to adults but that elimination is prolonged in infants (66
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