ILAR Journal Online, Volume 33(1-2) 1991: Pain in Animals and Humans

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ILAR Journal V33(1-2) 1991 [FORMERLY ILAR NEWS]
Pain in Animals and Humans

Pain in the Neonate: The Effects of Anesthesia
Peter J. Davis, M.D.

Peter J. Davis, M.D., is associate professor of Anesthesiology/Critical Care Medicine and Pediatrics at the University of Pittsburgh, and staff anesthesiologist at the Children's Hospital of Pittsburgh.

INTRODUCTION

Over the past 20 years, advances in patient monitoring and anesthetic techniques coupled with a better understanding of the pathophysiology underlying neonatal disease states have made a great impact on the practice of neonatal anesthesia. Nevertheless, whether anesthesia is necessary in neonates and what constitutes adequate anesthesia for neonates are still major concerns among parents, health care professionals, and the public. For the anesthesiologist, the issue of adequate anesthesia is paramount to providing quality medical care. Yet Lippmann et al. (1976) wrote that in surgery for patent ductus arteriosus (PDA), "anesthetic or analgesic agents in our experience are unnecessary," and in a recent article Gauntlett (1987) stated that only 85 percent of anesthetists responding to a survey believed that newborns perceived pain.

For some anesthesiologists the rationale of withholding anesthesia is still based on the notion that infants requiring surgery are too ill to withstand the significant cardiovascular and respiratory depressant effects of anesthesia. For others, the knowledge that neonatal cortical connections and nerve myelination are incomplete, coupled with the neonate's primitive reflex (decorticate posturing) in response to pain, allow them to rationalize that operative procedures in neonates can be performed without the benefit of anesthesia.

The issue of pain management, however, is not limited to the operating room. In a survey of intensive care nurses, 59 percent of the responders believed that newborns did not perceive pain in a manner similar to adults, but 77 percent believed that pain medications were underutilized (Franke et al., 1986). Thus, it appears that pain management for newborns is frequently not undertaken or is inadequately administered.

NEONATAL PERCEPTION OF PAIN

Do newborns perceive pain? If one uses the definition of pain provided by the International Association for the Study of Pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage," then pain becomes a subjective phenomenon, and its occurrence in newborns may be impossible to determine. Anatomic, physiologic, and neuroendocrine data compiled over recent years, however, suggest that neonates do indeed perceive pain (nociception). Nociceptive pathways and anatomic substrates for pain transmission appear to be present in neonates, and with growth and development during infancy and childhood there are further refinements of the sensory modalities and intracortical connections. Anand et al. have recently reviewed this information, and consequently it will not be further discussed (Anand and Hickey, 1987; Anand et al., 1989). A schematic view of the developmental changes occurring in the central nervous system as they relate to pain perception is presented in Figure 1.

For health care providers involved in the care of sick newborns, the neonate's perception of nociception appears intuitively obvious. Invasive procedures such as heel lancing (Harpin and Rutter, 1983; Owens and Toot, 1984), circumcision (Williamson and Williamson, 1983), and intramuscular injections evoke such characteristic behavioral (facial grimacing, crying) (Porter et al., 1986; Grunau and Craig, 1987) and sympathetic responses (tachycardia, hypertension, palmar sweating) (Raju et al., 1980; Harpin and Rutter, 1982; Kelly and Finer, 1984; Marshall et al., 1984), that it is difficult to believe that the neonate is not feeling pain. Because it appears intuitively obvious that nociception is a real phenomenon in the neonate, the remainder of this paper will deal with two physiologic manifestations of nociception: the cardiovascular response and the neuroendocrine response. The modulating effects that anesthetics have on these two physiologic responses will also be addressed.

CARDIOVASCULAR RESPONSES TO PAIN

Tracheal intubation and tracheal suctioning are two noxious stimuli or stresses frequently experienced by neonates in both the operating room and the intensive care nursery. Significant changes in blood pressure, heart rate, transcutaneous oxygenation, and palmar sweating have been noted in neonates undergoing these painful procedures. Kelly and Finer (1984) prospectively studied the effects of nasotracheal intubation in infants with birth weights between 580 and 3,450 grams born between 25 and 40 weeks' gestation. In unanesthetized infants, nasotracheal intubation was associated with significant increases in mean arterial blood pressure and intra-cranial pressure, and significant decreases in heart rate and transcutaneous oxygen tension. Similar hemodynamic changes following awake oral intubation have been reported by others (Raju et al., 1980; Marshall et al., 1984).

Tracheal suctioning has also been shown to have hemodynamic consequences. Routine tracheal suctioning, a procedure necessary to remove secretions and prevent airway obstruction in patients with endotracheal tubes, has been associated with arrhythmias, circulatory instability, and increases in intracranial pressure (Anesthesia Study Committee, 1968; Shim et al., 1969; Fox et al., 1978; Simbruner et al., 1981; Fisher et al., 1982; White et al., 1982). Hickey et al. (1985) have shown that in infants, tracheal suctioning is associated not only with alterations in the systemic circulation, but also with increases in the pulmonary artery and pulmonary vascular resistances. In sick infants, this pulmonary vasoconstriction can result in an acute increase in right ventricular afterload and acute right ventricular failure. In addition to changes in the pulmonary vascular bed, changes in the cerebrovascular bed also occur with tracheal suctioning. Periman and Volpe (1983), using Doppler flow studies of anterior cerebral arteries in newborns being suctioned, noted increases in blood flow velocity that were accompanied by increases in systemic blood pressure.

The cardiovascular changes during the stress response to intubation and tracheal suctioning have significant implications. Since neonates have a relatively fixed stroke volume, a noncompliant myocardium, a heart rate-dependent cardiac output, and a lack of sympathetic innervation to the ventricles, decreases in heart rate will significantly decrease cardiac output, and this decreased cardiac output cannot be compensated with an increase in stroke volume. In addition, acute increases in pulmonary vascular resistance from tracheal suctioning and intubation can result in right heart failure and further compromise cardiac output and perfusion of vital organs. Hypoxia and increases in intracranial pressure that occur during intubation and tracheal suctioning may compromise cerebral blood flow and cerebral oxygen delivery. Moreover, clinical as well as experimental evidence suggests that abrupt increases in systemic blood pressure, a frequent occurrence during intubation and suctionlng, with resultant increases in cerebral blood flow, may be an important factor in the pathogenesis of neonatal intra-ventricular hemorrhage.

What about the effects of anesthesia? Can anesthetics attenuate the cardiovascular effects of noxious stimuli? Friesen et al. (1987) examined the effects of intubation both in awake infants and in those anesthetized with different anesthetics. Infants intubated while awake had significant increases in systolic blood pressure and ante-riot fontanelle pressure. In the anesthetized infants, intuba-tion had little effect on anterior fontanelle pressure or systemic blood pressure (see Figure 2).

Hickey et al. (1985) also have shown that fentanyl, an opiate, can blunt the stress response of the pulmonary circulation to tracheal suctionlng. In a study of infants after operative repair of a congenital heart defect, Hickey et al. (1985) showed that infants pretreated with fen-tanyl had minimal changes in pulmonary artery pressure and resistance during tracheal suctioning. Vacanti et al. (1984) have shown that continued administration of fentanyl anesthesia in the postoperative period can significantly reduce mortality and pulmonary shunt fractions in neonates with congenital diaphragmatic hernias.

Even local anesthetics can influence the cardiovascular responses to pain. Williamson and Williamson (1983) have compared the cardiovascular responses of infants with and without a dorsal penile nerve block undergoing elective circumcision. In this study the anesthetized infants experienced less stress, as evidenced by smaller increases in heart rate, less time crying, and smaller decreases in transcutaneous oxygen tension. In a similarly designed study, Maxwell et al. (1987) noted statistically significant differences in heart rate and oxygen saturation between anesthetized and unanesthetized infants undergoing circumcision. Heart rate increased 34 percent in nonanesthetized circumcised patients and was virtually unchanged in infants receiving lidocaine, while oxygen saturation decreased 16 percent in unanesthetized patients compared with six percent in anesthetized patients.

HORMONAL AND METABOLIC RESPONSES TO PAIN

In addition to cardiovascular changes, significant hormonal and metabolic changes occur with surgical stress. In preterm infants requiring mechanical ventilation, Gre-isen et al. (1985) showed that chest physiotherapy and endotracheal suctioning produced significant increases in plasma levels of epinephrine and norepinephrine. These increases were attenuated in sedated infants. Anand et al. have studied the metabolic and hormonal effects of stress in preterm and full-term neonates undergoing surgery. Surgical stress with minimal anesthesia resulted in a marked release of catecholamines, growth hormone, glucose, cortisol, and aldosterone, as well as suppression of insulin release. These intraoperative hormonal changes resulted in severe and prolonged hyperglycemia, accompanied by increases in blood lactate, pyruvate, ketones, and nonesterified fatty acids, and increased protein catabolism that persisted into the postoperative period (Anand et al., 1985a,b; Anand, 1986; Anand and Aynsley-Green, 1988, 1985).

In a randomized clinical study of premature infants undergoing PDA ligation, Anand et al. (1987) compared the hormonal stress response and surgical outcome between infants anesthetized with a combination of nitrous oxide, oxygen, fentanyl, and d-tubocurarine and infants receiving only nitrous oxide, oxygen, and d-tubocurarine (i.e., potent narcotics were omitted). In addition to the hormonal changes mentioned previously, Anand et al. (1987) noted that the infants receiving no narcotic supplementation had a higher incidence of postoperative bradycardia, apnea, and poor perfusion. The same group has studied the effects of anesthesia in a more heterogeneous group of infant surgical patients. In a similarly designed study of infants undergoing a variety of surgical procedures, the metabolic and endocrine-modulating effects of nitrous oxide and d-tubocurarine were compared with those of nitrous oxide, d-tubocurarine, and halothane. As in the preterm infants undergoing PDA ligation, this group of infants anesthetized with unsupplemented nitrous oxide demonstrated more perioperative instability and greater hormonal responses to surgery (Anand and Aynsley-Green, 1988).

If anesthetic agents can reduce perioperative morbidity and decrease the cardiovascular response to stress, why is there even a question as to whether infants should be anesthetized? The answer to this lies in the side effects of the various anesthetic agents. General anesthesia in newborns frequently involves the use of potent inhalational anesthetics (halothane or isofiurane) or intravenous opioids (morphine, fentanyl, or fentanyl derivatives).

CARDIOVASCULAR EFFECTS OF INHALATIONAL ANESTHETICS

Although over the years numerous studies have demonstrated a decline in anesthesia morbidity and mortality, the tendency of infants and small children to have higher incidences of bradycardia, hypotension, and cardiac arrest during inhalational anesthesia still exists (Rackow et al., 1961; Friesen and Lichtor, 1982; Keenan and Boyan, 1985; Friesen and Henry, 1986). The difference in anesthesia morbidity and mortality has been attributed to an increased sensitivity of the young cardiovascular system to potent agents. Rao et al. (1986) noted that halothane and isoflurane depress the force of contraction in isolated neonatal rat atria significantly more than in the adult atria. Studies by Krane and Su (1987) have shown similar findings when using rabbit ventricle strips. This increased depression observed in neonatal myocardial fibers may be related to the decreased number of contractile elements observed in the neonatal myocardium, differences in Ca²⁺efflux from myocardial sarcoplasmic reticulum, or differences in anesthetic uptake and distribution (Brandom et al., 1983; Krane and Su, 1989).

Brandom et al. (1983) have demonstrated that myocardial and brain concentrations of anesthetic at equal inspired concentrations are higher early in anesthetic induction in the infant than in the adult. The need for higher anesthetic concentrations to provide adequate anesthesia in neonates and the high myocardial anesthetic concentrations achieved early in the anesthetic induction may be the reasons for the hypotension and bradycardia frequently seen in neonates. Direct measurements of cardiac output, contractility, preload, and afterload involve invasive techniques and consequently are unlikely to be performed in awake infants or children. Thus, animal models are frequently used to evaluate the effects of anesthetics on the developing heart. Boudreaux et al. (1984) have evaluated the hemodynamic effects of halothane in the developing piglet. Cardiac index (CI), mean arterial pressure, heart rate, and all contractility indexes (LV peak dP/dT, shortening fraction, and mean rate of LV circumferential fiber shortening) decreased with increasing halothane concentration. Schieber et al. (1986), in a similarly designed study using piglets anesthetized with isoflurane, noted that equipotent concentrations of isoflurane showed a greater reduction in mean arterial pressure and peripheral vascular resistance, and a smaller reduction in cardiac output than did halothane.

In addition to direct cardiac effects, anesthetics can also modulate cardiac action through effects on the barore-ceptors. The baroreceptor responses of both humans and animals can be depressed by anesthetics. Wear et al. (1982) have demonstrated in rabbits that the pressor baroresponse of infant animals is less potent than that of adult animals and that halothane depresses this response more in infant than in adult animals. In a series of clinical studies of preterm infants anesthetized with halothane undergoing PDA ligation, Gregory (1982) reported an age-related difference in the baroreceptor response. Depression of both the depressor and pressor baroreceptor response in neonates by narcotics has also been demonstrated by Murat et al. (1988). Why anesthesia depresses the baroreceptor reflexes more in infants is unknown, but the phenomenon may be related to developmental differences in the autonomic nervous system.

Unlike the hemodynamic instability associated with potent inhalational anesthetics, it has been found that cardiovascular stability can be maintained in severely ill patients by using a large dose of intravenous morphine in combination with oxygen administration. This discovery has resulted in the emergence of narcotic anesthesia as a basic anesthetic technique (Lowenstein et al., 1969).

NARCOTIC ANESTHESIA IN INFANTS

In the operating room and the neonatal care unit, fentanyl and its congeners, as well as morphine, are the primary narcotics administered to infants. However, it was not until 10 years after the reported use of high-dose narcotics in adults that high-dose narcotics were administered to infants. This delay stemmed partly from earlier work suggesting that infants were more sensitive than adults to the depressant effects of narcotics (Kupferberg and Way, 1963; Way et al., 1965). In an elaborate set of experiments, Kupferberg and Way (1963) showed that newborn rats had a lower LDs0 (the dose that is lethal to 50 percent of the animals) than adult rats. Further studies demonstrated that with similar doses (on a mg/kg basis) of morphine, plasma concentrations were similar in newborns and adults but brain levels were much higher in the newborns. In studies with newborn infants about to undergo circumcision, Way et al. (1965) noted that in infants sedated with intramuscular morphine, ventilatory drive was suppressed to a greater degree compared with presedation values and that intramuscular morphine depressed venti-latory drive more than equipotent doses of meperidine.

From these two studies, it was concluded that infants were extremely sensitive to narcotics and that this sensitivity was probably related to the water solubility of morphine and the immaturity of the newborn infant blood-brain barrier. These studies of Kupferberg and Way et al. were often cited as the basis for withholding narcotics from newborns. The role of opioids in pediatric anesthesia practice was not changed until the appearance of a paper (Robinson and Gregory, 1981) in which fentanyl--a synthetic opioid with a potency of 1,000 times that of morphine--was shown to be a safe and efficacious anesthetic agent for premature infants undergoing PDA ligation. Subsequently, others (Hickey and Hansen, 1984; Moore et al., 1985; and Davis et al., 1987) demonstrated the safety, efficacy, and hemodynamic stability associated with narcotic anesthesia in severely ill infants undergoing repair of complex congenital heart defects.
The use of morphine and fentanyl, however, is somewhat limited by certain pharmacokinetic characteristics. Studies have shown that fentanyl and morphine have a delayed clearance and a prolonged half-life in infants (Koehntop et al., 1986; Collins et al., 1985; Lynn and Slattery, 1987; Greeley and de-Bruijn, 1988). Using the hypothesis that increased potency is associated with specific opiate effects and decreased nonspecific cardiovascular effects, chemical congeners of fentanyl have been developed. One such fentanyl congener is alfentanil. Its physicochemical properties are a low pKa and, consequently, a small ionized fraction at pH 7.4. Its high protein binding and low octanol:water coefficient should give alfentanil a small volume of distribution and relatively short half-life. Indeed, numerous investigators have demonstrated that alfentanil does have a short half-life in children and adults (Goresky et al., 1987; Meistelman et al., 1987; Roure et al., 1987; Davis et al., 1989a,b). In premature neonates in the first few days of life, however, Davis et al. have demonstrated that alfentanil's half-life is dramatically prolonged compared with that in older children (See Figure 3) (Davis et al., 1989a). More recent studies by these investigators have shown that the pharma-cokinetic profile is unaffected by gestational age. Both full-term newborns greater than 37 weeks' gestation and newborns born at 26 to 37 weeks' gestation, all studied during the first 3 days of life, had similar drug disposition and elimination (Killlan et al., 1990). Thus, for all newborns, it appears that "short-acting" narcotics have a markedly long elimination half-life and that a prolonged respiratory depressant effect can be anticipated.

REGIONAL ANESTHESIA

Regional anesthesia can be used either as an alternative to inhalational or intravenous anesthetics or as a supplement to general anesthesia. Although the mechanisms of local anesthetic action on the immature nervous system have not been well studied, the pharmacology of some of the local anesthetic agents in newborns has been evaluated (Dohi et al., 1979; Abajian et al., 1984; Ecoffey et al., 1984; Ecoffey et al., 1985; Mahe and Ecoffey, 1988). The main feature of local anesthetics is the hemodynamic stability they afford following subcutaneous, intrathecal, or epidural injection and in peripheral nerve blocks. When administered as a supplement to general anesthesia, local anesthetics can diminish the requirement for potent inhalational anesthetics and the need for postoperative opioids. The main factors limiting their use are the type, location, and duration of the surgical procedure.

SUMMARY

At present there is no single ideal anesthetic agent for infants. Potent inhalational anesthetic agents are myocardial depressants, and hemodynamic instability is a frequent side effect when they are administered. Narcotic anesthesia, on the other hand, can provide hemodynamic stability; but in the first few days of life, alterations in the drug's disposition and elimination usually result in a prolonged half-life and, consequently, in a delay of spontaneous respirations. From the data of other investigators it is clear that newborns feel pain, and the work of Anand et al. suggests that inadequate pain relief may have detrimental effects. The purpose stated by an unnamed 15th century French physician, "to cure sometimes, to relieve often, and to comfort always," has significant applicability to today's providers of neonatal health care. No longer can the rationale that infants do not feel pain or that infants are too sick to withstand the effects of anesthesia be used as a reason for performing surgery without the benefit of anesthesia.

The Committee on Fetus and Newborn, the Committee on Drugs, the Section on Anesthesiology, and the Section on Surgery of the American Academy of Pediatrics (Poland et al., 1987) wrote that "local or systemic pharmacologic agents now available permit relatively safe administration of anesthesia or analgesia to neonates undergoing surgical procedures, and that such administration is indicated according to the usual guidelines for the administration of anesthesia to high-risk, potentially unstable patients. In occasional situations, physiologic instability will be so great that the anesthetic agents must be reduced or discontinued. However, the decision to withhold such medication should be based on the same medical criteria used for older patients. The decision should not be based solely on the infant's age or perceived degree of cortical maturity."

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FIGURE 1 Schematic diagram of neurologic development in the human fetus and neonate (Anand and Hickey, 1987, P. 1322).

FIGURE 2 Changes in anterior fontanel pressure in preterm infants intubated awake (Figure 2A), and anesthetized (Figure 2B) (Friesen et al., 1987, P. 876).

FIGURE 3 Pharmokinetics of alfentanil in premature infants and older children (Davis et al., 1989, P. 25).