Chapter 9 - Effects of perinatal pain and stress

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Introduction

Surgical operations without adequate anesthesia were performed routinely in newborn infants less than a decade ago. Widespread medical beliefs supported this practice, which questioned the sensory capability of pain perception in neonates and may have exaggerated the risks of complications or side effects from the use of anesthetic drugs in newborns (Anand and Hickey, 1987). Some of these practices changed after randomized clinical trials of potent vs. inadequate anesthesia showed significant reductions in the incidence of postoperative complications following major surgery in preterm and term neonates (Anand and Aynsley-Green, 1985; Anand et al., 1987; Anand et al., 1988). These data stimulated systematic changes in the clinical practice of neonatal anesthesia (Rogers, 1992) and a greater scientific interest in the development of pathways and mechanisms associated with pain perception in early life. Clinical and experimental research have contributed to a major reorientation in our understanding of the developmental biology of pain (Fitzgerald et al., 1988; Anand and Carr, 1989; Craig et al., 1993; Johnston et al., 1993; Fitzgerald, 1994), and have stimulated a re-evaluation of the definition of pain (Anand and Craig, 1996).

Complementary investigations in preterm neonates and neonatal rat pups have identified a predominant role for early pain and stress in altering neonatal clinical outcomes, brain development and subsequent behavior. Much of these data were obtained from infant rats, because of similar pain pathways and mechanisms in the human and rodent species and similar neurological maturity of the rat pup at birth and the viable preterm neonate at 23–24 weeks gestation. Based on these data, we propose the following four hypotheses:

  • (a)

    the perinatal period is associated with an increased sensitivity to pain, mediated by immature peripheral and central mechanisms in the developing pain system;

  • (b)

    a hyperalgesic state occurs following acute painful stimuli, and the duration of this physiological state is prolonged in preterm neonates and newborn rat pups;

  • (c)

    the exposure to multiple invasive procedures required for the resuscitation and clinical management of preterm neonates after birth stimulates acute physiologic and behavioral responses and increases their vulnerability to gross neurologic damage (intraventricular hemorrhage and/or periventricular leukomalacia);

  • (d)

    the plasticity of the developing pain system provides a critical window for producing long-term changes in subsequent behavior, responses to stress, and susceptibility to psychosomatic complaints and psychiatric disorders in later life.

Section snippets

Increased pain sensitivity in neonates

The traditional view, supported by the early experiments of McGraw and others, held that newborn infants were relatively insensitive to pain (McGraw, 1941). More recently, thresholds for the withdrawal reflex were investigated using calibrated Von Frey hairs to stimulate the dorsal cutaneous flexor withdrawal reflex in preterm and term newborn infants. These thresholds correspond with the pain threshold and are inhibited by opioid or other analgesics (Woolf and Wall, 1986). In marked contrast

Prolonged hyperalgesia following acute painful stimuli

Afferent impulses in the late embryonic and early postnatal period produced a long-lasting excitation of dorsal horn cells, and repetitive stimuli caused considerable background activity in areas of the spinal cord above and below the site of stimulation (Fitzgerald, 1985). The exaggerated nociceptive reflexes, large receptive fields of dorsal horn cells, and prolonged excitation following stimulation in newborn rats parallel the low pain thresholds and sensory hypersensitivity noted in preterm

Exposure to multiple invasive procedures

There is an increasing awareness amongst physicians and nurses regarding pain perception in neonates and that that repetitive pain and stress during intensive care may worsen the clinical outcomes of preterm neonates (Barker and Rutter, 1996; Anand et al., 1998). However, clinical practices incorporating neonatal analgesia are rare and nascent. In answering recent questionnaires, almost all physicians and nurses felt that infants experience the same degree or greater degrees of pain than adults

Increased vulnerability to early neurologic injury

Painful procedures in neonates are generally associated with diaphragmatic splinting, forced expiratory movements (crying), and sympathetic activation leading to tachycardia and hypertension. Changes in the intrathoracic pressure of ventilated neonates cause substantial oscillations in the intracranial pressure, cerebral oxygen delivery (Pokela, 1994) and intracranial blood volume (Perlman and Thach, 1988; Zernikow et al., 1994). The magnitude and rapidity of these physiological changes is

Long-term effects of pain and stress

The perinatal period is recognized as a critical period of increased plasticity in the early development of most mammalian species, including the human. Perinatal synaptic activity is crucial because inactive synapses are solubilized and inactive neurons undergo apoptosis in early development (Rakic, 1985; Rabinowicz et al., 1996). Thus, repetitive exposure to early pain or stress would cause more profound effects on brain development than similar experiences in later life (Bower, 1990; Leon,

Long-term effects of early stress in neonatal rat pups

Temporary separation of the mother from rat pups, causes an interruption of maternal care, tactile stimulation (licking, grooming, urogenital toilet), source of nutrition and warmth, and contact with littermates. Neonatal rat pups exposed to maternal separation for 15 min each day (from P2 to P14) developed an adult phenotype (Meaney et al., 1988, 1991; Viau et al., 1993) characterized by increased exploratory activity and decreased pituitary-adrenal responses to stress, resulting from an

Long-Term effects of pain in neonatal rat pups

Preliminary data suggest that invasive procedures associated with neonatal skin injury and repetitive pain may cause permanent changes in the peripheral and/or central pain systems. Skin injury occurring on the day of birth was associated with subsequent hyperinnervation from exuberant nerve sprouting in the area of injured skin. The degree of nerve sprouting in neonatal rats occurred earlier, was greater in magnitude, and lasted longer than the innervation following skin injury at 7 days, 14

Long-term effects of pain and stress in full-term human neonates

Few clinical studies have investigated the long-term effects of pain in full-term healthy infants, with limited data suggesting the prolonged effects of neonatal pain on subsequent behavior. Altered behavior following circumcision was associated with poor orientation, decreased coordination of motor processes, impaired ability to regulate their behavioral states, and altered feeding or sleep patterns (Emde et al., 1971; Marshall et al., 1980; Dixon et al., 1984). These behavioral changes

Long-term effects of pain or stress in premature infants

Follow-up studies of ex-premature infants in their early school years have reported an increased incidence of non-specific pain symptoms, decreased affective responses to subsequent pain, neurological and developmental deficits, social difficulties, cognitive and learning defects. Based on parent report, 18-month old ex-preterm neonates who were exposed to multiple noxious stimuli while in the NICU, were noted to be under-responsive to subsequent pain (Grunau et al., 1994a). Follow-up of older

Long-term effects of analgesia or comfort measures

Selective pharmacological interventions may reduce the adverse consequences of pain in human neonates (Fitzgerald et al., 1989; Taddio et al., 1997; Anand et al., 1999a). In a blinded, randomized multicenter trial, low-dose continuous infusions of morphine significantly decreased the composite incidence of neonatal death and severe neurologic damage (defined as grade III or IV intraventricular hemorrhage, or periventricular leukomalacia) (Anand et al., 1999a). These differences may result from

Summary

Neonatal intensive care exposes preterm neonates to a series of repeated, randomly occurring invasive procedures and handling, resulting in acute pain, chronic pain, and prolonged stress during a critical window associated with epochal brain development. Characteristics of the immature pain system in preterm neonates (such as a low pain threshold, prolonged periods of windup, overlapping receptive fields, immature descending inhibition) predisposes them to greater clinical and behavioral

Acknowledgements

Supported by grants from the University of Arkansas for Medical Sciences and the National Institute for Child Health and Human Development (HD01123-02).

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