Chapter 9 - Effects of perinatal pain and stress
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).
References (127)
- et al.
Prevention of intraventricular hemorrhage in the premature infant
Clin. Perinatol.
(1994) - et al.
Effects of early experience on adrenocortical reactivity
Physiol. Behav.
(1969) Neonatal stress responses to anesthesia and surgery
Clin. Perinatol.
(1990)- et al.
Can the human neonate mount an endocrine and metabolic response to surgery?
J. Pediatr. Surg.
(1985) - et al.
The neuroanatomy, neurophysiology and neurochemistry of pain, stress, and analgesia in newborns, infants, and children
Ped. Clin. N. Am.
(1989) - et al.
Long-term behavioral effects of repetitive pain in neonatal rat pups
Physiol. Behav.
(1999) - et al.
Randomized trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response
Lancet
(1987) - et al.
The cutaneous withdrawal reflex in human neonates: sensitisation, receptive fields and the effects of contralateral stimulation
Pain
(1994) - et al.
Use of analgesic agents for invasive medical procedures in pediatric and neonatal intensive care units
J. Ped.
(1992) - et al.
Pain in the preterm neonate: behavioural and physiological indices
Pain
(1993)
Mapping the development of the rat brain by GAP-43 immunocytochemistry
Neuroscience
Development of thermal nociception in rats
Pain.
Hyperalgesia in premature infants
Lancet
Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia
Pain
GAP-43 expression in the developing rat lumbar spinal cord
Neuroscience
Isolation-induced locomotor hyperactivity and hypoaldesia in rats are prevented by handling and reversed by resocialization
Physiol. Behav.
Human fetal sympathoadrenal responsiveness
Early Human Dev.
Pain sensitivity and temperament in extremely-low-birthweight premature toddlers and preterm and full-term controls
Pain
Early pain experience, child and family factors as precursors of somatization: a prospective study of extremely premature and fullterm children
Pain
The behavioral response to formalin in pre-weaning rats
Pain
Vagal response to feeding tube insertion in preterm infants: has the key been found?
Early Hum. Dev.
Developmental changes in pain expression in premature, full-term, two- and four-month-old infants
Pain
Plasma catecholamines following nursing procedures in a neonatal ward
Early Human Dev.
Circumcision: Effects Upon Newborn Behavior
Infant Behav. Dev.
The Plasticity of the hippocampus is the reason for its vulnerability
Neurosciences
Tonic nociception in neonatal rats
Pharmacol. Biochem. Behav.
Neonatal pain: a comprehensive survey of attitudes and practices
J. Pain Symptom Manag.
The effects of neonatal handling on the development of the adrenocortical response to stress: implications for neuropathology and cognitive deficits in later life
Psychoneuroendocrinology
Early environmental programming of hypothalmic-pituitary-adrenal responses to stress
Neurosciences
Postnatal handling alters glucocorticoid, but not minerallocorticoid messenger RNA expression in the hippocampus of adult rats
Brain Res. Mol. Brain Res.
Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome
J. Pediatr.
Postnatal maturation of primary afferent terminations in the substantia gelatinosa of the rat spinal cord: An electron microscope study, brain
Brain Res.
Early postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stressinduced release in adult rats
Mol. Brain Res.
Individualized developmental care for the very low-birth weight preterm infant: medical and neurofunctional effects
JAMA
Relationships between stress responses and clinical outcome in newborns, infants, and children
Crit. Care Med.
Clinical importance of pain and stress in preterm newborn infants
Biol. Neonate
Metabolic and endocrine effects of surgical ligation of patent ductus arteriosus in the human preterm neonate: are there implications for further improvement of postoperative outcome?
Mod. Probl. Paediatr.
Editorial: New perspectives on the definition of pain
Pain
Pain and its effects in the human neonate and fetus
N. Eng. J. Med.
Future directions
Analgesia and sedation in ventilated preterm neonates: results from the pilot NOPAIN trial
Arch. Pediatr. Adolesc. Med.
Does halothane anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation?
Brit. Med. J.
Exposure to invasive procedures in neonatal intensive care unit admissions
Arch. Dis. Childhood
Stress, severity of illness. and outcome in ventilated preterm infants
Arch. Dis. Childhood
Randomised, double blind trial of two loading dose regimens of diamorphine in ventilated newborn infants
Arch. Dis. Child Fetal Neonatal Edn.
Outcomes of developmentally supportive nursing care for very low birth weight infants
Nurs. Res.
Axonal and dendritic development of substantia gelatinosa neurons in the lumbosacral spinal cord of the rat
J. Comp. Neurol.
Mother as shield: differential effects of contact and nursing on pain responsivity in infant rats-evidence for non-opioid mediation
Behav. Neurosci.
Attention deficit hyperactivity disorders and other psychiatric outcomes in very low birth weight children at 12 years
J. Child Psychol. Psychiat.
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