Construcción del Dispositivo

2.4.1 ANATOMICAL AND FUNCTIONAL REQUIREMENT FOR PAIN PERCEPTION IN NEONATES.

Neural pathways for pain may be traced from sensory receptors in the skin to sensory areas in the cerebral cortex of newborn. The density of nociceptive nerve endings in the skin of the newborn is similar to or greater than that in adult skin.

Quantitative neuroanatomical data have shown that nociceptive nerve tracts in the spinal cord and brain stem and thalamus are completely myelinated by thirty weeks of intrauterine life.

Whereas the thalamocortical pain fibres in the posterior limb of the internal capsule and corona radiata are myelinated by thirty-seventh week.

Development of the fetal neocortex is present at eighth week of gestation, and by twentieth week each cortex has a full complement of 10⁹ neurons. The dendritic processes of the cortical neurons undergo profuse arborizations and develop synaptic targets for the incoming thalamocortical fibres and intracortical connections. The timing of the thalamocortical connection is of crucial importance for cortical perception. Since most pathways to the neocortex have synapses in the thalamus.^{49, 50}

Several lines of evidence suggest that the complete nervous system is active during prenatal development and that detrimental and developmental changes in any part would affect the entire system. Human newborns do have the anatomical and functional components required for the perception of painful stimuli. These stimuli may undergo selective transmission, Inhibition, or modulation by various neurochemical mechanism associated with pain pathways in the fetus and newborn.⁵⁰

Researchers studying fetal and newborn neuroanatomy and physiology confirmed that newborns, both term and preterm, have the peripheral structures needed to transmit pain that are similar to those of adults but with the following important differences: Pain impulses are predominantly transmitted through the nonmyelinated C-fibers. Signal transmission is less specific within the spinal cord. Sensory nerve cells in the spinal tract are more excitable leading to a greater and more prolonged reflex response. Descending modulation is immature and ineffective. These differences may result in newborns perceiving pain in a more intense fashion than adults.^{49, 50}

A study demonstrated that premature infants have a lower pain threshold than term infants, indicating a more intense transmission of painful stimuli via the spinal cord, which can be further intensified with repeated painful stimulation.⁵¹ The heal prick procedure can be used as an example of the reaction and response to pain: An infant senses the lance and immediately withdraws the foot. In the preterm infant this withdraw reflex may be less dramatic because of less muscle strength compared with the term newborn. Following the withdrawal reflex, the infant cries and responds with the classic cry face, squeezed eyes, marked nasolabial folds, and gaping mouth. This response, commonly witnessed by health care providers during circumcision and venipuncture are examples of an intact sensory pathway that transmits painful stimuli.⁵¹ 2.4.2: NEUROCHEMICAL SYSTEMS ASSOCIATED WITH PAIN PERCEPTION.

Diverse alleged neurotransmitters called the tachykinins (substanceP,neurokinin A, neuromedin K ) have been well known in the central nervous system, but only substance P has been investigated thoroughly and shown to have a role in the transmission and control of pain impulses.^48-51 Neural elements containing substance P and its receptors appear in the dorsal-root ganglia and dorsal horns of the spinal cord at twelve to sixteen weeks of gestation.⁵¹ A high

stem associated with pathways for pain perception and control and visceral reactions to pain.⁵² Substance P fibers and cells have also been found in the hypothalamus, mamillary bodies, thalamus, and cerebral cortex of human fetuses early in the development.⁵² Many studies have found higher densities of substance P and its receptors in neonates than in adults of the same species.^49-52

2.4.3. ENDOCRINE RESPONSE TO PAIN IN NEONATES.

Hormonal and metabolic changes have been measured primarily in neonates undergoing surgery, although there are limited data on the neonatal responses to venipuncture and other minor procedures. Plasma renin activity increased significantly five minutes after venipuncture in full-term neonates and returned to basal levels sixty minutes thereafter; no changes occurred in the plasma levels of cortisol, epinephrine, or norepinephrine after venepuncture.⁵² In preterm neonates receiving ventilation therapy, chest physiotherapy and endotracheal suctioning produced significant increases in plasma epinephrine and norepinephrine; this response was decreased in sedated infants.^51,51 In neonates undergoing circumcision without anesthesia, plasma cortisol levels increased markedly during and after the procedure.⁴⁹ Similar changes in cortisol levels were not inhibited in a small number of neonates given a local anaesthetic,⁴⁹ but the efficacy of the nerve block was questionable in these cases.

Further detailed hormonal studies in preterm and full-term neonates who underwent surgery under minimal anaesthesia documented a marked release of catecho-lamines, growth hormone, glucagon, cortisol, aldosterone, and other corticosteroids, as well as suppression of insulin secretion.⁵⁰ These responses resulted in the breakdown of carbohydrate and fat stores, leading to severe and prolonged hyperglycemia and marked increases in blood lactate, pyruvate, total ketone bodies, and nonesterified fatty acids.^49,50 Increased protein breakdown was documented during and after surgery by changes in plasma amino acids, elevated nitrogen excretion, and increased 3-methyl- histidine: creatinine ratios in the urine. Marked differences also occurred

between the stress responses of premature and full-term neonates and between the responses of neonates undergoing different degrees of surgical stress.⁵² Possibly because of the lack of deep anaesthesia, neonatal stress responses were found to be three to five times greater than those in adults, although the duration was shorter.⁵¹ These stress responses could be inhibited by potent anaesthetics, as demonstrated by randomized, controlled trials of halothane and Fentanyl. These trials showed that endocrine and metabolic stress responses were decreased by halothane anaesthesia in full-term neonates.⁵¹

The stress responses of neonates undergoing cardiac surgery were also decreased in randomized trials of high-dose fentanyl and sufentanil anesthesia.52These results indicated that the nociceptive stimuli during surgery performed with minimal anaesthesia were responsible for the massive stress responses of neonates.

Neonates who were given potent anaesthetics in these randomized trials were more clinically stable during surgery and had fewer postoperative complications as compared with neonates under minimal anaesthesia.^{51, 52} There is preliminary evidence that the pathologic stress responses of neonates under light anaesthesia during major cardiac surgery may be associated with an increased postoperative morbidity and mortality. Changes in plasma stress hormones (e.g., cortisol) can also be correlated with the behavioural states of newborn infants,which are important in the postulation of overt subjective distress in neonates responding to pain.^51,52

The endocrine responses to pain originate in the cerebral cortex. The intact cerebral cortex of a newborn is functionally mature and able to mount an adequate response to pain and stress.

Through a complex array of interactions, the cerebral cortex orchestrates the release of catecholamines, inflammatory markers, and other important enzymes that mobilize the body to

to mount an endocrine and hormonal response to pain can be modulated with sufficient anaesthesia during surgery.⁵²

2.4.4 PHYSIOLOGIC CHANCES ASSOCIATED WITH PAIN.

Circumcision is a surgical procedure that involves separating the foreskin from the glans and then cutting it off. It is typically accomplished with a special clamp device. Several studies confirm that circumcision is extremely painful.⁵³ It has been described as the most painful amongst the procedures performed in neonatal medicine because of the rich innervations of the perineal region. In one study, researchers concluded that the pain was severe and persistent.⁵³

Changes in cardiovascular variables, transcutaneous partial pressure of oxygen, and palmar sweating have been observed in neonates undergoing painful clinical procedures. In preterm and full-term neonates undergoing circumcision or heel lancing, marked increases in the heart rate and blood pressure occurred during and after the procedure. The magnitude of changes in the heart rate was related to the intensity and duration of the stimulus and to the individual temperaments of the babies.^{51, 50}

Increases in heart rate of fifty-five beats per minute have been recorded, about a fifty percent increase over the baseline. After circumcision, the level of blood cortisol increased by a factor of three to four times the level prior to circumcision. Investigators reported, there is no doubt that circumcisions are painful for the baby. Indeed, circumcision has become a model for the analysis of pain and stress responses in the newborn.⁵³ They report that the infant will cry vigorously, tremble, and in some cases become mildly cyanotic because of prolonged crying.

2.4.5 BEHAVIOURAL CHANGES ASSOCIATED WITH PAIN.

According to adult listeners in one study, the infant’s response during circumcision included a cry that changed with the level of pain being experienced. The most invasive part of the procedure caused the longest crying.⁵³ Changes in the patterns of neonatal cries have been correlated with the intensity of pain experienced during circumcision and were accurately differentiated by adult listeners.⁵² In other studies of the painful procedures, neonates were found to be more sensitive to pain than older infants ,those two to twelve months old, but had similar latency periods between exposure to a painful stimulus and crying or another motor response.^49,50,51

This supports the contention that slower conduction speed in the nerves of neonates is offset by the smaller inter-neuron distances traveled by the impulse. These cries were high pitched and were judged most urgent. A subsequent study confirmed that cries with higher pitch were perceived to be more distressing and urgent. Excessive crying can itself cause harm. Using a pacifier during circumcision reduced crying but did not affect hormonal pain response.⁵² Therefore, while crying may be absent; other body signals demonstrate that pain is always present during circumcision.

Beginning in the 1970s, a few studies investigated the effect of circumcision on infant behaviour.

Alterations in complex behavioural and sleep-wake cycles have been studied mainly in newborn infants undergoing circumcision without anesthesia. Emde and coworkers observed that painful procedures were followed by prolonged periods of non-rapid-eye-movement sleep in newborns and confirmed these observations in a controlled study of neonates undergoing circumcision without anaesthesia.⁵¹ Similar observations have been made in adults with prolonged stress.

circumcision, an altered arousal level in circumcised male infants as compared with female and uncircumcised male infants, and an altered sleep-wake state in neonates undergoing heel-stick procedures.⁴⁹ In a double-blind, randomized controlled study using the Brazelton Neonatal Behavioral Assessment Scale, ninety percent of neonates had changed behavioral states for more than twenty-two hours after circumcision, whereas only sixteen percent of the uncircumcised infants did.⁵¹ It was therefore proposed that such painful procedures may have prolonged effects on the neurologic and psychosocial development of neonates.

Some studies found differences in sleep patterns and more irritability among circumcised infants.

In addition, changes in infant-maternal interaction were observed during the first twenty-four hours after circumcision. For example, breast- and bottle-fed infants’ feeding behavior has been shown to deteriorate after circumcision. Other behavior differences have been noted on the day following the procedure.⁵⁴

The American Academy of Pediatrics (AAP) Task Force on Circumcision noted these various behavioral changes resulting from circumcision in their report. Researchers found that European reports of newborn infant responses to hearing and taste stimulation showed little difference in responses between males and females, while related tests on American infants showed significant gender differences. Investigators suggested that these differences could be the result of circumcision and not gender. ⁵⁴

In one of the most important studies by Joyce et al, the behaviour of nearly 90 percent of circumcised infants significantly changed after the circumcision. Some became more active, and some became less active. The quality of the change generally was associated with whether they were crying or quiet respectively at the start of the circumcision. This suggests the use of

different coping styles by infants when they are subjected to extreme pain. In addition, the researchers observed that circumcised infants had lessened ability to comfort themselves or to be comforted by others.⁵⁵ Untreated newborn pain can contribute significantly to neonatal morbidity and mortality. High postoperative mortality, poor growth related to prolonged protein catabolism, and increased time on mechanical ventilation have been attributed to untreated or poorly treated pain. Additionally, there may be long-term consequences for the fragile infant exposed to multiple painful procedures during a critical time in brain development. The International Evidence-Based Group for Neonatal Pain, describe a propensity toward anxiety disorders and an exaggerated response to pain in rat pups exposed repeatedly to painful procedures.

In general, untreated or undertreated pain in the newborn includes the following physiologic and biochemical sequalae: hyperglycemia, increased protein catabolism, increased oxygen consumption, decreased gut motility, increased heart rate and blood pressure, and decreased transcutaneous oxygenation.

2.4.6 MEMORY OF PAIN IN NEONATES.

The perseverance of specific behavioral changes after circumcision in neonates implies the presence of memory. In the short term, these behavioral changes may disrupt the adaptation of newborn infants to their postnatal environment, the development of parent-infant bonding, and feeding schedules. ⁵⁵