Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Anesthesia in the Neonate
Developmental Challenges of Neonatal Anesthesia
The administration of anesthesia to the neonatal patient requires knowledge and understanding of neonatal anatomy and pathophysiology in addition to the ability to understand how the pharmacology of standard anesthetic drugs is altered in preterm and term neonates. Anesthetic care of these oftentimes critical patients is best performed by specialty trained pediatric anesthesiologists. The creation of a surgical environment that is tailored to the neonatal patient with appropriate monitors, equipment, and personnel allows for both general and regional anesthetics to be safely and successfully carried out. The safety of modern anesthetics in this vulnerable population continues to be an area of concern, as animal studies have shown neuronal apoptosis and neurocognitive deficits as a result of exposure to most modern anesthetics. While recent human data suggests that brief anesthesia exposure early in life appears to be safe, it continues to be an area of intense focus and research.
Surgery in neonates is accompanied by a humoral stress response that leads to increased complications and mortality, as shown in the landmark study by Anand and colleagues in 1987. This response is diminished by adequate anesthesia ( Fig. 39.1 ; Table 39.1 ), resulting in improved surgical outcomes. Consequently, over the subsequent decades, anesthesia for all surgical procedures in neonates has been accepted as both a clinical and an ethical imperative.
TABLE 39.1
Perioperative Complications
Data from Anand KJ, et al. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet. 1987;1:62.
| Complication | Control | Fentanyl |
|---|---|---|
| Frequent bradycardia | 4 | 1 |
| Hypotension, poor circulation | 4 | 0 |
| Glycosuria | 1 | 0 |
| Acidosis | 2 | 0 |
| Increased ventilatory requirements | 4 | 1 |
| Intraventricular hemorrhage | 2 | 0 |
| Total complications | 17 | 2 |
It is also now generally accepted that neonates are capable of sensing pain and discomfort. We have no recallable memories before 3-4 years of age (termed infantile amnesia ), but neonates do possess consciousness and a sense of self and can form implicit memories, that is, changes in behavior based on prior experience that do not require intentional recall. Plasticity is an inherent characteristic of the developing nervous system, and early pain experiences can lead to exaggerated responses to later painful stimuli or stress, as well as impaired neurodevelopmental outcome. Activation of brain regions in response to graded moderate pain stimuli is significantly different in school-age children and adolescents with neonatal intensive care (NICU) experience compared with controls, as measured by functional magnetic resonance imaging (MRI). Based on such evidence, the goals of anesthesia in neonates are not restricted to prevention of the stress response to surgery but also effective management of pain and discomfort.
Coincident with a new understanding of the importance of anesthesia and pain management in neonates, numerous animal studies, including some in nonhuman primates, have demonstrated abnormal neuroapoptosis and, in some, long-term cognitive deficits including delayed learning, impaired memory formation and retention, altered motor development, and altered behavioral development. These studies have shown effect after early exposure to virtually all commonly used anesthetic and analgesic agents. Development of the nervous system is complex, involving neuronal proliferation, migration, differentiation, and “pruning” accomplished by apoptosis. This development is in part dependent on the balance of excitatory and inhibitory stimuli and neurotransmitters. Given the complexity of the process, as well as the obvious physiologic and developmental differences inherent in application of animal studies to humans, the overall impact of these studies remains uncertain. Concerns have been raised with respect to the animal data regarding dosing and the time course of exposure. A clinically appropriate dose is the minimum necessary to induce anesthesia in the species. In some species, and with some agents, this dose also results in significant mortality, increasing the difficulty of interpreting the significance. Synaptogenesis in rats occurs postnatally over the first 2 weeks of life. An analogous period in humans would range from the third trimester of pregnancy through the first 3 years of life. Whether the child might be susceptible to anesthetic toxicity during this entire period is unknown. Elucidation of the critical period is of prime importance in anesthetic management. Studies in nonhuman primates are assumed to be more translatable to humans. Infant macaques exposed to multiple sevoflurane or isoflurane anesthetics exhibited increased anxiety behaviors and motor reflex deficits. Finally, most of the animal studies of apoptosis involve anesthesia without surgery. Because neurodevelopment is related to the balance of stimulatory and inhibitory neurotransmitters, there is some indication that the absence of surgical stress may alter the neurodevelopmental response to anesthetics.
Confirmation of long-term and relatively subtle effects in humans is, of course, a daunting task. Prior to 2015, human studies of the long-term effects of anesthetic exposure on the developing brain were largely retrospective and observational, employed varying study designs, and used a wide range of tools to assess neurodevelopmental outcomes. The results were inconsistent and at times conflicting. Exposure to multiple anesthetics during infancy and early childhood was often associated with poorer neurodevelopmental outcomes, whereas a single anesthetic exposure varied between no adverse outcomes to some degree of neurodevelopmental impairment.
Two recent prospective studies with more robust methodology reveal that a single brief anesthetic in early life may have no effect on long-term neurocognitive development. The GAS study, a prospective randomized controlled trial comparing sevoflurane general anesthesia to awake regional anesthesia (spinal or caudal) for herniorrhaphy in infancy, did not reveal any difference in neurodevelopmental outcome at 2-year follow-up. The PANDA study, a prospective sibling-matched cohort study, compared neurocognitive outcomes in infants receiving a short inhaled general anesthetic for herniorrhaphy to a biological sibling with no anesthetic exposure. Follow-up neuropsychological assessment of sibling pairs at ages varying from 8-15 years old showed no difference in neurocognitive outcomes.
In addition, three large retrospective matched cohorts with greater than 59,000 children combined did not find sufficient data to conclude that young age at initial exposure or multiple anesthetic exposures contributed to adverse neurodevelopmental outcomes.
Despite these more recent studies pointing to the safety of brief anesthetic exposure, the US Food and Drug Administration (FDA), as a result of their ongoing initiative to study the risk of anesthetic exposure on brain development, has published a warning against repeated or lengthy use of general anesthetic and sedation drugs during surgeries and procedures in children younger than 3 years of age or in pregnant women. Many questions still remain regarding anesthetic safety. What is the maximum duration or dose of safe anesthetic exposure? What are the long-term risks to those requiring multiple or longer anesthetic exposures? Do additional comorbid conditions predispose patients to a higher risk of neurocognitive impairment?
No one can question the overwhelming benefit of anesthesia in the setting in which a surgical procedure, or any noxious procedure with significant stress, is required. The detrimental effects of surgical stress have been well shown. Similarly, the benefits of early repair of some surgical problems, such as tetralogy of Fallot or neonatal hernia with risk of incarceration, have been shown, although such repair may lead to anesthesia at a younger, and potentially more susceptible, age. Current human studies suggest that a short anesthetic during early development is safe.
When deciding to proceed with an anesthetic, the benefit versus the risk of delay in surgical procedures, particularly if performed in premature infants, should be carefully considered. Second, it seems reasonable to perform a “simple” anesthetic. There is virtually no extensive experience with many anesthetic agents in neonates. This lack of extensive experience is not unusual in neonates or pediatrics in general but may be of increased importance given the small therapeutic margin of most anesthetics. One preference is to use a predominantly narcotic technique in premature infants who may be most at risk, when appropriate. Fentanyl has little, if any, activity as either an N -methyl- d -aspartate (NMDA) antagonist or gamma-aminobutyric acid (GABA) agonist. It is well tolerated hemodynamically and effective at preventing the surgical stress reaction. This particular technique may prevent extubation at the conclusion of the procedure, but in this generally ill population, that is not always a consideration.
The goals of neonatal anesthesia are the same as in adults but require different skills, knowledge, and care. The differences between adults and children are most profound in neonates, particularly premature infants. Advances in neonatology and the almost routine survival of infants weighing greater than 1000 g have led to new challenges for pediatric anesthesiology. Successful anesthetic management in a neonate requires meticulous attention to detail and a thorough understanding of neonatal physiology and development, pharmacology, and pathophysiology. The neonatal period is characterized by immaturity of organ systems, homeostasis, and metabolic pathways. It is a time of major developmental changes, and the effects of anesthesia on that development are not well characterized.
Personnel, equipment, and the operating room environment need to be specifically adapted for neonates. Anesthesia-related morbidity is decreased in children anesthetized by pediatric anesthesiologists compared with children cared for by nonpediatric anesthesiologists. Monitors, anesthesia delivery systems, mechanical ventilators, and environmental controls all need to be appropriate for use with neonates.
It is important to emphasize the perioperative nature of anesthetic management. Anesthesia care does not start and end at the door to the operative suite, and this is as critical in neonates as in older children and adults. Preoperative condition and management affect intraoperative care. Transport to the operating room can be one of the most critical aspects of an operation in a premature neonate. The postoperative period requires close monitoring and management of ventilation, fluid balance, and an environment tailored to the special needs of neonates. Assessment and control of postoperative pain require methods and tools specific to neonates.
Knowledge of the anatomic and physiologic differences among neonates, children, and adults is critical to careful anesthetic administration and management. Maturity of organ systems and metabolic processes varies significantly not only between adults and neonates but also between preterm and term neonates.
Anesthesia, Neonatal Physiology, and Specific Concerns
Transition Phase and Persistent Pulmonary Hypertension of the Neonate
In utero, the pulmonary circulation is a high-resistance circuit so that the lungs receive little blood flow, and oxygenation is a placental function. At birth, approximately 35 mL of amniotic fluid is expelled from the lungs, the lungs re-expand, and respiration begins. The lungs are initially very stiff (compliance very low), and the first breath may require negative forces of 70 cm H 2 O or more. Pulmonary vascular resistance (PVR) decreases rapidly with lung distention, while oxygenation, pulmonary blood flow, and cardiac output increase. The increase in pulmonary blood flow coupled with decreased venous return from the inferior vena cava with clamping of the placenta causes left atrial pressure to exceed right atrial pressure, resulting in closure of the foramen ovale. The ductus arteriosus closes between 1 and 15 hours after birth.
Although PVR decreases, the pulmonary arterioles possess abundant smooth muscle, and the pulmonary vascular bed remains very reactive. In this setting, hypoxia, hypercarbia, or acidosis can cause a sudden increase in PVR and a return to a fetal circulatory pattern, a condition known as persistent fetal circulation or persistent pulmonary hypertension of the neonate (PPHN). Persistent pulmonary hypertension of the neonate is an acute, life-threatening condition, as shunt fraction increases to 70%-80%, and profound cyanosis results. Many factors during anesthesia can affect this transitional state. Anesthetic agents can markedly diminish systemic vascular resistance (SVR), resulting in a right-to-left shunt. Hypoxia or hypercarbia and acidosis from inadequate ventilation can increase PVR, as can increased sympathetic stimulation during surgical stress, with similar effects on right-to-left shunt.
Respiratory Physiology: Apnea, Central Control of Ventilation, and Respiratory Distress Syndrome
Anesthetic agents are respiratory depressants. Central regulation of breathing is obtunded under anesthesia, with a significant decrease in the ventilatory response to increased carbon dioxide (CO 2 ). Compared with older children and adults, in neonates, lung volume and functional residual capacity (FRC) as a percentage of body size are much less. Alveolar ventilation per unit lung volume is very high, because the neonate's metabolic rate is about twice that of an adult. Most of this alveolar ventilation is provided by a rapid respiratory rate of 35-40 breaths/min, because tidal volume is limited, owing to the structure of the chest wall.
One consequence of the reduced FRC and high metabolic rate in a neonate is a diminished reserve. Changes in the fraction of inspired oxygen (F io 2 ) are rapidly seen as changes in P o 2 , and the neonate quickly desaturates if ventilation is interrupted. This situation limits time for intubation, and airway management can be difficult. The high alveolar ventilation also accounts for a very rapid uptake of inhalational anesthetic agents, especially in premature infants, making it easy to overdose with these agents. Closing volume, which is the lung volume at which smaller airways tend to collapse, is very close to FRC in neonates. It is well known that anesthesia causes decreases in FRC. In a neonate, this low closing volume can result in airway closure at end expiration, with resultant atelectasis, ventilation/perfusion mismatch, and increased intrapulmonary shunting.
An awake infant uses laryngeal braking, resulting in an auto-positive, end-expiratory pressure (auto-PEEP) to maintain FRC, but laryngeal braking is diminished by anesthesia. In a premature neonate, alveoli are immature and thick-walled and saccular. Surfactant production begins at 23-24 weeks’ gestation, but it may remain inadequate until 36 weeks’ gestational age; because of this, lung volumes and compliance are decreased further in very premature infants. Although the lung is less compliant in an infant than in an older child, the chest wall in an infant is very compliant. This combination results in increased work of breathing. Because resistance to airflow is inversely proportional to the fourth power of the radius of the airway, the work of breathing is increased further in neonates, particularly small premature infants.
Changes in airway resistance are also common during anesthesia, often resulting from small endotracheal tubes and equipment factors such as inspiratory and expiratory valves in the breathing circuit. Kinking of the endotracheal tube or the presence of secretions also can adversely affect resistance. Respiratory failure from fatigue can occur easily. Most neonates require controlled positive pressure ventilation during operative procedures because of the low FRC, increased closing volume, and increased work, along with changes induced by anesthetics. Infants already being ventilated require some increase in their ventilator settings after induction of anesthesia, and some infants require increased postoperative ventilatory support.
Tracheomalacia is common in premature infants, and if low in the airway, it may not be obviated by intubation. Bronchomalacia may result in airway collapse on expiration. Continuous positive airway pressure (CPAP) or PEEP increases FRC and decreases closing volume and helps to stent open the airway during anesthesia. Slower respiratory rates should be used with positive pressure ventilation to allow time for passive exhalation and prevent air trapping. The premature lung is very susceptible to barotrauma and oxygen toxicity. Pneumothorax and interstitial emphysema may develop if high peak inspiratory pressures are used.
Periodic breathing with intermittent apneic spells is common in neonates up to 3 months of age. Small premature infants have a biphasic ventilatory response to hypoxia, with an initial increase in ventilation, followed by a progressive decrease and eventual apnea. The ventilatory response to CO 2 is decreased in premature infants and, as noted, is decreased further by anesthesia. Postoperative apneic spells are common in premature infants, although incidence decreases with advancing postconceptional age. These episodes can be secondary to the immature respiratory control system (central), a floppy airway (obstructive), or both (mixed or combined). Cote and coworkers did a meta-analysis of data from eight separate studies and found wide variability among institutions. It was clear, however, that the risk of apnea was strongly inversely related to gestational age and postconceptional age. A full-term neonate is unlikely to experience significant postoperative apnea after 45 weeks’ postconceptual age, while an infant born prematurely is at risk for postoperative apnea until 55-60 weeks’ postconceptual age.
Airway Anatomy
Airway anatomy in infants differs from anatomy in older children. The infant's head is much larger compared to body size, with a more prominent occiput and shorter neck than that of older children. The infant's tongue is large, but the larynx is higher and anterior, with the cords located at C4 in the infant compared with C5 or C6 in an adult. The epiglottis of the infant is soft and folded. The neonate's larynx has historically been described as conical, with the narrowest point in the subglottic area at the cricoid ring. Studies have revisited this anatomy using magnetic resonance imaging (MRI) and video-bronchoscopic imaging. Based on these studies, the larynx is cylindrical, although not round in cross-section but rather elliptical, with the anteroposterior dimension slightly greater. A tight-fitting, round endotracheal tube might compress the lateral laryngeal mucosa; subglottic stenosis remains a common complication, especially with longer-term intubation. Although uncuffed endotracheal tubes previously were used in neonates and children, use of newer cuffed tubes, composed of very thin, low-pressure cuffs and thin walls, is feasible in many infants, although an uncuffed tube is still required in the smallest neonates. New tubes are available with very thin cuffs, and without the Murphy eye, which decreases the length of the tube below the cuff. This ensures that the entirety of the cuff is below the cords, avoiding pressure on the cords. A cuffed tube can be sized smaller, because the cuff prevents leakage and could decrease the incidence of subglottic stenosis rather than increase it as previously believed, especially when attention is paid to cuff pressures. Intraoperatively, a cuffed tube may be essential to minimize air leakage and allow for effective positive pressure ventilation during surgical procedures that may significantly affect respiratory mechanics (laparoscopy, intrathoracic and intracardiac procedures with an open chest). Laryngeal and tracheal trauma is important because even modest airway edema can be serious. At the cricoid ring, 1 mm of edema results in a 60% reduction in the cross-sectional area of the airway, causing increased airway resistance and increased work of breathing. Laryngomalacia is also common in premature infants and can result in obstruction.
Cardiac Physiology
Transitional cardiac changes were discussed earlier. Immediately after birth, with an open ductus arteriosus, most of the cardiac output is from the left ventricle, and left ventricular end-diastolic volume is very high. Consequently, the neonatal heart functions at the high end of the Starling curve. As PVR decreases, output from the two ventricles becomes balanced at 150-200 mL/kg per minute. Heart rate is rapid at 130-160 beats/min. Because end-diastolic volumes are already high, the infant heart is unable to increase stroke volume to a significant degree, and increases in cardiac output depend entirely on increases in heart rate. Baseline blood pressure is lower in infants than in older children, particularly in preterm infants, because cardiac output is increased owing to a low SVR.
Almost all anesthetic agents have significant effects on the cardiovascular system. Inhalational agents tend to be cardiovascular depressants, and they can result in decreased myocardial contractility with bradycardia and subsequent decreased cardiac output. Most anesthetic agents cause decreased autonomic tone and peripheral vasodilation, decreasing afterload and preload. Because baroreceptor reflexes also are blunted by anesthesia, these decreases may make it impossible for the infant to compensate for pre-existing volume contraction or volume losses during anesthesia. Inotropic support may be necessary in a sick neonate, and almost all infants require some degree of volume loading during anesthesia. This belief may be at odds with contemporary thoughts on respiratory management, which emphasize diuresis; volume therapy needs to be carefully balanced to support tissue perfusion, urine output, and metabolic needs.
Patent ductus arteriosus is common in preterm neonates and can result in pulmonary overcirculation and congestive heart failure. The patent ductus arteriosus may close spontaneously. Medical therapy with nonsteroidal anti-inflammatory drugs is sometimes successful. A patent ductus arteriosus may require surgical ligation or, more recently, catheter-based occlusion. The potential adverse effects of anesthesia associated with ductal closure remain controversial.
Fetal Hemoglobin
The infant has approximately 80% fetal hemoglobin (hemoglobin F) at birth. Hemoglobin F has a P50 (partial pressure of oxygen at which hemoglobin is 50% saturated) of 20 mm Hg compared with a P50 of 27 mm Hg for hemoglobin A, which means that hemoglobin F has a higher affinity for oxygen and that the hemoglobin dissociation curve is shifted to the left. In utero, this hemoglobin dissociation curve favors transport of oxygen from the maternal to the fetal circulation. Put another way, for any given oxygen saturation, the infant has a lower P o 2 . Unloading of oxygen at the tissue level also is diminished, although this is compensated for by an increased hemoglobin level of approximately 17.5 g/dL at birth. The decreased unloading can result in tissue hypoxia, however, if P o 2 , hemoglobin, or cardiac output decreases during surgery, with secondary development of metabolic acidosis. The hemoglobin increases slightly just after birth, then decreases progressively to a level of 9.5-11 g/dL by 7-9 weeks of life, owing to decreased red blood cell life span, increasing blood volume, and immature hematopoiesis. Hemoglobin F synthesis begins to decrease after 35 weeks’ gestation, and hemoglobin F is completely replaced by hemoglobin A by 8-12 weeks of life, paralleling the decrease in hemoglobin and helping to maintain tissue oxygenation.
Renal Physiology
Nephrogenesis is complete at 34 weeks’ gestation, and the term neonate has as many nephrons as an adult, although they are immature, with a glomerular filtration rate (GFR) approximately 30% of the adult GFR. With increasing cardiac output and decreasing renal vascular resistance, renal blood flow and GFR increase rapidly over the first few weeks of life and reach adult levels by about 1 year of life. The diminished function over the first year is well balanced to the infant's needs, because much of the neonate's solute load is incorporated into body growth, and excretory load is smaller.
Several aspects of renal physiology are pertinent to anesthesia care. First, the neonatal kidney has only limited concentrating ability, apparently owing to a diminished osmotic gradient in the renal interstitium, whereas antidiuretic hormone secretion and activity are normal. Coupled with an increased insensible loss owing to a “thin” skin and increased ratio of surface area to volume, the limited concentrating ability of the kidney implies a tendency to become water depleted if intake or administration is inadequate. The neonatal kidney also is unable to excrete dilute urine efficiently and cannot handle a large free water load. In addition, primarily owing to a short, immature proximal tubule, infants are obligate sodium wasters. There is a tendency toward hyponatremia, especially if too much free water is administered during surgery, which can easily happen with continuous infusions from invasive pressure transducers, especially if adult transducers are used. Because of the lower GFR, the neonate also cannot handle a large sodium load and can easily develop volume overload and congestive heart failure. One final aspect concerns acid-base status: The neonatal kidney wastes small amounts of bicarbonate owing to an immature proximal tubule; infants are born with a mild proximal renal tubular acidosis, with serum bicarbonate of approximately 20 mmol/L. All these changes are greater in preterm infants, particularly before nephrogenesis is complete at 34 weeks.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here