Limited physiologic reserve

Care of the critically ill neonate requires an appreciation of the special structural and functional features of immature organs. The neonate appears to respond more quickly and extremely to physiologically stressful circumstances; this may be expressed in terms of rapid changes in, for example, pH, lactic acid, glucose, and temperature [17].

The physiology of the preterm and full‐term neonate is characterized by a high metabolic rate and oxygen demand (two‐ to three‐fold increase compared with adults), which may be compromised at times of stress because of limited cardiac and respiratory reserve. The myocardium in the neonate is immature: contractile tissue constitutes only 30% of the myocardial mass, compared with 60% in mature myocardium. In addition, neonates have a lower velocity of shortening, a diminished length–tension relationship, and a reduced ability to respond to afterload stress [18, 19]. Because the compliance of the myocardium is reduced, the stroke volume is relatively fixed, cardiac output is heart rate‐dependent, and the Frank–Starling relationship is functional only within a narrow range of left ventricular end‐diastolic pressure compared with the mature myocardium. The cytoplasmic reticulum and T‐tubular system are underdeveloped, and the neonatal heart is dependent on the trans‐sarcolemmal flux of extracellular calcium both to initiate and sustain contraction. It is important to note that much of this information is derived from animal data.

Cardiorespiratory interactions are important in neonates and infants. In simple terms, ventricular interdependence refers to the fact that a relative increase in ventricular end‐diastolic volume and pressure causes a shift of the ventricular septum and diminishes the diastolic compliance of the opposing ventricle [20]. This effect is particularly prominent in the immature myocardium. Therefore, a volume load from an intracardiac shunt or valve regurgitation, and a pressure load from ventricular outflow obstruction or increased vascular resistance, may lead to biventricular dysfunction. For example, in neonates with tetralogy of Fallot and severe outflow obstruction, hypertrophy of the ventricular septum may contribute to diastolic dysfunction of the left ventricle and an increase in end‐diastolic pressure. This does not improve immediately after repair in the neonate as it takes some time for the myocardium to remodel. A persistent volume load to the left ventricle following surgery, such as from a residual ventricular septal defect (VSD), may further exacerbate this situation.

The mechanical disadvantage of an increased chest wall compliance and reliance on the diaphragm as the main muscle of respiration limits ventilatory capacity in the neonate. The diaphragm and intercostal muscles have fewer type I muscle fibers (slow‐contracting, high‐oxidative fibers for sustained activity) and this contributes to early fatigue when the work of breathing is increased. In the newborn, only 25% of fibers in the diaphragm are type I, reaching a mature proportion of 55% by 8–9 months of age [21]. The diaphragmatic function may be significantly compromised by raised intra‐abdominal pressure such as from gastric distension, hepatic congestion, and ascites.

The tidal volume of full‐term neonates is between 4 and 6 mL/kg and, because of the above mechanical limitations, minute ventilation is dependent on respiratory rate. The resting respiratory rate of the newborn infant is between 30 and 40 breaths/min, which provides the optimal alveolar ventilation to overcome the work of breathing and match the compliance and resistance of the respiratory system. When the work of breathing increases, such as with parenchymal lung disease, airway obstruction, cardiac failure, or increased pulmonary blood flow, a larger proportion of total energy expenditure is required to maintain adequate ventilation. Infants, therefore, fatigue readily and fail to thrive.

The neonate has a reduced functional residual capacity (FRC); FRC is determined by the balance between the chest wall and lung compliance. Closing capacity is increased in newborns with airway closure occurring during normal tidal ventilation [22]. Neonates have reduced oxygen reserve, and in conjunction with the increased basal metabolic rate and oxygen consumption that is two to three times adult levels, are at risk for hypoxemia. Atelectasis and hypoxemia do not occur in the healthy neonate because FRC is maintained by dynamic factors including tachypnea, breath stacking (early inspiration), expiratory breaking (expiratory flow interrupted before zero flow occurs), and from laryngeal breaking (auto positive end‐expiratory pressure). The propensity of the neonatal capillary system to leak fluid out of the intravascular space is especially pronounced in the neonatal lung [23], in which the pulmonary vascular bed is almost fully recruited at rest and the increases in lymphatic flow required to handle elevated mean capillary pressures (due to augmented pulmonary blood flow) are limited [24].

The glomerular filtration rate is generally low at birth but normalizes over the first few months of life. Urinary sodium excretion increases slowly during the first 2 years of life, and the inability of immature kidneys to concentrate urine and to excrete acute water and sodium loads makes fluid management in neonates, especially preterm infants, difficult. Urinary acidification capability is limited in neonates and the bicarbonate threshold is reduced. Thus, premature infants have decreased serum bicarbonate levels and lower serum pH (a non‐anion gap acidosis). Neonates tolerate fluid restriction poorly, so fasting should be kept to a minimum and intravenous (IV) fluid started early; however, excessive fluid administration (as after CPB) is also poorly tolerated.

Drug pharmacodynamics and kinetics may be different in the newborn because of immature hepatic and renal function. In addition to altered drug metabolism, protein binding and clearance, the drug volume of distribution is affected by the increase in total body water of the neonate compared with the older patient. The dosing of drugs that mainly depends on renal excretion will have to be reduced and, if possible, the plasma concentration should be closely assessed to avoid accumulation and side effects. Larger doses of furosemide are needed to induce diuresis in neonates compared with adults.

The caloric requirement for neonates, especially preterm neonates, is high (100–150 kcal/kg/24 hours) [25]. Supplying adequate nutrition can be a difficult task, especially if the total amount of fluid, administered either parenterally or enterally, must be restricted, as is the case in premature neonates with CHD. Hyperosmolar feedings have been associated with an increased risk of necrotizing enterocolitis (NEC) in the preterm neonate or in the full‐term neonate who has decreased splanchnic blood flow of any cause (e.g., left‐sided obstructive lesions).

Stress response

In general terms, the “stress response” is a systemic reaction to injury, with hemodynamic, endocrinologic, and immunologic effects (Box 19.2). Stress and adverse postoperative outcomes have been linked in critically ill newborns and infants. This is not surprising given their precarious balance of limited metabolic reserve and increased resting energy demand. Metabolic derangements, such as altered glucose homeostasis, acidosis, salt and water retention, and a catabolic state contributing to protein breakdown and lipolysis, are commonly seen following major stress in sick neonates and infants [17]. This complex of maladaptive processes may be associated with prolonged mechanical ventilation and intensive care unit (ICU) stay as well as with increased morbidity and mortality.

The neuroendocrine stress response is activated by afferent neuronal impulses from the site of injury, traveling via sensory nerves through the dorsal root of the spinal cord to the medulla and hypothalamus. Anesthesia can therefore have a substantial modulating effect on this neuroendocrine pathway by virtue of providing analgesia and loss of consciousness. Outcomes after major surgery in neonates and infants may be improved when the stress response is attenuated. This was initially reported in two controlled, randomized trials comparing N₂O/O₂/curare anesthesia with or without fentanyl in neonates undergoing patent ductus arteriosus (PDA) ligation [17], and with or without halothane in neonates undergoing general surgery [26]. Fentanyl doses as low as 10 μg/kg may be sufficient for effective baseline anesthesia in neonates, although larger doses are necessary for prolonged anesthesia [27].

It is important to distinguish between suppression of the endocrine response and attenuation of hemodynamic response to stress. Because of their direct effects on the myocardium and vascular tone, anesthetic agents can readily suppress the hemodynamic side‐effects of the endocrine stress response. However, the postoperative consequences of the endocrine stress response, in particular fluid retention and increased catabolism, remain unabated. Relying on hemodynamic variables to assess the level of “stress” is therefore often inaccurate. Metabolic indices such as hyperglycemia and lactic acidosis are also indirect markers of “stress”, particularly as they are influenced by other factors such as cardiac output and catecholamine levels.

The effect of surgical stress has been specifically evaluated in neonates and infants undergoing cardiac surgery. Wood et al. first demonstrated a substantial increase in epinephrine and norepinephrine levels in response to profound hypothermia and circulatory arrest in infants [28]. The hormonal and metabolic response was further characterized by Anand et al. and noted such response to be more extreme and distinct from that seen in adults [29]. In addition to an increase in catecholamine, glucagon, endorphin, and insulin levels, hyperglycemia and hyperlactatemia persisted into the postoperative period. In an important subsequent study, Anand and Hickey compared a high dose sufentanil technique with halothane/morphine anesthesia in 45 neonates undergoing cardiac surgery and deep hypothermic CPB [30]. They reported a significant attenuation of hormonal and metabolic responses to surgery and bypass in the sufentanil group, with less postoperative morbidity and mortality. A conclusion from these studies supported the notion that reducing the stress response with high‐dose opioid anesthesia and extending this into the immediate postoperative period is important to reduce the morbidity and mortality associated with congenital heart surgery in neonates.

These studies were performed over two decades ago. During the intervening period, there have been substantial changes in the perioperative care of infants with heart disease as well as in the management of CPB in general; along with these changes, outcomes have considerably improved. Changes in surgical practice, especially the timing of surgery, have altered the perioperative course of numerous defects and reduced the incidence of certain pathophysiologic consequences. Currently, it is less likely to see neonates in the immediate post‐bypass period with extensive peripheral edema, anasarca, or other associated complications such as impaired ventricular function, reactive pulmonary hypertension, and substantial alterations in lung compliance and airway resistance. For example, just one or two decades ago, postoperative pulmonary hypertensive crises were relatively common events in infants who had been exposed to weeks or months of high pulmonary pressure and flow, such as truncus arteriosus, complete atrioventricular canal defects, and the transposition of the great arteries with VSDs. High‐dose opioids were an important management component for patients at risk for pulmonary hypertensive crises. In current practice, however, these patients are operated upon at an earlier age and are therefore less likely to have significant or irreversible changes in the pulmonary vascular bed. Consequently, a strategy of high‐dose opioid anesthesia to blunt the stress response may be a less critical determinant of outcome.

Further, it has been well demonstrated that high‐dose opioid anesthetic techniques do not consistently block the endocrine stress response to cardiac surgery. The dose of sufentanil used by Anand and Hickey was extremely high and difficult to translate to the more common practice of fentanyl‐based anesthesia. More recent studies in neonates, infants, and older children undergoing cardiac surgery have demonstrated attenuation of the pre‐bypass endocrine and hemodynamic response to surgical stimulation with a variety of anesthetic techniques. These studies have included high‐dose fentanyl (50 μg/kg) either by bolus or infusion [31, 32], high‐dose bolus fentanyl (25–150 μg/kg) with or without low‐dose isoflurane [33], remifentanil infusions at various rates (0.25–5 μg/kg/min) [34], and more recently low‐dose fentanyl (10‐25 μg/kg) with dexmedetomidine [35, 36]. Based upon the lack of significant stress responses reported in these studies, it is reasonable to conclude that there was appropriate neuraxial inhibition in these patients and that they were adequately anesthetized during the surgery. It is not possible to conclude, however, that one technique is superior to another. No specific dose‐response between plasma opioid level and level of hormone or metabolic stress response has been established, nor has a specific benefit been demonstrated for the method or route of opioid administration, i.e., bolus or continuous infusion.

The use of lower doses of opioids may reduce the duration of mechanical ventilation and ICU length of stay by avoiding the resulting respiratory depression from a high‐dose opioid technique [37]. Recent studies have described successful early extubation of neonates undergoing heart surgery involving CPB with general anesthesia using low‐dose fentanyl, volatile anesthetic agent and dexmedetomidine, administered as a continuous infusion without loading [37–39].