Respiratory System

The small airways predispose the micropremie to obstruction and difficulty with ventilation. Resistance to airflow is inversely proportional to the fifth power of the radius in the upper airway and to the fourth power of the radius beyond the fifth bronchial division (see also Fig. 12-7). As a result, insertion of an endotracheal tube (ETT) increases resistance and work of breathing far greater for the micropremie (2.5 or 3 mm inside diameter [ID]) than for a larger infant (4 mm ID), child (5 mm ID), and adult (7 mm ID) (Fig. 35-1). Similarly, partial occlusion of the ETT by secretions, blood, or kinking increases the work of breathing to a much greater extent in the micropremie. Partial occlusion of the natural airway from loss of muscle tone during anesthesia and sedation also increases the work of breathing more in the micropremie. Consequently, general anesthesia often requires placement of an ETT to ensure airway patency, and assisted ventilation to overcome the increased work of breathing.

FIGURE 35-1 Change in work of breathing after placement of an appropriate size endotracheal tube in extremely low–birth-weight infants (less than 1000 g), premature infants (1500 g), full-term infants, children, and adults (see text for details).

(Redrawn with permission from Spaeth JP, O’Hara IB, Kurth CD. Anesthesia for the micropremie. Semin Perinatol 1998;22:390-401.)

Diseases that narrow the airway, such as subglottic stenosis, tracheal stenosis, and tracheobronchomalacia, occur commonly in the micropremie, and the associated reduction in airway diameter further increases both resistance to airflow and work of breathing. Subglottic stenosis necessitates the placement of a smaller ETT than would otherwise be placed, further increasing airflow resistance. Tracheal stenosis often occurs near the carina and, although not necessitating a smaller ETT, it increases airway resistance from the stenosis distal to the ETT. With tracheobronchomalacia, the intrathoracic airways collapse during exhalation, again increasing resistance and the work of breathing (see also Fig. 12-10). Positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) helps stent open the airway. Mechanical ventilation, rather than spontaneous ventilation during anesthesia, prevents fatigue from increased work of breathing, and maintains ventilation and oxygenation. During anesthesia the use of smaller inspiratory-to-expiratory ratios prevent air trapping and hyperinflation of lung segments.

The structure and function of the immature lung predisposes to alveolar collapse and hypoxia. The alveoli are primarily composed of thick-walled, fluid-filled saccular spaces that are surfactant deficient and require greater pressures to initially expand. Production of surfactant begins at between 23 to 24 weeks gestation, although surfactant concentrations often remain inadequate until 36 weeks gestation. These factors lead to reduced lung volumes and lung compliance, increased intrapulmonary shunting, and ventilation-perfusion mismatch. Decreased lung volumes and ventilation-perfusion mismatch may also occur as a consequence of anesthesia. The effects of immature structure, disease, and anesthesia on lung function all increase the risk of hypoxia during surgery and anesthesia.

Micropremie lungs are particularly susceptible to oxygen toxicity, volutrauma, and the development of bronchopulmonary dysplasia (BPD). Mechanical lung injury is no longer thought to be caused by the use of high peak-inspiratory pressures, but rather related to increased end-inspiratory lung volumes and frequent collapse and reopening of alveoli. A ventilation strategy using small tidal volumes (4 to 6 mL/kg), greater respiratory rates, PEEP sufficient to avoid alveolar collapse, and permissive hypercapnia reduces lung injury in the premature lung.⁴ Randomized controlled trials of permissive hypercapnia (Paco₂ 45 to 55 mm Hg) showed smaller periods of assisted ventilation, reduced incidence of BPD, and no increase in adverse neurodevelopmental effects.⁵ The use of high inspired oxygen concentrations leads to the development of free radical species, which contribute to pulmonary epithelial cell injury.

A severity index for BPD based on the need for supplemental oxygen and/or positive-pressure ventilation or nasal CPAP has been developed and shown to identify a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in preterm infants (Table 35-1).⁶ Although this severity index has not been studied in the context of anesthetic risk, experience suggests that such infants requiring supplemental oxygen, positive pressure, or medications for reactive airways are at greater risk for perioperative pulmonary complications. Anesthetic goals include minimizing the inspired oxygen concentration and tidal volumes while maintaining oxygen saturation (Sao₂ 90% to 94%) and ventilation (Paco₂ 50 to 55 mm Hg). The use of smaller tidal volumes decreases the risk of pneumothoraces and interstitial emphysema.

TABLE 35-1 Severity-Based Diagnostic Criteria for Bronchopulmonary Dysplasia (BPD)

From Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-60.

Respiratory Control

Micropremies possess a biphasic ventilatory response to hypoxia. Initially, ventilation increases in response to hypoxia, but after several minutes, ventilation decreases and apnea may ensue.⁷ The ventilatory response to carbon dioxide is decreased in the micropremie, and hypoxia further blunts this response.^8,9 Anesthetic drugs depress the ventilatory responses to both hypoxia and hypercapnia. Hypoxia and hypercapnia occur commonly as a result of apnea and hypoventilation during emergence and recovery from anesthesia. Thus the combination of anesthetic effects and an immature respiratory control system, as well as immature intercostal and diaphragmatic muscles,^10,11 increase the risk of hypoxia, hypercapnia, and apnea in the postoperative period.

Apneic episodes occur commonly in the micropremie but decrease with advancing postconceptional age.¹² These apneic episodes usually involve both a failure to breathe (central apnea) and a failure to maintain a patent airway (obstructive apnea). Central apnea results from decreased respiratory center output, although it may be precipitated by abrupt changes in oxygenation, pulmonary mechanics, brain hemorrhage, hypothermia, or airway stimulation. Apnea may also occur without a precipitating event (i.e., idiopathic). Preterm infants with apnea do not increase ventilation in response to hypercapnia, compared with those without apnea, thereby delaying resumption of breathing and prolonging the apneic episode.¹³ During obstructive apnea, the airway becomes obstructed in the hypopharynx and larynx as a result of pharyngeal muscle incoordination. Anesthetic drugs may further decrease pharyngeal muscle tone, precipitating airway obstruction during recovery from anesthesia. The combination of anesthetic effects and immature respiratory control place the micropremie at risk for central and obstructive apnea for a prolonged period of time during recovery from anesthesia.

Not surprisingly, apnea occurs commonly after anesthesia and surgery in preterm infants.^14,15 Like apnea of prematurity, postoperative apnea may be central, obstructive, or mixed in origin.¹⁶ The term postoperative apnea usually means prolonged apnea (greater than 15 seconds) or brief apnea accompanied by bradycardia (heart rate 80 beats per minute or less). Postoperative apnea typically occurs as a cluster of episodes over several minutes, with minutes of normal breathing in between the clusters. Bradycardia may occur with apnea, usually beginning at the onset of apnea and not in response to hypoxia. Arterial oxygen desaturation usually follows the apnea, although many apneic episodes may not have any associated desaturation. Arterial desaturation is worse with obstructive apnea than with central apnea.¹⁶

Several different terms have been used to describe the age of the fetus, leading to some confusion in the literature. Gestational age, menstrual age, conceptional age, and postnatal age are all used with somewhat different meanings, even in this book, so we present here the definitions of these terms according to the American Academy of Pediatrics, Committee on the Fetus and Newborn from 2004.¹⁷ The gestational or menstrual age of the neonate is the interval from the first day of the mother’s last menstrual cycle until birth of the fetus. The postmenstrual age is the sum of the menstrual age and the postnatal age. The conceptional age is defined as the interval between conception and birth, although the former is generally unknown. The postconceptional age (PCA) is the sum of the conceptional age and the postnatal age. Postconceptual age actually refers to a concept, not conception, but this term has been used interchangeably with postconceptional age in the apnea literature in anesthesia. The postnatal (or chronological) age is the age of the infant since birth. Controversy over this terminology continues, as some argue that the menstrual age overestimates the “in utero” age of the fetus because 10 to 14 days may lapse between the onset of menses and conception. On the other hand, terms such as conceptional (and postconceptional) age are imprecise because the date of conception is usually unknown, and thus these terms are not recommended.¹⁷

The incidence of postoperative apnea depends on PCA, hematocrit, and the type of surgical procedure (Fig. 35-2; see also Fig. 4-7 and E-Fig. 4-5).^14–1618 The most significant risk factor is the PCA; the lesser the PCA, the greater the risk, with the incidence of postoperative apnea in the micropremie greater than 50%.^14,15 Postoperative apnea can occur in the micropremie even without a history of apnea of prematurity.¹⁴ Anemia (hematocrit less than 30%) and younger gestation increase the risk of apnea for a given PCA.^15,18

FIGURE 35-2 Time from the end of anesthesia to the last episode of postoperative apnea in prematurely born infants. (r² = 0.49.)

(Redrawn with permission from Kurth CD, Spitzer AR, Broennle AM, et al. Postoperative apnea in preterm infants. Anesthesiology 1987;66:483-8.)

Postoperative apnea usually begins within an hour of emergence from anesthesia.¹⁴ In the micropremie, it can continue to occur up to 48 hours postoperatively, despite the elimination of anesthetic agents (see Fig. 35-2). In fact, postoperative apnea can occur after surgery with desflurane- or sevoflurane-based anesthetics, or even after surgery for which a regional anesthetic was administered and no general anesthetic drugs were used.^19,20 Postoperative apnea is more common after major procedures, such as a laparotomy, compared with peripheral surgical procedures, such as inguinal hernia repair. These observations indicate that the neurohormonal response to surgery and postoperative pain may play an important role in the origins of postoperative apnea. Management of postoperative apnea includes close observation with a cardiorespiratory monitor and pulse oximeter, administration of intravenous (IV) methylxanthines (e.g., caffeine, theophylline),²¹ and prevention of anemia or hypovolemia. Nasal CPAP or tracheal intubation and mechanical ventilation may be required for several days postoperatively if these measures fail.

N7-methylation of theophylline (or aminophylline) to produce caffeine is well-developed in the neonate, whereas oxidative demethylation (CYP1A2) responsible for caffeine metabolism is deficient. Theophylline is effective for the management of postoperative apnea in the preterm neonate, in part because it is a prodrug of caffeine, which is effective in controlling apnea in this age group and can only be cleared slowly by the immature kidney. Consequently, the half-life of caffeine is ∼72 hours in the extreme premature neonate, which decreases to 4 to 6 hours by 6 months of age. Clearance increases from 0.004 L/kg/hr in the premature neonate to 0.119 L/kg/hr by 6 months.^22–26 Although therapeutic drug monitoring is not required, target concentrations 5 to 20 mg/L are considered therapeutic.²⁷ One study suggests a loading IV or oral dose of 10 mg/kg followed by 2.5 mg/kg by mouth, once daily.²⁶

Cardiovascular System

The micropremie remains at greater risk of cardiovascular collapse during anesthesia and surgery than does the full-term infant for several reasons. The fetal heart differs from the infant heart in that it has more connective tissue, less organized contractile elements, and increased dependence on extracellular calcium concentration. In addition, the less compliant fetal heart has a flatter Frank-Starling curve and is less sensitive to catecholamines because of near-maximal baseline β-adrenergic stimulation (see Chapter 16).^28,29 Consequently, cardiac output depends more on heart rate in the micropremie than it does in the term neonate. The increased resting heart rate in the micropremie also does not permit cardiac output to increase to the same extent as in an infant or child. The micropremie has a small absolute blood volume (Table 35-2). Therefore, relatively little blood loss during surgery can cause hypovolemia, hypotension, and shock. Because autoregulation is not well developed in the micropremie, the heart rate may not increase with hypovolemia, and blood flow and oxygen delivery to the brain and heart may decrease with relatively little blood loss.³⁰ Anesthesia blunts baroreceptor reflexes in the micropremie, further limiting the ability to compensate for hypovolemia.³¹ The combination of limited ventricular stroke volume reserve, an increased heart rate, small blood volume, and limited autoregulation predispose the micropremie to cardiovascular collapse during major surgery.

Failure of the ductus arteriosus to close in the micropremie further increases this risk. A patent ductus arteriosus (PDA) promotes pulmonary hypertension and congestive heart failure. Changes in systemic or pulmonary vascular resistance alter the direction of flow through the PDA or the foramen ovale.³² Increased pulmonary vascular resistance predisposes to right-to-left shunting that worsens with hypoxia, hypercarbia, acidosis, and hypothermia. Paradoxical embolism is another concern.³³ Fluid restriction and diuretic therapy, often used to treat congestive heart failure from left-to-right shunting through a PDA, further increase the risk of hypotension during surgery. In contrast to full-term neonates, the success of inhaled nitric oxide in the micropremie with hypoxic respiratory failure and pulmonary hypertension remains unclear.^34–36

Neurologic Development

Although mortality in extremely preterm infants has improved over the years, many survivors experience cognitive impairment and long-term disability.^37,38 Regions of the central nervous system develop at different times during gestation; consequently, the impact of premature birth on the central nervous system (CNS) depends on gestational age at birth and the severity of cardiovascular, respiratory, and other postnatal stressors. The area of the brain most susceptible to injury in the micropremie is the periventricular white matter.³⁸ The white matter consists of preoligodendrocytes, astrocytes, and neuronal axons. Late in the second trimester (24 to 27 weeks gestation), preoligodendrocytes and astrocytes multiply tremendously and most cortical and subcortical structures begin to develop.³⁸ During this period, the periventricular white matter is particularly susceptible to neurologic injury. The periventricular white matter is perfused by arteries penetrating from the cortical surface and by lenticulostriate arteries from the circle of Willis. As a result, the periventricular white matter is a “watershed region” and susceptible to poor perfusion and hypoxic-ischemic injury during conditions of hypotension, reduced cardiac output, hypoxemia, and hypocarbia.

Neural pathways allowing for perception of pain develop during the first, second, and third trimesters (see Chapter 43).³⁹ During the first trimester, peripheral sensory receptors and spinal reflex arcs develop that lead to the presence of a “withdrawal reflex” to non-noxious stimuli. Neurons that transmit nociception appear in the dorsal root ganglia at 19 weeks gestation, and afferent neurons from the thalamus reach the cortical subplate and cortical plate between 20 and 24 weeks gestation. However, it is not until early in the third trimester (29 weeks) that pathways between the thalamus and somatosensory cortex are functional. Significant controversy exists regarding the exact gestational age at which perception and memory of pain occur. Nevertheless, our approach in the micropremie is to administer anesthesia during surgery and provide pain management postoperatively.

Long-Term Neurologic Complications of Prematurity

Long-term neurologic and developmental disabilities remain common in the micropremie and include cerebral palsy, cognitive deficits, behavioral abnormalities, as well as hearing and visual impairment. In one cohort of ELBW infants, only 25% were classified as normally developed at 5 years of age, whereas 20% exhibited major disabilities.³⁷ Brain magnetic resonance imaging (MRI) identifies a spectrum of abnormalities. The most common abnormality is diffuse high signal intensity on T2-weighted imaging in the periventricular cerebral white matter. Diffusion-weighted imaging shows increased apparent diffusion coefficient values, indicative of increased water content and delayed white matter maturation, suggesting ischemia-reperfusion injury in periventricular white matter, which has activated microglia and damaged preoligodendrocytes.^38,40 Damage to preoligodendrocytes impairs myelination of cerebral white matter axons and accounts for many of the fine motor, speech, and cognitive deficits. On MRI, tissue volumes in the basal ganglia, corpus callosum, amygdala, and hippocampus are reduced and correlate with smaller full-scale, verbal, and performance IQ scores.⁴¹ Collectively, these MRI findings indicate that different regions of the brain vary in their susceptibility to injury during development and that such injuries lead to specific long-term disturbances in neurocognitive function.

Intraventricular Hemorrhage

Intraventricular hemorrhage (IVH) occurs in as many as one-third of micropremie infants. The severity of IVH, as defined by head ultrasound, is graded as follows:

Although micropremie infants with grade 3 or 4 IVH are more likely to exhibit severe long-term neurocognitive sequelae, even micropremie infants with grade 1 and 2 IVH display poorer neurodevelopmental outcomes compared with those without IVH.⁴² Early onset of IVH appears during the first day of life. Risk factors include fetal distress, vaginal delivery, reduced Apgar scores, metabolic acidosis, severe hypercapnia, and the need for mechanical ventilation.^43,44 Late onset of IVH appears days to weeks after birth. Risk factors include respiratory distress syndrome, seizures, pneumothoraces, hypoxemia, acidosis, severe hypocarbia, and the use of vasopressor infusions.⁴³ Rapid fluctuations in cerebral blood flow, cerebral blood volume, and cerebral venous pressure appear to play a role in the development of IVH.⁴⁵ Factors that may decrease the incidence and severity of IVH include administration of antenatal glucocorticoids, or indomethacin.

Retinopathy of Prematurity

Retinopathy of prematurity (ROP) occurs in approximately 50% of ELBW infants, with the incidence being inversely proportional to birth weight and gestational age (see Chapter 32).⁴⁶ Although the pathogenesis of ROP is not completely understood, extremes in arterial oxygenation (hypoxia or hyperoxia)⁴⁷ and exposure to bright light appear to play a role.⁴⁸ One theory holds that the combination of hyperoxic vasoconstriction of retinal vessels (also known as vaso-obliteration), induction of vascular endothelial growth factor, and free oxygen radicals damage the spindle cells in the retina.⁴⁹ A Cochrane review concluded that liberal oxygen delivery to a preterm infant is more harmful to the retina than restrictive oxygen delivery, although the data reviewed failed to specify the optimum blood oxygen concentrations that should be delivered.⁵⁰ Evidence points to additional factors in the pathogenesis of ROP, including genetic polymorphisms⁵¹ and antenatal and neonatal exposure to inflammation.⁵²

ROP appears to be multifactorial in origin and oxygen tension is just one of many contributory factors. During anesthesia, our goal is to deliver the minimum inspired oxygen concentration that provides oxygen saturations between 90% and 94% and to avoid significant fluctuations in oxygen saturations. It should be noted however that ROP has occurred in children with cyanotic congenital heart disease⁵³ and that no anesthesia-associated cases have been reported over the past 25 years. Nevertheless it is reasonable to aim for saturation values in the ranges described here.

Temperature Regulation

The micropremie is susceptible to hypothermia. Heat loss in children occurs by four possible routes: radiation (39%), convection (34%), evaporation (24%) and conduction (3%). In the micropremie, evaporative heat loss and insensible fluid loss are increased because the epidermis has less keratin.⁵⁴ Conductive and convective heat losses are also increased because the micropremie has little subcutaneous fat for insulation and a large surface area to mass ratio. Thermal regulation is not well developed in the micropremie. Nonshivering thermogenesis, which depends on brown fat stores, is decreased and regulation of skin blood flow is less efficient.⁵⁵ During anesthesia, measures should be undertaken to minimize radiation and convective heat loss by warming the operating room (OR) to 78° F to 80° F (25.5° C to 26.6° C) before the neonate arrives, and minimize convective heat loss during transport (i.e., use a thermoneutral incubator). Using a warming pad on the operating table reduces conductive heat loss; use of overhead heat lamps reduces radiant heat loss; and keeping the skin dry reduces evaporative heat loss. The most effective means for warming is a forced-air warmer. Temperature should be carefully monitored as overheating the infant may readily occur.

Renal and Metabolic Function

In the micropremie, kidney function is decreased as a result of fewer nephrons and smaller glomerular size.⁵⁶ Glomeruli continue to form postnatally until approximately 40 days.⁵⁷ During this period, reduced cardiac output, hypotension, and nephrotoxic drugs may inhibit glomerular growth and development. Creatinine concentrations depend on production that is reduced in micropremies with limited muscle mass, and on excretion that is reduced because of immature renal function. Baseline plasma creatinine concentrations increase with increasing prematurity and remain increased until 3 weeks of age.⁵⁸ In addition, the normal increase in creatine clearance in term infants occurs more slowly in the micropremie. Creatinine concentrations in the first few days after birth are increased and reflect maternal transplacental transfer.⁵⁹ It is for this reason that antibiotic dosing must be adjusted to take renal immaturity into consideration, so as not to administer excessive doses that might result in ototoxicity.⁶⁰

Very preterm infants easily become hyponatremic because of reduced proximal tubular reabsorption of sodium and water, and reduced receptors for hormones that influence tubular sodium transport. As many as one-third of ELBW neonates develop hyponatremia.⁶¹ Frequent assessment of sodium and free water requirements is important during critical illness. Increased plasma potassium concentrations occur in preterm infants during the first few days after birth. The increase results from a shift in potassium from the intracellular to extracellular space.⁶² These increases are greater as gestational age and birth weight decrease.⁶³ Reduced cardiac output and urine output may further increase serum potassium concentrations and predispose to cardiac arrhythmias.⁶⁴

Glucose Regulation

The micropremie is at risk for both hypoglycemia and hyperglycemia. Decreased glycogen and body fat predispose to fasting hypoglycemia, whereas decreased insulin production with infusion of dextrose predisposes to hyperglycemia.^65,66 Glucose production is poorly regulated within a large range of glucose and insulin concentrations. The micropremie is also relatively insulin resistant and requires a greater infusion rate of insulin to achieve normoglycemia.⁶⁷ The use of total parenteral nutrition and glucocorticoids places the micropremies at increased risk for hyperglycemia.

Glucose and the Brain

Multiple animal models and clinical studies implicate hyperglycemia as detrimental to the adult brain during global and focal ischemia.⁶⁸ In contrast, hyperglycemia in neonates appears to protect the brain from ischemic damage.^69–71 Studies in both neonatal rat and pig hypoxia-ischemia models observed less brain damage with greater glucose concentrations. Many mechanisms exist for this strikingly different outcome between neonates and adults.⁷² Relatively mild hypoglycemia is known to cause brain damage in preterm infants.⁷³ Micropremies with critical illness are especially prone to hypoglycemia because they contain limited stores of glucose and consume glucose anaerobically. Thus the administration of dextrose-containing fluids (carefully controlled with an infusion pump so as to minimize wide fluctuations in glucose values) and close monitoring of blood glucose concentrations is vital during anesthesia. Mild or moderate hyperglycemia during surgery is best managed by reducing the rate of infusion of dextrose-containing solutions and not administering insulin, with its attendant risk of hypoglycemia.

Hepatic and Hematologic Function

Immature hepatic function leads to a reduction in many hepatic proteins important for drug metabolism. In addition, reduced albumin synthesis decreases albumin concentrations compared with term neonates (see Fig. 6-6), thus enhancing the “free” (unbound) concentration of anesthetic drugs that are highly bound to albumin (see Chapter 6). The micropremie is at particular risk for spontaneous liver hemorrhage.^74,75 This occurs most commonly during laparotomy for necrotizing enterocolitis (NEC), is associated with large IV fluid resuscitation, and is difficult to control surgically. Recombinant factor VIIa has been used to stop liver hemorrhage when administration of other blood products has been unsuccessful.⁷⁶

The ideal hematocrit level for the micropremie remains controversial. In the micropremie with reduced oxygen saturations and cardiac output, tissue oxygen delivery will be maximized by maintaining the hematocrit between 44% and 48%. In a randomized study of liberal versus restrictive transfusion in neonates between 500 and 1300 grams, intraparenchymal brain hemorrhage, periventricular leukomalacia, and episodes of apnea occurred more frequently in the restrictive transfusion group.⁷⁷ The risks of blood transfusion in the micropremie must be balanced against the benefits of improved oxygen delivery and fewer medical complications.

Thrombocytopenia (platelet count less than 150,000/mm³) occurs in as many as 70% of micropremies.⁷⁸ Although the etiology of thrombocytopenia is often unknown, pathophysiologic processes such as sepsis, disseminated intravascular coagulation, and NEC are common causes. Preoperative evaluation should include a recent platelet count and the availability of platelets for major procedures.

Anesthetics and the Immature Brain

Research in immature animals indicates that anesthetics are both neuroprotective and neurotoxic. Inhalational anesthetics protect against hypoxic-ischemic injury in neonatal pigs and rats.^79–81 The anesthetic must be administered before and during the ischemic event at a concentration of 1 MAC (minimal alveolar concentration) to be effective. Thus for surgery in which there is a risk of brain ischemia, use of an inhalational anesthetic may afford some advantage over IV agents. Cardiac surgery, ventricular shunt insertion, and vein of Galen embolization represent examples of procedures that are performed in preterm infants and that carry a risk of brain ischemia. The MAC for sevoflurane has not been established in preterm infants and many sick preterm infants cannot tolerate even relatively modest concentrations of potent anesthetic agents.

Of particular concern are the reports in immature rats and other animals, including primates, that prolonged exposure to commonly used anesthetics, such as isoflurane, ketamine, and midazolam, induces apoptosis in many regions of the brain (see Chapter 23).^82,83 In rodents, exposure for at least 2 hours at 1 MAC of isoflurane produces apoptosis. A combination of isoflurane, midazolam, and nitrous oxide produces more neuronal degeneration than isoflurane or midazolam alone; nitrous oxide alone is not neurotoxic. When affected rats matured to adulthood, neurocognitive impairment was detected.⁸² The neurotoxicity is brain-region specific and very dependent on the developmental age of the rodent. Rats are most sensitive to the neurotoxic effects of anesthetics on postnatal day 7, more so than on postnatal day 4 or beyond postnatal day 10.⁸⁴ The most susceptible age in rats, 7 days, corresponds to human brain development around mid-gestation. This suggests that if this phenomenon applies to humans, the preterm infant could potentially be more susceptible to anesthetic neurotoxicity than is the full-term infant.

The mechanism for the neurotoxicity appears to be attributable to the neurotransmitters glutamate and γ-aminobutyric acid, which act as trophic factors in the developing brain.⁸⁵ In the immature brain, these trophic factors promote synaptic growth and plasticity and are obligate for neuronal survival. The inhaled anesthetics, ketamine, and midazolam exert their anesthetic effects by altering synaptic transmission through blockade of glutamate and γ-aminobutyric acid receptors. In the immature brain, this blockade also precipitates neuronal cell death by apoptosis.⁸⁶ In contrast, several anesthetics and medications may protect against apoptosis (see Chapter 23). A confounding factor is that neurodegeneration and apoptosis is a normal developmental phenomenon in the maturing fetal brain. Furthermore, anesthesia-induced neuronal cell death in neonatal animals may not directly translate into long-term neurologic abnormalities. Indeed, evidence suggests that sevoflurane-induced cognitive impairment, in the form of short-term memory deficiency in neonatal rodents, is offset by delayed exercise.⁸⁷ Moreover, immature animals that undergo painful procedures without anesthesia experience neuronal degeneration.^88,89 Preterm infants who receive anesthesia and sedation for painful procedures experience less morbidity and mortality than those who do not.⁹⁰ Curiously, the combination of surgery and anesthesia in neonatal rats produces more apoptosis than either intervention alone suggesting that in this model, anesthetics are neither neuroprotective themselves nor do they offset the apoptotic effects of surgery.⁹¹ In summary, the neurodegeneration precipitated by inhaled anesthetics, ketamine, and benzodiazepines depends on developmental age, brain region, and duration of exposure. Based on the animal models, the micropremie exposed to several hours of large concentrations of inhaled agents with nitrous oxide and midazolam is potentially at risk, as is the micropremie exposed to surgery with insufficient anesthesia. Thus our approach at the present time for emergency surgery is to use small concentrations of inhaled agent with opioids and regional anesthesia whenever possible.