Respiration

Control of respiration in newborn infants, especially premature neonates, is poorly developed. The incidence of central apnoea (defined as a cessation of respiration for 15 s or longer) is not uncommon in this group. The likelihood of this increases if the patient is given a drug with a sedative effect. Potentially life-threatening apnoea may occur. The incidence is reduced by postoperative administration of xanthine derivatives such as caffeine and theophylline which act as central respiratory stimulants. Because of this problem, it is wise to admit for overnight oximetry and apnoea monitoring all children under 60 weeks’ postconceptual age who have had surgical procedures, no matter how minor. Hypoxaemia in the neonate and small child appears to inhibit rather than stimulate respiration and this is contrary to what one might expect.

The newborn has between 20 and 50 million terminal air spaces. At 18 months of age, the adult level of 300 million is reached by a process of alveolar multiplication. This explains why infants who suffer with respiratory distress of the newborn improve as they grow older. Subsequent lung growth occurs by an increase in alveolar size. The lung volume in infants is disproportionately small in relation to body size. The metabolic rate is nearly twice that of the adult, and therefore ventilatory requirement per unit lung volume is increased. Thus, they have far less reserve for gas exchange.

Before the age of 8 years, the calibre of the airways is relatively narrow. Airway resistance is therefore relatively high. Small decreases in the diameter of the airways as a result of oedema or respiratory secretions significantly increase the work of breathing. Elastic tissue in the lungs of small children is poorly developed. As a result of this, compliance is decreased. This has important consequences in that airway closure may occur during normal tidal ventilation, thereby bringing about an increase in alveolar–arterial oxygen tension difference (P_A − aO₂). This explains why PaO₂ is lower in the infant than in the child. The decreased compliance results in ventilatory units with short time constants. Consequently, the infant is able to achieve adequate alveolar ventilation whilst maintaining a high respiratory rate. However, because of the increased resistance and decreased compliance, the work of breathing may represent up to 15% of total oxygen consumption (Table 36.1). The high respiratory rate is necessary because the metabolic rate of the infant is nearly twice that of the adult. The high alveolar minute ventilation explains why induction and emergence from inhalational anaesthesia are relatively rapid in small children. The high metabolic rate also explains why desaturation occurs very rapidly in children.

The ratio of physiological dead space to tidal volume (V_D/V_T) is similar to that of the adult at about 0.3. However, because the volumes are smaller, modest increases in V_D produced by equipment such as humidification filters may have a disproportionately greater effect (Table 36.2).

Ventilation in small children is almost entirely diaphragmatic. Because the ribs are horizontal, there is no ‘bucket handle’ movement of the ribs as occurs in the adult. It is therefore important to appreciate that normal minute ventilation is respiratory rate-dependent. The infant’s diaphragm is made of fast twitch fibres. This type of muscle fibre exhausts easily if it has to work against a load. This implies that in infancy, when lung compliance is low, the work of breathing is reduced by breathing rapidly. Consequently if the work of breathing is increased by an increase in airway resistance, respiratory failure may easily ensue.

It is important to appreciate that the infant’s response to hypoxaemia may be bradypnoea and not tachypnoea as occurs in the adult.

Cardiovascular System

The process of growth demands a high metabolic rate. It is, therefore, not surprising that infants and children have a higher cardiac index compared with the adult, so that oxygen and nutrients may be delivered to actively growing tissues. The ventricles of neonates and infants are poorly compliant, so even though the ventricles of infants demonstrate the Frank-Starling mechanism, the main determinant of cardiac output is heart rate. Infants tolerate heart rates of 200 beat min⁻¹ with ease (Table 36.3). Bradycardia may occur readily in response to hypoxaemia and vagal stimulation and it results in a decrease in cardiac output. Immediate cessation of the stimulus, and treatment with oxygen and atropine, are absolutely crucial. A heart rate of 60 beat min⁻¹ in an infant is considered a cardiac arrest and requires cardiac massage. Arrhythmias are rare in the absence of cardiac disease. The usual cardiac arrest scenarios are electromechanical dissociation and asystole, not ventricular fibrillation.

Even though infants and children have a higher cardiac index, arterial pressure tends to be lower than in adults because of a reduced systemic vascular resistance associated with an abundance of vessel-rich tissues in the infant. The arterial pressure increases from approximately 80/50 mmHg at birth to the normal adult value of 120/70 mmHg by the age of 16 years. Children under the age of 8 years who are normovolaemic at the start of anaesthesia tend not to exhibit a decrease in arterial pressure when central neural blockade such as spinal anaesthesia is administered. They do not require fluid preloading as an adult would to avoid hypotension, because venous pooling tends not to occur as venous capacitance cannot increase. The reasons for this are, first, that the sympathetic nervous system is less well developed and so infants tend to be venodilated at rest. Second, they have a lower extremity:body surface ratio and as a consequence have a smaller venous capacitance.

As in all patients, the cardiovascular system must be monitored carefully. Pulse oximeter probes placed on the extremities provide a good index of peripheral perfusion. Auscultation of heart sounds, especially by an oesophageal stethoscope, is useful as the volume of heart sounds tends to be diminished as cardiac output decreases. Non-invasive measurement of arterial pressure is undertaken easily using an appropriately sized cuff. Complications preclude the use of invasive monitoring of arterial and central venous pressures for all but major cases.

Renal Function and Fluid Balance

Body fluids constitute a greater proportion of body weight in the infant, particularly the premature infant, compared with the adult (Table 36.4). In an adult, most of the total body water is in the intracellular compartment. In a newborn infant, most of the total body water is in the extracellular compartment. With increasing age, the ratio reverses. Plasma volume remains constant throughout life at about 5% of body weight.

The kidneys are immature at birth. Both glomerular filtration rate (GFR) and subsequent reabsorption by the renal tubules are reduced. The GFR at birth is of the order of 45 mL min⁻¹ 1.7 m⁻². This increases rapidly to about 65 mL min⁻¹ 1.7 m⁻² and then gradually approaches the adult value of 125 mL min⁻¹ 1.7 m⁻² by the age of 8 years. Thus, there is inability to handle excessive water and sodium loads. Overtransfusion may lead to pulmonary oedema and cardiac failure. The maturation in renal function is produced by hyperplasia in the first 6 months of life and then by a process of hypertrophy in the first year. Care must also be exercised when drugs eliminated by the renal route are used in infants; either reduced doses or an increased dosage interval should be employed. Renal maturation is not just an increase in size but also of function. The ability to modify the ultrafiltrate produced at the glomerulus increases with age. It follows that sodium bicarbonate and glucose homeostasis mechanisms are not fully developed. Medical intervention may be required to ensure that biochemical values are kept within normal ranges.

Poorly developed mechanisms exist for conserving water in the kidneys and gastrointestinal tract. Increased cutaneous water loss because of a large surface area:volume ratio through poorly keratinized skin may lead to a turnover of fluid in the infant of about 15% of total body water per day. Dehydration ensues very rapidly in an infant who is kept fasted.

Fluid Therapy

An intravenous infusion delivering maintenance fluids should be in place for all neonates requiring surgery. Maintenance fluid requirements increase over the first few days of life (Tables 36.5, 36.6). The normal infant requires of the order of 3–5 mmol kg⁻¹ of sodium and an equivalent amount of potassium per day to maintain normal serum electrolyte concentrations. The ability of the infant’s kidneys to eliminate excess sodium is limited. Exceeding this amount in the absence of loss results in hypernatraemia and its sequelae. Infants undergoing any procedure more than the briefest should also have their calorific needs addressed. This may be achieved by including glucose-containing fluids in the regimen; failure to do so results in hypoglycaemia and ketosis. This may occur rapidly because of the limited glycogen stores and high metabolic rate of the infant.

It is imperative that the anaesthetist recognizes and resuscitates the dehydrated infant appropriately before surgery. Clinical examination of skin turgor, capillary refill, tension of fontanelles, arterial pressure and venous filling may aid estimation of hydration, but electrolyte and haemoglobin concentrations and haematocrit, urine volumes and plasma and urine osmolalities should be monitored if problems of fluid balance exist (Table 36.7).

Intravenous fluids should be administered using a system that allows small volumes to be given accurately. This may vary from the anaesthetist injecting fluid using a syringe to microprocessor-controlled syringe driver pumps. The latter are preferable, as fluid is given at a steady rate and the anaesthetist’s hands are free to attend to other tasks. During surgery, fluid administration should be increased to account for increased losses occurring through evaporation from exposed viscera and third-space losses.

The intraosseous route may be used to carry out fluid resuscitation and drug therapy in shocked children. The needle should be inserted in an aseptic fashion to minimize the risk of osteomyelitis. Although various sites have been described for needle insertion, the proximal end of the tibia below the tuberosity is probably the easiest to perform. The intraosseous route is safer than attempting central venous cannulation in the shocked child in whom veins are difficult to discern. The usual fluid administered in this situation is a colloid solution. This is given as a 10 mL kg⁻¹ bolus and repeated until clinical improvement occurs.

Temperature Regulation and Maintenance

Homeothermic animals possess the ability to produce and dissipate heat. Heat loss occurs by one of four processes: radiation, convection, evaporation and conduction. The environment in which the patient is situated governs the relative contribution of each. The neutral thermal environment is defined as the range of ambient temperatures at which temperature regulation is achieved by non-evaporative physical processes alone.

The metabolic rate at this temperature is minimal. The temperature of such an environment is 34°C for the premature neonate, 32°C for the neonate at term and 28°C for the adult.

Heat may be produced by one of three processes: voluntary muscle activity, involuntary muscle activity and non-shivering thermogenesis. Infants under the age of 3 months do not shiver. The only method available to increase their temperature in the perioperative period is non-shivering thermogenesis. The process is mediated by specialized tissue termed brown fat. It differentiates in the human fetus between 26 and 30 weeks of gestation. It comprises between 2% and 6% of total body weight in the human fetus and is located mainly between the scapulae and in the axillae. It is also found around blood vessels in the neck, in the mediastinum and in the loins. Brown fat is made of multinucleated cells with numerous mitochondria and has an abundant blood and nerve supply. Its metabolism is mediated by catecholamines. The substrate used for heat production is mainly fatty acids.

Radiation accounts for about 60% of the heat loss from a neonate in a 34°C incubator placed in a room at 21°C. If the infant was in a thermoneutral environment of 34°C, the percentage loss by radiation would decrease to about 40% of the total heat loss, and, in addition, the total heat loss in this environment would be lower. The reason for this is that heat loss by radiation is a function of skin surface area and the difference in temperature between the skin and the room. The second major source of heat loss in the neonate is convection. This is a function of skin temperature and ambient temperature. The neonate possesses minimal subcutaneous fat that may act as thermal insulation and as a barrier to evaporative loss. A neonate has a body surface area:volume ratio about 2.5 times greater than the adult; thus, a neonate may become hypothermic very rapidly.

If neonates are allowed to become hypothermic during anaesthesia, unlike adults they attempt to correct this by non-shivering thermogenesis. Metabolic rate increases and oxygen consumption may double. The increase in metabolic rate puts an additional burden on the cardiorespiratory system and this may be critical in neonates with limited reserves. The release of noradrenaline in response to hypothermia causes vasoconstriction, which in turn causes a lactic acidosis. The acidosis favours an increase in right-to-left shunt, which causes hypoxaemia. As a result, a vicious positive feedback loop of hypoxaemia and acidosis is set up. The protective airway reflexes of a hypothermic neonate are obtunded, thereby increasing the risks of regurgitation and aspiration of gastric contents. The action of most anaesthetic drugs is potentiated by hypothermia. This effect is particularly important with regard to neuromuscular blocking drugs. The combination of hypothermia and prolonged action of these drugs increases the chances of the neonate hypoventilating after surgery.

Many precautions should be taken to ensure that the neonate’s body temperature is maintained. First, the child must be transported to theatre wrapped up and in an incubator set at the thermoneutral temperature. The theatre should be warmed up to the thermoneutral temperature, ideally a few hours before the planned start of surgery. This interval allows the walls of the theatre to warm up and this reduces the net heat loss by radiation. Heat loss by radiation is a two-way process. The child loses heat by radiation to the walls and also gains heat from the walls. All body parts which are not needed for insertion of cannulae and for monitoring should remain covered until the child has been draped with surgical towels. If the child has to be exposed, overhead radiant heaters may be used. During surgery, the child should lie on a thermostatically controlled heated blanket. Forced air warming systems are effective in maintaining the child’s temperature during surgery; these work on the principle of blowing filtered, warmed air into quilted blankets with perforations. This allows warmed air to come into direct contact with the patient. Simple measures such as using a bonnet to reduce heat loss from the head are very effective. Intravenous fluids and fluids used to perform lavage of body cavities must be warmed. Anaesthetic gases should be humidified and warmed in order to preserve ciliary function and to reduce heat loss from the respiratory tract.

Monitoring

It is important in all procedures to measure temperature. For short procedures, an axillary temperature probe may be sufficient. In longer operations, core temperature should be measured at one of a variety of sites, such as rectal, bladder, nasopharyngeal or oesophageal. The oesophageal probe is often the preferred method, as most modern oesophageal probes may be connected to a stethoscope. The anaesthetist is therefore able to listen to heart sounds in addition to recording the patient’s temperature. When active heating methods such as cascade humidifiers and heated blankets are used, it is important that temperature gradients between the patient and the warming device are kept to less than 10°C. Failure to observe this may result in burns to the skin and the respiratory tract. In the ICU, simultaneous measurement of core and peripheral temperatures, though not often used in theatre, may serve as a useful guide to adequacy of the cardiac output. Decreases in cardiac output result in a reduction of blood flow to the peripheries and this is reflected in a core-peripheral temperature gradient greater than 3–4°C.

Developmental Pharmacology

Drugs given via the oral or rectal route are absorbed by a process of passive absorption. This process is dependent on the physicochemical properties of the drug and the surface area available for absorption. Most drugs are either weak bases or weak acids. The un-ionized portion of the drug therefore depends on the pH of the fluid in the gut. The gastric pH of the neonate is higher than that of the older child and adult. The consequence is that drugs inactivated by a low pH undergo greater absorption. Examples of these include antibiotics such as penicillin G.

Factors which determine the distribution of intravenously administered drugs include protein and red cell binding, tissue volumes, tissue solubility coefficients and blood flow to tissues. Neonates, in particular preterm infants, have lower plasma concentrations of albumin. In addition, the albumin is qualitatively different in that its ability to bind drugs is lower than that of adult albumin. The concentration of α₁-acid glycoprotein is also lower in this group of patients; this protein is the major binding protein for alkaline drugs, which include opioid analgesics and local anaesthetics.

The blood–brain barrier is immature at birth; thus, it is more permeable to drugs. In addition, the neonate’s brain receives a larger proportion of the cardiac output than does the adult brain. Consequently, brain concentrations of drugs are higher in neonates than in adults. For example, administration of morphine, which has low lipid solubility, results in high concentrations in the neonate’s brain and therefore it should be used with caution and in reduced amounts.

In a neonate, total body water, extracellular fluid and blood volume are proportionally larger in comparison with an adult. This results in a larger apparent volume of distribution for a parenterally administered drug. This explains in part why neonates appear to require larger amounts of some drugs on a weight basis to produce a given effect. However, plasma concentrations tend to remain high for longer because they have smaller muscle mass and fat stores to which drugs redistribute.

The action of most drugs is terminated by metabolism or excretion through the liver and kidneys. In the liver, phase I reactions convert the original drug to a more polar metabolite by the addition or unmasking of a functional group such as -OH, -NH₂ or -SH. These reduction/oxidation reactions are a function of liver size and the metabolizing ability of the appropriate microsomal enzyme system. The volume of the liver relative to body weight is largest in the first year of life. The enzyme systems in the liver responsible for the metabolism of drugs are incompletely developed in the neonate. Their activity appears to be a function of postnatal rather than post-conceptual age, because premature and full-term infants develop the ability to metabolize drugs to the same degree in the same period after birth. Adult levels of activity are achieved within a few days of birth. Phase II reactions which involve conjugation with moieties such as sulphate, acetate, glucuronic acid, etc., are severely limited at birth. Most of these conjugation reactions are in place by the age of 3 months. The kidneys ultimately eliminate most drugs. As mentioned above, GFR is lower in young children than in adults. However, by the age of 3 months, the clearance of most drugs approaches adult values.

Specific Drugs in Paediatric Anaesthesia