Head and Neck

When compared to adults, neonates and infants have a comparatively big head and tongue, but a relatively small body, necessitating a particular neutral shoulder roll for anesthesia induction [Reference Höhne, Haack, Machotta and Kaisers3, Reference Dalal, Murray, Messner, Feng, McAllister and Molter4]. The “sniffing position” is less advantageous for bag–mask ventilation or glottic visualization because of an infant’s relatively large head. Neonates have a more cephalad and anterior larynx, situated at the C3–4 vertebrae, rather than at the C6 vertebral level in adults [Reference Kaye, Fox and Padnos2, Reference Höhne, Haack, Machotta and Kaisers3]. The epiglottis is narrow, omega-shaped, and angled away from the axis of the trachea, thus obscuring the vocal cords [Reference Kaye, Fox and Padnos2]. Whereas an adult’s larynx is cylindrical in nature, a child’s larynx is funnel-shaped [Reference Butterworth, Mackey and Wasnick5]. Additionally, the cricoid cartilage is the narrowest portion of the airway in children aged 5 years or younger; the glottis is the narrowest section of the airway in older children and adults [Reference Butterworth, Mackey and Wasnick5]. The cricoid cartilage reaches adult proportions at the age of 10–12 years. Neonates are obligate nasal breathers until the age of 3–5 months. Prior to this age, the delicate nasal passages can be obstructed or compromised by secretions, nasal congestion, stenosis, canal atresia, endotracheal tubing, or even the tongue [Reference Trabalon and Schaal6].

Respiratory

Oxygen consumption in a full-term neonate is twice that of an adult. In preterm neonates, oxygen consumption is three times an adult’s oxygen consumption. In comparison to adult patients, infants have the most resistance to airflow in small airways and the bronchi. The relatively smaller diameter of the neonatal airway and greater compliance of the trachea, bronchi, and chest wall provide less support to maintain negative intrathoracic pressure. Combined with low lung compliance (stiff lungs), increased chest wall compliance results in diminished functional residual capacity (FRC). Neonates and infants are more susceptible to hypoxia and respiratory failure because of a lower proportion of type 1 muscle fibers in the diaphragm and other respiratory muscles [Reference Kaye, Fox and Padnos2, Reference Butterworth, Mackey and Wasnick5]. Type 1 fibers allow prolonged, repetitive movement and the percentage of these muscle fibers increases with age. Therefore, preterm neonates have significantly fewer type 1 fibers, compared to even a 2-year-old child.

Loss of tone in pharyngeal and laryngeal structures is responsible for airway obstruction during sedation and anesthesia. This occurs in a dose-dependent fashion. The greater the depth of sedation, the greater the loss of airway muscle tone. Continuous positive airway pressure (CPAP), chin lift, and jaw thrust, as well as lateral positioning, improve airway patency and ventilation.

Cardiovascular

Newborns have a different cardiovascular physiology than older children and adults. Throughout growth, the cardiovascular system undergoes constant shifts in preload, afterload, contractility, loading, and flow patterns [Reference Vrancken, van Heijst and de Boode7]. There are characteristic differences in cytoarchitecture, metabolism, and function between the immature neonatal myocardium and the adult myocardium. For example, the neonatal myocardium has poorly formed T tubules and fewer mitochondria and sarcoplasmic reticulum, and depends on extracellular calcium for contractility. Carbohydrates and lactate serve as its primary energy source. However, the neonatal myocardium is parasympathetic-dominant, and has limited cardiac output increase with increased preload, as well as decreased compliance. Therefore, contractility cannot be enhanced to improve stroke volume with increased fluid volume. As a result, blood pressure is increased by increasing the heart rate [Reference Miller and Pardo8]. Anesthetic overdose can quickly result in bradycardia, which decreases cardiac activity. The neonatal heart is more vulnerable to unpredictable anesthetics and narcotics than the adult heart [Reference Kaye, Fox and Padnos2]; however, the neonatal myocardium can tolerate ischemia much better than the adult myocardium. Of note, cardiovascular events, such as bradycardia and asystole, frequently occur following inadequate oxygenation and ventilation. Thus, the origin of cardiovascular events seems to be secondary to respiratory complications.

Renal

Renal function is immature at birth and approaches adult values by the age of 2 years [Reference Bueva and Guignard9, Reference Rodieux, Wilbaux, van den Anker and Pfister10]. At birth, the newborn is in a condition of hypofiltration, with 20% of an adult’s glomerular filtration rate [Reference Musso, Ghezzi and Ferraris11, Reference Sulemanji and Vakili12]. Renal blood flow doubles in the first 2 weeks after birth and will reach adult values by the age of 2 years. As a result, the glomerular filtration rate parallels renal blood flow, and also doubles in the first 2 weeks following birth and increases until it reaches adult values, occurring at the age of between 1 and 2 years [Reference Kaye, Fox and Padnos2, Reference Sulemanji and Vakili12].

Fluid and volume management is an important task by the anesthesiologist because the neonatal kidney cannot conserve or excrete water in the same manner compared to older children and adults. Neonates are less efficient at excreting potassium and tend to have a higher normal serum value of potassium than adults. Neonates are also limited in their ability to respond to an acid load and tend to maintain a slightly acidic pH (7.37) and decreased plasma bicarbonate concentration, compared to older children and adults.

Kidney function impairment throughout adolescence has an impact on opioid clearance, intake, delivery, and metabolism [Reference Rodieux, Wilbaux, van den Anker and Pfister10].

Hepatic

A major function of the liver is to transform lipid-soluble drugs into water-soluble metabolites that are excreted by the kidney. At birth, the liver is structurally and physiologically immature. Hepatic blood supply is decreased in neonates and gradually improves as heart activity increases [Reference Rodieux, Wilbaux, van den Anker and Pfister10]. Drug-metabolizing enzymes, delivery mechanisms, and protein-binding systems are also impaired [Reference Kaye, Fox and Padnos2, Reference Rodieux, Wilbaux, van den Anker and Pfister10]. At birth, cytochrome P450 enzyme levels are 30% of adult levels [Reference Doherty and Salik13]. Cytochrome P450 enzymes are responsible for drug biotransformation. In neonates, phase I behavior is decreased but eventually increases to adult levels by late puberty [Reference Hines14]. Due to physiologic immaturity of neonatal hepatic metabolism, medications administered to neonates remain metabolically active for extended amounts of time, raising their susceptibility to general anesthetics, barbiturates, and opioids [Reference Kaye, Fox and Padnos2]. Furthermore, impaired liver function raises the likelihood of hypoglycemia, hyperbilirubinemia, and coagulopathy [Reference Doherty and Salik13].

Hematologic

Fetal hemoglobin (HbF) accounts for 70–90% of hemoglobin molecules in newborns, but is replaced by adult hemoglobin (HbA) at the age of 3 months [Reference Doherty and Salik13]. Thus, physiologic anemia is observed in preterm infants at 3–6 postnatal weeks and in term infants aged 8–12 weeks. HbF has a greater affinity for oxygen, which shifts the oxygen–hemoglobin dissociation curve to the left, thus shielding red blood cells from sickling [Reference Doherty and Salik13]. Due to an inactive liver during the first few months of development, there is a deficiency of vitamin K-dependent clotting factors II, VII, IX, and X. As a result, preterm and term neonates have prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT).

Central Nervous System

Children are more vulnerable to head and spinal trauma than adults due to poor neck muscles and ligaments and a comparatively big head in comparison to body height [Reference Figaji15]. Additionally, the neonate’s spinal cord and dural sac stretch to the L3 and S4 vertebral levels, respectively. Since weak blood vessels and an abnormal cerebral autoregulation system predispose neonates born before 32 weeks’ gestation to intraventricular hemorrhage, up to 20% of children born before 32 weeks’ gestation suffer from interventricular hemorrhage [Reference Szpecht, Szymankiewicz, Nowak and Gadzinowski16]. Neonatal blood–brain barriers are immature, which increases resistance to lipid-soluble medications, and immature myelination reduces the influence of local anesthetics on the central nervous system [Reference Doherty and Salik13].

Absorption

Volatile anesthetics enter the body by inhalation through lung alveoli where they enter the capillary beds. Owing to their increased alveolar airflow and comparatively poor functional residual potential, neonates and young children absorb volatile anesthetics more rapidly [Reference Stoelting, Hines and Marschall24, Reference Olsson25]. Drugs administered enterally in pediatric patients are usually absorbed more slowly than drugs administered in adults. This is because of narrower gastrointestinal tract, sluggish gastric emptying, immature secretion, and fewer protein transporters in children, as well as higher gastric pH in early childhood [Reference Edginton, Fotaki, Dressman and Reppas26, Reference Lu and Rosenbaum27].

Distribution

Factors affecting drug distribution include rate of blood flow, molecular size and solubility of the medication, and drug binding to plasma proteins and tissues. Pediatric patients usually have lower levels of plasma protein, lower body fat level, and a higher body water content, all of which affect the intensity of opioid delivery [Reference Lu and Rosenbaum27]. Reduced plasma protein levels result in an increase of free opioid molecules, while reduced body fat content results in an increase in drug level in the bloodstream due to lower volume for drug delivery [Reference Kaye, Fox and Padnos28]. On the other hand, higher amounts of overall body water increase the amount of drug delivery. The immature neonatal blood–brain barrier often affects opioid distribution, leading to heightened susceptibility to anesthetic agents in neonates [Reference Pardo and Miller29].

Metabolism

While the liver is the primary site of anesthetic agent metabolism, other sites of drug metabolism include the kidney, bowel, lung, and skin [Reference Lu and Rosenbaum27]. The cytochrome P450 pathway is largely responsible for completing drug metabolism in the liver. These enzymes are found at the cellular level within the endoplasmic reticulum and mitochondrial membranes. Drugs may remain in their prodrug form, from which the biologically active form is synthesized, but most drugs are inactivated during metabolism. Neonates have slightly lower hepatic enzyme levels and blood supply, which results in medications being metabolically active over a more prolonged period than in adult patients.

Excretion

Drug metabolites are excreted from the body via water, saliva, or exhaled breath. The liver excretes metabolites into bile, which then travels through the gastrointestinal tract to the intestines before excretion in the feces. Certain metabolites are reabsorbed from the gastrointestinal tract and eventually excreted in the urine via the kidneys. Children’s slower gastrointestinal activity lengthens the time required for metabolites to be reabsorbed from the intestines. The kidneys are not fully functioning before the 20th week of life, with decreased glomerular filtration rates, thus resulting in metabolites being excreted more slowly [Reference Pardo and Miller29].