In this issue of Acta Anaesthesiologica Taiwanica, Dr. Wang and Dr. Fang publish a review article about dental anesthesia for those with special needs.¹ The most common “special need” patients for dentistry or orthodontic procedures are in the pediatric population. Without doubt, pediatric anesthesia is a challenging field. It has long been noted that children are at greater risk than adults for anesthesia-related complications. The difficulty became more salient for those who had airway problems, disabling congenital anomalies, or major medical diseases. Growing children with uncorrected cardiac or other pathologies present a new challenge.² Pediatric patients undergoing diagnostic or therapeutic procedure at a far-off location will likewise require anesthesia and sedation service. Unfortunately, most remote sites do not have the capabilities to support modern anesthesia. Usually it takes a longer time to have anesthesia personnel back-up available for succor when unexpected events happen at extramural locations. Anesthesia for the dental treatment for those with special needs performed at a location far from the central surgical theater needs extra consideration.

The requirements for anesthesia or sedation service outside the operating room are increasing. Pediatric anesthesiologists have expanded their service beyond those tasks confined to operating rooms to provide pain management, sedation and anesthesia for examinations, especially for children throughout the hospital and outpatient centers. We appreciate that progress in pediatric medical science and novel technologies can lead to obvious reductions in morbidity and mortality. More very-low-birth-weight (VLBW) babies could survive and children with complex congenital malformations or serious medical disease could grow. Nevertheless such infants may have a multitude of residual problems to be solved, due to comprehensive but rather invasive intensive care and prolonged intubation. Anesthetic management is complex for these “survivors”.² With rapid innovation of mini-invasive surgical techniques, anesthesia has become more complex and difficult. It will be a formidable challenge to the anesthesiologists throughout the perioperative period to care for small infants undergoing complicated major surgery.

“Special needs” is a term used to describe those who require assistance for disabilities related to medical, mental, or psychological problems.¹ In the author's personal view, neonates and fragile small infants are those who could be called “special needs”. They have immature organs, unstable vital functions, and inability of self-expression. Current monitors and anesthesia ventilators are not good enough for surveying babies weighing under 1 kg. Development of more delicate equipments for VLBW patients has become an urgent need. Since neonates and small infants are at higher risk of and intolerable of errors, even minor ones, training of skills and techniques for novice practitioners or junior staff is a difficult and arduous piece of work. Delicate techniques and complex instrumentation are no place for beginners. Anesthesia for small infants, especially of those with VLBW, is a unique challenge. Improper anesthesia modalities may lead to long-term neurological and pulmonary morbidities. They may not have tentative profound effects until they emerge many years later. Although anesthesia modalities for small infants are well described in textbooks and journals, there are many unsolved problems and new challenges to emerge.

1. Does anesthesia harm the developing brain?

In Dr. Davidson's recent survey, “In Search of the Big Question”, a group of academic pediatric anesthetists were asked to state their opinions of five questions.³ Neurotoxicity of anesthetics to the developing brain was the issue that gave the most concerned. Neonates were highlighted as the age group with the greatest knowledge gap in pharmacology. Late prenatal and early postnatal neural development was vulnerable to pharmacologic and environmental influences. The safety of anesthetics administered to infants and young children during sensitive periods of brain development is a growing public health concern.⁴ Early in 1991, neurobehavioral toxicology of halothane in rats were demonstrated. The influence of exposure to halothane, started in uterus and continued for several days after birth, leading to impaired synaptogenesis, reduced dendritic branching, suppressed axonal growth, and reduced myelination in rodents.⁵ Ikonomidou et al reported in 1999 that N-methyl-d-aspartate (NMDA) antagonists, including MK801 and ketamine, produced evident neurotoxicity in newborn animals.⁶ Many reports on neuronal toxicity arising from anesthetic exposure in the immature and developing animals were published later. Such neurotoxicity has now been demonstrated to involve not only ketamine but also isoflurane,⁷ midazolam,⁸ diazepam, pentobarbital, thiopental, nitrous oxide, and propofol.⁹ Anesthesia-induced injury has also been demonstrated in the spinal cord of the newborn rat.¹⁰ Collectively, from the results of animal studies and in vitro work using human neuron-like cells, the prevailing view indicates that anesthetics are indeed harmful to the developing brain at sufficient doses and for durative exposure.11, 12, 13, 14 Due to speices diversity, the vulnerability of brain to injury and brain growth are different. However, the dose and duration of anesthetic exposure chosen in most laboratory studies are substantially higher than those used in clinical circumstances. The relevance of anesthetic neurotoxicity in animal models to human pediatric anesthesia is still under debate.¹⁵

Another big issue is how to access the long-term adverse effects of anesthetic-related neurotoxicity in human. Learning disability (LD), developmental, and behavioral disorders may be appropriate outcome measures.¹⁶ The downside is that it takes a long time to have appropriate follow-up and it is hard to have an equitable peer control group. Several retrospective cohort studies demonstrate correlation between anesthetic exposure early in life and LD and behavioral abnormalities in later years. A population-based birth cohort study of Wilder et al. showed that there was a significant risk factor for the later development of LD (i.e., math, written language, and reading disabilities) in children receiving multiple, but not single, anesthesia before age 4 years. The incidence of LD among those with repeated anesthetic exposures was almost twice as high (35.1%) compared with children not exposed to anesthesia (20.0%).¹⁷ In Kalkman et al's epidemiologic study, children undergoing urologic surgery at age <2 years showed more behavioral disturbances than children in whom surgery was performed after age 2 years.¹⁸ Children requiring anesthesia early in life, having a higher burden of illness and stress response of surgery, may differ in important ways in learning from those who do not. Moreover, genetic, family, and socioeconomic factors may have significant influences on children's learning performance. At present, no firm conclusion can be made regarding an association between early anesthetic exposure and subsequent learning and behavior abnormalities in children.

2. Ideal oxygen saturation

It is well established that high inspired levels of oxygen can result in retinal damage to the preterm neonates.19, 20, 21, 22 Vascular endothelial growth factor is suppressed by high oxygen levels, resulting in cessation of normal vessel growth and regression of retinal vessels. The effects of excessive oxygen are not just confined to the brain; there is evidence of an association of increased bronchopulmonary dysplasia with high oxygen saturations.²³ The cause of the injury is likely to be secondary to the oxidative stress experienced by immature infants who lack appropriate antioxidant defense mechanisms. Chronically high levels of oxygen are associated with increased periventricular leukomalacia, loss of auditory or visual acuity, and adverse neurological outcomes. Deulofeut et al suggested that the application of acceptable limits of oxygen saturations (85–93%) could not only reduce retinopathy and severity of lung disease but could also improve mental developmental index at 18 months of age.¹⁹ A recent large prospective study that examined the benefits of lower oxygen saturations (85–95%) compared with relatively higher ones (91–95%), indicated a lower incidence of severe retinopathy in the lower saturation group but the mortality was higher.²⁴ It remains unclear what the ideal oxygen saturation for VLBW infants should be. During short-term surgery, hypoxia due to limitation of higher concentrated inspired oxygen will be more harmful to the fragile preterm infants.

3. Ideal glucose control

Incidence of hyperglycemia is high in VLBW infants, especially in those who are born small for gestational age, and it is also associated with both mortality and morbidity.²⁵ The pathogenesis of hyperglycemia in VLBW infants remains unclear. Low postnatal insulin levels that lead to deprivation of rational utility of intracellular glucose could initiate counter-regulatory responses and catabolism. Early insulin therapy could increase serum levels of insulin-like growth factor I, which might forestall the development of retinopathy of prematurity and enhance postnatal brain growth.²⁶ The study by Beardsall et al showed that elective early insulin therapy in VLBW infants might lead to a significant improvement in glucose control. Their results verified that tighter glucose control could improve energy intake, body weight gain, and clinical outcomes. In the meantime, they advised that this treatment was not without risk and tighter glucose control had to balance with the risk of hypoglycemia.²⁷ Two years later, a multicenter trial by Beardsall et al., with sample size of 389 infants, showed that tight glucose control in the VLBW infants with early insulin treatment is associated with hypoglycemia. The 28-day mortality was higher in the early-insulin group than in the control group.²⁸ The optimal target range for blood glucose in critically ill patients remains controversial. Good analgesia during surgery and afterward should prevent great rises in glucose.²⁹ Normal glucose concentration during infancy is between 40 and 60 mg/dL. During brief surgical period, hypoglycemia may be more hazardous than hyperglycemia for small infants.³⁰

4. Do newborns have sufficient brain maturation to experience pain?

Many articles on research of neonatal pain have been published. A systematic multidisciplinary review reported that thalamocortical fibers begin appearing between 23 and 30 weeks' gestational age, while electroencephalography suggests that the capability for conscious perception of pain does exist.³¹ The magnitude of cortical responses to noxious stimulation increases with maternal postmenstrual age. In 18 infants with maternal postmenstrual age between 25 and 45 weeks, real-time near-infrared spectroscopy to measure the cortical hemodynamic response, revealed that heel lance stimulus could produce a cortical response, increased cerebral blood flow and total hemoglobin concentration in contralateral somatosensory cortex.³² Because infants are unable to report pain directly, indirect physiological and behavioral methods are required to assess its existence and severity. In most clinical practices, pain was under-recognized and under-treated in neonates and infants. Adequate analgesia should be given to suppress stress that can induce adverse metabolic and hormonal responses.

5. Conclusion

The intent of management of the small infant is to provide optimal outcome not only in terms of survival but also with a goal of limiting long-term neurological and pulmonary morbidities. Although it has been convincingly demonstrated that anesthetics are neurotoxic to the developing brain in animal studies and cell models, withholding anesthesia from infants who need surgical intervention is unreasonable. Despite the fact that there are not enough data to indicate the ideal anesthetic, optimal oxygen saturation, and glucose control for such fragile patients, scrupulous attention to detailed problems during the perioperative period is necessary to achieve both short-term safety and optimal long-term outcomes.