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Departments of
*Anesthesiology and
Pediatrics, Children’s Hospital and Regional Medical Center, Seattle, Washington
Address correspondence and reprint requests to Lynn D. Martin, MD, Department of Anesthesiology, CH-05, Children’s Hospital and Regional Medical Center, 4800 Sand Point Wy. N.E., Seattle, WA 98105.
The Society for Pediatric Anesthesia (SPA) held its 13th annual meeting on October 8, 1999, in Dallas, TX, in conjunction with the annual meeting of the American Society of Anesthesiologists. The society president, Dr. Steven C. Hall (Northwestern University School of Medicine, Children’s Memorial Hospital, Chicago, IL) emphasized the importance of combining both basic science and clinical advances in our practice in his opening remarks. SPA Program Chair, Dr. Lynn D. Martin (University of Washington School of Medicine, Children’s Hospital and Regional Medical Center, Seattle, WA), then introduced the day’s program–an update on current knowledge in the area of neonatal intensive care, followed by current controversy in the selection of anesthetic technique in the afternoon session.
The morning program focused on scientific advances in our understanding of the neonatal central nervous system. The first session, moderated by Dr. Jayant K. Deshpande (Vanderbilt University Medical Center, Nashville, TN), centered on the plasticity of the developing brain and its response to extended exposure to opioids. Speakers for this session were Dr. Michael V. Johnston (Johns Hopkins University and Kennedy-Krieger Institute, Baltimore, MD) and Dr. Santhanam Suresh (Northwestern University Medical School, Children’s Memorial Hospital, Chicago, IL).
Dr. Michael V. Johnston
Plasticity of the Neonatal Brain. Our understanding of how the brain assigns regions of the cerebral cortex to a particular function has advanced because of development in functional brain imaging. "Functional MRI imaging" has supplanted PET (positron emission tomography) scanning as a means of studying metabolically active regions of the brain without radioactive substances. This imaging technique is able to discern areas of lower oxygen saturation and can distinguish the individual areas of the brain used for hearing and generating words, sight, and speech.
Beginning with the homunculus, that gargoyle-like mapping of skin sensation onto the sensory cortex, Dr. Johnston showed with several examples that this map is dynamic and responds to repeated sensory input. Monkeys subjected to repeated fingertip stimulation will increase the area of the sensory cortex devoted to fingertip sensation. In a series of people skilled at tuning violins, the brain region assigned to tuning the instrument was larger in those who had begun playing at an earlier age. It’s not just that we "use it or lose it," but rather we grow new neurons to handle more frequently used information. Our brain map continually changes with human experience.
Even more intriguing is the ability of the brain to reassign neuronal function to a new task. In monkeys subjected to a stroke affecting their hand, extensive physiotherapy increased the amount of brain reassigned from the damaged hand area to the more proximal arm area. In a patient who had become blind, functional imaging showed that the occipital or visual cortex had been reassigned to the sensory task of reading braille! Likewise, in children who have half their brain removed for refractory seizure disorders, "cross system reassignment" occurs (especially in the youngest patients) to allow a remarkable amount of function bilaterally.
What is happening at the synaptic level? There is a complex interplay of trophic hormones and cellular processes that can respond to repeated neuronal firing by enhancing a particular pathway, growing new synaptic connections, or even growing new neurons. One such phenomenon, "long-term potentiation," is not merely the gradual enhancement of a well worn path like those in ancient stone steps. In this process, repeated stimulation of a synaptic pathway will suddenly cause a quantum leap in the signals generated as cellular processes reorganize to facilitate that pathway. The metabolic basis is being elucidated for this finding that "neurons that fire together, wire together."
A molecular basis is also coming to light for certain behavioral phenomena. The density of synapses in the brain reaches a dramatic peak at age two and declines to adult levels beyond age eight. This overabundance of synapses at age two facilitates the ability of toddlers to learn complexities like language so readily, but may also overload their processors, leading to the hyperactive behavior affectionately referred to as the "terrible two’s." This excess of synapses is pruned or "sculpted" down to the adult level by repeated use as we interact with our world. At age two, the brain is at its peak of plasticity.
There is a price to pay for such tremendous brain plasticity. A global hypoxic insult produces a very different clinical picture in the elderly than in the neonate. The basal ganglia are very active at birth and use glutamate as the predominant neurotransmitter. Glutamate is taken up from the synapses by a very energy-rich process, much like the bilge pump in a boat. It may, in fact, be the glutamate buildup from the hypoxic insult that causes the damage that leads to spastic diplegia in newborns.
Dr. Johnston concluded by stating that we are in an exciting era for research in brain plasticity–neuronal reassignment and neuronal circuitry are a physical and architectural reality that can actually be studied in detail with current techniques.
Dr. Santhanam Suresh
Pharmacologic Plasticity of the Brain: Opioid Tolerance.
In this presentation, the molecular mechanisms surrounding opioid tolerance in the neonate were discussed. Tolerance is defined as the requirement for increasing doses to attain the same clinical effect after repeated administration of a drug. Receptor studies have demonstrated that this occurs as a result of adaptation of the neuronal cells and is not caused by altered drug metabolism. These adaptations of receptor-mediated effects are being studied in detail.
For the opioid receptor, these adaptations are best studied at the locus ceruleus in the floor of the fourth ventricle. The opioids decrease signal transmission in pain pathways through an array of cellular effects, including decreased neuron excitability, decreased cyclic AMP production, and increase nitric oxide synthetase. When the opioid receptor is chronically stimulated, this is met with altered cellular mechanisms that attempt to restore neuronal function and response to baseline levels. For instance, as tolerance develops, there is up-regulation of the cyclic AMP pathway to restore this pathway to baseline levels before opioid treatment. In addition, down-regulation and desensitization of the receptors occurs. There is also an internalization or endocytosis of the opioid receptors, which begins with the first dose and continues in a dynamic pattern with subsequent doses. The response is complex and follows a unique pattern for chronic administration of each opioid, invoking each of these adaptations to a different degree.
These studies may have particular relevance for two groups of neonates–those born to opioid-addicted mothers and those subjected to chronic opioid administration during prolonged intensive care treatment. Neonates are particularly susceptible to developing tolerance because more opioid reaches their brain through a more permeable blood-brain barrier; they metabolize opioids more slowly and have lower protein binding.
Opioid withdrawal is a significant concern in premature infants. Studies have shown that a fentanyl infusion for as little as five days can lead to withdrawal symptoms, and after nine days, 100% of neonates manifested withdrawal in one study. Dr. Suresh reviewed the symptom scoring system being used to evaluate children for evidence of withdrawal. Symptoms such as tremor, irritability, diaphoresis, and fist-sucking compose the score. Subacute symptoms of withdrawal can last as long as six months. He emphasized that withdrawal symptoms can interfere with feeding and weight gain and are more important than achieving rapid withdrawal of opioids. Withdrawal is treated with oral opioid agonists, sedatives, and antihypertensives, in addition to supportive care. Methadone is the mainstay of oral therapy, because many of the oral morphine preparations contain alcohol or other additives. Clonidine is also very effective in treating the symptoms of withdrawal and led to a 30-fold reduction in symptom scores in one study.
One benefit of research on the molecular mechanisms of receptors is the discovery of previously unsuspected beneficial interactions. Based on cellular mechanisms, the development of tolerance has been found to hinge on the NMDA receptor. Dextrome- thorphan, an over-the-counter cough suppressant, happens to be an excellent NMDA antagonist and could help prevent tolerance. If theory is borne out by clinical studies, physicians may in the future be giving cough suppressant along with chronic opioids.
The second morning session moved from basic science into the clinical arena. It was moderated by Dr. David M. Polaner (Tufts University School of Medicine, Floating Hospital for Children, Boston, MA), who remarked on the dramatic changes that have taken place in neonatal care over the last 15 years. An informative discussion regarding sequalae of prematurity was provided by Dr. Claire M. Brett, (University of California at San Francisco, San Francisco, CA). This lecture was followed by an examination of the implications of prematurity on anesthesia practice by Dr. Peter T. Rothstein (College of Physicians and Surgeons, Columbia University, New York, NY).
Dr. Claire M. Brett
Sequelae of Prematurity in the 1990s. There has been a tremendous improvement in all measures of outcome between infants born at 24 weeks and those at 26 weeks gestation. It is remarkable that the current survival rate for 500–700-g babies is now greater than 70%. The most significant advance that accounts for this was the release of surfactant in 1990. Babies that would not have survived the effects of prematurity only a few years ago are now surviving in ever-increasing numbers, albeit with more severe chronic disease.
Dr. Brett emphasized that "expremature" is not a diagnosis but an ever-broadening spectrum of disease in these survivors. Prematurity is the biggest contributor to chronic lung disease in children. Infant Respiratory Distress Syndrome is characterized not only by surfactant deficiency, but also by neutrophil inflammation and the release of elastase and other inflammatory mediators. Elastase destroys the elastic fibers that provide a structural support for alveolar septal development. Babies that develop chronic lung disease, also called bronchopulmonary dysplasia (BPD), are characterized by persistent neutrophil infiltration and inflammation in the lungs. The primary late sequela of BPD is obstructive airway disease. In expremature children with BPD, when respiratory variables were followed through during the preteen years, there appeared to be continuing improvement even at this age. Humans continue to grow new alveoli for years after birth (one new alveolus every second for eight years). This continuing growth of new alveoli may help the expremature child to improve some variables of lung function. However, it appears that this growth of alveoli never reaches normal adult numbers, at least in a baboon model of BPD.
Why is a high oxygen concentration so harmful in premature infants? In normal development, protective vitamin A is delivered transplacentally, and there is a surge in antioxidant enzyme production during late gestation. The premature infant, whose PO2 would otherwise be approximately 40 torr in utero, is missing both of these benefits, yet must contend with high inspired oxygen levels during treatment. Dr. Brett suggested that, in the future, treatment of premature lung disease might be aimed more at the root cause, with manipulation of the antioxidant enzyme systems, or forcing transcription of their genes ahead of schedule.
Dr. Peter T. Rothstein
Anesthetic Implications of Prematurity in the 1990s.
Dr. Rothstein reviewed the anesthetic concerns for premature infants, starting with the basics of temperature regulation and fluid requirements. Neuromuscular blockade is quite variable in the neonatal period, because the neuromuscular junction has not yet matured. He pointed out that the obstructive airway disease in BPD impedes not only inspiration by creating turbulent flow, but expiration because of slow alveolar emptying times; therefore, slower respiratory rates during controlled ventilation may be advantageous. An equipment issue for premature infants is the elbow connector between the circuit Y-piece and the endotracheal tube, which can contribute a proportionately large circuit dead space for the tiny infant. Another issue of importance to anesthesiologists caring for expremature infants is postoperative apnea. This issue has been difficult to deal with because of varying definitions and measurement methods in the literature. Anemia is clearly a contributing risk factor for postoperative apnea. Dr. Rothstein emphasized the need to develop a consistent policy in one’s institution on this issue so that colleagues and staff will know what to expect.
A brief business meeting was conducted during the noon luncheon. SPA President, Dr. Hall, paid tribute to Dr. Martin for serving as the SPA Program Chair for the last two years and introduced Dr. Frank H. Kern (Duke University Medical Center) as the SPA Program Chair for the next two years. He then divulged that there were more than 300 attendees at this year’s meeting, more than 2500 active SPA members, and that more than $10,000 had been raised by SPA to fund research efforts.
The afternoon session, titled "Pediatric Anesthesia in the Next Millennium," provided a lively and entertaining review of advances in pediatric anesthesia techniques. This session was moderated by Dr. Peter J. Davis (University of Pittsburgh, Children’s Hospital of Pittsburgh, Pittsburgh, PA). He prepared us for a lively debate on the merits of total IV anesthesia by Dr. Gregory B. Hammer (Stanford University School of Medicine, Packard Children’s Hospital, Stanford, CA) versus inhaled anesthesia by Dr. Jerrod R. Lerman (University of Toronto, Hospital for Sick Children, Toronto, Canada) versus regional anesthesia by Dr. Myron Yaster (Johns Hopkins University, Baltimore, MD).
Dr. Gregory B. Hammer
Total IV Anesthesia—the Only Way to Go! With skillful allusions to Stanley Kubrick’s Space Odyssey 2001, Dr. Hammer humorously described all alternatives to total IV anesthesia as prehistoric. Short-acting drugs, such as propofol and remifentanil, are extremely titratable, even with large doses, and in the presence of substantial systemic disease. Propofol has an increased volume of distribution and clearance in children, such that greater infusion rates than in adults are required. In extolling the virtues of using a propofol-remifentanil combination, he explained that they are synergistic. There is a requirement for much smaller doses of two agents given together than would be expected if the combination of their effects was simply additive. He described using 0.1 mg of remifentanil mixed with 100 mg of propofol, which is then titrated to give between 25 and 100 µg · kg-1 · min-1 of propofol.
Dr. Hammer explained that the cost of inhaled anesthesia is similar in adults and children because similar fresh gas flow rates are used, whereas the cost of IV anesthesia is markedly less in children than in adults because of the children’s smaller weight. He showed that a typical hour of anesthesia with isoflurane is 8 times as expensive as with halothane, while sevoflurane is 40 times as much. However, total IV anesthesia for a 15-kg child with a propofol-remifentanil combination for an hour costs an intermediate amount, 20 times as much as halothane, as compared with the prohibitive 100 times as much as halothane for a full-sized adult. However, he added that arguments based on drug cost carry little weight because the anesthetic drugs account for only 3% of a surgical procedure’s costs.
Dr. Hammer continued his argument by impressing on us that total IV anesthesia is devoid of the risks of malignant hyperthermia, Compound A or carbon monoxide exposure, and ozone depletion. He then illustrated the use of a propofol-remifentanil combination in airway surgery, strabismus surgery, cardiac catheterization, and cardiac surgery. In the future, we may have target-controlled infusions of multiple agents linked to depth of anesthesia monitors. With an over-dubbed video clip, he used the eerily calm and hypnotic voice of Hal, the computer in Space Odyssey 2001, to convince us that inhaled anesthesia would soon be outdated.
Dr. Jerrold R. Lerman
Inhaled Anesthesia—Perfect for Every Case! Dr. Lerman countered by describing modern inhaled anesthesia as rapid-acting and well tolerated. Unlike IV agents, both inspiratory and expiratory concentrations can be measured accurately, instantaneously, and continuously. The minimum alveolar concentrations are well established for these agents. Spontaneous ventilation can be maintained in many cases, which is in itself a negative feedback mechanism providing some degree of safety against overdose of the agent.
Three inhaled induction techniques have been described: spontaneous ventilation with incremental increases in volatile anesthetic, administration of the maximal concentration at the outset, or the single-breath induction technique (best reserved for those older than seven years). The "wash-in" or uptake of volatile anesthetic is remarkably fast in children. This is because of their high alveolar minute ventilation, their high cardiac output to the "vessel-rich group," and the low blood and tissues solubility of the newer agents.
To counter the argument about costs, Dr. Lerman stated that lowering the fresh gas flow rate could have a large impact on costs. He even went so far as to say, "there is no minimum fresh gas flow, provided gas analysis is used." Even with a Mapleson or other re-breathing circuit, moderate inspiratory CO2 levels are not a problem because the exhaled gases also contain heat, moisture, and anesthetic gases.
What about the issue of slow recovery from inhaled anesthetics? This depends on how the clinician uses the agent, because the concentration can be tapered during the case to speed recovery. Unlike the wash-in phase, the issue is not expelling the drug from the lungs but from the vessel-rich group, for which sevoflurane is no faster than isoflurane, although both are faster than halothane. In a recent study by Welborn, the emergence, recovery, and discharge times were all similar for groups of children who received sevoflurane, halothane, and another group in which sevoflurane was substituted for halothane during the last 45 minutes of the anesthetic. However, more importantly, perhaps rapid recovery is not good for patients, nor is it what they would prefer.
To address the issue of Compound A, the breakdown product of sevoflurane generated in the CO2-absorbent, Dr. Lerman pointed out that renal damage has been shown only in rats and not in primates. Furthermore, a newer formulation of CO2-absorbent does not make Compound A.
Dr. Myron Yaster
Epidural Anesthesia and Analgesia in the Perioperative Management of Pediatric Patients. Dr. Yaster was given a difficult premise—to argue that regional anesthesia alone suffices in children! He chose instead to talk about the benefits of epidural combined with general anesthesia. An epidural anesthetic achieves many goals in anesthesia; it reduces sensory input from the periphery, modulates ascending transmission from the spinal cord to the brain, and modulates descending control over sensory input.
Until the mid1980s, regional anesthesia in children was virtually unheard of. Several myths had been perpetuated: that children don’t sense pain, that caregivers can identify pain, that treating pain risks addiction, and that pain builds character. Now that these myths are dispelled and clinicians are willing to take on the small risk of performing a block after the induction, regional anesthesia is enjoying a resurgence. The disadvantages of regional anesthesia include the extra time and resources involved, the technical difficulty, and the potential for local anesthetic toxicity. Because epidural anesthetic is injected into a virtual "lake of blood" amongst the epidural veins, the clinician must test for intravascular placement carefully.
The final session of the day was moderated by Dr. Jeffrey P. Morray (University of Washington School of Medicine, Children’s Hospital and Regional Medical Center, Seattle, WA). Dr. Adrian T. Bosenberg (University of Natal, Durban, South Africa) was invited to provide contrast to the rapid advances in anesthesia care for children in the developed world. He highlighted the desperate financial situation and its impact on anesthesia care in sub-Saharan Africa. As in previous years, the meeting closed with an entertaining presentation on a locally important topic loosely related to medicine. For this purpose, Mr. James Marrs, a local investigative reporter and author, was chosen to give a fascinating presentation of the controversies surrounding the assassination of President John F. Kennedy in Dallas in 1963.
Dr. Adrian T. Bosenberg
Pediatric Anesthesia for the Next Millennium: The Rest of the World. The birth rate in developing nations is such that 50% of population is under 20 years old. The doctor to patient ratio is vanishingly small, and the health budget of an entire country can be similar to that of a single US hospital. Not only are children victims of war, famine, or economic or natural disasters, but their superstition, ignorance, or fear result in remarkably late presentation of disease.
Dr. Bosenberg illustrated this from his own experience with pictures of a huge retinoblastoma, abdominal leiomyoma, and a 5-kg Wilm’s tumor. He described how parents in one region would ignore instructions and fill their child’s stomach with food in case they should die during surgery. He described the difficulties imposed by metal rings adorning and elongating the necks of women from Burma–their neck muscles atrophy, making their neck unstable, and the ribs are displaced inferiorly, restricting chest expansion.
Besides the lack of basic equipment like IV cannulae, IV solution, anesthesia machines and monitors, there is at best an unreliable source of electricity, water, and oxygen. The choice of anesthetic drugs is very limited.
Dr. Bosenberg did not fail to mention practical solutions to which every anesthesiologist can contribute. A group practice of anesthesiologists can adopt a Third World hospital, send their trainees to the site; send their disposable supplies and equipment and outdated goods, journals and texts; or set up an internet link and discussion groups. Anesthesia literature devoted to help solve the unique problems of providing anesthesia in the developing world.
Mr. James Marrs
The John F. Kennedy Assasination Conspiracy–Fact or Fiction? Mr. Jim Marrs, noted investigative reporter, author, and a recognized expert on the issues surrounding the assassination of President John F. Kennedy, gave a thought-provoking and stimulating presentation. He was present in Dallas on the fateful day in 1963 and began his personal investigation of the facts and mysteries of the subsequent 1964 Warren Commission investigation. He provided contradictory evidence from the staff from Dallas’ Parkland Hospital and the autopsy results obtained at Naval Medical Center in Bethesda. Mr. Marrs described the improbability of the "magic bullet" that was reported to first strike President Kennedy and Texas Governor John Connally. He also explained the difficulties with the lone assassin theory, particularly the improbability of firing four shots and striking a moving target three times in a span of six seconds with a poor quality bolt-action rifle. An animated discussion with multiple members of the audience followed.
The meeting adjourned to a buffet reception at the Dallas World Aquarium, complete with entertainment from an electric harp in a tropical rain forest. It was a chance to explore new ideas amongst old and new friends. The day’s meeting had spanned a broad range, from cutting-edge reseearch to everyday challenges in pediatric anesthesia, and the unique problems of the developing world.
The winter meeting of the SPA, jointly sponsored with the American Academy of Pediatrics Section of Anesthesiology, is scheduled for February 24–27, 2000, at the Sanibel Harbor Resort and Spa in Fort Meyers, Florida (Dr. Lynda J. Means, Program Chair). The 14th annual meeting of the SPA will precede the ASA annual meeting in San Francisco, CA on October 13, 2000 (Dr. Frank H. Kern, Program Chair). A limited supply of program syllabi and reference lists from the 1999 meeting are available at nominal cost from the Society’s headquarters. Further information is available by mail from the SPA, PO Box 11086, 1910 Byrd Ave., Ste 100, Richmond, VA 23230-1096; by phone 282-9780; or by e-mail at spa@societyhq.com, or visit our web site at www.pedsanesthesia.org.
References
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