Moderator: Theodore W. Striker, MD, FAAP
Reviewed by: Joseph Tobin, MD
This morning breakfast panel was arranged and coordinated by Dr. Constance Houck on behalf of the AAP. Speakers were requested to discuss current controversies in the use of FDA "Black Box Warning" drugs in pediatric anesthesia. The agents chosen for presentation have been of contemporary controversy due to described side effect profiles of concern.
Dr. Frederic (Fritz) Berry initiated the discussions with a history of the use of succinylcholine in anesthesia. Succinylcholine has been used for decades with a very strong safety profile following experience with hundreds of millions of doses. Its known profile as a depolarizing neuromuscular agent includes attendant release of potassium from muscle tissues and as a trigger of malignant hyperthermia. In the late 1990s, the FDA made an announcement of the decision to attach a "Black Box Warning", noting significant risks associated with use of succinylcholine in children and adolescents. Acknowledging that succinylcholine is an anesthetic trigger of malignant hyperthermia, Dr. Berry reviewed the nearly two decades of data and previous anecdotal reports that did not include any report of problems specific to adolescents. He also noted that with pretreatment by nondepolarizing agents, he had never noted the `jaws of steel' described as masseter muscle rigidity noted with succinylcholine. He reviewed the pharmacology of succinylcholine in that it elicits a short duration muscular contraction (including the masseter muscle) as one of its known effects.
Following the initial decision by the FDA to attach a black box warning, an open forum for public comment occurred following which the FDA reduced the language of the warning to inform physicians to carefully consider the risk benefit profile when using succinylcholine, and that routine use in children (primarily males with undiagnosed myopathy) is not recommended. A reference was also made to the as yet unsuccessful development of a nondepolarizing relaxant that may substitute for succinylcholine.
The second presentation was by Dr. Joe Tobin who reviewed the recent FDA decision to attach a Black Box Warning to droperidol. First approved in 1970, droperidol has been in widespread use as an antiemetic, and adjuvant for anesthesia. The FDA received information regarding action in other countries where a manufacturer of droperidol is discontinuing its production following reports of development of Torsade de Pointe ventricular fibrillation in patients with a prolonged QTc interval, possible associated with its use. Over two hundred reports of dangerous dysrhythmias have been reviewed and the FDA believed it was prudent to apply a BBW to droperidol instructing the medical community to seriously consider its use and the potential for side effects. The information that the FDA reviewed was independently assessed by members of the anesthesia community and multiple `letters to the editor' in the journals Anesthesiology, Anesthesia and Analgesia, and the Anesthesia Patient Safety Foundation newsletter were highlighted. Considering that the newer 5-HT3 antagonist antiemetics have both known potential prolongation of the QTc and we have many years less experience than droperidol, Dr. Tobin suggested that the current recommendations of preoperative ECG and two hours monitoring following any use of droperidol are unlikely to improve the safety profile of this very useful agent. Although some hospitals have now deleted droperidol from their pharmacies, many anesthesiologists will continue to rationally utilize this effective agent while the FDA pursues a prospective trial examining the incidence of problems associated with droperidol.
Dr. David Polaner presented the increasing data reported over the last ten years regarding deaths associated with the use of propofol. Propofol, which is labeled for induction of anesthesia in children and adults and for maintenance of anesthesia in adults, has received increasing use in intensive care units as an agent of choice due to its pharmacokinetic profile, reduction of ICP, and ability to examine patients quickly following its discontinuation. Without a prolonged hypnosis or narcosis following its discontinuation as an intravenous infusion, propofol has found widespread use in ICUs. Reported in the British Medical Journal and then followed by many other reports, propofol has now been associated with development of fatal metabolic acidosis and multiorgan failure in both children and more recently, adults. Reported dose ranges associated with these reports include midlevel maintenance of anesthesia (> 64 mcg/kg/min) to high dosing ranges which provided adequate conditions for nursing care. Studies to examine the association have examined propofol, its metabolite and vehicle. To date the problem is incompletely understood and deserving of further study.
Attendees and presenters agreed on the usefulness of propofol in pediatric anesthesia and many acknowledged use of propofol in off label conditions such as diagnostic and therapeutic procedures in children under the age of recommended use. Great caution was advised regarding prolonged propofol use in the ICU and speculation was raised regarding the possibility of propofol-induced problems during prolonged (> 6 hours) use in the operating room as the base intravenous anesthetic.
The session concluded with opportunities for discussion among the participants. Although the anesthesia community appreciates the diligent work by the FDA, it was recognized that nearly 80% of all pharmaceuticals used in pediatric anesthesia are `off label'. This indicates that the sponsors of these agents have not studied and provided data for recommended use in children. It does not indicate a lack of safety or enhanced risk profile of use of these agents in children. The FDA restricts labeling of pharmaceuticals to those indications and populations for which the sponsor has provided data. The FDA does not restrict use of any approved agent to labeled indications only, except in rare circumstances. Further study of many pharmaceuticals in children is warranted. Participants were requested to be active in reporting adverse events associated with any pharmaceutical to the FDA via the Medwatch system (www.fda.gov).
Scientific Papers-Poster Session
Wednesday Morning Pediatric Anesthesia: Cardiac Anesthesia
Moderators: Steven R. Tosone, MD and Maria Zestos, MD
Reviewed by: Anne E. Dickison, MD
During the first half-hour, the audience had opportunity to review posters and interact with the presenters. Eight studies were presented, then opened for comments and questions from the audience. Two of these studies are summarized below.
Paula M. Bokesch, MD (The Cleveland Clinic Foundation, Cleveland, Ohio): "Cardiopulmonary Bypass Causes Dysfunction of the Blood Brain Barrier." The etiology of CBP-associated neurologic injury was studied in the lamb model. Animals were divided into groups with differing duration of circulatory arrest (0, 15, 30, 60, 120 minutes). All were subjected to 2 hours of CPB and isoflurane anesthesia, and all were maintained with conditions of hemodilution (hct 22-24), hypothermia, and pressures similar to those encountered in pediatric cardiac surgery. At the end of CPB and reestablished normocirculation, tagged albumin was injected and the animals were sacrificed. Cerebral vascular integrity, distribution, and permeability were assessed with computerized tracer mapping. When there was no circulatory arrest time, no changes in BBB permeability or vascular distribution were observed; all pathology in the other groups correlated directly with length of circulatory arrest time. Hippocampal functions (e.g., memory) seem particularly vulnerable to bypass-related injury, but this study found no increased leakage in that anatomical area, possibly reflecting decreased perfusion of the area rather than sparing of BBB disruption. Though HCA caused profound leakage everywhere in the brain, the cerebellum was especially affected; due to extensive leakage of protein and fluid into the brain parenchyma, one could barely distinguish vessels. It was suggested that since the CPB and HCA have different patterns and apparently different etiologies of injury, solutions for avoidance are undoubtedly different as well.
George M. Hoffman, MD (Children's Hospital of Wisconsin, Milwaukee, WI): "Changes in Relative Cerebral and Renal Saturations During Stage I Norwood Procedure for Hypoplastic Left Heart Syndrome." In neonates undergoing palliative surgery using partial hypothermic cardiac arrest and selective cerebral perfusion (antegrade through the innominate artery), reflectance oximetry demonstrated that following discontinuation of CPB, renal oxygenation was maintained or increased but cerebral oxygenation was diminished. At the conclusion of the procedure the brain, in fact, was less well oxygenated than the kidneys. The avoidance of circulatory arrest did not alter these observations. A question was raised whether these results were more indicative of oxygen extraction differences than the methods of circulatory delivery. All babies received phenoxybenzamine preoperatively to blunt sympathetic influences on vascular beds. Whether PBZ played a role in the observed changes in oxygenation was unknown, but might be analyzed as a variable in future studies.
Monday Afternoon Pediatric Anesthesia: Perioperative Management and Pharmacology
Reviewed by: Reviewed by: Jeffrey L. Galinkin, MD
Thirty abstracts were presented during this session, what follows are some of the highlights.
The use of preoperative CK levels as predictors of MH risk was presented by Dr. Drum (A-1237) from Temple University in Philadelphia. The authors of this study found that elevated CK preoperatively in patients at high risk for MH was not predictive of risk for MH or MH-like reactions. Additionally, the relationship between MH and musculokeletal diseases other than Duchenne's was questioned and resolved to require further study.
The pharmacokinetics of orally administered fentanyl (IV formulation) was examined by Dr. Wheeler et al from Children's Memorial Hospital in Chicago. They found that the IV formulation of fentanyl was rapidly absorbed with a prolonged and flat elimination profile similar to what is seen for gastric absorption of the fentanyl oraletÒ. In this study, a 10-15 mcg/kg oral dose of fentanyl provided a Cmax = 1.83 ± 1.19, T1/2 = 4.7 ± 2.8 and AUC 6.49 ± 3.97.
Perioperative behavior in children was examined in two abstracts. Dr. Kain et al from Yale University Medical Center presented work examining the perioperative stress response in children (A-1242). They looked at 107 children undergoing T&A surgery to see if increased preoperative behavioral stress and anxiety increased pain, analgesic requirements, recovery, and hospital stay. Their results showed that children with high preoperative anxiety had more postoperative pain, required more medication to control their pain while in the hospital and were more likely to have emergence agitation upon awakening from anesthesia than their less anxious counterparts. On a related topic, Dr. Przybylo from Children's Memorial Hospital in Chicago examined the use of DSMD-IV (psychiatric) symptoms for anxiety and delirium to more reliably evaluate post-emergence behavior in children 3-7 years old (A-1244). The results showed that both PACU nurses and anesthesiologists could reliably evaluate post-anesthesia behavior using these DSMD-IV symptoms. The authors postulated that this methodology might provide a more consistent means for classifying behavior during emergence from general anesthesia in children.
Two studies examined the utility of the BiSpectral Indexä (BISä) in children. The first of these studies, presented by Dr Terrier from the University of Rennes in Rennes (A-1253), France, looked at variations of sevoflurane level and their correlation to BISä values. Their results demonstrated a lack of correlation of BISä value to sevoflurane level and a paradoxical increase in BISä value when alfentanil was added to their anesthetic mixture. Similarly in a study presented by Dr Viviand from Hôpital Nord, Marseille, France, venous blood concentrations of propofol were correlated to BISä levels in children (A-1254). Their study demonstrated good correlation between BISä and propofol concentrations in a non-linear fashion. An inhibitory sigmoid Emax model best described the relationship between BISä and venous propofol level. They also noted that age and premedication exhibited significant effects on BISä value.
Finally, 3 abstracts examined the properties of existing pharmacologic agents in children and pediatric models. Dr Bebee et al from University of Minnesota examined resuscitation following the administration of three commonly used local anesthetics in piglets (A-1266). In this study, piglets were administered intravenous levobupivicaine, ropivicaine or bupivicaine until cardiac arrest. Resuscitation followed with either epinephrine or vasopressin. The results showed ropivicaine to be the least cardiotoxic of the three agents; 3 times as much ropivicaine was required to elicit cardiac arrest than either bupivicaine of levobupivicaine. Additionally, epinephrine was far superior to vasopressin in the treatment of cardiovascular collapse from intravascular injection of local anesthetic. The pharmacokinetics of intravenous ondansetron in children aged 1 24 months was presented by Dr Roth from Children's Memorial (A-1267). In this study, 6 infants in each of two age groups (1-<4 months and >4 24 months) had serum drawn for pharmacokinetic testing of drug levels at multiple time points after ondansetron administration. Their results demonstrate adult values of AUC and clearance in the older age group and a decreased clearance of ondansetron in the < 4 month age group. Thus, young infants may require a longer time interval for repeated ondansetron dosing. Finally, Dr Verghese from Children's National Medical Center evaluated the use of intranasal remifentanil to facilitate tracheal intubation during sevoflurane induction (A-1250). The intranasal route was chosen to duplicate conditions where an anesthesiologist would perform a "deep" intubation without the presence of an intravenous line. Their results showed that, when compared to placebo (nasal saline), a single dose of intranasal remifentanil 4 mcg/kg significantly improved intubation conditions at both two and three minutes following drug administration during inhalation general anesthesia.
Wednesday Afternoon Pediatric Anesthesia: Pain
Moderators: Kumar Beeline, MD and Patrick
Birmingham, MD
Reviewed by: Anne E. Dickison, MD
During the first half-hour, the audience reviewed posters and interacted with presenters. Eight studies were presented and opened for questions; three are summarized below. The session's first two abstracts were submitted by the same group of investigators of (Imperial College, University of London) who studied antinociceptive effectiveness of alpha-2 adrenoceptor agonists and Xenon on responses to the Formalin Test (for acute inflammatory pain) in newborn Fischer rats. Alternative approaches to neonatal pain relief are being sought because N2O lacks antinociceptive activity in infants. Dr. Mariangela Giambini introduced the studies, and presented Dexmedetomidine (potent alpha-2 agonist) which was clinically demonstrated to offer antinociceptive effects equal in newborn and adult rats. Dexmedetomidine's adult human dose is 0.2 – 0.5 mcg/kg but the rat dose is 100 times greater. With species differences it is not known how well this study would extrapolate to human neonates. To an audience question about whether or not Dexmedetomidine was being considered for central use, came the answer that no central toxicities to the drug are known, but presently there are no plans to develop a formulation. In Europe, DuraClon is presently available, and another new alpha-2 adrenoceptor for central administration will be ready for marketing soon. The same study design with newborn Fischer rats exposed to the Formalin Test was used to assess the antinociceptive effectiveness of Xenon. Mervyn Maze, M.B., observed that Xenon had a depressive, not antinociceptive, effect on the spinal cord; baby rats would have altered mental states but were not rendered unconscious. In 7-day old animals, behavioral responses to formalin pain were entirely eliminated by inhaled Xenon, but 15-day old rats did not show the same behavioral effects. Xenon, which is four times denser than air, odorless, and very expensive (more than $10 per liter), requires specially designed closed circuits for administration. These delivery limitations and the apparent impact of nervous system maturity on its effectiveness could reduce the likelihood that Xenon will prove useful in pediatric populations. Santhanam Suresh, MD (Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL): “A randomized double-blind controlled trial of Infraorbital Nerve Block versus Intravenous Morphine Sulfate for children undergoing endoscopic sinus surgery: are post-operative outcomes different?” Group 1 patients received bilateral Infraorbital Nerve (ION) blocks with 2cc 0.25% bupivacaine with epi, plus 2cc IV saline, while Group II patients receive ION blocks with 2cc NS and 2cc of intravenous Morphine Sulfate at 0.1 mg/kg. Rescue by MS (0.05 mg/kg was available, as was ondansetron for postoperative nausea or vomiting. Study patients did not receive steroids, ibuprofen, or any other NSAIDS. Both groups had similar pain relief, but PONV was found in 80% of the morphine group, but was reported by none of the ION block group. It was concluded that the routine use of ION blocks during endoscopic sinus surgery in children could reduce postoperative delays to discharge. #include ./footer_include.iphtml