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Literature Reviews

Clinical Predictors of Anaesthetic Complications in Children with Respiratory Track Infections (RTI)

Paediatric Anaesthesia 2001;11:29-40.

Summary: The authors sought to find an association between specific respiratory symptoms and anesthetic complications, develop a scoring system from the above data , and determine if there was an association between a specific respiratory pathogen and anesthetic complications. During the peak respiratory disease season in Australia all children presenting for anesthesia were evaluated by an extensive respiratory symptom prevalence/severity questionnaire administered by a research nurse. The anesthetic technique was at the discretion of the individual anesthesiologist. Any complications were noted by the anesthesiologists. All symptoms and complications were scored from a 1 to 4 scale. Patients whose surgery was cancelled by the anesthesiologist were included in the data base. In the second part of the study all patients with one or more symptoms of RTI were randomized to have viral cultures or not.

Data was obtained from 2,051 children with a mean age 5.8 years. Interestingly, the prevalence of children having a history of RTI in previous six weeks, living with a smoker, or snoring at night were all 46%. Twenty-two percent reported one or more symptom consistent with an RTI and 24% of children were reported by their parents to have a "cold" on the day of surgery. Twenty-two percent of all patients had at least one intraoperative complication. Step-wise logistic regression yielded eight final variables that could be considered useful predictors of an adverse event. The following variables were predictive of an adverse event:

1. Tracheal intubation as compared to face mask or LMA.
2. Parents reporting their child had a "cold."
3. Presence of snoring.
4. Passive smoke exposure.
5. Pentothal or halothane induction rather than with sevoflurane or propofol.
6. Presence of a "productive cough."
7. Lack of anticholinesterase administration.
8. Presence of nasal congestion.

Lastly, 293 children had viral cultures with 4.8% positive results. Isolation of a viral agent could not be correlated with specific predictive symptoms. The 35 patients having surgery cancelled because of a "cold" were compared with those patients who were anesthetized having one or more symptoms of an RTI. Cancelled children were younger, more likely to be scheduled for a major surgical procedure, and more likely to have the symptoms of rhinorrhea, cough, wheeze, malaise, or fever.

Comments: This study is a comprehensive survey that should be read by all pediatric anesthesiologists. The authors devise an eight point scoring system from the above variables that can be used to calculate the probability of having an adverse
anesthetic event. Like many of our practices, the authors typically proceeded with mask anesthesia for patients undergoing BMT. Most of the identified risk factors have logical explanations including the relative safety of propofol over pentothal given propofol's greater suppression of laryngeal reflexes and bronchiolar smooth muscle relaxation at equal anesthetic doses. The study confirms the relative safety of an LMA instead of tracheal intubation in the presence of a URI. Despite some potential biases, the results of this study seem valid and consistent with previous studies.

Reveiwed by: Samuel E. Golden, MD, FAAP, Loyola University, Chicago, IL

Publications on paediatric anaesthesia: a quantitative analysis of publication activity and international recognition.

Brambrink AM, Ehrier D and Dick DW. Br J Anaesth 2000: 85: 556-562

The aim of this study was to identify all articles on clinical practice in pediatric anesthesia, to name the respective journals, and to assess the publication activity and international recognition of selected countries for a 6-year period: 1993-1998. The search was limited to original articles, case reports, reviews, and editorials involving the pediatric population aged 0 to 14 years. Historical articles, reports of meetings, and abstracts were excluded. The authors identified 2259 publications on pediatric anesthesia in 295 peer reviewed journals, an average of 377 publications per year. Over 58%, 1325 articles, were published in 12 peer-reviewed publications, namely, Acta Anaesthesiologica Scandinavia, Anaesthesia, Anaesthesiologie-Intensivmedizin-Notfallmedizin-Schmerztherapie, Anesthesia & Analgesia, Anesthesiology, British Journal of Anaesthesia, Canadian Journal of Anaesthesia, Der Anaesthesist, European Journal of Anaesthesiology, Paediatric Anaesthesia, Pain, Regional Anesthesia and Pain Medicine. These 1325 articles represented 8.7% of the total numbers of articles (15,268) published in these journals. The majority of the articles, 85%, were in English. A further analysis showed that 46% of all publications were in a total of 5 journals, Pediatric Anaesthesia (428), Anesthesia & Analgesia (190), Canadian Journal of Anaesthesia (172), British Journal of Anaesthesia (130), and Anesthesiology (121).

Comments: The authors, after a very exhaustive search, have shown that publications on pediatric anesthesia, though scattered, are primarily clustered in five English language journals. Furthermore, the authors have tried to determine the impact factor of these publications by using the Science Citation Index. The anesthesia journals were listed according to the number of articles on pediatric anesthesia published during the 6 year study period and the respective impact factor was averaged from 1993 to 1998. The cumulative impact factor for the journal was obtained by the multiplication of the number of articles therein by the respective impact factor. This calculation of the journal's impact factor changed the dynamics of the ranking. The journal Pediatric Anaesthesia, which carried the highest number of articles amongst the top five journals, had the lowest impact factor: but the journal Anesthesiology, which had the lowest number of articles, had the highest impact factor. However, the authors question the relevance of using the Citation Index to determine the scientific merit and importance of a particular paper or journal. They acknowledge that the literature is replete with debate on this subject, as it may only suggest visibility rather than quality or importance. I concur.

The authors also calculated the number of publications per million children of potential study population, and the number of publications per thousand anesthesiologists. They noted that using these relative measures, the United Kingdom published the largest number of articles, followed by those from Canada, Switzerland, Sweden, and Denmark. The United States of America did not make the top 5, as there are 32,344 anesthesiologists for a potential study population of 57,276,000 children: whereas the United Kingdom has 3,000 anesthesiologists for a population of 10,033,594. The numbers perhaps would have been different if the authors had subdivided the total number of anesthesiologists in a country from those with a special interest in pediatric anesthesia. By the same token, if one looks at the countries of origin of the publications, there were 800 from the United States of America and 284 from the United Kingdom. Another way of looking at the data would show that 35% of all publications originated from the United States and 13% from the United Kingdom. Thus, these two countries dominate the field.

As anesthesiologists, practically all of us have access to the two main anesthesia journals, namely, Anesthesia & Analgesia and Anesthesiology. In an ideal world, one would recommend that anesthesiologists should read the top five journals mentioned above to get a balanced and comprehensive view of the subject. For those of us who are in clinical practice five days a week, this is indeed a tall order. Let us face it, in the final analysis there are other things in life besides reading about pediatric anesthesia. If the reader would only add the journal Paediatric Anaesthesia, it would provide a major review of the subject. For those who have no time to spare, well there is always the Literature Review section of our Newsletter!

Reviewed by Hoshang J. Khambatta, MD, Columbia University, New York, NY

Plasma concentrations and pharmacokinetics of bupivacaine with and without adrenaline following caudal anaesthesia in infants.

T.G. Hansen, N.S. Morton, P.M. Cullen and D.G. Watson. Acta Anaesthiologica Scandinavica 2001;45:42-47.

Review: The authors present a randomized pharmacokinetic study looking at the systemic absorption of 0.25% bupivacaine with and without 1/400,000 epinephrine after caudal administration to infants. The study examined 15 infants less then 5 months of age undergoing minor lower abdominal procedures. Seven of these infants were randomized to receive 2.5 mg/kg of 0.25% bupivacaine and eight infants were randomized to receive 2.5 mg/kg of 0.25% bupivacaine with 1/400,000 epinephrine by caudal administration. Blood was sampled at 30, 60, 90, 180, 240, and 360 minutes and analyzed for total and free bupivacaine concentrations.

Both the maximal total plasma concentration and the time to maximal plasma concentration (median of 60 minutes in each group) were comparable in both groups. All plasma concentrations were below 2.0 ng/ml except for a single sample (level 2.195 ng/ml) from a patient in the plain bupivacaine group. The bupivacaine with epinephrine group demonstrated a significantly prolonged apparent terminal half-life (median of 363 min vs. 165 min for the plain bupivicaine group) and a significantly higher total bupivacaine concentration at 360 minutes (median of 742 ng/ml vs. 400.5 ng/ml in the plain bupivacaine group). The authors thus concluded that the addition of 1/400,000 epinephrine to caudal bupivicaine prolongs systemic absorption.

Comments: This is the first study to detail the effects of epinephrine on the systemic absorption of caudally administered bupivacaine. The results go against the classic theory that the addition of epinephrine to lipophilic local anesthetics such as bupivacaine does little to prolong action as opposed to the hydrophilic local anesthetics such as lidocaine. It is still controversial whether this will cause any clinically evident difference in duration of effect and would be a good topic for future study.

Reviewed by Jeffrey L. Galinkin, MD, Children's Hospital, Philadelphia, PA

The Effect of Dexamethasone on Postoperative Vomiting after Tonsillectomy.

Aouad, MT, et al, Anesthesia and Analgesia 2001: 92;636-640.

Summary: Corticosteroids have well established anti-inflammatory, antiemetic, and appetite simulating properties. In addition, dexamethasone has a low cost and long half-life of 36 to 48 hours. The authors investigated whether or not patients undergoing tonsillectomy would benefit from intravenous dexamethasone administered intraoperatively.

One-hundred ten 2-12 year old, ASA 1-2 patients undergoing tonsillectomy with or without adenoidectomy where randomized to receive placebo or dexamethasone 0.5 mg/kg to a maximum of 8 mg IV. The anesthetic was standardized using midzolam for sedation and sevoflurane for induction and maintenance of anesthesia. The incidence of early and late vomiting, quality of oral intake, and parental satisfaction score were recorded. A 24-hr hospital stay was routine. The study was randomized, double-blinded, and placebo controlled.

The incidence of vomiting on the floor (39% vs. 10%), total number of patients who vomited (51% vs. 23%) time to first oral intake (11 vs. 5 hr), quality of oral intake (23% vs. 67%), excellent or good outcome (43% vs. 84%) and duration of IV hydration (18 vs. 12 hrs) for the saline and dexamethasone groups, respectively, all favored the dexamethasone group. No bleeding episodes were noted.

Discussion: The design of this study, and its results are nearly identical to those of Pappas, et al (Anesthesia and Analgesia, 1998;87:157-61). In that study a much larger dose of dexamethasone was used (1 ml/kg up to a maximum of 25 mg). No postoperative bleeding episodes were noted in either study representing a total of 231 patients. The reproducible beneficial effects, low cost, and lack of side effects make a strong argument that dexamethasone should become a routine part of our care for patients having tonsillectomy.

Reveiwed by: Samuel E. Golden, MD, FAAP, Loyola University, Chicago, IL

Noninvasive Blood Pressure Measurement in the Upper and Lower Limbs of Anaesthetized Children.

J.A. Short. Paediatric Anaesthesia, 2000;10:591-593.

Summary: The author measured upper and lower limb noninvasive blood pressures using appropriately sized cuffs for each limb. This was done during a
stable time of anesthesia and two consecutive measurements were made on each limb using the M1008BNBP module of the Hewlett Packard monitoring system.

The results showed an overall average MAP 5 mmHg higher in the arm group than the leg group for all ages studied (<1-16 years). The best correlation was obtained in children ages 5-16. In these age groups the mean pressures were within 3 mmHg with a standard deviation ranging from 5-9. In children less than one year of age the mean arm blood pressure was 58 while the mean leg blood pressure was 49 mmHg with a standard deviation of approximately 10. In children ages 1-4 the respective values were 61 and 52, with a large standard deviation of 16. In children <4 years of age there was "little predictability of agreement between arm and leg pressures."

Comment: These results are opposite those found in adults where leg blood pressures are typically higher than arm. The author believes that this may be explained by lack of sympathetic tone in young children. The poor correlation between pressures observed in young children does not preclude the use of lower extremity blood pressures for trending purposes. Repeated measurements on each extremity should have been done to determine if any reproducibility problems with instrumentation contributed to the lack of correlation.

Reveiwed by: Samuel E. Golden, MD, FAAP, Loyola University, Chicago, IL

Concentrations of Bupivacaine after Combined Spinal Epidural Anaesthesia in Infants and Neonates.

Geoff Frawley, et.al. Paediatric Anaesthesia 2000;10:619-625.

Summary: The authors wish to study total and free bupivacaine plasma concentrations following CSEA.

Fifty infants less than 55 weeks postconceptual age having predominantly herniorrhaphy and orchidopexy repair were studied. All infants had lumbar puncture using 1 mg/kg bupivacaine followed by threading of a 24 gauge epidural catheter to approximate T12. The epidural catheter was then dosed with 1.25 mg/kg of a 0.25% bupivacaine solution over 30 seconds. No epinephrine was used for either injection. EKG, blood pressures, and clinical observation for gross toxicity were made intraoperatively and postoperatively for 60 minutes. One ml blood samples were obtained from an in dwelling intravenous cannula at 15, 30, 45 and 60 minutes for analysis of total bupivacaine levels. Free plasma bupivicaine levels were determined at 45 minutes.

The mean birth weight was 2500 grams and post-conceptual age 36 weeks, with values of 3800 grams and 43 weeks at the time of surgery. Total plasma bupivacaine levels peaked between 45 and 60 minutes. The maximal mean was 1.16 mg/ml and in 10% of samples exceeded the adult toxic threshold for CNS toxicity of 2.5 mcg/ml. The mean unbound concentration at 45 minutes was 0.18 mcg/ml with a range from 0.01 to 1.88 mcg/ml. This measurement exceeded the presumed toxic level of 0.25 mcg/ml in 16% of cases. No clinical seizure activity or EKG changes were noted. Two infants had brief postoperative apneas requiring stimulation 15 minutes post surgery. These two infants had normal total plasma bupivacaine levels but elevated free concentrations of 0.33 and 0.52 mcg/ml. Interestingly, the infant having a free bupivacaine level of 1.88 mcg/ml had no perioperative problems.

Comment: The total dosage of bupivacaine given to these infants was 2.25 mg/kg. The exact plasma concentrations of bupivacaine causing toxicity in young children remains unresolved with this study. Previously published reports document toxicity with total concentrations as low as 2.1 mg/ml and lack of symptoms with concentrations as high as 7 mg/ml. Undoubtedly, the free concentrations are most important. A recent study in adults suggested early CNS and CV toxicity at a concentration of 0.3 mcg/ml. The data in the current study show that bupivacaine undergoes rapid redistribution and supports McIlvaine's suggestion that toxicity may be more dependent on the rate of rise of plasma bupivacaine concentrations than the absolute value.

The exact meaning of this study is unclear. As of yet, there are no well defined toxic concentrations for total and free plasma bupivacaine in neonates & infants. Remarkably, an average of only 87 seconds
elapsed between placement of the spinal and beginning dosage of the epidural catheter. Combined spinal and epidural anesthesia is feasible and a valuable technique in these infants. I will continue to add epinephrine for subarachnoid and epidural blocks in infants in my practice.

Reveiwed by: Samuel E. Golden, MD, FAAP, Loyola University, Chicago, IL

Response Variability to Analgesics: A Role for Non-specific Activation of Endogenous Opiods.

Amanzio, M, Pollo, A, Maggi, G, Bendetti, F, Pain 2000; 90:205-215.

The authors investigated both the mechanism and magnitude of the placebo response associated with the administration of analgesics in adults. Sequential clinical investigations in 278 randomized adult surgical patients compared the effects of intravenous injection of analgesics when administration was "hidden" and unknown to the patient and when administration was "open" and directly observed by the patient. Patients were divided into eight groups and received one of four analgesics (buprenorphine, tramadol, ketorolac and metamizol), based upon the anticipated severity of postoperative pain. Hidden injection of analgesics was less effective, that is, higher doses of analgesic were required to achieve similar reduction in pain scores. Although "open" injection of analgesics was more effective, it was associated with greater variability in response than observed with hidden injection.

A companion non-clinical study evaluated the effect of "open" vs. "hidden" intravenous injection of ketorolac in 86 volunteers subjected to ischemic arm pain. Naloxone was administered to subjects in three of six experimental groups to determine the magnitude of the analgesic effect attributable to the release of endogenous opioids. "Open" injection of ketorolac produced lower pain scores but was associated with greater variability in analgesic response. Administration of naloxone prior to injection of ketorolac did not alter the analgesic effect of "hidden" injection but eliminated the additional analgesic effect observed with "open" injection. The authors conclude that an
important source of variability in analgesic response is due to activation of endogenous opioid systems. Furthermore, these systems can be blocked psychologically by eliminating patients' awareness of drug administration or pharmacologically by blocking opioid receptors with naloxone.

Comments: This study supports the hypothesis that the placebo effect upon pain relief is mediated by the activation of endogenous opioid systems. Moreover, variability in this response may contribute to the variability in analgesic effect observed both among patients and in the same patient over time. The study also reminds us of the importance of our patients' perceptions as we minister to their needs. Their awareness and belief in what we are doing influences analgesic response. Of course, many of our patients are unable to comprehend the significance of our interventions. For these patients, however, does the surrogate response of parents influence analgesic response?

Reviewed by John T. Algren, MD, Vanderbilt Children's Hospital

Outcomes Worse in Premature Infants When Oxygen Saturation Kept High

Arch Dis Child Fetal Neonatal Ed 2001;84: F106-F110.

Babies of less than 28 weeks' gestation are more likely to experience worse outcomes, including severe retinopathy of prematurity, if oxygen saturation is maintained at 88% to 98% than if it is kept between 70% and 90%, according to this study. The authors evaluated records of 295 babies who survived infancy after delivery before 28 weeks gestation. Among those maintained at the higher range of oxygen saturation, 27.7% experienced retinopathy requiring cryotherapy or causing permanent retinal scarring, compared with 6.2% of those maintained at lower oxygen saturation.

The higher oxygen saturation was also associated with longer time spent on ventilation and lower weight at discharge. Babies managed at lower saturations rarely had arterial lines inserted or arterial blood gas measurements taken, with the result that only 13 of 65 required more than 2 blood transfusions prior to discharge. In comparison, 55 of 65 managed at higher
oxygen saturations, where use of arterial lines was more liberal, required more than 2 transfusions. The result certainly calls into question the unsubstantiated belief that arterial sampling is essential if the risk of retinopathy is to be minimized. Noting that the higher oxygen saturation levels are higher than the brain or retina experiences during fetal life the article concludes, "Attempts to keep oxygen saturation at a normal `physiological' level may do more harm than good in babies of less than 28 weeks' gestation."

COMMENT: Another big pinhole in the dogma of ICU care.

Reveiwed by: Alan S. Klein, MD

Adverse Sedation Events in Pediatrics: Analysis of Medications Used for Sedation

Cote C, Karl H, Notterman D, et al. Pediatrics 2000; 106:633-44.

Review: This study analyzed case reports of medications associated with adverse sedation events in pediatric patients. Initially, one hundred eighteen case reports were examined by four reviewers. The case reports were obtained from the adverse drug reporting system of the Food and Drug Administration, the US Pharmacopoeia, and the results of a survey of pediatric specialists were used. This study focused on the "relationship between outcome and medications: individual and classes of drugs, routes of administration, drug combinations and interactions, medication errors and overdoses, patterns of drug use, practitioners, and venues of sedation."

Ninety-five of one hundred case reports were accepted in the study. The reviewers came to the conclusion that there was no relationship between outcome and drug class nor route of administration. They point out in this study that negative outcomes such as death and permanent neurologic injury were often associated with drug overdose. The study also concluded that negative outcomes were associated with drug combinations and interactions. The use of nitrous oxide combined with sedating medication was often associated with adverse outcomes. The study also indicates that dental practitioners, using three or more sedating medications had the greatest frequency of negative outcomes. Sedating medications administered by nonmedical trained personnel and drugs administered at home were associated with negative outcomes. Despite the long-time use of sedating medications such as chloral hydrate and pentobarbital, several deaths or permanent neurologic injury were noted, particularly after discharge.

Comments: Outpatient sedation for procedures is a common practice. It is also not uncommon that sedating medications are administered by non-anesthesiologist. It is interesting to note, as this study points out that adverse outcomes were not related to a particular drug category nor route of drug administration. The use of Propofol was not addressed in this study. It is the conclusion of this study that the sedation guidelines and training requirements of the American Academy of Pediatric Dentistry (AAPD) conform to those adopted by the ASA and AAP. This study raises some important issues that need to be addressed by any specialist administering sedation to pediatric patients.

Reviewed by Cheryl K. Gooden, MD, Mount Sinai Medical Center, New York, NY

Midazolam Effects on Amnesia and Anxiety in Children

Kain Z, Hofstader M, Mayes L, et al. Anesthesiology 2000; 93:676-84.

Review: This double blind, placebo-controlled, randomized trial examined the minimum amount of time necessary for effective anterograde amnesia to develop in children after administration of oral midazolam. The study consisted of 113 children, aged 5 - 10 years, American Society of Anesthesiologists physical status I or II, undergoing general anesthesia and elective, outpatient surgery scheduled for less than two hours duration.

The initial study protocol consisted of a baseline memory test session with picture cards. Five correct responses for either the recall or the recognition test were necessary for participation in the study. Patients were assigned to one of three midazolam groups or a control group. At 5, 10, or 20 minutes after receiving oral midazolam (0.5 mg/kg) or 15 minutes after receiving a placebo, a second memory test that used pictures was administered. Subsequently, patients
were taken to the operating room (OR). On arrival to the OR, anxiety of the child was assessed as well as at the introduction of the anesthesia mask. Prior to discharge from the PACU, the patients underwent a third memory session for implicit, recall and recognition memory. Following final analysis of the four groups, this investigation showed that anterograde amnesia exists as early as 10 minutes after administration of oral midazolam.

Comments: This study is the first to look at the issue of timing and the development of amnesia following the administration of midazolam in children. Previous studies have examined the time relationship between the onset of anxiolytic effects and the administration of midazolam. The preoperative use of midazolam has been shown to decrease the incidence of postoperative negative psychologic outcomes. However, in spite of this and other known benefits of premedication a recent survey as mentioned in this article indicates "that midazolam is not widely used for young children undergoing anesthesia and surgery." The results of this study are important, and can be incorporated even in the busiest operating room setting.

Reviewed by Cheryl K. Gooden, MD, Mount Sinai Medical Center, New York, NY

Pharmacokinetics and pharmacodynamics of vecuronium in children receiving phenytoin or carbamazepine for chronic anticonvulsant therapy.

S.G. Soriano, L.J. Sullivan, K. Venkatakrishnan, D.J. Greenblatt and J.A.J. Martyn. British Journal of Anaestheisa 2001;86:223-229.

Review:This study examined the pharmacokinetics and time course of action of vecuronium in children receiving chronic anti-seizure medications. Vecuronium was administered to 30 subjects age 4-22. Of these subjects 10 were healthy controls (no history of seizures or administration of anti-convulsants), 10 were chronically maintained on phenytoin (preoperative levels 5-20 mcg/ml) and 10 maintained on carbamazepine (preoperative levels 6-10 ng/ml) all 30 of whom were age and weight matched. Blood samples were collected at 5, 10, 15, 30, 60, 90, 120, and 240 minutes after administration of vecuronium and analyzed for both parent drug and metabolite. The authors found that the elimination half-life of vecuronium was significantly decreased in both the carbamazepine (18.4 ± 16.6 min) and phenytoin (23.5 ± 13.1 min) groups when compared to control (48.2 ± 40.3 min) and the vecuronium clearance was increased in both the carbamazepine (18.8 ± 13.1 ml/kg/min) and phenytoin (15.1 ± 8.9 ml/kg/min) groups versus control (9.0 ± 3.6 ml/kg/min). The recovery index was also faster with both carbamazepine (10.6 ± 5.9 min) and phenytoin (12.5 ± 8.3 min) subjects when compared to control (21.8 ±11 min). Thus, the authors conclude that anticonvulsant-induced resistance to vecuronium exists in children and their results support a pharmacokinetic component contributes to this resistance.

Comments: This study confirms previous work done in adults that chronic administration of phenytoin and carmbamazepine result in resistance to neuromuscular blockade caused by steroidal relaxants such as vecuronium. Clinically, this study implies that these patients may require frequent administration of relaxant closely guided by a twitch monitor and clinical signs of decreased relaxation.

Reviewed by Jeffrey L. Galinkin, MD, Children's Hospital, Philadelphia, PA #include ./footer_include.iphtml