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Anesth Analg 2001;93:1380-1386
© 2001 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

A Randomized Multicenter Study of Remifentanil Compared with Halothane in Neonates and Infants Undergoing Pyloromyotomy. I. Emergence and Recovery Profiles

Peter J. Davis, MD*, Jeffrey Galinkin, MD{dagger}, Francis X. McGowan, MD{ddagger}, Anne M. Lynn, MD§, Myron Yaster, MD||||, Mary F. Rabb, MD, Elliot J. Krane, MD#, C. Dean Kurth, MD**, Richard H. Blum, MD{dagger}{dagger}, Lynne Maxwell, MD{ddagger}{ddagger}, Rosemary Orr, MD§§, Peter Szmuk, MD, Daniel Hechtman, MD||||||||, Suzanne Edwards, DrPH¶¶, and Lynn Graham Henson, PharmD##

*Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, and Departments of Anesthesiology, Critical Care Medicine, and Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania; {dagger}Department of Anesthesiology, Children’s Hospital of Philadelphia, and Department of Anesthesiology, University of Pennsylvania, Philadelphia, Pennsylvania; {ddagger}Department of Cardiac Anesthesia, Children’s Hospital, and Department of Anesthesia, Harvard Medical School, Boston, Massachusetts; §Children’s Hospital and Regional Medical Center, Departments of Anesthesiology and Pediatrics, University of Washington, School of Medicine, Seattle, Washington; ||||Departments of Anesthesiology, Critical Care Medicine, and Pediatrics, The Johns Hopkins University, Baltimore, Maryland; ¶Department of Anesthesiology, University of Texas-Houston Medical School, Houston, Texas; #Department of Anesthesiology, Lucile S. Packard Children’s Hospital at Stanford, and Departments of Anesthesiology and Pediatrics, Stanford University, Stanford, California; **Departments of Anesthesiology and Pediatrics, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; {dagger}{dagger}Department of Anaesthesia, Harvard Medical School, and Department of Anesthesia, Children’s Hospital, Boston, Massachusetts; {ddagger}{ddagger}Departments of Anesthesiology, Critical Care Medicine, and Pediatrics, The Johns Hopkins University, Baltimore, Maryland; §§Children’s Hospital and Regional Medical Center, and Department of Anesthesiology, University of Washington, School of Medicine, Seattle, Washington; ||||||||Children’s Hospital of Pittsburgh, and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ¶¶Clinical Statistics Department and ##Anesthesia Clinical Development, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina

Address correspondence and reprint requests to Peter J. Davis, MD, Department of Anesthesiology, Children’s Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213-2583. Address e-mail to davispj{at}anes.upmc.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Pyloric stenosis is sometimes associated with hemodynamic instability and postoperative apnea. In this multicenter study we examined the hemodynamic response and recovery profile of remifentanil and compared it with that of halothane in infants undergoing pyloromyotomy. After atropine, propofol, and succinylcholine administration and tracheal intubation, patients were randomized (2:1 ratio) to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. Pre- and postoperative pneumograms were done and evaluated by an observer blinded to the study. Intraoperative hemodynamic data and postanesthesia care unit (PACU) discharge times, PACU recovery scores, pain medications, and adverse events (vomiting, bradycardia, dysrhythmia, and hypoxemia) were recorded by the study’s research nurse. There were no significant differences in patient age or weight between the two groups. There were no significant differences in hemodynamic values between the two groups at the various intraoperative stress points. The extubation times, PACU discharge times, pain medications, and adverse events were similar for both groups. No patient anesthetized with remifentanil who had a normal preoperative pneumogram had an abnormal postoperative pneumogram, whereas three patients with a normal preoperative pneumogram who were anesthetized with halothane had abnormal pneumograms after.

IMPLICATIONS: The use of ultra-short-acting opioids may be an appropriate technique for infants less than 2 mo old when tracheal extubation after surgery is anticipated.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Because of immaturity in brain development and respiratory control mechanisms, coupled with possible increased myocardial sensitivity to anesthetics, neonates and infants may be particularly susceptible to the myocardial depressant effects of inhaled anesthetics as well as the ventilatory depressant effects of inhaled anesthetics and IV opioids (1–9). In infants with pyloric stenosis, underlying electrolyte imbalance and fluid deficits coupled with residual anesthetics may affect recovery from anesthesia and increase the incidence of postoperative apnea (9–17). We performed this multicenter study to examine the hemodynamic response and recovery profile of remifentanil and compare it with that of halothane in a group of neonates and infants undergoing pyloromyotomy and who were at risk for postoperative respiratory complications.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This multicenter study was conducted at seven sites (Children’s Hospital of Pittsburgh, Pittsburgh, PA; The Children’s Hospital of Philadelphia, Philadelphia, PA; The Boston Children’s Hospital, Boston, MA; The Johns Hopkins Hospital, Baltimore, MD; Children’s Hospital and Regional Medical Center, Seattle, WA; Hermann Hospital, Houston, TX; and Lucile Packard Children’s Hospital at Stanford, Palo Alto, CA) from January 1998 to June 1999. This open-label study was approved by the IRB of each institution, and written informed consent was obtained from each patient’s parents or guardian. All patients were ASA physical status I or II, born at term (>=37 wk gestational age) weighed >=2500 g at birth, and were <=8 wk old at the time of surgery. All patients underwent pyloromyotomy after normalization of their fluid and electrolyte imbalance. At the time of entry into the study, each patient had a preoperative pneumocardiogram evaluation. Each site was scheduled to enroll patients in a 2:1 (remifentanil/halothane) randomization scheme. Randomization tables were computer generated.

Patients were randomized to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. No patients were premedicated. Before the induction of anesthesia, with the patient awake, the gastric contents were suctioned, and the patient was allowed to breathe 100% oxygen. Anesthesia was induced with atropine (10 µg/kg), propofol (2.0 mg/kg), and succinylcholine (2 mg/kg). After the trachea was intubated, IV cisatracurium (0.5–0.1 mg/kg) was administered to maintain muscle relaxation, and rectal acetaminophen (120 mg) was administered for postoperative pain relief. The maintenance anesthesia consisted of the study drug along with 60% nitrous oxide and 40% oxygen.

Supplemental cisatracurium was administered as clinically indicated and by monitoring the patient’s train-of-four ratio. Throughout the operative procedure, end-tidal carbon dioxide was monitored and maintained at 40–45 mm Hg. In patients randomized to receive remifentanil, a continuous infusion was begun at 0.4 µg · kg-1 · min-1, whereas for patients randomized to receive halothane, the expired anesthetic concentration was targeted at 0.4%. Surgical incision was performed after the steady-state concentration was maintained for 5 min.

In both groups, signs of light or inadequate anesthesia (increases in systolic arterial blood pressure >90 mm Hg for 1 min, increase in heart rate >=170 bpm for 1 min, or somatic or autonomic responses such as tearing, sweating, or movement were treated with increasing the delivered maintenance anesthetics. For patients receiving remifentanil, signs of inadequate anesthesia were treated with a supplemental bolus (1 µg/kg), and the continuous infusion rate could also be increased by 50% if the investigator believed that the response would be sustained. Bolus administrations and 50% increments in the rate of remifentanil administration could be performed every 2 to 5 min until a maximum infusion rate of 2 µg · kg-1 · min-1 was achieved. In patients randomized to receive halothane, responses to inadequate anesthesia were treated by increasing the expired anesthetic concentrations in 0.4% increments. In both groups, if after infusion rate changes or increases in inhaled anesthetic concentration were made in response to inadequate signs of anesthesia and the vital signs had remained stable for 10 min, the remifentanil infusion rate or the inhaled halothane concentration could be decreased to the previous infusion rate or inspired concentration.

In patients who had a hypotensive response to anesthesia (systolic blood pressure <60 mm Hg for 1 min on two consecutive readings), lactated Ringer’s solution (5–20 mL/kg) was infused. If hypotension persisted, the remifentanil infusion was decreased by 50% or the halothane decreased in 0.4% increments. If fluid administration and dosage adjustments failed to alleviate hypotension, further treatment was left to the discretion of the investigator. Atropine (0.01 mg/kg) was administered for bradycardia. Bradycardia was defined as a heart rate <100 bpm for longer than 1 min.

At the start of skin closure (approximately 10 min before the end of surgery), the surgical wound site was infiltrated with bupivacaine 0.25% (1 mL/kg), and the remifentanil was decreased to 0.05 µg · kg-1 · min-1 or the halothane was discontinued. At the end of surgery, residual neuromuscular block was antagonized with neostigmine (70 µg/kg) and glycopyrrolate (10 µg/kg). Once the train-of-four ratio had returned to baseline and a sustained tetanus was present, nitrous oxide and the remaining anesthetics were discontinued. For 10 min after the discontinuation of anesthesia, no physical stimulation (e.g., no suctioning of the oropharynx, no jaw thrust or triple airway maneuver) was performed. If, after 10 min, the patient was not ready for tracheal extubation, then stimulation was allowed. In the Remifentanil group, an opioid antagonist was administered if adequate ventilation (respiratory rate >=10 breaths/min; SpO2 >=90%) was not achieved within 10 min of anesthetic discontinuation. With the patient spontaneously breathing 100% oxygen and adequate airway reflexes present, the patient’s trachea was extubated, and then the patient was transferred to the postanesthesia recovery unit (PACU).

In the PACU, a study nurse recorded the time the patient met the PACU discharge criteria. The PACU discharge time (time from cessation of the anesthetic until the patient was discharged from the PACU) was predicated on meeting a postanesthesia assessment recovery score of 6 (18). PACU scores were assessed every 5 min from entry into the recovery room until discharge. In addition, a quality of recovery score was assessed every 15 min. This score uses a four-point scale and is based on whether the patient was sleepy (Score 1), awake and oriented (Score 2), crying but consolable with nonnutritive sucking (Score 3), or crying inconsolably (Score 4). Postoperative pain was initially treated with nonpharmacologic interventions (nonnutritive sucking [pacifier] and parental comforting). Any subsequent postoperative pain was treated with acetaminophen if more than 8 h had elapsed since the operative dose. IV morphine 100 µg/kg could also be administered for postoperative pain at the discretion of the investigator.

The study nurse also recorded the adverse events of vomiting, cardiovascular side effects, and hypoxemia. Cardiovascular events—bradycardia, dysrhythmias, and hypotension—were recorded. The incidence of postoperative hypoxemia was also noted. Hypoxemia was defined as a room air SpO2 <90% for longer than 1 min. Monitoring for adverse events occurred throughout surgery and after surgery until the patient was discharged home.

At the time of entry into the study, each patient had a preoperative pneumocardiogram evaluation. A minimum of 2 h of recording had to occur before the surgery. In addition, pneumocardiograms were obtained in the postoperative period beginning within 15 min of entry into the PACU. An A2000 Assurance Home Monitor System, EdenTrace II Plus Digital Recorded System, and EdenTrace File Archiving Software (Nellcor Puritan Bennett, Ottawa, Ontario, Canada) were used at each site to collect and record pneumocardiogram data. Pneumocardiograms were evaluated and interpreted by using the EdenTrace Analysis Software System and EdenTrace II Plus Digital Printer System by an expert blinded to the patient’s randomization. Details of the pneumocardiograms collection and data analysis are further discussed in Part II (19).

Summary statistical computations were performed with SAS version 6.12 (SAS Institute, Inc., Cary, NC). Two-sided statistical tests were performed to detect a difference between treatment groups. P values <0.05 were considered statistically significant. Cox proportional hazards modeling, adjusting for site effects, was used to detect among treatment differences in time-to-event variables, e.g., time to extubation or time to discharge.

Logistic regression analysis, adjusting for site effects, was used to detect treatment differences in dichotomous response variables. Fisher’s exact test was performed when logistic regression exhibited convergence problems, e.g., when every subject had the same dichotomous response within at least one treatment group. Analysis of variance, adjusting for sites and baseline, was used to detect between-treatment differences in normally distributed continuous variables, e.g., hemodynamic changes after surgical stimuli. The initial sample size was chosen to have an 80% power to detect a 3.5-min difference between treatments with respect to extubation times.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Sixty patients were entered into the study; 38 patients received remifentanil, and 22 received halothane. All patients were included in the demographic analysis as well as the analysis of the recovery variables. There were no significant differences for age, weight, gestational age at birth, location of incision, duration of surgery, or duration of anesthesia between the two groups (Tables 1 and 2). There were no significant differences between the two groups with regard to time from the start of the maintenance anesthetic to incision (14.3 ± 4.9 min versus 15.6 ± 8.4 min) and from the maintenance anesthetic to the gastric manipulation (22.1 ± 6.1 min versus 22.8 ± 8.8 min). The mean rate of remifentanil administration before decreasing the infusion at the end of the procedure was 0.55 µg · kg-1 · min-1 (range, 0.39–1.0 µg · kg-1 · min-1), whereas the mean expired concentration of halothane at the end of surgery was 0.5 minimum alveolar anesthetic concentration (MAC) (range, 0.4–1.2 MAC).


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  		Table 1. Patient Demographics (mean ± sd)
 

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  		Table 2. Surgical Demographics
 
There were no instances of bradycardia or dysrhythmias in either group. There were no significant differences in blood pressure and heart rate between the two groups at baseline, skin incision, and gastric manipulation (Fig. 1). The incidences of hypertension and tachycardia at the time of the incision were similar for both groups. Twenty-four percent of patients in the Remifentanil group and 18% in the Halothane group had hypertensive responses, whereas 42% in the Remifentanil group and 41% in the Halothane group had a tachycardic response to skin incision. The incidence of hypertension and tachycardia at the time of gastric manipulation was also similar for both groups. Thirty-nine percent of the remifentanil-anesthetized patients and 55% of the patients receiving halothane had a hypertensive response, whereas 47% of patients anesthetized with remifentanil and 55% of patients anesthetized with halothane had a tachycardic response to gastric manipulation.



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  		Figure 1. Blood pressure (A) and heart rate (B) at baseline, skin incision, and gastric manipulation for the two anesthetic groups. Mean ± 95% confidence interval.

 
Seventy-one percent of the patients receiving remifentanil and 82% of the halothane-anesthetized patients required an increase in anesthetic concentration during the operation (P = 0.54), whereas 11% and 32% of the remifentanil- and halothane-anesthetized patients, respectively, required treatment for hypotension (P = 0.08).

There was no difference in the early anesthesia recovery variables between the two groups. The time to tracheal extubation and the time to purposeful movement were similar in both groups (Table 3). The incidence of stimulation required before tracheal extubation was similar for both groups. Eight percent of patients in the Remifentanil group and 9% of patients in the Halothane group required stimulation by either suctioning or jaw thrust. No patient required naloxone.


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  		Table 3. Recovery Variables (mean ± sd)
 
There was no significant difference between the groups with regard to the late anesthetic recovery variables of time to eligibility of discharge from the PACU (22.5 ± 12.3 min versus 28.5 ± 20.7 min, mean ± SD) or time to the first analgesic medication (370 ± 277 min versus 316 ± 354 min, mean ± SD) for the Remifentanil and Halothane groups, respectively. In the recovery room period, there were no significant differences in the respiratory rates or SpO2 values between the groups. In the recovery room, there were no increased incidences of SpO2 <90% for the Remifentanil group compared with the Halothane group. Except for admission to the PACU, the quality of recovery scores was similar at 15, 30, 45, 60, 75, 90, 105, and 120 min after arrival in the PACU. On arrival, mean quality of recovery scores was significantly higher for patients anesthetized with remifentanil than with halothane (P = 0.004) (Table 4).


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  		Table 4. Summary of Quality of Recovery Scores
 
Adverse events were noted in 45% of the patients. The most common adverse event, postoperative vomiting, occurred in 45% of the patients anesthetized with halothane and in 34% of the patients anesthetized with remifentanil. In the Remifentanil group, 5 of 38 patients experienced surgical complications, compared with 0 of 22 in the Halothane group. One patient sustained a bowel perforation, one patient sustained a serosal tear, one patient developed peritonitis and a peritoneal leak, one patient was reexplored for postoperative bleeding and required a blood transfusion, and one patient developed postoperative drainage from the surgical wound site.

Fifty-one of the 60 patients had a preoperative pneumocardiogram (32 of the 38 patients in the Remifentanil group and 19 of the 22 patients in the Halothane group). Fifty-six patients had postoperative pneumocardiograms (36 patients in the Remifentanil group and 20 of the patients in the Halothane group). No patient anesthetized with remifentanil and who had a normal preoperative pneumocardiogram had an abnormal postoperative pneumocardiogram. In patients who received halothane, three individuals with normal pneumocardiograms had abnormal pneumocardiograms in the postoperative period. A more complete analysis and discussion of the pneumocardiogram data is presented in Part II.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
As the practice of anesthesia for infants evolves, providing patients with hemodynamic stability, minimizing adverse events, and allowing patients to emerge rapidly with minimal respiratory depression become important considerations for the selection of anesthetics. This is especially significant for infants who may be at risk for postoperative apnea (9,14,15,20,21). In this open-label study in infants younger than two months of age, we noted that in clinically relevant doses, halothane and remifentanil have similar safety and recovery profiles. Both anesthetics provided patients with hemodynamic stability, and opioid-induced respiratory depression was not observed in the remifentanil-anesthetized infants.

As in an earlier open-label study, in which time to extubation and time to PACU discharge were similar for remifentanil, alfentanil, propofol, and isoflurane, this open-label study showed similar recovery variables (extubation times and PACU discharge times) for remifentanil and halothane (22). The design of this study may have precluded finding a difference in the early recovery variables, because the anesthetics were administered by using clinical practice methods (discontinuing the halothane 10 minutes before the end of surgery and remifentanil at the end of surgery) as opposed to continuing both anesthetics at equipotent doses until the end of surgery. This study design involving anesthetic administration was intended to mimic clinical practice and thereby minimize the differences between the anesthetics. In addition, because no physical stimulation was allowed for the first 10 minutes after discontinuation of the anesthetics, it is conceivable that with physical stimulation, some patients may have been extubated earlier. As with extubation times, we noted that PACU discharge times were also similar for both anesthetics. Although we noted similar mean times of the recovery variables between the two anesthetic groups, the smaller variability (SD) observed with the remifentanil-anesthetized patients suggests that remifentanil may allow for more predictable times in patient recovery.

As opposed to previous studies of remifentanil in children, in this study of infants we noted that the infants’ pain scores (quality of recovery score) were similar for both remifentanil- and halothane-anesthetized infants. This finding of similar quality of recovery scores is in contrast to the previous open and blinded pediatric studies, in which objective pain discomfort scores in the PACU were significantly higher (i.e., the patients were significantly more uncomfortable) in the remifentanil-anesthetized patients compared with the comparative anesthetic groups (22,23). Part of the explanation for differences in the pediatric and infant studies may be the different postoperative analgesic regimens that were used. In the earlier pediatric studies, morphine (50 µg/kg) was administered during surgery, whereas in this study, large-dose rectal acetaminophen (approximately 40 mg/kg) was administered at the onset of surgery, and local anesthesia (bupivacaine 0.25%) was injected into the incision at the closing of surgery. Although McNicol et al. (24) noted that perioperative bupivacaine administration to infants undergoing pyloromyotomy resulted in alterations in heart rate and respiratory rate as well as behavioral changes that were compatible with pain relief, others have questioned the value of local anesthesia for infants undergoing pyloromyotomy (25). Sury et al. (25) have noted that wound infiltration with bupivacaine did not decrease heart rate, respiratory rate, or behavioral scores (facial expression, posturing, and crying) in the first two hours after pyloromyotomy. However, these observations by Sury et al. may reflect the fact that the administered intraoperative maintenance anesthetic for infants in their study consisted only of nitrous oxide and oxygen. Consequently, their intraoperative anesthetic management may have been less than optimal.

The cardiovascular side effects of remifentanil seemed similar to the cardiovascular effects of halothane. However, these similarities may be a function of the prior administration of atropine at the induction of anesthesia. Although there was no statistical difference between the two anesthetics with regard to heart rate and systolic blood pressure at predetermined stress points during the operative procedure, there was a trend (P = 0.08) for the halothane-anesthetized patients to require treatment for hypotension, suggesting increased myocardial depression with halothane compared with remifentanil.

In addition to cardiorespiratory events, other adverse events were also documented. Postoperative emesis was a frequent but anticipated event after pyloromyotomy. Although opioids are highly emetic, there was no difference in the incidence of emesis between the remifentanil- and halothane-anesthetized patients. The lack of a difference in the incidence of postoperative emesis between the two groups may be related to the frequent incidence of emesis associated with the disease and surgery. Other studies have reported postoperative emesis rates of 36%–90% in infants after pyloromyotomy (26–29). Untoward surgical events, as opposed to anesthetic-related complications, were the major complications encountered in this study. Surgical complications (bowel perforation, peritoneal leak, serosal tear, and postoperative bleeding necessitating blood transfusion) occurred in 5 of 60 patients, a complication rate in keeping with pyloromyotomy (26–29). Even though all of these surgical complications occurred in patients receiving remifentanil, all of these adverse events were believed to be unrelated to the anesthetic.

Case reports with small patient numbers have shown conflicting data about the effects of anesthetics on respiratory patterns in infants with pyloric stenosis (24,25). The anesthetics in this study were administered in an open-label fashion, with the investigator interpreting the pneumograms blinded to the randomization of the anesthetics. Although a detailed discussion of the pneumograms follows in Part II (19), the administration of remifentanil, a drug with a rapid elimination (30–32), was not associated with clinically observed postoperative respiratory depression or new onset of pneumogram abnormalities. However, given the small sample size of this study, further studies will be needed to determine what, if any, influence anesthetics have on postoperative pneumograms.

A possible criticism of our study is that the doses of remifentanil and halothane may not have been comparable. Although no remifentanil dose-dependent studies were performed in infants, the doses that were chosen were based on clinical practice. The fact that the number of changes in the dosages administered to patients was similar in both groups suggests that the two drugs were used in a clinically equivalent fashion. Another criticism of the study is its small sample size. We initially based our sample size on the power to detect an anticipated difference in time to extubation.

In summary, infants anesthetized with remifentanil have similar hemodynamic stability and anesthetic recovery variables when compared with patients anesthetized with halothane. Remifentanil was not associated with clinically observed postoperative respiratory depression, nor was remifentanil associated with a new onset of pneumogram abnormalities in the postoperative period. The use of ultra-short-acting opioids combined with nitrous oxide and oxygen seems to be a safe and appropriate anesthetic technique for infants less than two months old in whom tracheal extubation after surgery is anticipated.


   Acknowledgments
 
This research was supported by Glaxo Wellcome, Inc., Research Triangle Park, NC.

We thank the Research Study Coordinators/Research Nurses: Ruth M. Lebet, RN, PNP, Study Nurse, Pediatric Pain Service, Children’s Center, The Johns Hopkins Hospital, Baltimore, Maryland; Mary Kay Nespeca, RN, Research Coordinator, University of Washington School of Medicine, Seattle, Washington; Rosetta Chiavacci, RN, and Kathleen Harris, RN, Study Coordinators, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and Lorna Sullivan, RN, Children’s Hospital of Boston, Boston, Massachusetts.


   Footnotes
 
Presented at the meetings of the Society for Pediatric Anesthesia, Ft. Meyers, FL, February 26, 2000, the American Society of Anesthesiologists, San Francisco, CA, October 17, 2000, and the American College of Clinical Pharmacy, Tampa, FL, October 22, 2001.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 26, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press