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PEDIATRIC ANESTHESIA

The Safety and Efficacy of Sevoflurane Anesthesia in Infants and Children with Congenital Heart Disease

Isobel A. Russell, MD, PhD^*, Wanda C. Miller Hance, MD^*, George Gregory, MD^*, Michel C. Balea, MS^*, Lydia Cassorla, MD^*, Anil DeSilva, MD^*, Robert F. Hickey, MD^*, Lynne M. Reynolds, MD^*, Kathryn Rouine-Rapp, MD^*, Frank L. Hanley, MD, V. Mohan Reddy, MD, and Michael K. Cahalan, MD^*

Departments of *Anesthesia and Perioperative Care and Surgery, Division of Pediatric Cardiac Surgery, University of California, San Francisco, California

Address correspondence to Isobel A. Russell, MD, PhD, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 521 Parnassus Ave., C450, San Francisco, CA 94143-0648.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

 
We tested the hypothesis that sevoflurane is a safer and more effective anesthetic than halothane during the induction and maintenance of anesthesia for infants and children with congenital heart disease undergoing cardiac surgery. With a background of fentanyl (5 µg/kg bolus, then 5 µg · kg^-1 · h^-1), the two inhaled anesthetics were directly compared in a randomized, double-blinded, open-label study involving 180 infants and children. Primary outcome variables included severe hypotension, bradycardia, and oxygen desaturation, defined as a 30% decrease in the resting mean arterial blood pressure or heart rate, or a 20% decrease in the resting arterial oxygen saturation, for at least 30 s. There were no differences in the incidence of these variables; however, patients receiving halothane experienced twice as many episodes of severe hypotension as those who received sevoflurane (P = 0.03). These recurrences of hypotension occurred despite an increased incidence of vasopressor use in the halothane-treated patients than in the sevoflurane-treated patients. Multivariate stepwise logistic regression demonstrated that patients less than 1 yr old were at increased risk for hypotension compared with older children (P = 0.0004), and patients with preoperative cyanosis were at increased risk for developing severe desaturation (P = 0.049). Sevoflurane may have hemodynamic advantages over halothane in infants and children with congenital heart disease.

Implications: In infants and children with congenital heart disease, anesthesia with sevoflurane may result in fewer episodes of severe hypotension and less emergent drug use than anesthesia with halothane.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

 
For decades, halothane has been the inhaled anesthetic of choice for infants and children (1–3). Studies of sevoflurane in adults and in healthy children suggest that it may have significant advantages over halothane in infants and children with heart disease (4–11). However, no prior published studies have confirmed this contention. Specifically, sevoflurane has three theoretical advantages. First, because it is roughly fourfold less soluble in blood than halothane (8,12), the induction of anesthesia and subsequent adjustments of anesthetic depth can be accomplished quickly without using large inspired concentrations, as is required with halothane. Overdose with halothane is a rare but known cause of intraoperative cardiac arrest in infants and children (13). Second, sevoflurane produces fewer dysrhythmias than halothane (5,9–11,14). Often, infants and patients with heart disease require normal sinus rhythm to produce adequate blood pressure and cardiac output. And third, sevoflurane decreases contractility of the myocardium less than halothane (15–18). When cardiac reserve is limited, avoidance of decrease of myocardial contractility is preferred.

Therefore, we designed the following randomized, double-blinded, open-label study in infants and children with congenital heart disease to compare the safety of sevoflurane with that of halothane during the induction and maintenance of anesthesia for cardiac surgery.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

 
We prospectively enrolled 182 pediatric patients who were <12 yr old and who were scheduled for elective correction or palliation of congenital heart disease. After approval of the study by our committee on human research, we obtained written informed consent from the parents or legal guardians of all patients before surgery. One of the investigators obtained a history of the cardiac disease and reviewed the findings from the echocardiographic examination or cardiac catheterization to confirm the principal cardiac diagnosis. Patients were excluded if they were already intubated before surgery. Otherwise, consecutive patients were studied within the limitations of consent and study personnel availability.

Preoperative cyanosis was defined as any of the following: 1) systemic arterial oxygen saturation of 90% or less and right to left intracardiac shunting during the preoperative cardiac catheterization, 2) arterial saturation of <90% measured by pulse oximetry and right to left intracardiac shunting as documented by echocardiography, or 3) physician-observed and -documented cyanosis at rest or with exercise within 1 mo of admission and right to left intracardiac shunting documented by echocardiography or catheterization. Preoperative congestive heart failure was defined as a mention of this diagnosis on the admission history by the referring pediatric cardiologist or treatment with digitalis, diuretics, or both within 1 wk of the study.

During the initial contact with the patient, baseline arterial saturation, heart rate, and automated blood pressure measurements were made and repeated in the preoperative holding area. The age-adjusted normal resting blood pressure and heart rate were estimated from published nomograms (19–21). From these three different estimates of resting blood pressure and heart rate, the lowest estimate of each variable was used.

After arrival in the operating room, the patient was constantly observed by a technician trained to recognize and record the primary and secondary variables (see below and Appendix 1). This individual was unaware of the principal anesthetic, and he wore acoustic headphones to completely isolate himself from verbal stimuli that might bias his interpretation of the variables.

After premedication with oral midazolam (0.5–1.0 mg/kg) in children more than 1 yr old and placement of standard noninvasive monitors, patients underwent inhaled induction of anesthesia with the randomly assigned anesthetic administered in 3 L of nitrous oxide and 2 L of oxygen. The initial delivered dose of halothane was 0.5% and of sevoflurane, 1.0%. The halothane concentration was increased by 0.5% increments and the sevoflurane concentration, by 1.0% increments every three breaths until the onset of rhythmic breathing and the loss of the eyelid reflex occurred (the maximum delivered concentration of volatile anesthetic did not exceed 4% halothane or 8% sevoflurane). In patients with congestive heart failure (see definition above), all delivered anesthetic concentrations and the rate of their increase were decreased by half compared with patients without congestive heart failure. Then, the delivered concentrations of the volatile anesthetic were decreased to 1 minimum alveolar anesthetic concentration (MAC) (see Appendix 1 for MAC values), an IV catheter was placed, and pancuronium (0.1 mg/kg) was administered. Thereafter, positive-pressure ventilation was provided via face mask, nitrous oxide was turned off, and the oxygen flow rate was increased to 5 L/min. In patients with unrestricted systemic to pulmonary shunting, the inspired oxygen concentration was decreased to minimize further left to right shunting. The total fresh gas flow was always maintained at 5 L/min. Laryngoscopy and intubation were performed 5 min after the administration of pancuronium. Immediately before incision, a bolus of 5 µg/kg and then a continuous infusion of 5 µg · kg^-1 · h^-1 of IV fentanyl was administered and the delivered volatile anesthetic concentration adjusted as needed to maintain an appropriate level of anesthesia and hemodynamics for the surgical procedure. In patients who required cardiopulmonary bypass, the study was terminated with placement of the partial aortic occlusion clamp for insertion of the aortic cannula. Thereafter, anesthesia was provided with IV anesthetics or isoflurane as most appropriate for the expected postoperative course (large-dose narcotic and midazolam or small-dose narcotic and isoflurane). In patients not requiring cardiopulmonary bypass, the study was continued until the conclusion of surgery. Anesthetics were administered by, or under the immediate supervision of, experienced pediatric cardiac anesthesiologists.

Hemodynamics and arterial saturations were recorded continuously by using commercially available software and hardware for analog-to-digital conversions (LabVIEW; National Instruments, Austin, TX). Blood pressure was measured every 60 s with oscillometry (Dinamap; Critikon, Tampa, FL) until an arterial line was placed after the induction of anesthesia, and thereafter continuously. Respiratory gases were monitored by a calibrated infrared analyzer and recorded continuously. Six seconds of lead II of the electrocardiogram were recorded automatically every minute for subsequent evaluation of cardiac rhythm. The echocardiogram recordings were reviewed by two independent observers blinded to anesthetic assignment, and the rhythm was determined as junctional, ventricular, other, or uninterpretable. When the observers’ independent evaluations of rhythm differed, they jointly reviewed the echocardiogram epoch to reach consensus.

For safety purposes, our protocol required an interim analysis after enrollment of 90 patients and termination of the study if a statistically significant difference between groups was found in the incidence of cardiovascular events (CVE) or arterial desaturation (AD) (see definitions below). No statistically significant difference was found, so the study continued. However, a frequent incidence of hypotension was noted in both groups. To determine whether this hypotension compromised global perfusion, we measured serum lactate at the same two points of care in all subsequent patients: after radial artery cannulation and after heparin administration (YSI 1500 Sport Lactate Analyzer; Yellow-Springs Instruments, Inc., Yellow Springs, OH).

Randomization was performed immediately before taking each patient into the operating room. Assignments were made in lots of 10, with each lot containing an equal number of sevoflurane and halothane assignments. Separate lots were used for patients with preoperative cyanosis and congestive heart failure to ensure that these subpopulations were equally balanced within the study groups.

The incidence of CVE and AD, the primary outcome variables (see definitions below), were estimated to be 30% in the study population. Assuming that sevoflurane would reduce the incidence of one or both of these outcomes by 50%, we estimated that 90 patients would be required in each group to provide an 80% chance of detecting this decrease with a significance level of 0.05. All analyses were performed with SAS (SAS Institute, Inc., Cary, NC) procedures, Microsoft Excel (Microsoft Corp., Redmond, WA), and Statview (version 4.02; Abacus Concept, Berkeley, CA). Continuous variables were compared by using Fisher’s exact test, and nominal variables were compared with the Mann-Whitney U-test. The Mann-Whitney U-test was used rather than t-testing because our data were not normally distributed (most of our patients were <1 yr old). For comparison of the median number of CVE and AD, the median test was used (22). Multiple logistic regression analysis was used to assess the independence of predictors for developing CVE and AD. These variables included the anesthetic used, age less or more than 1 yr, and the presence or absence of cyanosis and congestive heart failure. Data are mean ± SD. Statistical significance was accepted for P < 0.05. The study design, data management, and statistical analysis were performed independently of the study sponsor.

Two primary outcome variables were defined a priori: CVE and AD. CVE was defined as any of the following occurring during the study period: bradycardia (more than a 30% decrease in the resting heart rate for 30 s or more), hypotension (more than a 30% decrease in the resting mean arterial blood pressure for 30 s or more), electrical cardioversion, defibrillation, or cardiac massage. AD was defined as more than a 20% decrease in the resting arterial saturation for 30 s or more during the study period. Arterial saturations were measured by pulse oximetry. Resting arterial saturation was estimated as the mean of multiple measurements before surgery. During the study period, arterial saturation was defined as the mean of values measured from two pulse oximeter probes (from a finger and toe). Fifteen secondary variables were investigated (see Appendix 2 for definitions).

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

 
Our randomization resulted in comparable study groups. Two patients were withdrawn from the study: one because of vaporizer malfunction and one because of preoperative dysrhythmias. Patients with a wide variety of congenital heart disease were studied ( Table 1). Eighty-nine patients were assigned to receive halothane and 91 to receive sevoflurane, with similar numbers of patients with cyanotic heart disease, congestive heart failure, or both included in each study group ( Table 2). Anesthetic management, including premedication, narcotic dose, MAC levels of sevoflurane and halothane, inspired oxygen concentration, and fluid administration was similar in both groups (Table 2).

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

Our study design did not allow us to definitively specify the underlying causes for our results. The development of more bradycardic episodes and use of more emergent drug in the halothane-treated patients may result from halothane’s greater depression of cardiac contractility and higher blood solubility (8,12,15–18). Another limitation of our study was that the anesthesiologists administering the study drugs were aware of the drugs’ identity and thus could have treated patients differently on the basis of that knowledge. However, our data do not support that possibility: patients in the two groups received comparable anesthetic depth, oxygen, fluid administration, and ventilation. Furthermore, because of the marked differences in potency and pharmacokinetics of halothane and sevoflurane, we were unable to devise a way to effectively blind the administering anesthesiologists to the study drugs without introducing some additional risk to our patients.

In summary, we conclude that sevoflurane may have hemodynamic advantages over halothane in infants and children with congenital heart disease.

	Appendix 1. MAC Values of Halothane and Sevoflurane

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

 

	Appendix 2. Secondary Outcome Variables (Efficacy Criterion)

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

1. 1. Time for anesthetic induction: minutes elapsed from the placement of the face mask until the first attempt at IV catheter placement.
   
2. 2. Patient acceptance of the induction: good if, after face mask placement, the patient made no purposeful movements to remove it, and poor if purposeful movements were made to remove it.
   
3. 3. Agitation during the induction: present if struggling or marked motor activity was noted during the induction, and absent if no or mild motor activity was noted.
   
4. 4. Moderate hypotension: 15%–30% decrease in the resting mean arterial blood pressure for 30 s or more during the study period.
   
5. 5. Moderate bradycardia: 15%–30% decrease in the resting heart rate for 30 s or more during the study period.
   
6. 6. Tachycardia: 20% or more increase in the resting heart rate for 30 s or more during the study period.
   
7. 7. Junctional dysrhythmia: loss of the P wave or the presence of retrograde P wave without change in the QRS complex in lead II for three or more consecutive beats documented on any of the 6-s epochs recorded every minute during the study period.
   
8. 8. Ventricular dysrhythmia: one or more wide QRS complexes (>0.12 ms) in lead II not preceded by a P wave documented on any of the 6-s epochs recorded every minute during the study period.
   
9. 9. Emergent drug use (phenylephrine, epinephrine, atropine, and ephedrine): use of any of the above drugs according to protocol for the treatment of hypotension, bradycardia, or cyanosis during the study period. According to protocol, a 1 µg/kg bolus of IV phenylephrine would be administered for severe hypotension without bradycardia if it persisted for more than 15 s and did not resolve with discontinuation of nitrous oxide and decreasing the inspired concentration of vapor to a 0.33-MAC level. The same dose of phenylephrine was also administered for severe cyanosis if it persisted for more than 15 s and did not respond to discontinuation of nitrous oxide, and if the cause of the cyanosis was deemed to be inadequate systemic vascular resistance. According to protocol, a 0.1 µg/kg bolus of IV epinephrine was administered for severe hypotension with bradycardia if both persisted for more than 15 s and did not resolve with discontinuation of nitrous oxide and decreasing the inspired concentration of vapor to a 0.33-MAC level. During the study, it became apparent that some episodes of bradycardia and hypotension were treated with ephedrine and atropine because of the clinical preference of the attending anesthesiologist. We prospectively recorded these administrations and included them in our total emergent drug assessment.
   
10. 10. Cough: two or more consecutive, forceful contractions of the diaphragm associated with venous engorgement of the neck and face during the induction of anesthesia.
    
11. 11. Breath holding: cessation of respiration without evidence of upper airway obstruction during the induction of anesthesia.
    
12. 12. Excess salivation: the presence of saliva on the face or neck during the induction of anesthesia.
    
13. 13. Upper airway obstruction: inspiratory retraction of the chest wall associated with tracheal tugging during the induction of anesthesia.
    
14. 14. Bronchospasm: positive airway pressure more than 30 cm H₂O or a 50% increase in positive airway pressure in the absence of endotracheal tube occlusion at any time during the study period after intubation.
    
15. 15. Moderate desaturation: 10%–20% decrease in the resting arterial saturation for more than 15 s during the study period.
    

	Acknowledgments

 
Supported in part by a grant from Abbott Laboratories, Abbott Park, IL.

The authors acknowledge the help of and thank Dr. J. Lerman, who served as the referee for the interim safety analysis required by our Committee on Human Research. The authors also thank Deryck Lodrick, PhD, for editorial assistance and manuscript preparation.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1. MAC Values... Appendix 2. Secondary Outcome... References

 

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