Continuous alfentanil infusion in pediatric patients undergoing general anesthesia for complete oral restoration

Continuous Alfentanil Infusion in Pediatric Patients Undergoing General Anesthesia for Complete Oral Restoration Peter J. Davis, MD,* Jon-Bruce Chopyk, MD,? Mamoun Nazif, DDS, MDS,$ D. Ryan Cook, MD8 Departments burgh

of Anesthesiology

and the University

Study Qbjective:To

and Dental

of Pittsburgh

Medicine,

School

Children’s

of Medicine,

IHospital of Pitts-

Pittsburgh,

PA.

study the safety and ej,,cacy of continuous alfentanil infusions

in children.

*Assistant Professor of Anesthesiology, Critical Care Medicine, and Pediatrics, Department of Anesthesiology TAssistant Professor of Anesthesiology, partment of Anesthesiology $Professor of Pediatric Dentistry, ment of Dental Medicine SProfessor of Anesthesiology, of Anesthesiology

De-

Depart-

Department

Design: Randomized open study. Setting: Outpatient pediatric anesthesia at a university medical center. Patients: Forty pediatric patients aged 2 to 12 years about to undergo anesthesia .for complete oral restoration.

Interventions:

Twenty patients

alfentanil followed by a continuous alfentanil infusion.

Measurements

and Main Results: Hemodynamic measurements, emergence times,

and postoperative side effects were measured. Hemodynam,ic stability was maintained in both groups. Although children emerged faster and were gxtubated earlier when anesthetized with alfentanil, they required longer times until they could be discharged from the outpatient anesthesia area. Children anesthetized with alfentanil had. a higher occurrence

Address reprint requests to Dr. Davis at the Department of Anesthesiology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, PA 15213-2583, USA. Supported in part by ,Janssen Pharmaceutica Inc., Piscataway, NJ

were anesthetized with halothane and nitrous oxide

(NnO), and 20 patients were anesthetized with N,O and a 100 IJ,glkg bolus of

anesthetized with halothane.

of postoperative

emesis compared with children

These d$,ferences, however,

were not statistically

signzficant.

Conclusions: Alfentanil appears to be a safe anesthetic. The reason for prolonged discharge time in the alfentanil-anesthetized patient is unclear, but it rnaJ> be related to postoperative vomiting. Keywords:

Anesthesia,

intravenous;

pediatrics;

alfentanil.

Received for publication April 18, 1990; revised manuscript accepted for publication August 1, 1990.

Introduction

0 199 1 Butterworth-Heinemann

Alfentanil is a synthetic opioid congener of fentanyl. Its rapid onset and relatively short duration of action coupled with its stable cardiovascular J. Clin.

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19191

125

Originnl Contributions

properties’-:’ make alfentanil a potentially useful anesthetic agent in pediatric anesthesia. Alfentanil’s small volume of distribution and short elimination halflife’-” allow the drug to be administered either by bolus injection or as a continuous infusion. Compared with bolus injections, continuous infusions generally allow the level of anesthesia to be better titrated to the degree of surgical stimulation, thereby resulting in a lower total drug dosage and faster awakening time.? Thus, with the use of short-acting muscle relaxants and narcotics, it is thought that pediatric outpatient surgical procedures may be done with rapid recovery and minimal side effects. Although much is known about the pharmacokinetic properties of alfentanil in premature infants and older children,4m6.s the pharmacodynamic aspects of alfentanil in children have not been well studied. This study was undertaken to evaluate the pharmacodynamics of continuous alfentanil infusion and to compare it with halothane in pediatric patients requiring general anesthesia for complete oral restoration.

Materials and Methods This study was approved by the Human Rights Committee at the Children’s Hospital of Pittsburgh, and written informed consent from each patient’s parents was obtained. Forty unpremeditated patients 2 to 12 years of age (ASA physical status I and II) undergoing dental surgery were randomly divided into two groups. Any patient with known liver or kidney disease was excluded from the study. General anesthesia was induced in all patients with nitrous oxide (N,O), oxygen (O,), and halothane by mask. After venous access was established, atropine 0.1 mg and atracurium 0.5 mg/ kg were administered to prevent bradycardia and facilitate endotracheal intubation. In Group 1 (n = 20), the halothane was discontinued after the induction of anesthesia. With the halothane end-tidal concentration less than 0.1% and the patient breathing N,O and 02, alfentanil 100 pg/kg was infused slowly over 3 minutes. One minute later, a continuous infusion was begun at the rate of 2.0 pgi kg/min. Two minutes after the start of the continuous infusion, N,O was discontinued, and the patient’s trachea was nasally intubated. Following intubation, N,O with O2 was again administered in a 70:30 mixture. Increases in vital signs greater than 20% of baseline values (i.e., those values obtained upon admission to the hospital) were treated with up to three incremental bolus doses of alfentanil(7.0 to 10.0 pg/kg). If vital sign changes were not controlled after three bolus

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doses given over a 5-minute period, the infusion was increased by 0.5 pglkglmin to a maximum of 4.0 pgl kg/min. Decreases in vital signs less than 20% of the baseline value were treated by decreasing the infusion in decrements of 0.5 p,gikgimin. If, after 20 minutes at a steady infusion rate, there was no significant hemodynamic change, the alfentanil infusion was adjusted downward until there was some hemodynamic response to the surgical stimulation. During the anesthesia, any patient whose heart rate (HR) decreased by more than 25% of the baseline value was given 0.1 mg of intravenous (IV) atropine. Atracurium 0.3 mg/kg IV was administered as needed during the operative procedure. The alfentanil infusion was discontinued approximately IO minutes before the anticipated end of surgery. Following induction, patients in Group 2 (n = 20) were initially administered 1.5% halothane. Increases in vital signs greater than 20% of the baseline values were treated by increasing the inspired concentration of halothane by 0.5%. In the absence of vital sign changes, the halothane concentration was adjusted downward until some hemodynamic response to surgical stimulation was noted. The halothane was discontinued approximately 7 to 10 minutes before the anticipated end of surgery. Patients in Group 2 received atropine 0.1 mg when HR decreased by more than 25% of the baseline value and atracurium as clinically needed. In all patients, neuromuscular blockade was antagonized with neostigmine and atropine and assessed by neuromuscular monitoring of the train-of-four ratio. No patient in either group received local anesthesia for nerve blocks. In both groups, HR and systolic blood pressure (SP) were recorded at the following times: (1) upon arrival in the short-stay unit (baseline); (2) upon arrival in the operating room; (3) after administration of atropine but just before administration of the alfentanil bolus; (4) 1 minute after alfentanil infusion; (5) 1 minute before and 1 minute after intubation; (6) 1 minute before and 1 minute after the start of surgical stimulation. Emergence from anesthesia was quantified as the time after the last anesthetic agent was turned off until the trachea was extubated and the time after the last anesthetic agent was turned off until the patient was felt to be alert and appropriately responsive. in addition, the patient’s length of stay in the recovery room and in the short-stay unit after surgery (from arrival at the unit until discharge) was recorded. A throat pack was placed in all patients prior to the commencement of surgery. Upon completion of the procedure, the throat pack was removed, and an

Alfentunil

orogastric tube was placed to suction the stomach contents. The occurrence of postoperative side effects of anesthesia-namely, respiratory depression (e.g., slow respiratory rate, shallow respirations, or cyanosis), vomiting, and retching-was noted in the recovery room and in the short-stay unit by nurses unaware of the patients’ anesthetic agents. Statistical analysis included unpaired Student’s ttest, repeated measures analysis of variance with the Student-Newman-Keuls test, chi-square with Yates correction, and the Fisher exact test. Statistical significance was assumed for values of p < 0.05.

Results There were no significant differences between Groups 1 and 2 with respect to age (4.1 t 2.1 years US3.6 ? 1.2 years), body weight (17.8 ? 6.4 kg 21s 17.1 ? 6.4 kg), or duration of surgery (96 ? 35 minutes ~1.793 t 37 minutes). There were no differences between the groups in the baseline values of HR and SP. After the induction of anesthesia and the initial dose of atropine, no patient in either group required further atropine administration for bradycardia. In Group 1, no patient became hypotensive after alfentanil administration; SP remained stable after infusion and intubation. With the onset of surgical stimulation, however, there was a statistically significant increase

1. Systolic blood pressure at varying times during the operative procedure. Atropine and atracurium were administered to each patient in the time period between arrival in the operating room (OR) and 1 minute prealfentanil injection. For patients in the halothane group, 1 minute prealfentanil and postalfentanil injection correspond to a time period when alfentanil would have been administered.

Figure

infiion

in childrm:

Davis et al.

(20%) in SP above the baseline value. ‘I’his increase also was significant compared with the corresponding values in Group 2 (Figure 1). In Group 2 patients, there was no significant difference in SP during intubation and incision. In both groups, there was no significant change in HR. However, HR following induction was consistently higher (statistically significant) in the patients anesthetized with halothane compared with those receiving alfentanil {Figure 2). The mean 2 SD alfentanil drug requirement was 2.4 ? 0.5 pgikglmin. Three of 20 patients required a supplemental dose of 10 pgikg following intubation, and 8 of 20 patients required a supplemental dose of 10 kg/kg following incision. In the halothane group, 5 patients became hypertensive following intubation and required higher concentrations of inspired halothane. Table 1 summarizes the operative and postoperative data. No patient in either group had any clinical evidence of postoperative respiratory depression. There were significant differences between the groups with respect to the emergence from anesthesia. Patients anesthetized with alfentanil were extubated e,arlier and appeared to become alert faster than patients anesthetized with halothane. Although the group anesthetized with alfentanil had a higher frequency of postoperative emesis, this finding did not reach statistical significance (p < 0.08). Patients anesthetized with alfentanil did, however, have a l.onger postoperative stay {Table 1).

Figure 2. Heart rate at varying times tluring the operative procedure. Atropine and atracurium were administered to each patient in the time period between arrival in the operating room (OR) and 1 minute prealfentanil injection. For patients in the halothane group, 1 minute prealfentanil and postalfentanil injection correspond to a time period when alfentanil would have been administered. J. Clin. Anesth., vol. 3, March/April 1991

127

Original Contributions Table

1.

Halothane

Variables Observed (Group 2)

in Children

Time to Extubation (min)

Group Group

1 (n = 20) 2 (n = 20)

3.7 * 1.9* 13.6 +- 11.2

Undergoing

Anesthesia

with Continuous

Alfentanil

Infusion

(Group

1) or

Time to Alertness (min)

Incidence of Postoperative Emesis

Length of Stay in Recovery Room (min)

Length of Stay in Outpatient Unit (min)

11.0 t 9.0” 37.0 k 17.8

9 of 20 3 of 20

51 ” 15 51 ? 17

192 i 82” 143 + 51

*p < 0.05.

Discussion The ideal IV anesthetic agent for pediatric surgical patients should provide an adequate depth of anesthesia, minimal cardiovascular effects, rapid induction and emergence, and minimal postoperative side effects. In adults, alfentanil is a potent, short-acting narcotic that can provide hemodynamic stability.‘m3 In both children and adults, alfentanil’s small volume of distribution and short elimination half-life make the drug amenable to both bolus injection and continuous infusion.4m7 The cardiovascular effects of alfentanil have been assessed during both low-dose and highdose infusions in adults. No hemodynamic changes occurred in low-dose infusions (1.6 and 6.4 kg/kg) administered at slow rates to healthy volunteers1 Kay and Stephenson” demonstrated the hemodynamic stability of low-dose alfentanil in adult patients undergoing minor surgical procedures. At higher doses of alfentanil (150 kg/kg), HR, mean arterial pressure (MAP), and systemic vascular resistance (SVR) were noted to decrease, while pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR), right atria1 pressure (RAP), and pulmonary artery pressure (PAP) increased slightly.3 Previously, there were no published reports on the pharmacodynamics of alfentanil in pediatric patients. In the present study of children pretreated with atropine, hemodynamic stability appeared to be well maintained following alfentanil injection. Although there was no significant difference in BP between the two groups at the time of tracheal intubation, SP increased significantly above baseline values in the alfentanil group at the time of incision. Nevertheless, this 20% increase in SP was easily controlled with a single supplemental dose (10 pgikg) of alfentanil. Whether this increase in SP was a result of an insufficient alfentanil plasma concentration or an underestimation of the plasma concentration needed for the surgical stimulus is unclear. In both pediatric and adult studies, there appears to be a wide variability with respect to alfentanil’s 128

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pharnlacokinetics.l-T,!’ Using the Cpso measurements (i.~., the effective plasma concentration for 50% of patients) of Ausems et al.,“’ as well as data from previously published pharmacokinetic studies in children, l-7 we estimated that a 100 pg/kg bolus and a 2 pglkglmin continuous infusion would produce steadystate plasma concentrations of about 250 to 350 ngl m-a plasma concentration we thought sufficient for a procedure with minimal surgical stimulation. Unfortunately, we did not obtain plasma concentrations to help elucidate the problem. IV induction characteristics in pediatric surgical patients can be difficult to assess because the fear of needles and pain from injections can create such psychological trauma that inserting an IV catheter in an awake child becomes counterproductive. For this reason, we did not attempt to evaluate the induction characteristics of alfentanil. Consequently, we induced anesthesia in our patients with halothane, N,O, and 0, by mask. In adult studies, depending on the amount of alfentanil administered, recovery times following alfentanil administration were either similar to or shorter than those reported following the use of fentanyl or halothane.llzl’ The present authors also noted a shorter emergence time in patients anesthetized with alfentanil than in patients anesthetized with halothane. The pediatric patients who received alfentanil could be extubated earlier and appeared to become alert faster than patients anesthetized with halothane. Although there was no difference between the groups in the length of time spent in the postoperative recovery area, this finding may be a result of the institution’s policy of observing children for a minimum of 45 minutes after tracheal extubation. Vomiting can be a frequent and disturbing complication following certain types of surgery. The occurrence of postoperative vomiting following general anesthesia in pediatric patients ranges from 5% to 42%.‘3,‘4 In a study of pediatric outpatients, Pate1 and Hannallah’” reported that postoperative vomiting was the most frequent complication, occurring in 35% of

Alfentunil

patients, and that protracted vomiting accounted for one-third of the unscheduled admissions to the hospital following outpatient surgery. The high frequency of postoperative vomiting in the study patients receiving alfentanil is particularly worrisome. A high frequency has been reported in adults as well. White et u~.,~I in a randomized, doubleblind study of fentanyl and alfentanil used in surgical outpatients premeditated with droperidol and undergoing mid-trimester therapeutic abortions, noted that alfentanil administered either as a bolus or as a continuous infusion resulted in postoperative vomiting in 36% and 60% of the cases, respectively. These figures were not statistically different from those found with fentanyl. Factors that may influence postoperative emesis are the patient’s susceptibility and age, the anesthetic agents administered, the duration of the operative procedure, and the type of surgery. Purkiss’” noted that patients who are prone to motion sickness also appear more likely to have postoperative emesis. Age is another factor in postoperative emesis. Although the occurrence of emesis appears to decrease with age in adults, this finding does not appear to be true f-or children. Rowley and Brown,17 in a survey of 1,183 pediatric anesthetics conducted over 2 months, noted that postoperative vomiting was significantly more common in children older than 3 years than in younger children. Premeditation with narcotics can increase the frequency of postoperative emesis more than twofold.lf However, Bellville” suggested that there may be no linear correlation between opioid dose and the frequency of vomiting. Instead, there is an optimal effective dose. Doses of opioid greater or less than this optimal dose result in vomiting. The duration of anesthesia is another factor in the etiology of postoperative emesis. Bellville ut ~1.‘~ reported nausea and vomiting in 17% of their cases after surgical procedures lasting 30 to 90 minutes and in 46% of their cases after procedures lasting 150 to 2 10 minutes. Rowley and Brown” noted that after procedures lasting less than 30 minutes, children had significantly less vomiting (34%) than after procedures lasting more than 30 minutes (48%). Surgical factors also can influence the occurrence of postoperative emesis. Numerous studies have demonstrated that certain procedures-namely, strabismus repair, orchiopexy, dental procedures, tonsillectomy, and adenoidectomy-are associated with a high rate of postoperative emesis.14,15,17m26 Both groups of patients in the present study were scheduled for similar dental procedures. The authors cannot rule out swallowed blood from dental extractions as a

infzuion

in chiklren:

Davis

et al.

cause of the high frequency of vomiting seen in this study. In view of the faster times to extubation and alertness, the longer hospitalization time in the children anesthetized with alfentanil is surprising. Although we did not specifically evaluate the causes for this, we speculate that longer times to discharge may be related to the increased rate of vomiting. If the desirable characteristics of an anesthetic for pediatric surgical outpatients include a rapid emergence with minimal side effects and avoidance of a prolonged hospital stay, then alfentanil anesthesia in pediatric outpatients should be accompanied by an antiemetic. Although some practitioners consider the prophylactic administration of antiemetics unnecessary, *5 studies of pediatric outpatients having strabismus repair have shown that droperidol 75 kg/kg administered either IV or orally can significantly reduce the occurrence of postoperative vomiting without delaying emergence from anesthesia or discharge from the hospital.Z1,ZZ.‘”Recently, Broadman et al.” noted similar results with metoclopramide in a similar group of patients. In summary, this study indicates that continuous infusions of alfentanil are safe and efficacious in pediatric patients undergoing complete oral restoration. Patients anesthetized with alfentanil emerged from anesthesia more quickly and appeared alert earlier than patients anesthetized with halothane. However, patients anesthetized with alfentanil had an increased rate of vomiting and a significantly longer hospital stay. At present, the authors recommend that continuous infusions of alfentanil in pediatric patients be accompanied by prophylactic administration of antiemetics. Future studies with antiemetic agents are needed to determine whether these agenlts can decrease the occurrence of vomiting and possibly reduce the length of hospitalization.

Acknowledgments The authors thank Laura Dillman for secretarial support; Lisa Cohn for editorial assistance; Ellen Kretchman, B.S., C.R.N.A., and Jane D. Jandreau, B.S.N., C.R.N.A., for intraoperative assistance; and Wayne DellaMaestra for assistance with the statistical analysis.

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Pala~~o MGA, Strunin I,: Auaesthesia and emesis. I: Prevention and management. Can Aw~sIh Sot J 1984: 31: 178-87. 24. Palazzo MGA, Strunin L: Anaesthesia and emesis. 11: Etiology. Ccl,! Anac~th SocJ 1984;31:407-1.5. 23. Adriani .J, Summers FW, Anthony SO: Is the prophylactic use of’antiemetics in surgical patients justified? JAMA 1961; 175:666-71. 26. Abramowitz I, Oh TH, Epstein BS, Ruttimann UE, Friendly DS: ‘l‘he antiemetic effect of droperidol foliowing outpatient strabismus surgery in children. At~r.t23.

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