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EDITORIALS

Remifentanil for Neonates and Infants: Piano, Piano Con Calma

Departments of Clinical Anesthesiology and Clinical Pediatrics, College of Physicians and Surgeons of Columbia University, New York, New York

Address correspondence to Peter Rothstein, MD, 19 Overlook Road, Hastings on Hudson, New York 10706-2603. Address e-mail to ptr1{at}columbia.edu

In this issue of Anesthesia & Analgesia there are three reports dealing with the use of remifentanil in neonates and infants (1–3). The first describes the pharmacokinetics of the drug in infants and children, whereas the second and third deal with a comparison with halothane as the primary anesthetic for pyloromyotomy.

The pharmacokinetics of remifentanil in children appear to be similar to those of remifentanil in adults, demonstrating rapid elimination across all age groups. A potent opioid with a very rapid elimination, independent of cardiac output, renal or hepatic function, remifentanil’s short half-life promises rapid recovery of central nervous system and respiratory function. Thus, the drug appears to be one that anesthesiologists have sought for use in young children whose metabolic pathways or renal or hepatic function may be immature. The authors did find that the volume of distribution and clearance were highest in the youngest patients studied (<2 mo) (1). The extremes of biologic immaturity and patient variation lie in the neonatal population. The present study includes only three infants less than 1 mo of age, one being a 5-day-old infant. We will need to study more patients younger than 28 days (neonates), as well as those <7 days of age before we can say more definitively if there are differences in pharmacokinetics or pharmacodynamics in this age group compared with older infants and children.

Hypotension, defined as >20% decrease in blood pressure from baseline, developed in 17% of patients in the pharmacokinetic study. Although the authors ascribe this to the large bolus dose of remifentanil that was used, this incidence of hypotension has been described in previous studies of the drug (4). None of the hypotensive episodes was treated, and none of the patients who had hypotension received atropine before to remifentanil. Although the authors state that there was no difference in heart rate and blood pressure between children who received atropine and/or pancuronium and those who did not, I find this lack of vagolytic effect puzzling. Finally, the definition of hypotension used in this study is different than the definition used in the two subsequent articles, where a blood pressure <60 mm Hg was considered to be hypotension. It is apparent that a number of infants in the 0–2 month and 2 mo–32 yr group were hypotensive by the <60 mm Hg criteria. (Table 4)

Do pharmacodynamic effects go hand-in-hand with pharmacokinetic variables? The authors have expressed the hope that because of the smaller coefficient of variation (SD/mean) for remifentanil clearance, pharmacodynamics would be "more predictable." Responses to narcotics, including the synthetic opioids, tend to be quite variable, often with a three-fold difference between high and low responders to a given stimulus (5,6). Although the predictable clearance of the drug should lead to more predictable recovery characteristics, there will still remain a variability in the dose required to achieve a given end point intraoperatively.

Armed with this pharmacokinetic knowledge, the authors’ next step was to examine the use of remifentanil compared to halothane in infants <2 mo of age having surgery for pyloric stenosis (2,3). Outcome variables examined were changes in heart rate and blood pressure, time to extubation, recovery profiles, and measures of respiratory control (apnea). The two drugs appeared quite similar in cardiovascular effects, time to tracheal extubation, and recovery characteristics.

Galinkin et al. (3) describe abnormalities of respiratory control in infants preoperatively as well as postoperatively. Three previous reports discuss the issue of apnea in infants with pyloric stenosis. Wolf et al. (7) describe apnea >15 sec in 3 of 11 infants anesthetized with isoflurane. Andropoulos et al. (8) described four infants (8). One of these infants had apnea preoperatively. One who required cardiopulmonary resuscitation postoperatively had a significant intraoperative desaturation that could not be adequately explained, and 9 days postoperatively had a depressor response to 17% O₂ during testing. One patient had two episodes of "15–20" sec duration within the first 15 minutes after surgery. The last infant had two episodes lasting "5–10" sec during the first 15 min. The last reference, the only study to use methodology to detect apnea that was similar to that in the present study, found no apnea (9).

In the present study, several of the infants who had received halothane as their primary anesthetic had what is described as "the onset of new postoperative apnea," whereas patients receiving remifentanil had no instances of "new postoperative apnea." Is the implication that halothane causes apnea in the postoperative period in young infants? There are several possibilities.

1) Halothane can cause respiratory disturbances in the postoperative period in term infants in the first 8 wk of life.

2) What was observed was because of residual disturbances of respiratory control seen in pyloric stenosis and different lengths of recording time accounting for events seen in the postoperative period but not in the preoperative period.

3) What we are seeing are "normal" patterns of disordered respiratory control found in young infants.

The authors found no significant difference in the tendency to change from abnormal preoperative breathing patterns to postoperative normal patterns versus the change from normal to abnormal patterns. But why was "new apnea" not seen in the remifentanil group? An incidence of 0 in a study does not exclude the possibility that the real incidence is a number other than zero (10). As Galinkin et al. (3) point out, the numbers in this study were small and the incidence of pre- and postoperative apnea were the same between halothane-treated and remifentanil-treated infants.

How significant are these findings?

When interpreting the present results we must do so in light of what is known about disorders of respiratory control in infants with pyloric stenosis and normal patterns of respiratory control in term infants. Pyloric stenosis is a metabolic disease with a surgical cure (11). Because of continuing loss of acid resulting from vomiting, infants become progressively alkalotic. The respiratory compensation for metabolic alkalosis is respiratory acidosis, i.e., a decrease in minute ventilation to increase PaCO₂ and cerebrospinal fluid (CSF) PCO₂. The respiratory centers in the brain are bathed in CSF with pH that is approximately 7.3 under normal conditions. In the presence of metabolic alkalosis, CSF pH increases and respiratory drive decreases. Many of us have observed irregular postoperative respiratory patterns, including periodic breathing with respiratory pauses, in infants who had pyloromyotomies and who were hyperventilated, potentially aggravating their underlying metabolic imbalance.

Term infants do have periodic breathing, apnea, and desaturation in the absence of illness, surgery, and anesthesia (12–14). These events can occur weeks after birth and have not proven to be of any clinical significance. Some of the episodes of apnea seen in the present study are longer than what has been previously described. Importantly, in the present study, the infants with "new onset apnea" could not be clinically identified. They were only identified when pneumocardiograms were examined several weeks after the surgery took place. Thus, I would advocate caution before labeling events seen in the postoperative period in term infants as "new," and I would hesitate before claiming or implying that one anesthetic is better than another with respect to respiratory control after surgery.

In this paper and many other research reports there is a concern about statistics and significance. In this paper, significance was defined as P < 0.05. If an examination does not achieve this level of significance there are two possible reasons. The first is that there is in fact no significant difference between the two populations under study. The second is that the sample size was not large enough to detect a difference (Type II error). Potential bias is present when nonsignificant differences are labeled as a "trend," as appears in the discussion of the incidence of hypotension: "although there was no statistical difference between the two anesthetics with regard to heart rate and systolic blood pressure. . . there was a trend (P = 0.08) for the halothane-anesthetized patients to require treatment for hypotension" (2). Was there a treatment bias present? The administration of atropine was "left to the discretion of the investigator" (2).

Finally, a comment about "safety" of new drugs, and drugs used in new ways. The authors state that remifentanil is "safe." I would be more cautious. The safety of a drug or therapy is not established on the basis of 38 patients. We need only to look back at the recent history of rapacuronium to stress this point.

Remifentanil will find a place in anesthetic practice in infants and neonates. Its role is still to be defined. It may be most valuable in patients who are hemodynamically unstable. The authors have taken an important first step in the investigation of this drug. Questions that these studies generate will lead to further study of this unique drug.

Footnotes

"Piano, Piano Con Calma" translates to "Slowly, slowly, calmly."

References

1. Ross AK, Davis PJ, Dear GDEL, et al. Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg 2001; 93: 1393–401.[Abstract/Free Full Text]
2. Davis PJ, Galinkin J, McGowan FX, et al. A randomized multicenter study of remifentanil compared to halothane in neonates and infants undergoing pyloromyotomy. Part I: Emergence and recovery profiles. Anesth Analg 2001; 93: 1380–6.[Abstract/Free Full Text]
3. Galinkin J, Davis PJ, McGowan FX, et al. A randomized multicenter study of remifentanil compared to halothane in neonates and infants undergoing pyloromyotomy. Part II: Perioperative breathing patterns in neonates and infants with pyloric stenosis. Anesth Analg 2001; 93: 1387–92.[Abstract/Free Full Text]
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7. Wolf AR, Lawson RA, Dryden CM, Davies FW. Recovery after desflurane anaesthesia in the infant: comparison with isoflurane. Br J Anaesth 1996; 76: 362–4.[Abstract/Free Full Text]
8. Andropoulos DB, Heard MB, Johnson KL, et al. Postanesthetic apnea in full-term infants after pyloromyotomy. Anesthesiology 1994; 80: 216–9.[Web of Science][Medline]
9. Chipps BE, Moynihan R, Schieble T, et al. Infants undergoing pyloromyotomy are not at risk for postoperative apnea. Pediatr Pulmonol 1999; 27: 278–81.[Web of Science][Medline]
10. Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA 1983; 249: 1743–5.[Abstract/Free Full Text]
11. Winters RW. Metabolic alkalosis of pyloric stenosis. In: Winters RW, ed. The body fluids in pediatrics. New York: Little Brown and Co., 1973.
12. Stein IM, White A, Kennedy JL, et al. Apnea recordings of healthy infants at 40, 44, and 52 weeks post-conception. Pediatrics 1979; 63: 724–30.[Abstract/Free Full Text]
13. Richards JM, Alexander JR, Shinebourne EA, et al. Sequential 22-hour profiles of breathing patterns and heart rate in 110 full-term infants during their first 6 months of life. Pediatrics 1984; 74: 763–77.[Abstract/Free Full Text]
14. Stebbins VA, Poets CF, Alexander JA, et al. Oxygen saturation and breathing patterns in infancy: I. Full term infants in the second month of life. Arch Dis Child 1991; 66: 569–73.[Abstract/Free Full Text]

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