PEDIATRIC ANESTHESIA Section Editor Paul R. Hickey
Alfentanil-Induced Rigidity in Newborn Infants Marja-Leena Pokela, MD, Pauli T. Ryhanen, MD, Maila E. Koivisto, MD, Klaus T. Olkkola, MD, and Anna-Lisa Saukkonen, MD Departments of Pediatrics and Anesthesiology, University of Oulu, Oulu, and Departments of Anesthesiology and Clinical Pharmacology, University of Helsinki, Helsinki, Finland
The authors evaluated whether alfentanil could be given before treatment procedures in critically ill mechanically ventilated neonates without adverse effects. Alfentanil (mean dose 11.7pgkg, range 9-15) was given intravenously to 20 mechanically ventilated critically ill newborn infants (mean birth weight 2510 g, range 1490-3990) during the first 3 days of life before treatment procedures. Heart rate, arterial blood pressure, transcutaneous partial pressure of 0,, respiratory rate, and general activity were observed continuously from 10 min before the administration of alfentanil until 1 h after it. Plasma alfentanil concentrations were measured in 15 subjects. The pharmacokinetics of alfentanil varied greatly among the subjects. The hemodynamic changes were
I
ncreasing interest has recently been shown in the need for analgesia in newborn infants (1-5), even though the methods available for measuring pain in infants are limited. Some authors have, nevertheless, suggested that even preterm newborn infants have all the anatomic and physiologic components required for the perception of pain (6). Newborn infants with respiratory difficulties frequently become predisposed to hypoxemia and hazardous hemodynamic changes, such as a decrease in heart rate and an increase in arterial blood pressure and intracranial pressure, during even the most common treatment procedures, such as tracheal suction or the drawing of blood samples (7-10). Fluctuations in arterial blood pressure and hypoxemia in the preterm infant are associated with periventricular hemorrhagia and leukomalacia. Opiates, such as morphine, meperidine, fentanyl, and alfentanil (11-14), have been used for the sedation of mechanically ventilated neonates. Marlow et al. (15) used alfentanil (20 p g k g ) and muscle relaxThis work was supported by the A h a och K. A. Snellman Foundation and the Foundation for Paediatric Research in Finland. Accepted for publication April 10, 1992. Address correspondence to Dr. Pokela, Department of Pediatrics, University of Oulu, SF-90220 Oulu, Finland. 252
not clinically significant, and the most important side effect was muscle rigidity. Nine infants had mild or moderate rigidity, which had little or no effect on ventilation. Four infants had severe rigidity and jerking comparable to convulsive activity, transiently impairing ventilation and oxygenation for approximately 5-10 min. Increased inspired oxygen and increased pressure by manual ventilation were needed to prevent hypoxemia. Electroencephalographic recordings for three infants during alfentanil administration showed no evidence of increased seizure activity. We conclude that alfentanil should not be used for newborn infants without simultaneous muscle relaxation because of the danger of rigidity. (Anesth Analg 1992;75:252-7)
ants for preterm infants during the first 4 days after birth and noticed a significant decrease in heart rate, arterial blood pressure, and oxygenation. Yet, Killian et al. (16) found that the administration of alfentanil (25 @kg) to newborn infants produced no significant changes in arterial blood pressure or heart rate. There are a number of reports of drug-induced rigidity and even seizures in adults during the induction of anesthesia with the rapidly acting opiates fentanyl, alfentanil, and sufentanil (17-19), but this has not been reported in neonates. The purpose of this investigation was to evaluate whether alfentanil, given before treatment procedures, could be used in critically ill mechanically ventilated neonates to prevent hypoxemia and hazardous hemodynamic effects.
Methods Institutional approval and informed consent from the parents was obtained to study 20 newborn infants. The entry criteria were that the trachea of the infants should be intubated and the lungs mechanically ventilated because of respiratory difficulties. Furthermore, they should be in a hemodynamically stable state with acceptable oxygenation and need analgesia or sedation for necessary treatment procedures. The 01992 by the International Anesthesia Research Society
Anesth Analg 1992;75:252-7
0003-2999/92/$5.00
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCED RIGIDITY IN NEWBORNS
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253
Table 1. Clinical Characteristics of the 20 Mechanically Ventilated Neonates Given Alfentanil Intravenously Alfentanil dose Pt No.
Wt (g)
Age (h)
Rigidity" -
1 2 3 4 5
1760 2650 1690 2330 2630
18 25 38 22 41
11 15 12 15 12
6
1710
16
15
7 8 9 10 11 12 13 14 15 16
3950 3240 2930 2130 1460 2400 3170 2160 2540 1830
11 51 24 6 7 8 28 20 24 26
10 10 10 10 15 11 10 9 10 15
17 18
2670 2300
18 10
10 15
19
3190
38
10
+
Tracheal suction Blood sample Tracheal suction Tracheal suction Chest x-ray, daily routine care Chest x-ray, daily routine care Tracheal suction IV cannulation Tracheal suction Tracheal suction Tracheal suction Tracheal suction Tracheal suction Blood sample Tracheal suction Radial artery cannulation EEG, daily routine care Radial artery cannulation EEG, daily routine care
20
3320
19
11
-
EEG, daily routine care
(%%)
+++ ++ +++ + ++ ++ -
+
-
+++ ++ ++ +++ ++ -
Treatment procedure
Diagnosis RDS RDS RDS RDS RDS RDS PFC RDS Asphyxia RDS RDS RDS Asphyxia RDS RDS RDS RDS RDS Meconium aspiration Asphyxia
Pt, patient; RDS, respiratory distress syndrome; PFC, persistent fetal circulation; EEG, electroencephalography; IV, intravenous.
'-, No rigidity;
+, mild rigidity; + +, moderate rigidity; + + +, severe rigidity.
mean gestational age was 36 wk (range 3040), mean birth weight 2510 g (range 1490-3990), and mean age at the time of the investigation 22.5 h (range 6-51). The clinical diagnosis was respiratory distress syndrome in 15 subjects, meconium aspiration syndrome in 1, persistent fetal circulation in 1, and asphyxia in 3 (Table 1). A bolus dose of alfentanil (9-15 p g k g IV) was administered over a period of 1 min before the treatment procedures, which entailed tracheal suction in 10 subjects, venous or arterial cannulation in 5, chest radiograph and daily routine care procedures, such as washing and weighing, in 2 and routine care procedures in 3. No other drugs were used. Heart rate, respiratory rate, transcutaneous partial pressure of O2 (TcPo,), arterial blood pressure, and general activity were monitored continuously from 10 min before to 1 h after administration of alfentanil and were recorded before and at 2, 3, 5, 10, 30, and 60 min after administration. All observations were performed by the same investigator. Because rigidity and even convulsive activity were observed in some patients immediately after alfentanil administration, electroencephalographic (EEG) recordings were made in three infants 30 min before, during, and
30 min after the injection of alfentanil. One patient was given both alfentanil (10 pgkg) and saline solution (placebo) in a blinded manner. Rigidity was graded in terms of passive resistance to movement of the limbs relative to the pretreatment level of resistance based on subjective impression according to the following four categories: no rigidity, muscle tonus unchanged or decreased; mild rigidity, slightly increased muscle resistance relative to pretreatment level; moderate rigidity, moderately increased muscle resistance relative to pretreatment level, with partly limited passive movements; and severe rigidity, greatly increased muscle resistance with totally restricted limb movements and involved convulsive activity such as jerking. Arterial blood (1.5 mL) was sampled for the determination of alfentanil 0 (control), 2, 5, 10, 20, 60, 120, 240, and 360 min after injection in 15 cases. A maximum of five samples were drawn from any one patient. The samples were centrifuged and stored deep frozen until analyzed. Plasma concentrations of alfentanil were analyzed by capillary gas chromatography (20); the detection limit of the assay was 2 ng/mL. Arterial blood gas analysis was performed before and 1 h after alfentanil administration. The terminal log-linear phase of the plasma con-
254
ANESTH ANALG 1992;7'5252-7
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCED RIGIDITY IN NEWBORNS
kPa
2.0
i
,
60min
3o
Figure 1. Physiologic responses to 9-15 &kg of alfentanil in patients without (solid lines, n = 116)and with (dashed lines, n = 4) severe rigidity. Results expressed as means k SD. TcPo,, transcutaneous partial pressure of 0,.
1
r" 10
23 5
-
10 30
60min
Time
centration-time curve for each subject was identified visually. The elimination rate constant (ke,) was determined by regression analysis of the log-linear part of the curve. The elimination half-life (TI,,) was calculated from TI,, = In a,,. The areas under the alfentanil concentration-time curves (AUC,,) were calculated using the linear trapezoidal rule when successive concentration values increased and the logarithmic trapezoidal rule when successive concentration values decreased after the peak concentration value. The area under the alfentanil concentrationtime curve was extrapolated to infinity with the respective elimination rate constant value. Plasma clearance and steady-state volume of distribution of alfentanil were calculated using noncompartmental methods based on the statistical moment theory (21). The hemodynamic effects of the alfentanil injection and acid-base status were analyzed using repeated measures analysis of variance over time, the nonparametric Wilcoxon rank-sum test, and the paired t-test with the SAS (Statistical Analyses System, Inc., Cary, N.C.). The pharmacokinetic parameters were compared with the Mann-Whitney U test. A P value 4 . 0 5 was considered statistically significant. The results are presented as means t SD.
Results There were no problems after alfentanil injection in 7 of 20 patients, slightly increased muscle tonus in 3 of 20, and a moderate increase in muscle resistance in 6 of 20 for whom ventilation was slightly aggravated but manual ventilation was not needed. The muscle resistance of 4 of 20 patients increased markedly; the range of passive movements was substantially limited; and myoclonic jerking suggestive of seizure activity was observed. When TcPo, decreased, manual ventilation was begun with an increased inspired 0, concentration and increased pressure. The respiratory settings were not changed. Rigidity appeared immediately after alfentanil injection and before the beginning of the treatment procedure and disappeared within a few minutes. It had passed completely within 10 min (Figure 1).There was no correlation among the appearance of rigidity and gestational age, birth weight, and alfentanil dose or its maximal concentration (Table 1). Three of the patients who were given alfentanil twice showed similar rigidity on both occasions. An EEG was recorded in three patients, of whom two showed rigidity, including one who also had jerking and smacking
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCEDRIGIDITY IN NEWBORNS
ANESTH ANALG 1992;75:252-7
Rigidity
No rigidity
=
=
400
400
E
E \ w
\
-.-s
0)
c
c c
.-c0
300
c
2
c
c
g
255
5
200
0
0
0
0 V
200
c
c
V
100 m
c
c
=Q Q)
100
0
200
300
: o 0
400
Time ( m i d
100
200
300
400
Time (min)
Figure 2. Alfentanil concentration after a single dose (9-15 @kg IV) in patients without rigidity and with rigidity.
immediately after the administration of alfentanil but not after a saline solution (placebo). No seizure activity was observed in the EEG during drug administration, but a progressive slowing in frequency (delta waves) and an increase in amplitude were seen. This periodic activity typical of opioid-induced sleep was observed in all three patients. No major hemodynamic changes were seen. Mean arterial pressure and heart rate did not substantially change, and the only statistically significant difference was found in mean heart rate between the recordings made before and 60 min after medication (139 2 14 vs 133 11beatdmin; P = 0.012). Acid-base status did not differ between the arterial blood samples taken before alfentanil administration and 1 h afterward (P = 0.100) despite a transient decrease in TcPo, in the patients with severe muscle rigidity (Figure 1).There was a statistically significant difference in the amount of inspired 0, 5 min after the alfentanil injection in patients with severe rigidity (P = 0.008) compared with those not showing severe rigidity. The changes in the other variables were statistically insignificant (Figure 1). Plasma alfentanil concentration profiles were determined for 15 patients; those for patients with and without muscle rigidity are depicted separately in Figure 2 and the respective pharmacokinetic parameters in Table 2. The highest alfentanil concentration was observed in a patient with muscle rigidity, but the pharmacokinetic parameters did not differ between the groups.
*
Table 2. Pharmaeokinetie Variables of Alfentanil (9-15 &kg) After Intravenous Administration in Newborn Infants No rigidity (n = 5)
(min) CL (mL.kg-l.min-') v,, ( L W T,,2
43 (34-237) 2.1 (1.7-7.2) 0.27 (0.08-0.62)
Rigidity (n = 10) 153 (31-650) 2.9 (0.9-25.3) 0.66 (0.15-2.94)
elimination half-life; CL, plasma clearance; V,,, volume of distribution at steady state. Variables are given as median (range).
Discussion Opiates can cause unexpected side effectsin newborn infants because of immature hepatic and renal function and variable permeability of the blood-brain barrier. Data on the effects of various opiates on infants are still incomplete. The pharmacokinetics of alfentanil have shown great individual variability in newborn infants (14,1622). Our values for the pharmacokinetic variables differed slightly from those reported previously (14,16,22), partly because the small number of blood samples may have meant that the elimination phase was not described appropriately. This probably caused the values for elimination half-life to be lower and those for plasma clearance higher than the "true" ones. No hemodynamic side effects such as decreases in arterial blood pressure or heart rate were seen in the infants. We used small doses (9-15 pgkg) compared with Davis et al. (22) and Killian et al. (16), who gave
256
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCED RIGIDITY IN NEWBORNS
25 p e g of alfentanil to preterm and term infants to provide sedation during mechanical ventilation in the first 3 days without any significant hemodynamic changes. On the other hand, Marlow et al. (15) report a decrease in both heart rate and arterial blood pressure within 2 min after doses of 20 @kg of alfentanil given to premature infants (mean gestational age 30 wk). The gestational ages in the present series were higher (mean 36 wk). The patients were hemodynamically stable before the administration of alfentanil, and no other drugs were used. All of these factors might explain the difference. Rigidity, the most significant adverse effect recorded here, appeared immediately after alfentanil injection and was intense, even convulsive, in 4 of the 20 infants. There are several reports of seizures and drug-induced rigidity in adults during the induction of anesthesia with fentanyl, sufentanil, and alfentanil (17-19), but no seizure activity has ever been reported in an EEG during these episodes. The movements often resembled seizures, involving stiffness of the limbs and trunk with explosive onset of myoclonic limb movements. Narcotic rigidity is usually thought to be dose related and to be noticeable only at large doses, but our results show that it can appear in neonates even after small doses. The pharmacokinetic parameters did not differ among our patients with and without muscle rigidity, and the EEG showed no seizure activity during alfentanil injection in any of the three cases in which recordings were made. The rigidity disappeared in a few minutes, but an increased inspired 0,concentration and increased pressure by manual ventilation were needed to treat hypoxemia in the severe rigidity cases. Thus, the chest rigidity could predispose infants with hyaline membrane disease in particular to lung damage and pulmonary air leaks. We are unaware of any previous research carried out on this age group involving muscle rigidity. Newborn infants with respiratory difficulties react to the most minor treatment procedures or maneuvers, even when painless, and most neonatal intensive care units will use some type of sedation, analgesia, and muscle relaxation during mechanical ventilation for stabilization. The use of neuromuscular blockers in neonates requiring mechanical ventilation is controversial, as noted by Costarino and Polin (23). Rigidity can undoubtedly be prevented by muscle relaxants, but although sedation with meperidine or morphine is used routinely at our hospital, relaxants are not, partly because they eliminate the clinical, neurologic, and externally observable reactions of the infants. Alfentanil is a promising fast-acting drug for possible use in distressed, mechanically ventilated neonates during treatment procedures. The appearance
ANESTH A.NALG 1992;7!?252-7
of rigidity with the frequency described here after the use of such small doses of the drug nevertheless argues against its administration to newborn infants without simultaneous muscle relaxation. We have used alfentanil with suxamethonium and glycopyrrolate in connection with elective neonatal intubations without any serious adverse side effects. The experience of pain or other stress associated with routine care can cause unwanted hemodynamic effects and hypoxemia in ill neonates; however, opiates can also cause adverse effects, one example of which is the rigidity described here. The appropriate dose required to reduce the stress experienced by mechanically ventilated infants during the various procedures necessary for their care and treatment has yet to be defined. We thank the analytical department of Orion Pharmaceuticals for the measurements of plasma alfentanil concentration.
References 1. Yaster M. Analgesia and anaesthesia in neonates (editorial). J Pediatr 1987;111:394-5. 2. Editorial. Pain, anaesthesia, and babies. Lancet 1987;1:!%3-4. 3. Booker I'D. Postoperative analgesia for neonates. Anaesthesia 1987;42:34%5. 4. Fletcher AB. Pain in the neonate. N Engl J Med 1987;317 1347-8. 5. Fitzgerald M, McIntosch N. Pain and analgesia in the newborn. Arch Dis Child 1989;62:4413. 6. Anand KJS, Phil D, Hickey PR. Pain and its effects in human neonate and fetus. N Engl J Med 1987;3171321-9. 7. Perlman JM, Volpe JJ. Suctioning in the preterm infant: Effects on cerebral blood flow velocity, intracranial pressure, and arterial blood pressure. Pediatrics 1983;72:32%. 8. Danfors DA, Mske S, Headley J, Nelson RM. Effects of routine care procedures on transcutaneous oxygen in neonates: a quantitative approach. Arch Dis Child 1983;58:204. 9. Marshall TA, Deeder R, Pai S, Berkowitz G. Physiologic changes associated with endotracheal intubation in preterm infants. Crit Care Med 1984;12:501-3. 10. Friesen RH, Honda AT, Thieme RE. Changes in anterior fontanel pressure in preterm neonates during tracheal mtubation. Anesth Analg 1987;66:874-8. 11. Bhat R, Chari G, Gulati A, Aldana 0, Velamati R, Bhargava H. Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life. J Pediatr 1990;117477-81. 12. Mall-Allen VM, Whitelaw AGL. Effect of pancuronium and pethidine on heart rate and blood pressure in ventilated infants. Arch Dis Child 1987;62:1179-80. 13. Bell S, EUis L. Use of fentanyl for sedation of mechanically ventilated neonates. Neonatal Network 1987 Oct:2730. 14. Marlow N, Weindling AM,Van Peer A, Heykants J. Alfentanil pharmacokinetics in preterm infants. Arch Dis Child 1990;65: 349-51. 15. Marlow N, Weindling AM, Cooke RWI. Hazards of anaigesia for newborn infants. Arch Dis Child 1988;63:1293. 16. Killian A, Davis PJ, Stiller RL, Cicco R, Cook DR, Guthrie RD. Influence of gestational age on pharmacokinetics of alfentanil in neonates. Dev Pharmacol Ther 1990;15:82-5. 17. Murkin JM, Moldenhauer CG, Hug CC, Epstein CM. Absence of seizures during induction of anesthesia with high-dose fentanyl. Anesth Analg 1984;63:489-94.
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18. Smith NT, Benthuysen JL, Bickford RG, et al. Seizures during opioid anesthetic induction-are they opioid-induced rigidity? Anesthesiology 1989;71:85242. 19. Benthuysen JL, Smith NT, Sandford TJ, Head N, Dec-Silver H. Physiology of alfentanil-induced rigidity. Anesthesiology 1986; 64:440-6. 20. Hynynen M, Takkunen 0, SaImenpera M, Haataja H, Heinonen J. Continuous infusion of fentanyl and alfentad for coronary artery surgery. Plasma opiate concentrations, haemo-
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCED RIGIDITY IN NEWBORNS
257
dynamics and postoperative course. Br J Anaesth 1986;58: 1252-9. 21. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York Marcel Dekker, 1982. 22. Davis PJ, W a n A, Stiller RL, Cook DR, Guthrie RD, Sderka AM. Pharmacokinetics of alfentanil in newborn premature infants and older children. Dev Pharmacol Ther 1989;13:21-7. 23. Costarino AT, Polin RA. Neuromuscular relaxants in the neonate. Clin Perinatol 1987;14:965-89.
Alfentanil-Induced Rigidity in Newborn Infants Marja-Leena Pokela, MD, Pauli T. Ryhanen, MD, Maila E. Koivisto, MD, Klaus T. Olkkola, MD, and Anna-Lisa Saukkonen, MD Departments of Pediatrics and Anesthesiology, University of Oulu, Oulu, and Departments of Anesthesiology and Clinical Pharmacology, University of Helsinki, Helsinki, Finland
The authors evaluated whether alfentanil could be given before treatment procedures in critically ill mechanically ventilated neonates without adverse effects. Alfentanil (mean dose 11.7pgkg, range 9-15) was given intravenously to 20 mechanically ventilated critically ill newborn infants (mean birth weight 2510 g, range 1490-3990) during the first 3 days of life before treatment procedures. Heart rate, arterial blood pressure, transcutaneous partial pressure of 0,, respiratory rate, and general activity were observed continuously from 10 min before the administration of alfentanil until 1 h after it. Plasma alfentanil concentrations were measured in 15 subjects. The pharmacokinetics of alfentanil varied greatly among the subjects. The hemodynamic changes were
I
ncreasing interest has recently been shown in the need for analgesia in newborn infants (1-5), even though the methods available for measuring pain in infants are limited. Some authors have, nevertheless, suggested that even preterm newborn infants have all the anatomic and physiologic components required for the perception of pain (6). Newborn infants with respiratory difficulties frequently become predisposed to hypoxemia and hazardous hemodynamic changes, such as a decrease in heart rate and an increase in arterial blood pressure and intracranial pressure, during even the most common treatment procedures, such as tracheal suction or the drawing of blood samples (7-10). Fluctuations in arterial blood pressure and hypoxemia in the preterm infant are associated with periventricular hemorrhagia and leukomalacia. Opiates, such as morphine, meperidine, fentanyl, and alfentanil (11-14), have been used for the sedation of mechanically ventilated neonates. Marlow et al. (15) used alfentanil (20 p g k g ) and muscle relaxThis work was supported by the A h a och K. A. Snellman Foundation and the Foundation for Paediatric Research in Finland. Accepted for publication April 10, 1992. Address correspondence to Dr. Pokela, Department of Pediatrics, University of Oulu, SF-90220 Oulu, Finland. 252
not clinically significant, and the most important side effect was muscle rigidity. Nine infants had mild or moderate rigidity, which had little or no effect on ventilation. Four infants had severe rigidity and jerking comparable to convulsive activity, transiently impairing ventilation and oxygenation for approximately 5-10 min. Increased inspired oxygen and increased pressure by manual ventilation were needed to prevent hypoxemia. Electroencephalographic recordings for three infants during alfentanil administration showed no evidence of increased seizure activity. We conclude that alfentanil should not be used for newborn infants without simultaneous muscle relaxation because of the danger of rigidity. (Anesth Analg 1992;75:252-7)
ants for preterm infants during the first 4 days after birth and noticed a significant decrease in heart rate, arterial blood pressure, and oxygenation. Yet, Killian et al. (16) found that the administration of alfentanil (25 @kg) to newborn infants produced no significant changes in arterial blood pressure or heart rate. There are a number of reports of drug-induced rigidity and even seizures in adults during the induction of anesthesia with the rapidly acting opiates fentanyl, alfentanil, and sufentanil (17-19), but this has not been reported in neonates. The purpose of this investigation was to evaluate whether alfentanil, given before treatment procedures, could be used in critically ill mechanically ventilated neonates to prevent hypoxemia and hazardous hemodynamic effects.
Methods Institutional approval and informed consent from the parents was obtained to study 20 newborn infants. The entry criteria were that the trachea of the infants should be intubated and the lungs mechanically ventilated because of respiratory difficulties. Furthermore, they should be in a hemodynamically stable state with acceptable oxygenation and need analgesia or sedation for necessary treatment procedures. The 01992 by the International Anesthesia Research Society
Anesth Analg 1992;75:252-7
0003-2999/92/$5.00
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCED RIGIDITY IN NEWBORNS
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253
Table 1. Clinical Characteristics of the 20 Mechanically Ventilated Neonates Given Alfentanil Intravenously Alfentanil dose Pt No.
Wt (g)
Age (h)
Rigidity" -
1 2 3 4 5
1760 2650 1690 2330 2630
18 25 38 22 41
11 15 12 15 12
6
1710
16
15
7 8 9 10 11 12 13 14 15 16
3950 3240 2930 2130 1460 2400 3170 2160 2540 1830
11 51 24 6 7 8 28 20 24 26
10 10 10 10 15 11 10 9 10 15
17 18
2670 2300
18 10
10 15
19
3190
38
10
+
Tracheal suction Blood sample Tracheal suction Tracheal suction Chest x-ray, daily routine care Chest x-ray, daily routine care Tracheal suction IV cannulation Tracheal suction Tracheal suction Tracheal suction Tracheal suction Tracheal suction Blood sample Tracheal suction Radial artery cannulation EEG, daily routine care Radial artery cannulation EEG, daily routine care
20
3320
19
11
-
EEG, daily routine care
(%%)
+++ ++ +++ + ++ ++ -
+
-
+++ ++ ++ +++ ++ -
Treatment procedure
Diagnosis RDS RDS RDS RDS RDS RDS PFC RDS Asphyxia RDS RDS RDS Asphyxia RDS RDS RDS RDS RDS Meconium aspiration Asphyxia
Pt, patient; RDS, respiratory distress syndrome; PFC, persistent fetal circulation; EEG, electroencephalography; IV, intravenous.
'-, No rigidity;
+, mild rigidity; + +, moderate rigidity; + + +, severe rigidity.
mean gestational age was 36 wk (range 3040), mean birth weight 2510 g (range 1490-3990), and mean age at the time of the investigation 22.5 h (range 6-51). The clinical diagnosis was respiratory distress syndrome in 15 subjects, meconium aspiration syndrome in 1, persistent fetal circulation in 1, and asphyxia in 3 (Table 1). A bolus dose of alfentanil (9-15 p g k g IV) was administered over a period of 1 min before the treatment procedures, which entailed tracheal suction in 10 subjects, venous or arterial cannulation in 5, chest radiograph and daily routine care procedures, such as washing and weighing, in 2 and routine care procedures in 3. No other drugs were used. Heart rate, respiratory rate, transcutaneous partial pressure of O2 (TcPo,), arterial blood pressure, and general activity were monitored continuously from 10 min before to 1 h after administration of alfentanil and were recorded before and at 2, 3, 5, 10, 30, and 60 min after administration. All observations were performed by the same investigator. Because rigidity and even convulsive activity were observed in some patients immediately after alfentanil administration, electroencephalographic (EEG) recordings were made in three infants 30 min before, during, and
30 min after the injection of alfentanil. One patient was given both alfentanil (10 pgkg) and saline solution (placebo) in a blinded manner. Rigidity was graded in terms of passive resistance to movement of the limbs relative to the pretreatment level of resistance based on subjective impression according to the following four categories: no rigidity, muscle tonus unchanged or decreased; mild rigidity, slightly increased muscle resistance relative to pretreatment level; moderate rigidity, moderately increased muscle resistance relative to pretreatment level, with partly limited passive movements; and severe rigidity, greatly increased muscle resistance with totally restricted limb movements and involved convulsive activity such as jerking. Arterial blood (1.5 mL) was sampled for the determination of alfentanil 0 (control), 2, 5, 10, 20, 60, 120, 240, and 360 min after injection in 15 cases. A maximum of five samples were drawn from any one patient. The samples were centrifuged and stored deep frozen until analyzed. Plasma concentrations of alfentanil were analyzed by capillary gas chromatography (20); the detection limit of the assay was 2 ng/mL. Arterial blood gas analysis was performed before and 1 h after alfentanil administration. The terminal log-linear phase of the plasma con-
254
ANESTH ANALG 1992;7'5252-7
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCED RIGIDITY IN NEWBORNS
kPa
2.0
i
,
60min
3o
Figure 1. Physiologic responses to 9-15 &kg of alfentanil in patients without (solid lines, n = 116)and with (dashed lines, n = 4) severe rigidity. Results expressed as means k SD. TcPo,, transcutaneous partial pressure of 0,.
1
r" 10
23 5
-
10 30
60min
Time
centration-time curve for each subject was identified visually. The elimination rate constant (ke,) was determined by regression analysis of the log-linear part of the curve. The elimination half-life (TI,,) was calculated from TI,, = In a,,. The areas under the alfentanil concentration-time curves (AUC,,) were calculated using the linear trapezoidal rule when successive concentration values increased and the logarithmic trapezoidal rule when successive concentration values decreased after the peak concentration value. The area under the alfentanil concentrationtime curve was extrapolated to infinity with the respective elimination rate constant value. Plasma clearance and steady-state volume of distribution of alfentanil were calculated using noncompartmental methods based on the statistical moment theory (21). The hemodynamic effects of the alfentanil injection and acid-base status were analyzed using repeated measures analysis of variance over time, the nonparametric Wilcoxon rank-sum test, and the paired t-test with the SAS (Statistical Analyses System, Inc., Cary, N.C.). The pharmacokinetic parameters were compared with the Mann-Whitney U test. A P value 4 . 0 5 was considered statistically significant. The results are presented as means t SD.
Results There were no problems after alfentanil injection in 7 of 20 patients, slightly increased muscle tonus in 3 of 20, and a moderate increase in muscle resistance in 6 of 20 for whom ventilation was slightly aggravated but manual ventilation was not needed. The muscle resistance of 4 of 20 patients increased markedly; the range of passive movements was substantially limited; and myoclonic jerking suggestive of seizure activity was observed. When TcPo, decreased, manual ventilation was begun with an increased inspired 0, concentration and increased pressure. The respiratory settings were not changed. Rigidity appeared immediately after alfentanil injection and before the beginning of the treatment procedure and disappeared within a few minutes. It had passed completely within 10 min (Figure 1).There was no correlation among the appearance of rigidity and gestational age, birth weight, and alfentanil dose or its maximal concentration (Table 1). Three of the patients who were given alfentanil twice showed similar rigidity on both occasions. An EEG was recorded in three patients, of whom two showed rigidity, including one who also had jerking and smacking
PEDIATRIC ANESTHESIA POKELA ET AL. ALFENTANIL-INDUCEDRIGIDITY IN NEWBORNS
ANESTH ANALG 1992;75:252-7
Rigidity
No rigidity
=
=
400
400
E
E \ w
\
-.-s
0)
c
c c
.-c0
300
c
2
c
c
g
255
5
200
0
0
0
0 V
200
c
c
V
100 m
c
c
=Q Q)
100
0
200
300
: o 0
400
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Figure 2. Alfentanil concentration after a single dose (9-15 @kg IV) in patients without rigidity and with rigidity.
immediately after the administration of alfentanil but not after a saline solution (placebo). No seizure activity was observed in the EEG during drug administration, but a progressive slowing in frequency (delta waves) and an increase in amplitude were seen. This periodic activity typical of opioid-induced sleep was observed in all three patients. No major hemodynamic changes were seen. Mean arterial pressure and heart rate did not substantially change, and the only statistically significant difference was found in mean heart rate between the recordings made before and 60 min after medication (139 2 14 vs 133 11beatdmin; P = 0.012). Acid-base status did not differ between the arterial blood samples taken before alfentanil administration and 1 h afterward (P = 0.100) despite a transient decrease in TcPo, in the patients with severe muscle rigidity (Figure 1).There was a statistically significant difference in the amount of inspired 0, 5 min after the alfentanil injection in patients with severe rigidity (P = 0.008) compared with those not showing severe rigidity. The changes in the other variables were statistically insignificant (Figure 1). Plasma alfentanil concentration profiles were determined for 15 patients; those for patients with and without muscle rigidity are depicted separately in Figure 2 and the respective pharmacokinetic parameters in Table 2. The highest alfentanil concentration was observed in a patient with muscle rigidity, but the pharmacokinetic parameters did not differ between the groups.
*
Table 2. Pharmaeokinetie Variables of Alfentanil (9-15 &kg) After Intravenous Administration in Newborn Infants No rigidity (n = 5)
(min) CL (mL.kg-l.min-') v,, ( L W T,,2
43 (34-237) 2.1 (1.7-7.2) 0.27 (0.08-0.62)
Rigidity (n = 10) 153 (31-650) 2.9 (0.9-25.3) 0.66 (0.15-2.94)
elimination half-life; CL, plasma clearance; V,,, volume of distribution at steady state. Variables are given as median (range).
Discussion Opiates can cause unexpected side effectsin newborn infants because of immature hepatic and renal function and variable permeability of the blood-brain barrier. Data on the effects of various opiates on infants are still incomplete. The pharmacokinetics of alfentanil have shown great individual variability in newborn infants (14,1622). Our values for the pharmacokinetic variables differed slightly from those reported previously (14,16,22), partly because the small number of blood samples may have meant that the elimination phase was not described appropriately. This probably caused the values for elimination half-life to be lower and those for plasma clearance higher than the "true" ones. No hemodynamic side effects such as decreases in arterial blood pressure or heart rate were seen in the infants. We used small doses (9-15 pgkg) compared with Davis et al. (22) and Killian et al. (16), who gave
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25 p e g of alfentanil to preterm and term infants to provide sedation during mechanical ventilation in the first 3 days without any significant hemodynamic changes. On the other hand, Marlow et al. (15) report a decrease in both heart rate and arterial blood pressure within 2 min after doses of 20 @kg of alfentanil given to premature infants (mean gestational age 30 wk). The gestational ages in the present series were higher (mean 36 wk). The patients were hemodynamically stable before the administration of alfentanil, and no other drugs were used. All of these factors might explain the difference. Rigidity, the most significant adverse effect recorded here, appeared immediately after alfentanil injection and was intense, even convulsive, in 4 of the 20 infants. There are several reports of seizures and drug-induced rigidity in adults during the induction of anesthesia with fentanyl, sufentanil, and alfentanil (17-19), but no seizure activity has ever been reported in an EEG during these episodes. The movements often resembled seizures, involving stiffness of the limbs and trunk with explosive onset of myoclonic limb movements. Narcotic rigidity is usually thought to be dose related and to be noticeable only at large doses, but our results show that it can appear in neonates even after small doses. The pharmacokinetic parameters did not differ among our patients with and without muscle rigidity, and the EEG showed no seizure activity during alfentanil injection in any of the three cases in which recordings were made. The rigidity disappeared in a few minutes, but an increased inspired 0,concentration and increased pressure by manual ventilation were needed to treat hypoxemia in the severe rigidity cases. Thus, the chest rigidity could predispose infants with hyaline membrane disease in particular to lung damage and pulmonary air leaks. We are unaware of any previous research carried out on this age group involving muscle rigidity. Newborn infants with respiratory difficulties react to the most minor treatment procedures or maneuvers, even when painless, and most neonatal intensive care units will use some type of sedation, analgesia, and muscle relaxation during mechanical ventilation for stabilization. The use of neuromuscular blockers in neonates requiring mechanical ventilation is controversial, as noted by Costarino and Polin (23). Rigidity can undoubtedly be prevented by muscle relaxants, but although sedation with meperidine or morphine is used routinely at our hospital, relaxants are not, partly because they eliminate the clinical, neurologic, and externally observable reactions of the infants. Alfentanil is a promising fast-acting drug for possible use in distressed, mechanically ventilated neonates during treatment procedures. The appearance
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of rigidity with the frequency described here after the use of such small doses of the drug nevertheless argues against its administration to newborn infants without simultaneous muscle relaxation. We have used alfentanil with suxamethonium and glycopyrrolate in connection with elective neonatal intubations without any serious adverse side effects. The experience of pain or other stress associated with routine care can cause unwanted hemodynamic effects and hypoxemia in ill neonates; however, opiates can also cause adverse effects, one example of which is the rigidity described here. The appropriate dose required to reduce the stress experienced by mechanically ventilated infants during the various procedures necessary for their care and treatment has yet to be defined. We thank the analytical department of Orion Pharmaceuticals for the measurements of plasma alfentanil concentration.
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