1611061
©1991 S. Karger AG, Basel 0379-8305/91 /0174-0121 $2.75/0
Dev Pharmacol Ther 1991;17:121-127
Analgesia and Sedation in Neonatal Intensive Care Using Fentanyl by Continuous Infusion1,2 B. Rotha, C. Schlündera,
/•'.
Houhena, M. Günthera, M. Theisohnb
a Children’s Hospital and b Institute of Pharmacology, University of Cologne, FRG
Key Words. Neonatal intensive care unit • Preterm infants • Artificial respiration • Analgesia ■ Sedation • Fentanyl Abstract. To determine the effects of fentanyl in newborn and premature infants, we compared two groups of 20 newborn and premature babies under artificial ventilation for severe respiratory distress syndrome: a prospective group receiving fentanyl for analgesic and sedation and a historical control group, who did not receive fentanyl. Fentanyl serum levels during steady state were determined by radioimmunoassay. Average time of infusion was 86 ± 47 h with a mean dosage of 0.68 ± 0.24 pg/kg/h. The fentanyl group needed much less sedatives and catecholamines. Heart rate and blood pressure were not significantly changed by fentanyl. Meconium was excreted later, and higher values of bilirubin were reached earlier than in the control group. Although fentanyl proved to be helpful in the neonatal intensive care unit, the administration should remain under strict indication.
There is no doubt that even the smallest premature neonates have a sufficiently de veloped nociceptive system, therefore for all pain and stressful procedures, good analgesia must be guaranteed [1-8]. Specific diseases
1 Supported by Deutsche Forschungsgemeinschaft, grant Ro 799/1-1. 2 Presented at the Second European Neonatal Workshop, Klingenthal, France, June 15, 1991.
such as severe respiratory distress syndrome (RDS) under artificial ventilation require some degree of sedation to avoid disturbing respiratory attempts and adverse reactions to stressful measures. In the postoperative period, morphine has been used successfully [9-11]. Fentanyl has theoretical advantages relative to morphine: short duration of ac tion, easy to titrate and possibly less effects on the central nervous system, [12-14], This study was performed to observe the in fluence on tolerance to mechanical ventila tion in case of severe RDS in the neonatal Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
Introduction
122
Roth/Schlünder/Houben/Günther/Theisohn
Table 1. Distribution of patients of the fentanyl and control group in relation to weight, gestational age and diagnoses
Patients (m/f) Body weight, g Gestational age Cesarean section HMD- or adult RDS-like Vitium cordis Cerebral disorders
Fentanyl group
Control group
13/7 1,712 ± 765 (860-3,500) 32.5 ±3.6 (26-40) 14
9/11 1,823 ± 686 (850-2900) 32.3 ± 3.15 (26-37)
11
15 5
5 7
12
HMD = Hyaline membrane disease. Range values are in parentheses.
Table 2. Differences of fentanyl pharmacokinetics between infants with a gestational age of < 34 weeks and > 34 weeks Gestational age
Mean dosage, pg/kg/h Mean fentanyl serum levels, ng/ml Mean duration of infusion, h Total clearance, ml/kg/h
< 34 weeks
> 34 weeks
0.64±0.19 (0.25-1.05) 1.67 ±0.89 (0.18-4.1) 93 ± 55 (53-245) 727 ± 921 (122-4,291)
0.75±0.30 (0.25-1.50) 2.13 ± 1.57 (0.1-5.92) 75±24 (36-116) 782 ± 1,185 (192-5,102)
The differences are statistically not significant. Range values are in parentheses.
Patients and Methods Twenty newborn and premature babies, born in 1989 and 1990, 12 with a gestational age of less than 34 weeks (7 male, 5 female) and 8 with a gestational age of 34 weeks or more (6 male, 2 female), mean birth weight of 1,710 g (860-3,500 g), under artificial ventilation because of severe RDS of different origin receiving fentanyl, were compared to a historical con trol group of 20 newborn and premature infants, born
in 1988, who did not receive fentanyl. The patients of the historical control group were selected to combine in gestational age. body weight, diagnoses, additional drugs, duration of artificial ventilation, and respira tory parameter settings (table 1 ). The study was approved by the Ethics Committee of the medical Faculty of the University of Cologne and parental consent was obtained. The indication for fentanyl administration was the necessity of artifi cial ventilation because of severe respiratory prob lems with fractional inspired oxygen >0.7, peak in spiratory pressure > 25 cm HjO, and mean airway pressure > 12 cm HiO. After a loading dose of 5.012.5 pg/kg, administered over at least 10 min, fentanyl was given by continuous infusion of 0.5-2 pg/kg/h. Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
intensive care and to determine the pharma cological properties of fentanyl in the neona tal period.
123
Fentanyl in the Neonate
Fig. 1. Correlation between fentanyl dosage and serum levels: serum lev els observed correlate well with fentanyl dosage (r = 0.981).
and reaction to tracheal aspiration [15], It was judged to be satisfactory if the child was quiet, but reacting when stimulated, and tolerated endotracheal aspira tion well.
Results
Under fentanyl, artificial ventilation was tolerated well and we never observed rigidity of the thorax. Evaluation by the sedation scale showed satisfactory values for all pa tients. We did not observe any signs of opioid withdrawal. For infants with a gestational age of < 34 weeks, a mean dosage of 0.64 pg/kg/h was sufficient to produce appropriate sedation, whereas infants > 34 weeks needed 0.75 pg/ kg/h (table 2). In the fentanyl group, mean fentanyl serum levels of 1.85 ng/ml were measured at a mean dosage of 0.69 pg/kg/h. The correlation between fentanyl dosage and serum levels is demonstrated in fig ure 1. The need of additional analgesics, sedatives, muscular relaxants and catechol amines was much lower than in the control Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
In the beginning, a dose of 0.5 gg/kg/h was given and was increased incrementally by 0.5 gg/kg/h when clin ically necessary. Infusion was stopped when the in spired fraction of oxygen reached > cO
TD
Fentanyl group n = 20 Control group n = 20
4^
O) CD
E 3co U) CO
v>o 2o 1-
M
0 Diazepam
Pentobarb.
M
*7771
Phenobarb.
Vecuronium
Dopamine Dobutamine
Fig. 2. Differences in the ne cessities of additional drugs be tween mechanically ventilated newborn and preterm infants treated with fentanyl (fentanyl group) and without (control group). The need of additional analgesics and especially of cate cholamines in the fentanyl group was much lower than in the con trol group.
Fig. 3. Relation between fen tanyl dosage, serum levels and clearance in a male newborn, 38 weeks’ gestational age and birth weight 3,500 g.
premature infant are demonstrated in fig ures 3 and 4. Heart rate did not show any difference between both groups, but systolic and dia stolic blood pressure in the fentanyl group was slightly, statistically not significantly, higher. In the fentanyl group, mean systolic pressure was 55 ± 8 mm Hg and mean dia stolic pressure was 34 ± 6 versus 53 ± 6 mm Hg in the control group (fig. 5). Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
group (fig. 2). Mean serum levels for the group 34 weeks with 2.13 ng/ml, but for the first mean duration of infusion was 93 h against 75 h for the sec ond. Total clearance for the infants of 34 weeks (ta ble 2). Examples of fentanyl dosage, serum levels and clearance in a newborn and in a
Fentanyl in the Neonate
125
Fig. 4. Relation between fentanyl dosage, serum levels and clearance in a male newborn, 32 week’s gestational age and birth weight 1,000 g. 70 n
□ Fentanyl group 0 Control group
60-
40-
/ Z
zZ
O)
Z
^ 30E
20-
/ Z / / / / / /
10-
0
/ /Z Z /
/ /
/
it/
//
Fig. 5. Differences of mean values of blood pressure be tween mechanically ventilated newborn and preterm infants treated with fentanyl (fentanyl group) and without (control group). The differences were statistically not significant. SBP = Systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial blood pressure.
k
Z Z
I Z / / / / / /
/ / /
i/ZZ / //
a
Iit / /
/
/ /
/ /
/// /
ft
/
/
/ / /
z
/z z zZ
/
/
z
zZ
Z
z
Z
/ Z
/
z / Z
Z
z
Jd
/
z / /
/
z Z
I
/ /
ft
Z Z Z
z
/ /
z/
/ /
/
z
/z z
z
z
/
Z Z Z
SBP DBP MAP
SBP DBP MAP
^. SBP DBP MAP
Total
Day 1
Day 2
The peak arithmetic mean of total plasma bilirubin was 12.1 ± 4.3 mg/dl in the fenta nyl group, and was higher than the control group (9.7 ± 4.4 mg/dl). Maximum values were reached in average on day 4.2 ± 1.3 of life in the fentanyl group, and only on day 5.0 ± 1.8 in the control group. Meconium was eliminated after 3.6 ± 1.9 days in the fentanyl group, while in the control group elimination occurred after 2.0 ± 1.5 days.
✓
I
Z Z / / / / / /
/ / / / /
/Z Z / Jd
z z / Z
/
/
Z Z
Z
d
SBP DBP MAP
Day 3
Discussion
To avoid hormonal and metabolic changes during pain and stressful events that might be harmful to the patient in the NICU, sufficient analgesia and sedation are impor tant measures [1,2, 4-8]. Morphine has been used especially in the postoperative period [9-11]. It has a longer duration of action compared to fentanyl. There is the possibilDownloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
50-
ity of an increase of serum levels after termi nation of infusion in the newborn [16]. For alfentanil there are not many experiences in small children [17, 18]. Fentanyl with its early onset and shorter duration of action and the absence of liberation of histamine, is indicated for the neonatal period, although rigidity of the thorax has been reported [19]. Our findings indicate that with a lower gesta tional age, smaller quantities of fentanyl are sufficient to produce untroubled artificial ventilation. Total body clearance was com parable in both groups, and its value was in the range of adult data of 400-1,500 ml/min [20]. But since the volume of distribution is probably larger in small preterm infants, the rate constant of elimination must be slower in the newborn and preterm infant to coun terbalance these facts. This study suggests that during artificial ventilation in neonates with severe respira tory problems, fentanyl with its analgesic and sedative properties seems to be useful. Under fentanyl infusion, patients needed less additional medication. Especially there was a great difference in the quantity of bar biturates given between the fentanyl and the control group. Fentanyl itself with its seda tive action may contribute to explain this fact, as well as that with appropriate analge sia there is much less need of sedatives. The higher needs of catecholamines in the con trol group may be the result of the use of barbiturates, as these are possible cardiodepressants [21], Mechanical ventilation was tolerated well in all cases treated with fentanyl. Restless ness due to hypoxemia and hypercapnia can only be treated with optimal oxygenation and ventilation. The depressant action of fentanyl on the brain stem because of its nar cotic/analgesic properties may have helped
Roth/Schlünder/Houben/Günther/Theisohn
to avoid the disturbing respiratory attempts. The serum levels measured were between 0.5 and 6 ng/ml, and values of 1-3 ng/ml are considered to have an important depressant action on the respiratory center of the new born [22], The increase of total serum bilirubin con centration observed in the newborn and pre mature infant receiving fentanyl may be due to the depressant action of opioids on the smooth muscle. Consequently, gastrointesti nal transit is decreased and elimination of meconium is delayed. These disadvantages have to be counterbalanced against the ad vantages of better artificial ventilation. We conclude that using fentanyl there is a de creased need of additional analgesic and sed ative medication in neonates under artificial ventilation. No undesirable effects on the cardiovascular system, and good tolerance of artificial ventilation make fentanyl to be a good option for analgesia and sedation in the ventilated newborn and premature neonate. But increased values of bilirubin and delay in the elimination of meconium must not be forgotten, so that the administration of fen tanyl should remain under strict indication.
References 1 Anand KJS, Brown MJ. Bloom SR, et al: Studies on the hormonal regulation of glucose metabolism in the human newborn infant undergoing anaes thesia and surgery. Horm Res 1985;22:115-128. 2 Anand KJS, Brown MJ. Canson RC, et al: Can the human neonate mount an endocrine and meta bolic response to surgey? J Pediatr Surg 1985;20: 41-84. 3 Anand KJS, Hickey PR: Pain and its effect in the human neonate and fetus. N Engl J Med 1987; 317:1321-1329. 4 Anand KJS, Sippell WG, Aynsley-Green A: Ran domized trial of fentanyl anesthesia in preterm Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
126
Fentanvl in the Neonate
6 7 8 9
10
11
12
13
14
15 Flartwig S, Roth B, Thcisohn M: Clinical experi ence with continuous intravenous sedation using midazolam and fentanyl in the pediatric intensive care unit. Eur J Pediatr 1991;150:784-788. 16 Truog R, Anand KJS: Management of pain in the postoperative neonate. Clin Perinatol 1989:16: 61-78. 17 Maunuksela EL, Olkkola KT: Pediatric pain man agement. Int Anesthesiol Clin 1991;29:37-55. 18 Marlow N, Weindling AM, Peer A von, et al: Alfentanil pharmacokinetics in preterm infants. Arch Dis Child 1990;65:149-151. 19 Shapiro C: Pain in the neonate: Assessment and intervention. Nconalal Network 1989;8:17-21. 20 Mather LE: Clinical pharmacokinetics of fentanyl and its newer dérivâtes. Clin Pharmacokinet 1983;8:422-446. 21 Krebs R. Kersting F: Zur Ursache der hämodynamischen Nebenwirkungen einiger Narkotica. Anaesthesist 1972;21:153-165. 22 Hertzka RE. Gauntlett IS, Fisher DM, et al: Fentanyl-induced ventilatory depression: Effects of age. Anesthesiology 1989;70:213-218.
Prof. B. Roth Universitäts-Kinderklinik Köln Joseph-Stelzmann-Strasse 9 D-W-5000 Köln 41 (FRG)
Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
5
babies undergoing surgery: Effects on the stress response. Lancet 1987;i:62—65. Roth B: Erfahrungen zur Analgesie und Sedierung in der pädiatrischen Intensivmedizin; in Intensiv medizin, Anästhesiologie, Pädiatrische Intensiv medizin X. Stuttgart, Thieme, 1988, voi 69, pp 150-151. Gauntlett IS: Analgesia in the neonate. Br J Hosp Med 1987:37:518-519. Noerr B: Fentanyl citrate. Neonatal Network 1990;9:8 5. Koren G, Maurice L: Pediatric uses of opioids. Pediatr Clin North Am 1989;36:1141-1156. Koren G, Butt W, Chinyanga H, et al: Postopera tive morphine infusion in newborn infants: As sessment of disposition characteristics and safety. J Pediatr 1985:107:963-967. Lynn AM. Slattery JT: Morphine pharmacokinet ics in early infancy. Anesthesiology 1987:66.136— 139. Purcell-Jones G, Dormon F, Sumner E: The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia 1987;42:1320-1323. Collins C, Koren G, Cream P, et al: Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ducuts arteriosus. Anesth Analg 1985;64:1078-1080. Koehntop DE, Rodman JH, Brundage DM, et al: Pharmacokinetics of fentanvl in neonates. Anesth Analg 1986:65:227-232. Yaster M: The dose response of fentanyl in neona tal anesthesia. Anesthesiology 1987;66:433-435.
127
©1991 S. Karger AG, Basel 0379-8305/91 /0174-0121 $2.75/0
Dev Pharmacol Ther 1991;17:121-127
Analgesia and Sedation in Neonatal Intensive Care Using Fentanyl by Continuous Infusion1,2 B. Rotha, C. Schlündera,
/•'.
Houhena, M. Günthera, M. Theisohnb
a Children’s Hospital and b Institute of Pharmacology, University of Cologne, FRG
Key Words. Neonatal intensive care unit • Preterm infants • Artificial respiration • Analgesia ■ Sedation • Fentanyl Abstract. To determine the effects of fentanyl in newborn and premature infants, we compared two groups of 20 newborn and premature babies under artificial ventilation for severe respiratory distress syndrome: a prospective group receiving fentanyl for analgesic and sedation and a historical control group, who did not receive fentanyl. Fentanyl serum levels during steady state were determined by radioimmunoassay. Average time of infusion was 86 ± 47 h with a mean dosage of 0.68 ± 0.24 pg/kg/h. The fentanyl group needed much less sedatives and catecholamines. Heart rate and blood pressure were not significantly changed by fentanyl. Meconium was excreted later, and higher values of bilirubin were reached earlier than in the control group. Although fentanyl proved to be helpful in the neonatal intensive care unit, the administration should remain under strict indication.
There is no doubt that even the smallest premature neonates have a sufficiently de veloped nociceptive system, therefore for all pain and stressful procedures, good analgesia must be guaranteed [1-8]. Specific diseases
1 Supported by Deutsche Forschungsgemeinschaft, grant Ro 799/1-1. 2 Presented at the Second European Neonatal Workshop, Klingenthal, France, June 15, 1991.
such as severe respiratory distress syndrome (RDS) under artificial ventilation require some degree of sedation to avoid disturbing respiratory attempts and adverse reactions to stressful measures. In the postoperative period, morphine has been used successfully [9-11]. Fentanyl has theoretical advantages relative to morphine: short duration of ac tion, easy to titrate and possibly less effects on the central nervous system, [12-14], This study was performed to observe the in fluence on tolerance to mechanical ventila tion in case of severe RDS in the neonatal Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
Introduction
122
Roth/Schlünder/Houben/Günther/Theisohn
Table 1. Distribution of patients of the fentanyl and control group in relation to weight, gestational age and diagnoses
Patients (m/f) Body weight, g Gestational age Cesarean section HMD- or adult RDS-like Vitium cordis Cerebral disorders
Fentanyl group
Control group
13/7 1,712 ± 765 (860-3,500) 32.5 ±3.6 (26-40) 14
9/11 1,823 ± 686 (850-2900) 32.3 ± 3.15 (26-37)
11
15 5
5 7
12
HMD = Hyaline membrane disease. Range values are in parentheses.
Table 2. Differences of fentanyl pharmacokinetics between infants with a gestational age of < 34 weeks and > 34 weeks Gestational age
Mean dosage, pg/kg/h Mean fentanyl serum levels, ng/ml Mean duration of infusion, h Total clearance, ml/kg/h
< 34 weeks
> 34 weeks
0.64±0.19 (0.25-1.05) 1.67 ±0.89 (0.18-4.1) 93 ± 55 (53-245) 727 ± 921 (122-4,291)
0.75±0.30 (0.25-1.50) 2.13 ± 1.57 (0.1-5.92) 75±24 (36-116) 782 ± 1,185 (192-5,102)
The differences are statistically not significant. Range values are in parentheses.
Patients and Methods Twenty newborn and premature babies, born in 1989 and 1990, 12 with a gestational age of less than 34 weeks (7 male, 5 female) and 8 with a gestational age of 34 weeks or more (6 male, 2 female), mean birth weight of 1,710 g (860-3,500 g), under artificial ventilation because of severe RDS of different origin receiving fentanyl, were compared to a historical con trol group of 20 newborn and premature infants, born
in 1988, who did not receive fentanyl. The patients of the historical control group were selected to combine in gestational age. body weight, diagnoses, additional drugs, duration of artificial ventilation, and respira tory parameter settings (table 1 ). The study was approved by the Ethics Committee of the medical Faculty of the University of Cologne and parental consent was obtained. The indication for fentanyl administration was the necessity of artifi cial ventilation because of severe respiratory prob lems with fractional inspired oxygen >0.7, peak in spiratory pressure > 25 cm HjO, and mean airway pressure > 12 cm HiO. After a loading dose of 5.012.5 pg/kg, administered over at least 10 min, fentanyl was given by continuous infusion of 0.5-2 pg/kg/h. Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
intensive care and to determine the pharma cological properties of fentanyl in the neona tal period.
123
Fentanyl in the Neonate
Fig. 1. Correlation between fentanyl dosage and serum levels: serum lev els observed correlate well with fentanyl dosage (r = 0.981).
and reaction to tracheal aspiration [15], It was judged to be satisfactory if the child was quiet, but reacting when stimulated, and tolerated endotracheal aspira tion well.
Results
Under fentanyl, artificial ventilation was tolerated well and we never observed rigidity of the thorax. Evaluation by the sedation scale showed satisfactory values for all pa tients. We did not observe any signs of opioid withdrawal. For infants with a gestational age of < 34 weeks, a mean dosage of 0.64 pg/kg/h was sufficient to produce appropriate sedation, whereas infants > 34 weeks needed 0.75 pg/ kg/h (table 2). In the fentanyl group, mean fentanyl serum levels of 1.85 ng/ml were measured at a mean dosage of 0.69 pg/kg/h. The correlation between fentanyl dosage and serum levels is demonstrated in fig ure 1. The need of additional analgesics, sedatives, muscular relaxants and catechol amines was much lower than in the control Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
In the beginning, a dose of 0.5 gg/kg/h was given and was increased incrementally by 0.5 gg/kg/h when clin ically necessary. Infusion was stopped when the in spired fraction of oxygen reached > cO
TD
Fentanyl group n = 20 Control group n = 20
4^
O) CD
E 3co U) CO
v>o 2o 1-
M
0 Diazepam
Pentobarb.
M
*7771
Phenobarb.
Vecuronium
Dopamine Dobutamine
Fig. 2. Differences in the ne cessities of additional drugs be tween mechanically ventilated newborn and preterm infants treated with fentanyl (fentanyl group) and without (control group). The need of additional analgesics and especially of cate cholamines in the fentanyl group was much lower than in the con trol group.
Fig. 3. Relation between fen tanyl dosage, serum levels and clearance in a male newborn, 38 weeks’ gestational age and birth weight 3,500 g.
premature infant are demonstrated in fig ures 3 and 4. Heart rate did not show any difference between both groups, but systolic and dia stolic blood pressure in the fentanyl group was slightly, statistically not significantly, higher. In the fentanyl group, mean systolic pressure was 55 ± 8 mm Hg and mean dia stolic pressure was 34 ± 6 versus 53 ± 6 mm Hg in the control group (fig. 5). Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
group (fig. 2). Mean serum levels for the group 34 weeks with 2.13 ng/ml, but for the first mean duration of infusion was 93 h against 75 h for the sec ond. Total clearance for the infants of 34 weeks (ta ble 2). Examples of fentanyl dosage, serum levels and clearance in a newborn and in a
Fentanyl in the Neonate
125
Fig. 4. Relation between fentanyl dosage, serum levels and clearance in a male newborn, 32 week’s gestational age and birth weight 1,000 g. 70 n
□ Fentanyl group 0 Control group
60-
40-
/ Z
zZ
O)
Z
^ 30E
20-
/ Z / / / / / /
10-
0
/ /Z Z /
/ /
/
it/
//
Fig. 5. Differences of mean values of blood pressure be tween mechanically ventilated newborn and preterm infants treated with fentanyl (fentanyl group) and without (control group). The differences were statistically not significant. SBP = Systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial blood pressure.
k
Z Z
I Z / / / / / /
/ / /
i/ZZ / //
a
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/
/ /
/ /
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ft
/
/
/ / /
z
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/
/
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Z
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/
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Jd
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ft
Z Z Z
z
/ /
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/ /
/
z
/z z
z
z
/
Z Z Z
SBP DBP MAP
SBP DBP MAP
^. SBP DBP MAP
Total
Day 1
Day 2
The peak arithmetic mean of total plasma bilirubin was 12.1 ± 4.3 mg/dl in the fenta nyl group, and was higher than the control group (9.7 ± 4.4 mg/dl). Maximum values were reached in average on day 4.2 ± 1.3 of life in the fentanyl group, and only on day 5.0 ± 1.8 in the control group. Meconium was eliminated after 3.6 ± 1.9 days in the fentanyl group, while in the control group elimination occurred after 2.0 ± 1.5 days.
✓
I
Z Z / / / / / /
/ / / / /
/Z Z / Jd
z z / Z
/
/
Z Z
Z
d
SBP DBP MAP
Day 3
Discussion
To avoid hormonal and metabolic changes during pain and stressful events that might be harmful to the patient in the NICU, sufficient analgesia and sedation are impor tant measures [1,2, 4-8]. Morphine has been used especially in the postoperative period [9-11]. It has a longer duration of action compared to fentanyl. There is the possibilDownloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
50-
ity of an increase of serum levels after termi nation of infusion in the newborn [16]. For alfentanil there are not many experiences in small children [17, 18]. Fentanyl with its early onset and shorter duration of action and the absence of liberation of histamine, is indicated for the neonatal period, although rigidity of the thorax has been reported [19]. Our findings indicate that with a lower gesta tional age, smaller quantities of fentanyl are sufficient to produce untroubled artificial ventilation. Total body clearance was com parable in both groups, and its value was in the range of adult data of 400-1,500 ml/min [20]. But since the volume of distribution is probably larger in small preterm infants, the rate constant of elimination must be slower in the newborn and preterm infant to coun terbalance these facts. This study suggests that during artificial ventilation in neonates with severe respira tory problems, fentanyl with its analgesic and sedative properties seems to be useful. Under fentanyl infusion, patients needed less additional medication. Especially there was a great difference in the quantity of bar biturates given between the fentanyl and the control group. Fentanyl itself with its seda tive action may contribute to explain this fact, as well as that with appropriate analge sia there is much less need of sedatives. The higher needs of catecholamines in the con trol group may be the result of the use of barbiturates, as these are possible cardiodepressants [21], Mechanical ventilation was tolerated well in all cases treated with fentanyl. Restless ness due to hypoxemia and hypercapnia can only be treated with optimal oxygenation and ventilation. The depressant action of fentanyl on the brain stem because of its nar cotic/analgesic properties may have helped
Roth/Schlünder/Houben/Günther/Theisohn
to avoid the disturbing respiratory attempts. The serum levels measured were between 0.5 and 6 ng/ml, and values of 1-3 ng/ml are considered to have an important depressant action on the respiratory center of the new born [22], The increase of total serum bilirubin con centration observed in the newborn and pre mature infant receiving fentanyl may be due to the depressant action of opioids on the smooth muscle. Consequently, gastrointesti nal transit is decreased and elimination of meconium is delayed. These disadvantages have to be counterbalanced against the ad vantages of better artificial ventilation. We conclude that using fentanyl there is a de creased need of additional analgesic and sed ative medication in neonates under artificial ventilation. No undesirable effects on the cardiovascular system, and good tolerance of artificial ventilation make fentanyl to be a good option for analgesia and sedation in the ventilated newborn and premature neonate. But increased values of bilirubin and delay in the elimination of meconium must not be forgotten, so that the administration of fen tanyl should remain under strict indication.
References 1 Anand KJS, Brown MJ. Bloom SR, et al: Studies on the hormonal regulation of glucose metabolism in the human newborn infant undergoing anaes thesia and surgery. Horm Res 1985;22:115-128. 2 Anand KJS, Brown MJ. Canson RC, et al: Can the human neonate mount an endocrine and meta bolic response to surgey? J Pediatr Surg 1985;20: 41-84. 3 Anand KJS, Hickey PR: Pain and its effect in the human neonate and fetus. N Engl J Med 1987; 317:1321-1329. 4 Anand KJS, Sippell WG, Aynsley-Green A: Ran domized trial of fentanyl anesthesia in preterm Downloaded by: University of Exeter 144.173.6.94 - 5/3/2020 4:03:45 PM
126
Fentanvl in the Neonate
6 7 8 9
10
11
12
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15 Flartwig S, Roth B, Thcisohn M: Clinical experi ence with continuous intravenous sedation using midazolam and fentanyl in the pediatric intensive care unit. Eur J Pediatr 1991;150:784-788. 16 Truog R, Anand KJS: Management of pain in the postoperative neonate. Clin Perinatol 1989:16: 61-78. 17 Maunuksela EL, Olkkola KT: Pediatric pain man agement. Int Anesthesiol Clin 1991;29:37-55. 18 Marlow N, Weindling AM, Peer A von, et al: Alfentanil pharmacokinetics in preterm infants. Arch Dis Child 1990;65:149-151. 19 Shapiro C: Pain in the neonate: Assessment and intervention. Nconalal Network 1989;8:17-21. 20 Mather LE: Clinical pharmacokinetics of fentanyl and its newer dérivâtes. Clin Pharmacokinet 1983;8:422-446. 21 Krebs R. Kersting F: Zur Ursache der hämodynamischen Nebenwirkungen einiger Narkotica. Anaesthesist 1972;21:153-165. 22 Hertzka RE. Gauntlett IS, Fisher DM, et al: Fentanyl-induced ventilatory depression: Effects of age. Anesthesiology 1989;70:213-218.
Prof. B. Roth Universitäts-Kinderklinik Köln Joseph-Stelzmann-Strasse 9 D-W-5000 Köln 41 (FRG)
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babies undergoing surgery: Effects on the stress response. Lancet 1987;i:62—65. Roth B: Erfahrungen zur Analgesie und Sedierung in der pädiatrischen Intensivmedizin; in Intensiv medizin, Anästhesiologie, Pädiatrische Intensiv medizin X. Stuttgart, Thieme, 1988, voi 69, pp 150-151. Gauntlett IS: Analgesia in the neonate. Br J Hosp Med 1987:37:518-519. Noerr B: Fentanyl citrate. Neonatal Network 1990;9:8 5. Koren G, Maurice L: Pediatric uses of opioids. Pediatr Clin North Am 1989;36:1141-1156. Koren G, Butt W, Chinyanga H, et al: Postopera tive morphine infusion in newborn infants: As sessment of disposition characteristics and safety. J Pediatr 1985:107:963-967. Lynn AM. Slattery JT: Morphine pharmacokinet ics in early infancy. Anesthesiology 1987:66.136— 139. Purcell-Jones G, Dormon F, Sumner E: The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia 1987;42:1320-1323. Collins C, Koren G, Cream P, et al: Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ducuts arteriosus. Anesth Analg 1985;64:1078-1080. Koehntop DE, Rodman JH, Brundage DM, et al: Pharmacokinetics of fentanvl in neonates. Anesth Analg 1986:65:227-232. Yaster M: The dose response of fentanyl in neona tal anesthesia. Anesthesiology 1987;66:433-435.
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![[Sedation and analgesia practices among Spanish neonatal intensive care units].](/assets/img/hold.png)
