A Comparative Study of Two Remifentanil Doses for Procedural Pain in Ventilated Preterm Infants: A Randomized, Controlled Study* Seung Han Shin, MD1; Han-Suk Kim, MD, PhD1; Juyoung Lee, MD1; Ka young Choi, MD1; Jang Hoon Lee, MD, PhD2; Ee-Kyung Kim, MD, PhD1; Moon Sung Park, MD, PhD2; Jung-Hwan Choi, MD, PhD1
Objectives: Remifentanil is an ultrashort-acting synthetic opioid, and the metabolism of which is not influenced by hepatic or renal function. This study aims to compare the efficacy of two remifentanil doses during procedures in ventilated preterm infants. Design: Prospective, randomized, double-blind, noninferiority trial. Setting: Neonatal ICU. Patients: Preterm infants who were supported by a mechanical ventilator with tracheal tube and requiring central venous access. Interventions: Two remifentanil dosages were administered in mechanically ventilated preterm infants during peripherally inserted central catheter insertion. Fourteen preterm infants were randomly assigned to low-dose (0.1 μg/kg/min) or high-dose (0.25 μg/kg/min) remifentanil infusion. The Premature Infant Pain Profile was used to score pain during the procedure, and changes in the Premature Infant Pain Profile score between needle puncture and baseline were analyzed to investigate the noninferiority of low-dose to high-dose remifentanil. Occurrence of cardiorespiratory complications was also recorded. Measurements and Main Results: The median gestational age (minimum, maximum) was 26 weeks (24+3, 31+6), and the median birth weight was 825 g (610, 1,280). Changes in Premature Infant Pain Profile in the high-dose and low-dose groups were 1.43 ± 3.10 and –0.60 ± 5.32, respectively. The difference *See also p. 495. 1 Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea. 2 Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea. This study was performed at Seoul National University Children’s Hospital and Ajou University Hospital. Supported, in part, by a grant 11172MFDS291 from Korea Food & Drug Administration in 2011. All the authors received support for article research from the Korea Food & Drug Administration and their institutions received grant support from the Korea Food & Drug Administration. For information regarding this article, E-mail: Han-Suk Kim, MD, PhD, [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000123
Pediatric Critical Care Medicine
in changes in the Premature Infant Pain Profile score between the high-dose and low-dose groups was –2.03 ± 4.13. The corresponding lower limit of one-tailed 97.5% CI was –7.24, below the noninferiority margin. Apneic events and bradycardia did not occur in the low-dose group; however, there were three episodes of apnea (42.9%) and one of bradycardia (14.3%) in the highdose group (p = 0.683 and 0.366, respectively). Conclusion: For mechanically ventilated preterm infants, the use of remifentanil at 0.25 μg/kg/min as an analgesic for short procedures represents a therapeutic option. Our pilot study suggests the need for larger randomized trials. (Pediatr Crit Care Med 2014; 15:451–455) Key Words: analgesia; mechanical ventilation; premature infant; procedure; remifentanil; sedation
T
here have been great advances in neonatal intensive care; consequently, critically ill preterm infant survival has increased. Paradoxically, as part of this life-saving medicine, the infants are exposed to multiple stressors in the neonatal period, even though minimal handling is an important approach for preterm infant care (1, 2). Because of extreme physiologic instability, multiple invasive procedures such as tracheal intubation, tracheal suction, blood sampling, and insertion of venous or arterial catheters are inevitable, and the number of such painful procedure during the neonatal ICU (NICU) stay has been reported to be 6–14 procedures per day (3, 4). Alterations in somatosensory perception and behavioral activity resulting after pain exposure in preterm infants have been reported (5–7). Furthermore, postnatal growth in very preterm infants is disturbed by neonatal pain (8). The growing evidence of the long-term effects of repeated pain in preterm infants on neurodevelopment has been challenging for neonatologists, and accordingly, the importance of pain control has been increasingly recognized for preterm infants (1, 9–11). Nonpharmacologic approaches, such as the use of breast milk, sucrose, and kangaroo care, have been widely used for www.pccmjournal.org
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Shin et al
procedural pain (11–14). However, with regard to mechanically ventilated preterm infants, pharmacologic treatment is preferred for analgesia and sedation; for procedural pain during mechanical ventilation, a pharmacologic approach could be considered the first line for analgesia (11, 15, 16). Despite opioids such as morphine and fentanyl have been used for pain control in preterm infants, the choice and dosage of medication for these purposes have not yet been established. Remifentanil is an ultrashort-acting synthetic opioid that has been used in the neonatal ICU for the analgesia and sedation of preterm infants because of several pharmacokinetic benefits over other opioids (3, 11, 17, 18). It has a short b lood-brain equilibrium time of 1–1.5 minutes, with a rapid action and a short half-life of 3–5 minutes, which makes it optimal and predictable for short-term use (19). As remifentanil is the only opioid that is quickly degraded by nonspecific plasma and tissue esterase, its pharmacokinetics are not influenced by renal or liver function, making it adequate for the treatment of preterm infants (18). However, evidence for remifentanil usage in preterm infants is still lacking. In the existing studies, it has been used in combination with other analgesics for sedation, and the dosage was low (16, 20). In this study, we conducted a double-blinded, randomized, noninferiority comparison study to explore the efficacy of two remifentanil doses for short procedural pain in preterm infants with mechanical ventilation support.
MATERIALS AND METHODS This noninferiority, randomized, double-blind, controlled trial was conducted at the NICU of the Seoul National University Children’s Hospital and Ajou University Hospital between November 2011 and April 2012. The study protocol and data collection were approved by each hospital’s institutional review board, and written parental consent was obtained before enrollment. This study was conducted in compliance with the current revision of the Declaration of Helsinki and the Good Clinical Practice guidelines and registered with ClinicalTrials. gov (NCT01477892). Preterm infants who were supported by a mechanical ventilator with tracheal tube and requiring central venous access were eligible for the study. Before enrollment, no analgesics, sedatives, or muscle relaxants were administered to facilitate mechanical ventilation. The exclusion criteria were preterm infants with major congenital anomalies, cardiopulmonary instability, and medications of other sedative, antiepileptic, and anesthetic drugs. Infants with grade III or IV intraventricular hemorrhage before enrollment were also excluded. The infants were randomized sequentially using a w eb-based randomization program, which was run by the Medical Research Collaborating Center in Seoul National University Hospital. The enrolled infants were randomized into two remifentanil groups: 0.1 μg/kg/min dose (the low-dose [LD] group) and 0.25 μg/kg/ min dose (the high-dose [HD] group). The preparations of the study drugs were indistinguishable for the two groups that were administered different concentrations by pharmacists of the clinical trial center, who were the only personnel with the randomization table. The infusion was initiated 15 minutes before the procedure and stopped 10 minutes after the catheter had 452
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been secured to the skin and a dressing applied. The peripherally inserted central catheter (PICC) was inserted by each NICU’s dedicated nursing staff using polyurethane catheters with a 24-gauge cannula (Premicath, Vygon, Aachen, Germany). The analgesic effects of remifentanil were assessed using the Premature Infant Pain Profile (PIPP), a well-validated pain measurement instrument. The PIPP consists of three behavioral and two physiologic indicators and two contextual variables that modify pain (21, 22). Scores of 0–6 generally indicate the infant has minimal or no pain, 7–12 for moderate pain, and more than 12 for severe pain. In clinical relevance, changes of the scores between different situations and scores themselves are particularly important. Assessment was performed before study medication (P0), 10 minutes after infusion with skin preparation complete (P1), 15 minutes after infusion with needle puncture (P2), and 10 minutes after cessation of remifentanil infusion (P3). At each time point, a video recording was taken, focusing on the patient’s face. Simultaneously, heart rate (HR) and oxygen saturation (Spo2) were observed, and changes in HR or Spo2 were recorded for later scoring. The recorded files were stored, and the scoring was performed by a blinded neonatologist. The primary outcome was defined as changes in PIPP. Episodes of apnea, bradycardia, and desaturation during remifentanil infusion were recorded. The sample size was calculated based on another study, and the noninferiority margin (δ) was established as 1.5, considering the differences in PIPP scores between baseline and during the procedure (20). Based on the noninferiority margin, α = 5%, and β = 80%, 12 infants were calculated as being required for the study; based on a drop rate of 20%, a total of 16 infants was the target enrollment. Continuous variables were compared with the Wilcoxon rank sum test, and categorical variables were compared using the Fisher exact test. Statistical analyses were performed using SAS statistical software (SAS Institute, Cary, NC) and R 2.10.0 (The R Foundation for Statistical Computing Platform, Vienna, Austria).
RESULTS Fourteen preterm infants were enrolled, and two infants were dropped from the study due to consent withdrawal by the parents after randomization. After the 14 infants were enrolled including the two withdrawn infants, we closed the study with 12 infants completed according to the recommendation of the data monitoring committee because enrollment was behind schedule. Finally, 12 infants who fulfilled the sample size requirement were subjected to analysis. Seven infants were assigned to the HD group, and five infants were assigned to the LD group. The median gestational age (minimum, maximum) of the study population was 26 weeks (24+3, 31+6), and the median birth weight (minimum, maximum) was 825 g (610, 1,280). Gender, gestational age, birth weight, postmenstrual age, and weight at remifentanil infusion did not differ significantly between the groups (Table 1). The median postnatal ages (minimum, maximum) were 4 days (1, 32) and 7 days (2, 34), respectively. The levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine did not significantly differ between the groups. June 2014 • Volume 15 • Number 5
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Table 1.
Study Population Characteristics Low-Dose Group (Remifentanil, 0.1 μg/kg/min) (n = 5)
High-Dose Group (Remifentanil, 0.25 μg/kg/min) (n = 7)
p
Gestational age (wk)a
25+6 (24+3, 31+6)
26+1 (24+3, 30+4)
0.811
Birth weight (g)a
800 (610, 1,250)
850 (620, 1,280)
0.874
3 (60.0)
Gender (female)b
3 (42.9)
1.000
On study day 4 (1, 32)
Postnatal age (d)a Postmenstrual age (wk)
a
Weight (g)
a
0.529
950 (640, 1,250)
770 (650, 1,240)
0.692
27 (21, 45)
Alanine aminotransferase (IU/L)
a
Blood urea nitrogen (mL/dL)
a
Creatinine (mL/dL)
a
Urine of study day (mL/kg/d)
a
0.633
27 (24 , 30 )
+6
Aspartate aminotransferase (IU/L)
a
7 (2, 34)
30 (24 , 32) +1
+4
+6
+5
23 (20, 34)
0.706
6.5 (5, 8)
4 (3, 8)
0.097
13.5 (3, 49)
11 (3, 29)
0.782
0.635 (0.45, 0.9)
0.69 (0.47, 1.7)
0.367
2.58 (2.1, 3.7)
3.75 (2.4, 5.26)
0.077
Median (minimum, maximum). b n (%). a
With regard to the HD group, the mean PIPP gradually decreased to less than 6 during the procedure and in the recovery time, indicating minimal or no pain. In contrast, the mean PIPP increased during the procedure, indicating moderate pain, and then decreased during recovery in the LD group (Fig. 1). The changes in PIPP (CP0-P2) of the HD and LD groups were 1.43 ± 3.10 and –0.60 ± 5.32, respectively, and the CP0-P2 between the HD and LD groups was –2.03 ± 4.13. The corresponding lower limit of one-tailed 97.5% CI was –7.24 (Table 2). During remifentanil infusion, apneic events and bradycardia were not observed in the LD group; however, there were three infants with apneic events (42.9%) and one infant with bradycardia following apnea (14.3%) in the HD group, which was a nonsignificant difference (p = 0.683 and 0.366, respectively) (Table 3).
DISCUSSION The goal of this study was to explore the adequate remifentanil dose without serious adverse effects for procedural pain in mechanically ventilated preterm infants. The results of our study verified that 0.1 μg/kg/min of remifentanil infusion fails to show noninferiority to 0.25 μg/kg/min for procedural pain and that 0.25 μg/kg/min of remifentanil infusion during short procedures was an effective analgesic without serious adverse effects. Remifentanil could be a useful analgesic for procedural pain in preterm infants without serious adverse effects because of its pharmacokinetic characteristics (18, 23). First, because its metabolism is not influenced by renal and hepatic function, remifentanil may be a suitable drug for preterm infants with immature organs (23, 24). Furthermore, the short half-life of remifentanil makes it appropriate for short, pain-inducing procedures (18). To date, few clinical studies on remifentanil in preterm infants have been conducted and most involved premedication Pediatric Critical Care Medicine
before tracheal intubation (25–27). More recently, trials on remifentanil for analgesia and sedation during mechanical ventilation have been introduced. There was one randomized controlled trial by Lago et al (20) for short procedural pain in preterm infants (16, 28). The study by Lago et al (20) aimed to demonstrate the efficacy of LD remifentanil for PICC insertion, similar to the present study; however, there were important differences between the two studies in a clinical context. First, in this study, the study population was confined to mechanically ventilated preterm infants, which was not the case in the previous study. Because remifentanil has a suppressive effect on respiration, caution should be exercised when using remifentanil in preterm infants without ventilatory support. Second, therefore, including preterm infants without respiratory support, the study by Lago et al (20) used a LD of remifentanil (0.03 μg/kg/min) with sucrose instillation comparing to sucrose only, and the mean PIPP score of the remifentanil group during the procedure was higher than 8, which was less than the 6 in the HD group of the present study. A PIPP score less than 6 indicates no or minimal pain (21). A recommendation for remifentanil at 0.03 μg/kg/min for analgesia was not found elsewhere, and even though sucrose is a useful nonpharmacological intervention for procedural pain relief in neonates, the use of sucrose in extremely preterm, unstable, ventilated neonates is controversial (13). Therefore, for an appropriate analgesic effect, it is beneficial to confine the indication for remifentanil use to its use as a sufficient analgesia in preterm infants with ventilator assistance. Typically, remifentanil is used by gradual dose titration according to patient response for pain stressors during continuous infusion (24, 28). However, for short procedures, dose titration every 5 or 10 minutes is not suitable, especially for preterm infants fully draped for aseptic technique, interfering www.pccmjournal.org
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has been reported as being optimal for the analgesia and sedation of preterm infants during mechanical ventilation (24, 28). We hypothesized that in preterm infants, a lower remifentanil dose could be applicable for additional pain control, and we investigated the noninferiority of LD (0.1 μg/kg/min) to HD (0.25 μg/kg/min) remifentanil. As shown above, LD remifentanil failed to show noninferiority to HD remifentanil in control of procedural pain (Fig. 2). PIPP with LD remifentanil during the procedure scored more than 6, which indicates moderate pain. Our preliminary data revealed PIPP scores without analgesics during PICC insertion were 9–17 which indicated moderateto-severe pain (data not shown), so we decided not to use placebo group in this study because of ethical concerns. With regard to adverse Figure 1. The Premature Infant Pain Profile (PIPP) scores at baseline (P0), preparation (P1), skin puncture effects, apnea, bradycardia, (P2), and recovery (P3) showed a gradual decrease in the high-dose (HD) group, which was not shown in the and hypotension did not occur low-dose (LD) group. During procedure (P0 and P1), PIPP scores indicated minimal or no pain in HD group, whereas they indicated moderate pain in LD group. in the LD group. Among the seven patients in the HD group, with the assessment of pain. Therefore, it may be more practi- apnea developed in three patients, followed by bradycardia in cal to infuse a maintenance remifentanil dosage without titra- one patient; hypotension did not develop. Other laboratory tion during short procedures such as PICC insertion. findings did not show any differences after remifentanil infuWelzing and Roth (23) recommended commencing remision between the groups (data not shown). Although remifentanil infusion at a rate of 0.25 μg/kg/min for pain control fentanil of 0.25 μg/kg/min showed significantly comparable in neonates and infants. However, a lower dose of remifentanil adverse effects to 0.1 μg/kg/min, the symptoms of apnea and Table 2. Difference in Change of Premature Infant Pain Profile Value P2 From P0 Between Low-Dose and High-Dose Remifentanil Groups for the Noninferiority Test
Change of Premature Infant Pain Profile value P2 from P0
LD (n = 5)
HD (n = 7)
LD – HD
One-Sided Lower 97.5% CI
–0.60 ± 5.32
1.43 ± 3.10
–2.03 ± 4.13
–7.42
LD = low-dose remifentanil (0.1 μg/kg/min), HD = high-dose remifentanil (0.25 μg/kg/min).
Table 3. Comparisons of the Side Effects of the Low-Dose and High-Dose Remifentanil Groups Low-Dose Group (n = 5)
High-Dose Group (n = 7)
p
Apnea, n (%)
0 (0)
3 (42.9)
0.683
Bradycardia, n (%)
0 (0)
1 (14.3)
0.366
Hypotension, n (%)
0 (0)
0 (0)
—
Dash indicates data was statistically incomparable because no events occurred in both groups.
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June 2014 • Volume 15 • Number 5
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Figure 2. The difference in changes in Premature Infant Pain Profile score between the high-dose and low-dose groups was –2.03 ± 4.13 (diamond and bar), and the corresponding lower limit of one-tailed 97.5% CI was –7.24, which was less than the noninferiority margin (vertical line).
bradycardia were shown only in the HD group. Although each adverse event was controllable in infants with mechanical ventilation, careful, close monitoring is necessary during remifentanil infusion. Because this study has a relatively small sample size for comparing adverse effects directly, further large-scale cohort studies should be conducted to address the safety issue.
CONCLUSIONS Where continuous monitoring of vital signs is available and for infants with mechanical ventilation support, the use of remifentanil at 0.25 μg/kg/min as an analgesic for short procedures represents a therapeutic option, owing to its favorable pharmacokinetic characteristics. Further studies with larger sample sizes and including pharmacokinetic data in preterm infants are necessary to compare adverse effects.
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1. Dahl M, Kamper J: Physical outcome and school performance of very-low-birthweight infants treated with minimal handling and early nasal CPAP. Acta Paediatr 2006; 95:1099–1103 2. Jacobsen T, Grønvall J, Petersen S, et al: “Minitouch” treatment of very low-birth-weight infants. Acta Paediatr 1993; 82:934–938 3. Anand KJ, Johnston CC, Oberlander TF, et al: Analgesia and local anesthesia during invasive procedures in the neonate. Clin Ther 2005; 27:844–876 4. Simons SH, van Dijk M, Anand KS, et al: Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003; 157:1058–1064 5. Grunau RE, Holsti L, Haley DW, et al: Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain 2005; 113:293–300 6. Grunau RE, Holsti L, Peters JW: Long-term consequences of pain in human neonates. Semin Fetal Neonatal Med 2006; 11:268–275 7. Walker SM, Franck LS, Fitzgerald M, et al: Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm. Pain 2009; 141:79–87 8. Vinall J, Miller SP, Chau V, et al: Neonatal pain in relation to postnatal growth in infants born very preterm. Pain 2012; 153:1374–1381
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9. Bouza H: The impact of pain in the immature brain. J Matern Fetal Neonatal Med 2009; 22:722–732 10. Peterson BS, Vohr B, Staib LH, et al: Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA 2000; 284:1939–1947 11. Lago P, Garetti E, Merazzi D, et al; Pain Study Group of the Italian Society of Neonatology: Guidelines for procedural pain in the newborn. Acta Paediatr 2009; 98:932–939 12. Stevens B, Yamada J, Ohlsson A: Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2001; 4:CD001069 13. Stevens B, Yamada J, Lee GY, et al: Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2013; 1:CD001069 14. Stevens B, Yamada J, Ohlsson A: Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2010; 1:CD001069 15. Anand KJ; International Evidence-Based Group for Neonatal Pain: Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med 2001; 155:173–180 16. Welzing L, Oberthuer A, Junghaenel S, et al: Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: A randomized controlled trial. Intensive Care Med 2012; 38:1017–1024 17. McKechnie L, Levene M: Procedural pain guidelines for the newborn in the United Kingdom. J Perinatol 2008; 28:107–111 18. Penido MG, Garra R, Sammartino M, et al: Remifentanil in neonatal intensive care and anaesthesia practice. Acta Paediatr 2010; 99:1454–1463 19. Davis PJ, Cladis FP: The use of ultra-short-acting opioids in paediatric anaesthesia: The role of remifentanil. Clin Pharmacokinet 2005; 44:787–796 20. Lago P, Tiozzo C, Boccuzzo G, et al: Remifentanil for percutaneous intravenous central catheter placement in preterm infant: A randomized controlled trial. Paediatr Anaesth 2008; 18:736–744 21. Pasero C: Pain assessment in infants and young children: Premature infant pain profile. Am J Nurs 2002; 102:105–106 22. Stevens B, Johnston C, Taddio A, et al: The premature infant pain profile: Evaluation 13 years after development. Clin J Pain 2010; 26:813–830 23. Welzing L, Roth B: Experience with remifentanil in neonates and infants. Drugs 2006; 66:1339–1350 24. Stoppa F, Perrotta D, Tomasello C, et al: Low dose remifentanyl infusion for analgesia and sedation in ventilated newborns. Minerva Anestesiol 2004; 70:753–761 25. Choong K, AlFaleh K, Doucette J, et al: Remifentanil for endotracheal intubation in neonates: A randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2010; 95:F80–F84 26. Pereira e Silva Y, Gomez RS, Marcatto Jde O, et al: Morphine versus remifentanil for intubating preterm neonates. Arch Dis Child Fetal Neonatal Ed 2007; 92:F293–294 27. Pereira e Silva Y, Marcatto Jde O, Barbosa RF, et al: Is remifentanil an option for premedication for neonatal endotracheal intubation? Arch Dis Child Fetal Neonatal Ed; 95:F463–464 28. Giannantonio C, Sammartino M, Valente E, et al: Remifentanil analgosedation in preterm newborns during mechanical ventilation. Acta Paediatr 2009; 98:1111–1115
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Objectives: Remifentanil is an ultrashort-acting synthetic opioid, and the metabolism of which is not influenced by hepatic or renal function. This study aims to compare the efficacy of two remifentanil doses during procedures in ventilated preterm infants. Design: Prospective, randomized, double-blind, noninferiority trial. Setting: Neonatal ICU. Patients: Preterm infants who were supported by a mechanical ventilator with tracheal tube and requiring central venous access. Interventions: Two remifentanil dosages were administered in mechanically ventilated preterm infants during peripherally inserted central catheter insertion. Fourteen preterm infants were randomly assigned to low-dose (0.1 μg/kg/min) or high-dose (0.25 μg/kg/min) remifentanil infusion. The Premature Infant Pain Profile was used to score pain during the procedure, and changes in the Premature Infant Pain Profile score between needle puncture and baseline were analyzed to investigate the noninferiority of low-dose to high-dose remifentanil. Occurrence of cardiorespiratory complications was also recorded. Measurements and Main Results: The median gestational age (minimum, maximum) was 26 weeks (24+3, 31+6), and the median birth weight was 825 g (610, 1,280). Changes in Premature Infant Pain Profile in the high-dose and low-dose groups were 1.43 ± 3.10 and –0.60 ± 5.32, respectively. The difference *See also p. 495. 1 Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea. 2 Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea. This study was performed at Seoul National University Children’s Hospital and Ajou University Hospital. Supported, in part, by a grant 11172MFDS291 from Korea Food & Drug Administration in 2011. All the authors received support for article research from the Korea Food & Drug Administration and their institutions received grant support from the Korea Food & Drug Administration. For information regarding this article, E-mail: Han-Suk Kim, MD, PhD, [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000123
Pediatric Critical Care Medicine
in changes in the Premature Infant Pain Profile score between the high-dose and low-dose groups was –2.03 ± 4.13. The corresponding lower limit of one-tailed 97.5% CI was –7.24, below the noninferiority margin. Apneic events and bradycardia did not occur in the low-dose group; however, there were three episodes of apnea (42.9%) and one of bradycardia (14.3%) in the highdose group (p = 0.683 and 0.366, respectively). Conclusion: For mechanically ventilated preterm infants, the use of remifentanil at 0.25 μg/kg/min as an analgesic for short procedures represents a therapeutic option. Our pilot study suggests the need for larger randomized trials. (Pediatr Crit Care Med 2014; 15:451–455) Key Words: analgesia; mechanical ventilation; premature infant; procedure; remifentanil; sedation
T
here have been great advances in neonatal intensive care; consequently, critically ill preterm infant survival has increased. Paradoxically, as part of this life-saving medicine, the infants are exposed to multiple stressors in the neonatal period, even though minimal handling is an important approach for preterm infant care (1, 2). Because of extreme physiologic instability, multiple invasive procedures such as tracheal intubation, tracheal suction, blood sampling, and insertion of venous or arterial catheters are inevitable, and the number of such painful procedure during the neonatal ICU (NICU) stay has been reported to be 6–14 procedures per day (3, 4). Alterations in somatosensory perception and behavioral activity resulting after pain exposure in preterm infants have been reported (5–7). Furthermore, postnatal growth in very preterm infants is disturbed by neonatal pain (8). The growing evidence of the long-term effects of repeated pain in preterm infants on neurodevelopment has been challenging for neonatologists, and accordingly, the importance of pain control has been increasingly recognized for preterm infants (1, 9–11). Nonpharmacologic approaches, such as the use of breast milk, sucrose, and kangaroo care, have been widely used for www.pccmjournal.org
451
Shin et al
procedural pain (11–14). However, with regard to mechanically ventilated preterm infants, pharmacologic treatment is preferred for analgesia and sedation; for procedural pain during mechanical ventilation, a pharmacologic approach could be considered the first line for analgesia (11, 15, 16). Despite opioids such as morphine and fentanyl have been used for pain control in preterm infants, the choice and dosage of medication for these purposes have not yet been established. Remifentanil is an ultrashort-acting synthetic opioid that has been used in the neonatal ICU for the analgesia and sedation of preterm infants because of several pharmacokinetic benefits over other opioids (3, 11, 17, 18). It has a short b lood-brain equilibrium time of 1–1.5 minutes, with a rapid action and a short half-life of 3–5 minutes, which makes it optimal and predictable for short-term use (19). As remifentanil is the only opioid that is quickly degraded by nonspecific plasma and tissue esterase, its pharmacokinetics are not influenced by renal or liver function, making it adequate for the treatment of preterm infants (18). However, evidence for remifentanil usage in preterm infants is still lacking. In the existing studies, it has been used in combination with other analgesics for sedation, and the dosage was low (16, 20). In this study, we conducted a double-blinded, randomized, noninferiority comparison study to explore the efficacy of two remifentanil doses for short procedural pain in preterm infants with mechanical ventilation support.
MATERIALS AND METHODS This noninferiority, randomized, double-blind, controlled trial was conducted at the NICU of the Seoul National University Children’s Hospital and Ajou University Hospital between November 2011 and April 2012. The study protocol and data collection were approved by each hospital’s institutional review board, and written parental consent was obtained before enrollment. This study was conducted in compliance with the current revision of the Declaration of Helsinki and the Good Clinical Practice guidelines and registered with ClinicalTrials. gov (NCT01477892). Preterm infants who were supported by a mechanical ventilator with tracheal tube and requiring central venous access were eligible for the study. Before enrollment, no analgesics, sedatives, or muscle relaxants were administered to facilitate mechanical ventilation. The exclusion criteria were preterm infants with major congenital anomalies, cardiopulmonary instability, and medications of other sedative, antiepileptic, and anesthetic drugs. Infants with grade III or IV intraventricular hemorrhage before enrollment were also excluded. The infants were randomized sequentially using a w eb-based randomization program, which was run by the Medical Research Collaborating Center in Seoul National University Hospital. The enrolled infants were randomized into two remifentanil groups: 0.1 μg/kg/min dose (the low-dose [LD] group) and 0.25 μg/kg/ min dose (the high-dose [HD] group). The preparations of the study drugs were indistinguishable for the two groups that were administered different concentrations by pharmacists of the clinical trial center, who were the only personnel with the randomization table. The infusion was initiated 15 minutes before the procedure and stopped 10 minutes after the catheter had 452
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been secured to the skin and a dressing applied. The peripherally inserted central catheter (PICC) was inserted by each NICU’s dedicated nursing staff using polyurethane catheters with a 24-gauge cannula (Premicath, Vygon, Aachen, Germany). The analgesic effects of remifentanil were assessed using the Premature Infant Pain Profile (PIPP), a well-validated pain measurement instrument. The PIPP consists of three behavioral and two physiologic indicators and two contextual variables that modify pain (21, 22). Scores of 0–6 generally indicate the infant has minimal or no pain, 7–12 for moderate pain, and more than 12 for severe pain. In clinical relevance, changes of the scores between different situations and scores themselves are particularly important. Assessment was performed before study medication (P0), 10 minutes after infusion with skin preparation complete (P1), 15 minutes after infusion with needle puncture (P2), and 10 minutes after cessation of remifentanil infusion (P3). At each time point, a video recording was taken, focusing on the patient’s face. Simultaneously, heart rate (HR) and oxygen saturation (Spo2) were observed, and changes in HR or Spo2 were recorded for later scoring. The recorded files were stored, and the scoring was performed by a blinded neonatologist. The primary outcome was defined as changes in PIPP. Episodes of apnea, bradycardia, and desaturation during remifentanil infusion were recorded. The sample size was calculated based on another study, and the noninferiority margin (δ) was established as 1.5, considering the differences in PIPP scores between baseline and during the procedure (20). Based on the noninferiority margin, α = 5%, and β = 80%, 12 infants were calculated as being required for the study; based on a drop rate of 20%, a total of 16 infants was the target enrollment. Continuous variables were compared with the Wilcoxon rank sum test, and categorical variables were compared using the Fisher exact test. Statistical analyses were performed using SAS statistical software (SAS Institute, Cary, NC) and R 2.10.0 (The R Foundation for Statistical Computing Platform, Vienna, Austria).
RESULTS Fourteen preterm infants were enrolled, and two infants were dropped from the study due to consent withdrawal by the parents after randomization. After the 14 infants were enrolled including the two withdrawn infants, we closed the study with 12 infants completed according to the recommendation of the data monitoring committee because enrollment was behind schedule. Finally, 12 infants who fulfilled the sample size requirement were subjected to analysis. Seven infants were assigned to the HD group, and five infants were assigned to the LD group. The median gestational age (minimum, maximum) of the study population was 26 weeks (24+3, 31+6), and the median birth weight (minimum, maximum) was 825 g (610, 1,280). Gender, gestational age, birth weight, postmenstrual age, and weight at remifentanil infusion did not differ significantly between the groups (Table 1). The median postnatal ages (minimum, maximum) were 4 days (1, 32) and 7 days (2, 34), respectively. The levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine did not significantly differ between the groups. June 2014 • Volume 15 • Number 5
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Table 1.
Study Population Characteristics Low-Dose Group (Remifentanil, 0.1 μg/kg/min) (n = 5)
High-Dose Group (Remifentanil, 0.25 μg/kg/min) (n = 7)
p
Gestational age (wk)a
25+6 (24+3, 31+6)
26+1 (24+3, 30+4)
0.811
Birth weight (g)a
800 (610, 1,250)
850 (620, 1,280)
0.874
3 (60.0)
Gender (female)b
3 (42.9)
1.000
On study day 4 (1, 32)
Postnatal age (d)a Postmenstrual age (wk)
a
Weight (g)
a
0.529
950 (640, 1,250)
770 (650, 1,240)
0.692
27 (21, 45)
Alanine aminotransferase (IU/L)
a
Blood urea nitrogen (mL/dL)
a
Creatinine (mL/dL)
a
Urine of study day (mL/kg/d)
a
0.633
27 (24 , 30 )
+6
Aspartate aminotransferase (IU/L)
a
7 (2, 34)
30 (24 , 32) +1
+4
+6
+5
23 (20, 34)
0.706
6.5 (5, 8)
4 (3, 8)
0.097
13.5 (3, 49)
11 (3, 29)
0.782
0.635 (0.45, 0.9)
0.69 (0.47, 1.7)
0.367
2.58 (2.1, 3.7)
3.75 (2.4, 5.26)
0.077
Median (minimum, maximum). b n (%). a
With regard to the HD group, the mean PIPP gradually decreased to less than 6 during the procedure and in the recovery time, indicating minimal or no pain. In contrast, the mean PIPP increased during the procedure, indicating moderate pain, and then decreased during recovery in the LD group (Fig. 1). The changes in PIPP (CP0-P2) of the HD and LD groups were 1.43 ± 3.10 and –0.60 ± 5.32, respectively, and the CP0-P2 between the HD and LD groups was –2.03 ± 4.13. The corresponding lower limit of one-tailed 97.5% CI was –7.24 (Table 2). During remifentanil infusion, apneic events and bradycardia were not observed in the LD group; however, there were three infants with apneic events (42.9%) and one infant with bradycardia following apnea (14.3%) in the HD group, which was a nonsignificant difference (p = 0.683 and 0.366, respectively) (Table 3).
DISCUSSION The goal of this study was to explore the adequate remifentanil dose without serious adverse effects for procedural pain in mechanically ventilated preterm infants. The results of our study verified that 0.1 μg/kg/min of remifentanil infusion fails to show noninferiority to 0.25 μg/kg/min for procedural pain and that 0.25 μg/kg/min of remifentanil infusion during short procedures was an effective analgesic without serious adverse effects. Remifentanil could be a useful analgesic for procedural pain in preterm infants without serious adverse effects because of its pharmacokinetic characteristics (18, 23). First, because its metabolism is not influenced by renal and hepatic function, remifentanil may be a suitable drug for preterm infants with immature organs (23, 24). Furthermore, the short half-life of remifentanil makes it appropriate for short, pain-inducing procedures (18). To date, few clinical studies on remifentanil in preterm infants have been conducted and most involved premedication Pediatric Critical Care Medicine
before tracheal intubation (25–27). More recently, trials on remifentanil for analgesia and sedation during mechanical ventilation have been introduced. There was one randomized controlled trial by Lago et al (20) for short procedural pain in preterm infants (16, 28). The study by Lago et al (20) aimed to demonstrate the efficacy of LD remifentanil for PICC insertion, similar to the present study; however, there were important differences between the two studies in a clinical context. First, in this study, the study population was confined to mechanically ventilated preterm infants, which was not the case in the previous study. Because remifentanil has a suppressive effect on respiration, caution should be exercised when using remifentanil in preterm infants without ventilatory support. Second, therefore, including preterm infants without respiratory support, the study by Lago et al (20) used a LD of remifentanil (0.03 μg/kg/min) with sucrose instillation comparing to sucrose only, and the mean PIPP score of the remifentanil group during the procedure was higher than 8, which was less than the 6 in the HD group of the present study. A PIPP score less than 6 indicates no or minimal pain (21). A recommendation for remifentanil at 0.03 μg/kg/min for analgesia was not found elsewhere, and even though sucrose is a useful nonpharmacological intervention for procedural pain relief in neonates, the use of sucrose in extremely preterm, unstable, ventilated neonates is controversial (13). Therefore, for an appropriate analgesic effect, it is beneficial to confine the indication for remifentanil use to its use as a sufficient analgesia in preterm infants with ventilator assistance. Typically, remifentanil is used by gradual dose titration according to patient response for pain stressors during continuous infusion (24, 28). However, for short procedures, dose titration every 5 or 10 minutes is not suitable, especially for preterm infants fully draped for aseptic technique, interfering www.pccmjournal.org
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has been reported as being optimal for the analgesia and sedation of preterm infants during mechanical ventilation (24, 28). We hypothesized that in preterm infants, a lower remifentanil dose could be applicable for additional pain control, and we investigated the noninferiority of LD (0.1 μg/kg/min) to HD (0.25 μg/kg/min) remifentanil. As shown above, LD remifentanil failed to show noninferiority to HD remifentanil in control of procedural pain (Fig. 2). PIPP with LD remifentanil during the procedure scored more than 6, which indicates moderate pain. Our preliminary data revealed PIPP scores without analgesics during PICC insertion were 9–17 which indicated moderateto-severe pain (data not shown), so we decided not to use placebo group in this study because of ethical concerns. With regard to adverse Figure 1. The Premature Infant Pain Profile (PIPP) scores at baseline (P0), preparation (P1), skin puncture effects, apnea, bradycardia, (P2), and recovery (P3) showed a gradual decrease in the high-dose (HD) group, which was not shown in the and hypotension did not occur low-dose (LD) group. During procedure (P0 and P1), PIPP scores indicated minimal or no pain in HD group, whereas they indicated moderate pain in LD group. in the LD group. Among the seven patients in the HD group, with the assessment of pain. Therefore, it may be more practi- apnea developed in three patients, followed by bradycardia in cal to infuse a maintenance remifentanil dosage without titra- one patient; hypotension did not develop. Other laboratory tion during short procedures such as PICC insertion. findings did not show any differences after remifentanil infuWelzing and Roth (23) recommended commencing remision between the groups (data not shown). Although remifentanil infusion at a rate of 0.25 μg/kg/min for pain control fentanil of 0.25 μg/kg/min showed significantly comparable in neonates and infants. However, a lower dose of remifentanil adverse effects to 0.1 μg/kg/min, the symptoms of apnea and Table 2. Difference in Change of Premature Infant Pain Profile Value P2 From P0 Between Low-Dose and High-Dose Remifentanil Groups for the Noninferiority Test
Change of Premature Infant Pain Profile value P2 from P0
LD (n = 5)
HD (n = 7)
LD – HD
One-Sided Lower 97.5% CI
–0.60 ± 5.32
1.43 ± 3.10
–2.03 ± 4.13
–7.42
LD = low-dose remifentanil (0.1 μg/kg/min), HD = high-dose remifentanil (0.25 μg/kg/min).
Table 3. Comparisons of the Side Effects of the Low-Dose and High-Dose Remifentanil Groups Low-Dose Group (n = 5)
High-Dose Group (n = 7)
p
Apnea, n (%)
0 (0)
3 (42.9)
0.683
Bradycardia, n (%)
0 (0)
1 (14.3)
0.366
Hypotension, n (%)
0 (0)
0 (0)
—
Dash indicates data was statistically incomparable because no events occurred in both groups.
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Figure 2. The difference in changes in Premature Infant Pain Profile score between the high-dose and low-dose groups was –2.03 ± 4.13 (diamond and bar), and the corresponding lower limit of one-tailed 97.5% CI was –7.24, which was less than the noninferiority margin (vertical line).
bradycardia were shown only in the HD group. Although each adverse event was controllable in infants with mechanical ventilation, careful, close monitoring is necessary during remifentanil infusion. Because this study has a relatively small sample size for comparing adverse effects directly, further large-scale cohort studies should be conducted to address the safety issue.
CONCLUSIONS Where continuous monitoring of vital signs is available and for infants with mechanical ventilation support, the use of remifentanil at 0.25 μg/kg/min as an analgesic for short procedures represents a therapeutic option, owing to its favorable pharmacokinetic characteristics. Further studies with larger sample sizes and including pharmacokinetic data in preterm infants are necessary to compare adverse effects.
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