1 Department of Paediatric Surgery and 3 Department of Anaesthesiology, Erasmus MCSophia Children's Hospital, Rotterdam, The Netherlands. 2 Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. 4 Leiden/Amsterdam, Centre for Drug Research, Division of Pharmacology, University of Leiden, Leiden, The Netherlands
* Corresponding author. E-mail: j.illsley{at}erasmusmc.nl
Accepted for publication December 20, 2004.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. In a prospective cohort study, children admitted to the paediatric surgical intensive care unit following major craniofacial surgery were randomly allocated to sedation with propofol 6% or midazolam, if judged necessary on the basis of a COMFORT behaviour score. Exclusion criteria were respiratory infection, allergy for proteins, propofol or midazolam, hypertriglyceridaemia, familial hypercholesterolaemia or epilepsy. We assessed the safety of propofol 6% with triglycerides (TG) and creatine phosphokinase (CPK) levels, blood gases and physiological parameters. Efficacy was assessed using the COMFORT behaviour scale, Visual Analogue Scale and Bispectral IndexTM monitor.
Results. Twenty-two children were treated with propofol 6%, 23 were treated with midazolam and 10 other children did not need sedation. The median age was 10 (IQR 317) months in all groups. Median duration of infusion was 11 (range 618) h for propofol 6% and 14 (range 517) h for midazolam. TG levels remained normal and no metabolic acidosis or adverse events were observed during propofol or midazolam infusion. Four patients had increased CPK levels.
Conclusion. We did not encounter any problems using propofol 6% as a sedative in children with a median age of 10 (IQR 317) months, with dosages <4 mg kg1 h1 during a median period of 11 (range 618) h.
Keywords: anaesthesia, paediatric ; anaesthetics i.v., propofol ; sedation, postoperative ; safety
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In Diprivan®-10, propofol is formulated in Intralipid® 10 %. Long-term infusions of Diprivan®-10 have been associated with increases in serum lipid levels, notably TG.3 In order to reduce the volume and amount of lipids, a new formulation of propofol 6% in Lipofundin® MCT/LCT 10% (propofol 6%) was developed and tested in animals,5 adults6 and six children.7
In contrast with propofol, midazolam is a widely used sedative for children.8 9 On initial administration, it has a short duration of action.10 However, paradoxical reactions such as agitation,11 convulsions, hyperactivity and adverse reactions12 have been reported in neonates and children.13 Also, the active metabolites and prolonged effect of midazolam often delay awakening and weaning from mechanical ventilation.14 15 A new formula for propofol would be an alternative or additional sedative in children receiving intensive care. In view of the existing controversies, we present our experiences with propofol 6% as a postoperative sedative in non-ventilated children <2 yr of age following major craniofacial surgery.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
At least 1 day before surgery, the parents of eligible patients were asked to give written informed consent for either propofol or midazolam. If consent for propofol was refused, consent was asked for midazolam, even though midazolam is our standard of care. Four patients were excluded from receiving propofol on the grounds of familial hypercholesterolaemia, one patient was excluded as his TG level was 2.62 mmol litre1 the day before surgery, probably because he had been fed just before blood sampling, and parents of two patients refused consent for propofol. These seven patients received midazolam for sedation instead of propofol.
Perioperative procedure
Anaesthesia was induced with either sevoflurane or i.v. thiopental. An arterial line and a central venous line were placed for clinical purposes and blood was drawn to evaluate liver and kidney function, TG level and creatine phosphokinase (CPK) level. After i.v. administration of vecuronium 0.1 mg kg1 and fentanyl 2.5 µg kg1, the trachea was intubated and ventilated with air, oxygen and isoflurane. Approximately 2 h before anticipated extubation, acetaminophen 40 mg kg1 was administered rectally as previously described.16 After surgery, the trachea was extubated and the patient was transferred to the PSICU, where heart rate, arterial pressure, oxygen saturation and central venous pressure were monitored continuously. Body temperature was measured every 2 h. Routine postoperative care included evaluation of haemoglobin, haematocrit, thrombocytes, white blood count and arterial blood gases. The children received no parenteral nutrition during the study period.
Sedation and analgesia protocol
On admission to the PSICU, usually in the early afternoon, sedation and analgesia levels were assessed using the COMFORT behaviour scale and the Visual Analogue Scale (VAS). At COMFORT behaviour scores <17, no sedatives were given. At scores 17, propofol or midazolam was started. At VAS scores
4, more analgesia was given. During the first 2 h after start of sedation, sedation and analgesia levels were assessed at least three times using the COMFORT, VAS and Bispectral Index (BIS) values. After the first 2 h, the level of sedation was assessed every 2 h until the next morning. If the COMFORT behaviour score remained
17 after administration of a sedative, propofol and midazolam dosing were increased by 0.1 ml h1 and 0.025 mg kg1 h1, respectively. If scores remained
17 during propofol infusion of a maximum of 4 mg kg1 h1, midazolam was added. At scores <9, propofol and midazolam dosing were decreased by 0.1 ml h1 and 0.025 mg kg1 h1, respectively.
At 8 a.m. the next morning, the sedatives were stopped to allow the patients to wake up and prepare for transfer to medium care. The effects of stopping the infusion were assessed using the COMFORT, VAS and BIS scores for the next 2 h. At approximately 11 a.m., all children were transferred to medium care.
The COMFORT behaviour scale
The COMFORT behaviour scale is an adapted version of the scale that was originally developed by Ambuel and colleagues17 in 1992 and consists of six behavioural items and two physiological parameters, heart rate and blood pressure. Marx and colleagues18 showed that this scale was useful to assess sedation. We showed that, leaving out the physiological items, the scale was still valid for both postoperative pain and sedation in children aged 03 yr.19 The COMFORT behaviour scale assesses six patterns of behaviour: alertness, calmness, muscle tone, body movement, facial tension, crying (non-ventilated children) or respiratory response (ventilated children). The total score ranges from 6 to 30: the higher the score, the more uncomfortable the child is. All nurses were trained to use the COMFORT behaviour scale, as reported in our earlier analgesia study.19 Inter-observer reliability, represented by linearly weighted , was satisfactory, with
>0.65 for all nurses and the principal investigator. A COMFORT behaviour score <9 represents over-sedation, a score between 9 and 17 represents no distress and a score
17 represents distress.
Bispectral Index monitor
Sedation was assessed continuously using a Bispectral A 2000 version 3.12 monitor (Aspect Medical Systems, Natick, MA, USA) with commercially available paediatric BIS sensors applied according to the manufacturer's instruction manual. We used the impedance limits set in the monitor; if the signal quality index was >50, the BIS value was recorded.
Visual Analogue Scale
To determine whether restlessness might be induced by pain, analgesia levels were assessed using the VAS. At VAS scores 4, more analgesia was given. If the VAS score was <4 and the COMFORT behaviour score was
17, a sedative was given.
Determining safety
Before, during and 2 h after stopping the infusion of propofol or midazolam, we determined TG and CPK levels to evaluate the influence of propofol on these variables. We used an enzymatic and colorimetric in vitro test with a Hitachi analyser (Roche Diagnostics GmbH, Mannheim, Germany). TG levels in the range 01.6 mmol litre1 and CPK levels <230 U litre1 were considered normal.20 We defined desaturation as saturation <95% for >5 s and requiring intervention. Hypotension was defined as any period of time when a patient's arterial pressure was 1015% below the arterial pressure mentioned in Table 1. Bradycardia was defined as any period of time when a patient's heart rate was <80 beats min1 (see Table 1). Hyperthermia was defined as body temperature >38.3°C. Metabolic acidosis was defined as arterial pH <7.30 with a concomitant . All physiological parameters, except temperature, were screened hourly using a computer-guided patient data management system.
|
Medication preparation
Propofol 6% was prepared in the Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.21 Propofol 6% was given through a central venous line in order to prevent pain from injection. Midazolam hydrochloride was dissolved in glucose 5% to make an i.v. solution.
Statistical analysis
The data were analysed using SPSS for Windows (version 10.0; SPSS, Chicago, IL). The safety parameters of children receiving propofol 6% and those receiving no propofol 6% were compared using the MannWhitney U-test. Statistical differences were considered significant if P<0.05. A correlation r of 0.100.29 was considered small, 0.300.49 was considered medium and 0.50 was considered large.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In one patient the TG level was 2.00 mmol litre1 during propofol infusion without metabolic acidosis, disturbance of physiological parameters or increase of CPK levels (Fig. 1). Four patients had raised CPK levels, ranging from 261 to 313 U litre1 during and after the end of infusion (Fig. 2). Three patients had received propofol and one patient had no medication. Two patients receiving propofol had elevated CPK levels before the start of infusion and one of these patients had elevated CPK levels during and after infusion. The first patient had CPK levels of 261 U litre1 before infusion. The second patient had CPK levels of 336 U litre1before infusion, 276 U litre1 during infusion and 240282 U litre1 after infusion. One patient receiving propofol had a CPK level of 313 U litre1 after infusion. These patients showed no acidosis, no abnormal physiological parameters and no increased TG levels.
|
|
Median minimum arterial pressure was 56 mm Hg and 59 mm Hg for propofol 6% and no propofol 6%, respectively (MannWhitney U-test, 330; P=0.57). Median minimal heart rate was 110 beats min1 and 111 beats min1 for propofol 6% and no propofol 6%, respectively (MannWhitney U-test, 353; P=0.86). One episode of bradycardia lasting for 90 s (median 77 beats min1) was observed in a patient receiving midazolam. The median maximum temperature was 37.8°C during propofol administration and 37.7°C with no propofol (MannWhitney U-test, 352; P=0.84).
A total of 915 paired COMFORT behaviour scores, VAS and BIS values were obtained with a median of 15 (IQR 1318) observations per patient. During infusion of propofol 6% median COMFORT and BIS values were 11 (918) and 78 (6591), respectively. During infusion of midazolam, median COMFORT and BIS values were 11 (915) and 77 (6391), respectively. VAS was 4 in only seven observations in seven children (less than 1% of all observations). The starting dose of propofol was sufficient in three children (<14%). A propofol infusion of 4 mg kg1 h1 was not sufficient in five cases (
23% of the propofol group), and these patients received additional sedation with either a single dose of midazolam (two patients), multiple doses (two patients) or continuous midazolam infusion (one patient) (median rate 0.05 mg kg1 h1).
One of the patients receiving midazolam became agitated and more restless after administration of up to 0.2 mg kg1 h1 maintenance infusion and five doses of midazolam.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Propofol doses of 2 mg kg1 h1 were insufficient to maintain an adequate sedation level in >86% of the children. Midazolam was insufficient in only 21% of the children. The TG level was 2.0 mmol litre1 in only one patient, during propofol infusion, without abnormalities in other physiological parameters. This patient had been fed with formula milk Nutrilon 1 (Nutricia, Zoetermeer, The Netherlands) just before blood sampling. Four other patients had increased CPK levels, without other signs of the propofol infusion syndrome.22 23 An increase in the CPK level can also be a valid indication of the extent of muscle damage. Muscle damage due to major muscle-cutting surgery, such as craniofacial surgery, has been reported and should be taken into account when interpreting CPK levels postoperatively.23 CPK levels 10 times higher than normal are regarded as a warning sign for rhabdomyolysis.23
A review of the literature yields reports both for and against the use of propofol as a sedative in children. Seventeen publications support propofol use in children in the paediatric intensive care unit (PICU). Pepperman and Macrae24 found no differences in mortality between propofol and other sedative agents in 198 children. Cornfield and colleagues25 described continuous infusion of propofol in 142 critically ill children, with a mean age of 5 yr 9 months. Ten showed metabolic acidosis and 10 died during the first week of propofol infusion. These deaths could all be attributed to the primary diagnosis. Martin and colleagues20 described nine children on mechanical ventilation receiving propofol for sedation and concluded that it was useful and safe. Knibbe and colleagues7 evaluated propofol for <6 h sedation in six children aged 15 yr, following cardiac surgery, and found no adverse events. A number of authors have published guides to drug selection and use in the PICU.14 8 26 27 They acknowledge that propofol infusion may cause problems and therefore suggest avoiding it in patients with sepsis, respiratory infections or underlying metabolic problems,8 avoiding infusion for >24 h8 14 and taking into account the lipid content of propofol when calculating patients' daily caloric intakes.14 26
Fourteen publications and one unpublished trial outline adverse events and deaths associated with propofol. Twelve publications pertain to children, four of which are case reports describing a total of eight children, aged from 4 weeks to 13 yr.1 8 28 29 Parke and colleagues1 reported five critically ill children who received propofol for >90 h at a rate of >5 mg kg h1 and died. The high doses and long duration may explain these deaths. Regrettably, these case reports reveal no details on use of parenteral feeding. Bray2 reviewed propofol infusion in a PICU and found a significant association between long-term high-dose propofol infusion and the development of progressive myocardial failure. However, full details on comorbidity and parenteral feeding are lacking. Bray,22 30 31 Cray and colleagues29 and Cravero (unpublished data) expressed concerns about propofol as a sedative in children. Strickland and colleagues32 reported an 11-year-old girl with an astrocytoma who died after long-term propofol infusion. However, a cause-and-effect relationship could not be determined. More recently, Koch and colleagues33 described a 5-year-old child receiving short-term propofol infusion at a high rate who developed lactic acidosis.
Based on 14 publications, describing 27 patients, and one unpublished trial, the US Food and Drugs Administration contraindicated propofol for sedation of children <18 yr receiving intensive care.4 However, 17 other publications appeared in support of propofol, reviewing a total of 395 patients without evidence for a relationship between propofol infusion and death.
This paper describes a prospective cohort study comparing safety and efficacy of propofol and midazolam in children <2 yr. Clearly, our study has limitations. First, the number of children receiving propofol 6% in this study is too small to allow conclusions to be drawn. Reviewing the total of 422 children described in the above publications with regard to safety, eight children (<2%) had evidence of propofol infusion syndrome.3 Thus, to encounter one child with the propofol infusion syndrome, we would have had to include at least 50 patients receiving propofol. Secondly, all the children studied were healthy, apart from their major craniofacial deformities. Therefore these children are not representative of the general ICU population. Thirdly, the children received low doses of propofol; higher doses might have produced adverse events. Fourthly, blinding was not possible in this study because of propofol's characteristic consistency. Fifthly, randomization was aimed at but failed for unforeseen logistic reasons.
Despite the limitations of our study, it is important to note that we did not encounter any problems using propofol 6% as a sedative with dosages <4 mg kg1 h1 in children with a median age of 10 (IQR 317) months during a median period of 11 (6 to 18) h in postoperative patients without multiple organ failure or critical illness. Based on this study, it is too early to state that propofol is safe for sedation in children. However, we believe that it is important to share our experiences with propofol 6% and call for randomized controlled trials in paediatric patients to establish the safety of propofol as a sedative.
![]() |
Footnotes |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth 1998; 8: 4919[CrossRef][ISI][Medline]
3 Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003; 29: 141725[CrossRef][ISI][Medline]
4 FDA. Pediatric Exclusivity Labeling Changes: Center for Drug Evaluation and Research 2003
5 Cox EH, Knibbe CA, Koster VS, et al. Influence of different fat emulsion-based intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol. Pharm Res 1998; 15: 4428[CrossRef][ISI][Medline]
6 Knibbe CA, Naber H, Aarts LP, Kuks PF, Danhof M. Long-term sedation with propofol 60 mg ml1 vs. propofol 10 mg ml1 in critically ill, mechanically ventilated patients. Acta Anaesthesiol Scand 2004; 48: 3027[CrossRef][ISI][Medline]
7 Knibbe CA, Melenhorst-de Jong G, et al. Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery. Br J Clin Pharmacol 2002; 54: 41522[CrossRef][ISI][Medline]
8 Bennett NR. Paediatric intensive care. Br J Anaesth 1999; 83: 13956
9 Pitetti RD, Singh S, Pierce MC. Safe and efficacious use of procedural sedation and analgesia by nonanesthesiologists in a pediatric emergency department. Arch Pediatr Adolesc Med 2003; 157: 10906
10 Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther 1981; 30: 65361[ISI][Medline]
11 Cheng C, Roemer-Becuwe C, Pereira J. When midazolam fails. J Pain Symptom Manage 2002; 23: 25665[CrossRef][ISI][Medline]
12 Booker PD, Beechey A, Lloyd-Thomas AR. Sedation of children requiring artificial ventilation using an infusion of midazolam. Br J Anaesth 1986; 58: 11048[Abstract]
13 Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2000: CD002052
14 Tobias JD. Sedation and analgesia in paediatric intensive care units: a guide to drug selection and use. Paediatr Drug. 1999; 1: 10926
15 Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med 1998; 26: 94756[CrossRef][ISI][Medline]
16 van der Marel CD, van Lingen RA, Pluim MA, et al. Analgesic efficacy of rectal versus oral acetaminophen in children after major craniofacial surgery. Clin Pharmacol Ther 2001; 70: 8290[CrossRef][ISI][Medline]
17 Ambuel B, Hamlett KW, Marx CM, Blumer JL. Assessing distress in pediatric intensive care environments: the COMFORT scale. J Pediatr Psychol 1992; 17: 95109[Abstract]
18 Marx CM, Smith PG, Lowrie LH, et al. Optimal sedation of mechanically ventilated pediatric critical care patients. Crit Care Med 1994; 22: 16370[ISI][Medline]
19 van Dijk M, de Boer JB, Koot HM, Tibboel D, Passchier J, Duivenvoorden HJ. The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain 2000; 84: 36777[CrossRef][ISI][Medline]
20 Martin PH, Murthy BV, Petros AJ. Metabolic, biochemical and haemodynamic effects of infusion of propofol for long-term sedation of children undergoing intensive care. Br J Anaesth 1997; 79: 2769
21 Peeters MYM, Lange R, Aarts LPHJ, Talsma H, Knibbe CAJ. Stability of an intravenous fat emulsion containing 6% propofol and a low amount of emulsifier. Eur J Hosp Pharmacy 2004; 1: 2018
22 Bray RJ. Propofol-infusion syndrome in children Lancet 1999; 353: 20745
23 Laurence AS. Serum myoglobin and creatine kinase following surgery. Br J Anaesth 2000; 84: 7636[Abstract]
24 Pepperman ML, Macrae D. A comparison of propofol and other sedative use in paediatric intensive care in the United Kingdom. Paediatr Anaesth 1997; 7: 14353[CrossRef][ISI][Medline]
25 Cornfield DN, Tegtmeyer K, Nelson MD, Milla CE, Sweeney M. Continous propofol infusion in 142 critically ill children. Pediatrics 2002; 110: 117781
26 Aun CS. New i.v. agents. Br J Anaesth 1999; 83: 2941
27 Fulton B, Sorkin EM. Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation. Drugs 1995; 50: 63657[ISI][Medline]
28 Bray RJ. Fatal myocardial failure associated with a propofol infusion in a child. Anaesthesia 1995; 50: 94
29 Cray SH, Robinson BH, Cox PN. Lactic acidaemia and bradyarrhythmia in a child sedated with propofol. Crit Care Med 1998; 26: 208792[CrossRef][ISI][Medline]
30 Bray RJ. Heart block following propofol in a child. Paediatr Anaesth 2000; 10: 226[ISI][Medline]
31 Bray RJ. Propofol infusion for ICU sedation in children. Anaesthesia 2002; 57: 521[ISI][Medline]
32 Strickland RA, Murray MJ. Fatal metabolic acidosis in a pediatric patient receiving an infusion of propofol in the intensive care unit: is there a relationship? Crit Care Med 1995; 23: 4059[CrossRef][ISI][Medline]
33 Koch M, De Backer D, Vincent JL. Lactic acidosis: an early marker of propofol infusion syndrome? Intensive Care Med 2004; 30: 522[CrossRef][ISI][Medline]
|