Abstract

Background. After alarming reports concerning deaths after sedation with propofol, infusion of this drug was contraindicated by the US Food and Drug Administration in children <18 yr receiving intensive care. We describe our experiences with propofol 6%, a new formula, during postoperative sedation in non-ventilated children following craniofacial surgery.

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 Index™ 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 3–17) months in all groups. Median duration of infusion was 11 (range 6–18) h for propofol 6% and 14 (range 5–17) 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 3–17) months, with dosages <4 mg kg−1 h−1 during a median period of 11 (range 6–18) h.

Propofol for sedation in children has become controversial after reports describing the propofol infusion syndrome, which is characterized by increased triglyceride (TG) levels,12 myocardial failure,13 rhabdomyolysis,23 metabolic acidosis,13 hyperthermia1 and death.1 Therefore a warning was issued against use of propofol by infusion as a sedative in children <18 yr in intensive care.4

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.89 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.1415 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

With approval from the Erasmus MC research ethics board and written consent from a parent or legal guardian, from July 2002 until September 2003 we studied children aged between 1 month and 2 yr of age admitted to our paediatric surgical intensive care unit (PSICU) during the first 24 h after elective craniofacial surgery. Exclusion criteria for propofol were known allergies for proteins, egg or propofol, respiratory infections, hypertriglyceridaemia, epilepsy, familial hypercholesterolaemia or weight <6 kg.

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 litre−1 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 kg−1 and fentanyl 2.5 µg kg−1, the trachea was intubated and ventilated with air, oxygen and isoflurane. Approximately 2 h before anticipated extubation, acetaminophen 40 mg kg−1 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 h−1 and 0.025 mg kg−1 h−1, respectively. If scores remained ≥17 during propofol infusion of a maximum of 4 mg kg−1 h−1, midazolam was added. At scores <9, propofol and midazolam dosing were decreased by 0.1 ml h−1 and 0.025 mg kg−1 h−1, 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 0–3 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 κ, was satisfactory, with κ>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 0–1.6 mmol litre−1 and CPK levels <230 U litre−1 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 10–15% 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 min−1 (see Table 1). Hyperthermia was defined as body temperature >38.3°C. Metabolic acidosis was defined as arterial pH <7.30 with a concomitant

\(P\mathrm{a}_{\mbox{\textsc{\mathrm{co}}}_{2}}{<}4.7\ \mathrm{kPa}\)
. All physiological parameters, except temperature, were screened hourly using a computer-guided patient data management system.

Table 1

Patient characteristics.

Data are median (range).

*

N/a, not applicable

Total n=55
 
Propofol n=17
 
Propofol + midazolam n=5
 
Midazolam n=23
 
No sedatives needed n=10
 
Patients (m/f) 11/6 4/1 17/6 5/5 
Age (months) 9 (4–17) 12 (11–17) 11 (3–15) 9 (4–13) 
Weight (kg) 9 (6–13) 10 (9–10) 10 (5–12) 8 (6–10) 
Duration of surgery (h) 5 (4–7) 4 (4–5) 5 (3–7) 5 (3–6) 
Duration of infusion of sedatives (h) 12 (6–17) 10 (7–18) 13 (4–17) *N/a 
Doses (mg kg−1 h−12.4 (1.8–4.0) Propofol 3.0 (1.8–3.6) Midazolam 0.1 (0.05–0.10) 0.05 (0.05–0.20) *N/a 
Baseline arterial pressure (mm Hg) 55 (35–100) 50 (40–60) 51 (35–82) 52 (45–55) 
Baseline heart rate (beats min−1129 (90–180) 127 (95–150) 113 (80–153) 121 (105–140) 
Total n=55
 
Propofol n=17
 
Propofol + midazolam n=5
 
Midazolam n=23
 
No sedatives needed n=10
 
Patients (m/f) 11/6 4/1 17/6 5/5 
Age (months) 9 (4–17) 12 (11–17) 11 (3–15) 9 (4–13) 
Weight (kg) 9 (6–13) 10 (9–10) 10 (5–12) 8 (6–10) 
Duration of surgery (h) 5 (4–7) 4 (4–5) 5 (3–7) 5 (3–6) 
Duration of infusion of sedatives (h) 12 (6–17) 10 (7–18) 13 (4–17) *N/a 
Doses (mg kg−1 h−12.4 (1.8–4.0) Propofol 3.0 (1.8–3.6) Midazolam 0.1 (0.05–0.10) 0.05 (0.05–0.20) *N/a 
Baseline arterial pressure (mm Hg) 55 (35–100) 50 (40–60) 51 (35–82) 52 (45–55) 
Baseline heart rate (beats min−1129 (90–180) 127 (95–150) 113 (80–153) 121 (105–140) 

Determining efficacy

To compare the efficacy of propofol with that of midazolam, we considered COMFORT behaviour, VAS scores and BIS values in four groups: children receiving propofol, children receiving propofol with additional midazolam, children receiving midazolam and children who did not need sedation. Additionally, we determined the dose change frequency, i.e. the number of times that dosing of propofol or midazolam was adjusted.

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 Mann–Whitney U-test. Statistical differences were considered significant if P<0.05. A correlation r of 0.10–0.29 was considered small, 0.30–0.49 was considered medium and ≥0.50 was considered large.

Results

We studied 55 patients, with a median age of 10 (iqr 3–17) months and weight 9 (5–13) kg. Preoperative diagnoses were scaphocephaly (n=26), trigonocephaly (n=18), brachycephaly (n=2), encephalocele (n=1), plagiocephaly (n=5) and Saethre–Chotzen syndrome (n=3). There were no significant differences between the groups with regard to age, weight, duration of surgery or duration of infusion of sedatives (Table 1).

In one patient the TG level was 2.00 mmol litre−1 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 litre−1 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 litre−1 before infusion. The second patient had CPK levels of 336 U litre−1before infusion, 276 U litre−1 during infusion and 240–282 U litre−1 after infusion. One patient receiving propofol had a CPK level of 313 U litre−1 after infusion. These patients showed no acidosis, no abnormal physiological parameters and no increased TG levels.

Fig 1

Triglyceride levels.

Fig 1

Triglyceride levels.

Fig 2

Creatine phosphokinase levels.

Fig 2

Creatine phosphokinase levels.

There were no respiratory complications. Three patients, one receiving propofol and two receiving midazolam, experienced short periods of desaturation with spontaneous recovery.

Median minimum arterial pressure was 56 mm Hg and 59 mm Hg for propofol 6% and no propofol 6%, respectively (Mann–Whitney U-test, 330; P=0.57). Median minimal heart rate was 110 beats min−1 and 111 beats min−1 for propofol 6% and no propofol 6%, respectively (Mann–Whitney U-test, 353; P=0.86). One episode of bradycardia lasting for 90 s (median 77 beats min−1) 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 (Mann–Whitney 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 13–18) observations per patient. During infusion of propofol 6% median COMFORT and BIS values were 11 (9–18) and 78 (65–91), respectively. During infusion of midazolam, median COMFORT and BIS values were 11 (9–15) and 77 (63–91), 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 kg−1 h−1 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 kg−1 h−1).

One of the patients receiving midazolam became agitated and more restless after administration of up to 0.2 mg kg−1 h−1 maintenance infusion and five doses of midazolam.

Discussion

We did not encounter any problems with propofol 6% in dosages <4 mg kg−1 h−1 in children with a median age of 10 (iqr 3–17) months during a median period of 11 (range 6–18) h.

Propofol doses of 2 mg kg−1 h−1 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 litre−1 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.2223 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 1–5 yr, following cardiac surgery, and found no adverse events. A number of authors have published guides to drug selection and use in the PICU.1482627 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 h814 and taking into account the lipid content of propofol when calculating patients' daily caloric intakes.1426

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.182829 Parke and colleagues1 reported five critically ill children who received propofol for >90 h at a rate of >5 mg kg h−1 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,223031 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 kg−1 h−1 in children with a median age of 10 (iqr 3–17) 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.

S. A. Prins and M. Y. M. Peeters contributed equally to this paper.

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Author notes

1Department of Paediatric Surgery and 3Department of Anaesthesiology, Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands. 2Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. 4Leiden/Amsterdam, Centre for Drug Research, Division of Pharmacology, University of Leiden, Leiden, The Netherlands

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