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Propofol for procedural sedation/anaesthesia in neonates

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Authors

Prakeshkumar S Shah1, Vibhuti S Shah2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A, University of Toronto, Toronto, Canada [top]
2Associate Professor Departments of Paediatrics and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada [top]

Citation example: Shah PS, Shah VS. Propofol for procedural sedation/anaesthesia in neonates. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD007248. DOI: 10.1002/14651858.CD007248.pub2.

Contact person

Prakeshkumar S Shah

Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A
University of Toronto
600 University Avenue
Toronto Ontario M5G 1XB
Canada

E-mail: pshah@mtsinai.on.ca

Dates

Assessed as Up-to-date: 06 December 2010
Date of Search: 30 September 2010
Next Stage Expected: 06 December 2012
Protocol First Published: Issue 3, 2008
Review First Published: Issue 3, 2011
Last Citation Issue: Issue 3, 2011

What's new

Date / Event Description

History

Date / Event Description

Abstract

Background

Elective medical or surgical procedures are commonplace for neonates admitted to NICU. Agents such as opioids are commonly used for achieving sedation/analgesia/anaesthesia for such procedures; however, these agents are associated with adverse effects. Propofol is used widely in paediatric and adult populations for this purpose. The efficacy and safety of the use of propofol in neonates has not been defined.

Objectives

To determine the efficacy and safety of propofol treatment compared to placebo or no treatment or alternate active agents in neonates undergoing sedation or anaesthesia for procedures. To conduct subgroup analyses according to method of propofol administration (bolus or continuous infusion), type of active control agent (neuromuscular blocking agents with or without the use of sedative, analgesics or anxiolytics), type of procedure (endotracheal intubation, eye examination, other procedure), and gestational age (preterm and term).

Search methods

We searched MEDLINE (1950 to September 30, 2010), EMBASE (1980 to September 30, 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 2) for eligible studies without language restriction. We searched reference lists of identified articles and abstracts submitted to Pediatric Academic Societies (2002 to 2009), and international trials registries for eligible articles.

Selection criteria

We included randomised or quasi-randomised controlled trials of propofol versus placebo, no treatment or other sedative/anaesthetic/analgesic agents in isolation or combination used in neonates for procedures.

Data collection and analysis

We collected and analysed data in accordance with the standard methods of the Cochrane Neonatal Review Group.

Results

One open-label randomised controlled trial of 63 neonates was eligible for inclusion. Thirty-three neonates in the propofol group were compared to 30 infants in the morphine-atropine-suxamethonium group. There was no statistically significant difference in the number of infants who required multiple intubation attempts (39% in the propofol group versus 57% in the morphine-atropine-suxamethonium group; RR 1.40, 95% CI 0.85 to 2.29). Times required to prepare medication, to complete the procedure and for recovery to previous clinical status were shorter in the propofol group. No difference in clinically significant side effects was observed; however, the number of events was small.

Authors' conclusions

No practice recommendation can be made based on the available evidence regarding the use of propofol in neonates. Further research is needed on the pharmacokinetics of propofol in neonates and once a relatively safe dose is identified, randomised controlled trials assessing the safety and efficacy of propofol are needed.

Plain language summary

Propofol use for sedation in newborn babies undergoing procedures

Procedures performed in preterm and term neonates can be stressful and at times painful. Medications to reduce stress/pain for babies can lead to side effects. Propofol is a commonly used medication in adults and children to achieve sedation during minor procedures or major operations. Its use in newborn babies is studied in only one study of 63 babies. Propofol helped to reduce time to complete procedure, time of recovery and time to prepare drugs. However, with this small number of newborns studied, the safety can not be proven. Further studies are warranted.

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Background

Description of the condition

Elective or semi-elective procedures requiring sedation, analgesia, or anaesthesia are commonly performed in neonates admitted to neonatal intensive care units (NICU) or neonates admitted for elective procedures. In the NICU, these procedures may include endotracheal intubation, eye examination for retinopathy of prematurity and for some surgeries like ligation of patent ductus arteriosus or laser therapy for retinopathy of prematurity. Elective procedures in neonates include other scheduled surgical or investigative procedures requiring anaesthesia. Under most circumstances in the current practice environment, sedative, analgesic and/or anxiolytic agents are used for such events. These agents are perceived to reduce pain, stress and haemodynamic instability associated with these procedures and facilitate completion of the procedure in a timely manner (Oei 2002). However, all of these agents are associated with side effects. Major complications of the use of any such agent include hypotension and respiratory depression necessitating provision of respiratory support or escalation of respiratory support and ongoing intensive care.

Description of the intervention

Commonly used agents include combinations of neuromuscular blocking agents such as suxamethonium or pancuronium, anxiolytics such as diazepam or midazolam and analgesics such as morphine or fentanyl. At times, these are combined with atropine to counteract chronotropic side effects. For short-term sedation and anaesthesia, propofol has been widely used in adult and most paediatric intensive care units. Its rapid onset of action and rapid termination of effects when discontinued has attracted a wide interest and use. Propofol is a lipophilic anaesthetic agent that has rapid distribution from blood to central nervous system and fat and rapid redistribution (Allegaert 2007). Propofol is metabolised mainly via glucuronidation. Changes in the body fluid composition can affect the metabolism and clearance of propofol. Serious side effects have been reported. Parke 1992 reported deaths of five paediatric patients following prolonged infusion of propofol. A constellation of symptoms including lactic acidosis, myoglobinuria, bradyarrhythmia and myocardial failure was noted. Bray 1998 reviewed these and subsequent reported cases of side effects and coined the term “propofol infusion syndrome”; however, none of the patients had common characteristics except that most of them had respiratory infection as the cause of admission to a paediatric intensive care unit. Vasile 2003 reported that impairment of fatty acid metabolism accompanied by use of catecholamines and/or steroids in patients with acute neurological disease or inflammatory process was responsible for myocytolysis and subsequent deaths in patients who had propofol infused at rates greater than 5 mg/kg/hr for greater than 48 hours. A survey of paediatric intensive care units revealed that 47% of units routinely used propofol for induction and maintenance of anaesthesia (Playfor 2004). Reported side effects include persistent hypoxaemia, bradycardia, hypotension, and clonic convulsion (Gelber 1997). In contrast to Parke 1992, there are also reports and anecdotal experiences of the successful use of propofol without complications in paediatric patients (Crawford 2003; Sloan 2003).

How the intervention might work

Propofol is a lipophilic anaesthetic agent. Use of propofol for maternal anaesthesia during cesarean section led to the observation that propofol is transferred across the placenta (Sanchez-Alcaraz 1998) and secreted in breast milk. Case reports have identified neonatal respiratory depression associated with the maternal propofol administration during cesarean section. However, these effects were transient and required brief interventions only (Sanchez-Alcaraz 1998; Van de Velde 2004). Maturational changes in body composition are highest in the neonatal period. Allegaert 2007, Allegaert 2007a and Rigby-Jones 2002 observed that the distribution of propofol in neonates is markedly different from the distribution in children and adults. Among neonates, preterm neonates and neonates who had cardiac surgery were at the most risk for accumulation due to their slow clearance of propofol during both bolus and continuous infusion (Rigby-Jones 2002). This may lead to longer recovery periods compared to adults and paediatric patients.

Why it is important to do this review

Based on the experience in the paediatric population, propofol has been used in neonates (Golden 2001; Lim 2005). In a neonatal swine model, propofol infusion was not associated with alteration of systolic and diastolic function of left ventricle (Graham 1998). Case reports of the successful use of propofol in neonates (Bacon 1994; Golden 2001), especially for neonates with oropharyngeal complications, have raised the issue of the potential for the use of propofol in neonates. However, serious side effects associated with propofol use have been reported (Gelber 1997; Veyckemans 2001). The office of Food and Drug Administration reviewed concerns regarding neurotoxicity associated with use of certain anaesthetic agents in neonates and issued a cautionary note regarding the safety of these agents (Mellon 2007). Hatch 1999 agreed with a cautious approach in adopting propofol for neonatal anaesthesia as suggested by Bray 1998; however, Reed 1996 questioned the mechanism of these events and called for rigorous studies. This controversy still exists. If identified as effective without significant side effects, propofol could play a significant role in anaesthesia for neonates.

Objectives

Primary objective:

To determine the efficacy and safety of propofol treatment in neonates undergoing sedation or anaesthesia for procedures.

  1. Propofol compared with placebo or no treatment.
  2. Propofol compared with alternative active agents.

Secondary objectives:

To conduct subgroup analyses according to method of propofol administration (bolus or continuous infusion), type of active control agent (neuromuscular blocking agents with or without the use of sedative or anxiolytics), type of procedure (endotracheal intubation, eye examination, other procedure), and gestational age (preterm and term).

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Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised controlled trials of propofol versus placebo/no treatment or another regimen of anaesthesia/sedation for neonates were included. Cross-over studies were not included as there would not be time for a “wash out” period and the effects of individual agents could not be ascertained in such studies.

Types of participants

We included both term and preterm neonates (postnatal age maximum of 28 days after reaching 40 weeks corrected gestational age) undergoing any diagnostic and/or therapeutic procedure requiring sedation/analgesia/anaesthesia.

Types of interventions

We included propofol versus placebo, no treatment, or any other regimen for sedation/anaesthesia. We included studies of both bolus and continuous infusion of propofol and studies of any dose and duration of propofol.

Types of outcome measures

Primary outcomes

Success of achievement of proper sedation/anaesthesia as measured by:

  1. Completion of the targeted objective (sedation/anaesthesia) without use of any other agent.
  2. Achievement of adequate sedation/anaesthesia (as reported by trial authors).
Secondary outcomes
  1. Stress to infants during the procedure as measured by:
    1. need for repeated attempts to achieve primary goal (e.g. dichotomised as success with first attempt or not);
    2. change in heart rate or number of episodes of bradycardia (as defined by investigators);
    3. change in oxygen saturation or episode of hypoxaemia requiring intervention (as defined by investigators);
    4. change in blood pressure or hypotension episodes requiring intervention (as defined by investigators).
  2. Time to complete the procedure (time for successful completion of procedures among neonates who had completion of procedure in the first attempt and among those who required more than one attempt);
  3. Time for preparation of the anaesthetic agents (time from onset of preparation of medication to administration of medication);
  4. Time to achieve sleep/muscle relaxation (time from receipt of medication to achievement of sleep/muscle relaxation);
  5. Time to recovery to prior clinical status (time from completion of procedure to return of clinical status);
  6. Safety of propofol (occurrence of these side effects during or within 24 hours of stoppage of medication) (as defined by investigators):
    1. Incidence of sustained hypoxaemia > 1 minute (saturation below target limit);
    2. Incidence of hypotension (need for fluid bolus or inotropes to maintain blood pressure);
    3. Incidence of metabolic acidosis (need for correction of acidosis by fluid bolus or sodium bicarbonate);
    4. Incidence of lactic acidosis (serum lactate > 2 mmol/l);
    5. Incidence of rhabdomyolysis (myoglobinuria, rising creatinine);
    6. Incidence of hyperkalaemia (serum potassium > 5.5 mmol/l);
    7. Incidence of renal failure (serum creatinine > 125 umol/l);
    8. Incidence of seizures;
    9. Mortality (all cause mortality assessed at < 28 days of completion of therapy).

Search methods for identification of studies

Electronic searches

We searched MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) and EMBASE using the following strategies without language restriction:

Ovid MEDLINE(R) 1950 to September 30, 2010

Search strategy

  1. Infant, newborn/ or infant, low birth weight/ or infant, small for gestational age/ or infant, very low birth weight/ or infant, premature/ or exp Infant, Newborn, Diseases/ or pregnancy, high-risk/ or quadruplets/ or quintuplets/ or superfetation/ or triplets/ or twins/ or twins, dizygotic/ or twins, monozygotic/ or (infan: or neonat: or newborn: or prematur: or iugr or sga or vlbw or lbw or elbw).ti, ab. or ((intrauterine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2 retard:)).ti, ab. (765026)
  2. ("clinical trial, all" or clinical trial).pt. or clinical trials as topic/ or clinical trial, phase i.pt. or clinical trials, phase i as topic/ or clinical trial, phase iii.pt. or clinical trials, phase iii as topic/ or clinical trial, phase iv.pt. or clinical trials, phase iv as topic/ or controlled clinical trial.pt. or controlled clinical trials as topic/ or meta-analysis.pt. or meta-analysis as topic/ or multicenter study.pt. or multicenter studies as topic/ or randomised controlled trial.pt. or randomised controlled trials as topic/ or evaluation studies as topic/ or validation studies as topic/ or evaluation study.pt. or validation study.pt. or case-control studies/ or retrospective studies/ or cohort studies/ or longitudinal studies/ or follow-up studies/ or prospective studies/ or cross-sectional studies/ or double-blind method/ or random allocation/ or single-blind method/ or ((singl* or doubl* or tripl* or trebl*) adj5 (blin or mask or blinded or masked)).ti, ab. (1900654)
  3. propofol/ or (propofol or disoprofol or diprivan or disoprivan or fresofol or "ici-35, 868" or "ici 35, 868" or "ici35, 868" or "ici-35868" or "ici 35868" or "ici35868" or recofol or aquafol or ivofol).mp. (11838)
  4. 1 and 2 and 3 (114)
  5. 1 and 3 (320)
  6. from 4 keep 1-114 (114)

EBM Reviews - Cochrane Central Register of Controlled Trials (CENTRAL, 2nd Quarter 2010)

Search Strategy:

  1. Infant, newborn/ or infant, low birth weight/ or infant, small for gestational age/ or infant, very low birth weight/ or infant, premature/ or exp Infant, Newborn, Diseases/ or pregnancy, high-risk/ or quadruplets/ or quintuplets/ or superfetation/ or triplets/ or twins/ or twins, dizygotic/ or twins, monozygotic/ or (infan: or neonat: or newborn: or prematur: or iugr or sga or vlbw or lbw or elbw).ti, ab. or ((intrauterine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2 retard:)).ti, ab. (23255)
  2. propofol/ or (propofol or disoprofol or diprivan or disoprivan or fresofol or "ici-35, 868" or "ici 35, 868" or "ici35, 868" or "ici-35868" or "ici 35868" or "ici35868" or recofol or aquafol or ivofol).mp. (4764)
  3. 1 and 2 (64)

EMBASE (1980 to 2010 Week 38)

Search Strategy:

  1. newborn/ or newborn period/ or low birth weight/ or extremely low birth weight/ or small for date infant/ or very low birth weight/ or Prematurity/ or exp newborn disease/ or multiple pregnancy/ or twin pregnancy/ or twins/ or dizygotic twins/ or monozygotic twins/ or human triplets/ or intrauterine growth retardation/ or small for date infant/ or (infan: or neonat: or newborn: or prematur: or iugr or sga or vlbw or lbw or elbw or (intrautrine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2 retard:)).ti, ab. (774681)
  2. ct.fs. or clinical trial/ or controlled clinical trial/ or multicenter study/ or phase 1 clinical trial/ or phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/ or cohort analysis/ or double blind procedure/ or single blind procedure/ or triple blind procedure/ or meta analysis/ or randomised controlled trial/ or "systematic review"/ or case control study/ or longitudinal study/ or prospective study/ or retrospective study/ or multicenter study/ or validation study/ or (((evaluation or validation) adj2 study) or ((evaluation or validation) adj2 studies)).ti, ab. (882179)
  3. propofol/ or (propofol or disoprofol or diprivan or disoprivan or fresofol or "ici-35, 868" or "ici 35, 868" or "ici35, 868" or "ici-35868" or "ici 35868" or "ici35868" or recofol or aquafol or ivofol).mp. or 2078-54-8.rn. (23293)
  4. 1 and 3 (1380)
  5. 2 and 4 (249)

We also searched reference lists of identified trials, and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (2002 to 2009). No language restrictions were applied.

Searching other resources

We searched clinical trials registries for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy). No eligible study was identified from these registries.

Data collection and analysis

We collected and analysed data in accordance with the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

We assessed for inclusion all published articles identified as potentially relevant by the literature search.

Data extraction and management

Where published data provided inadequate information for the review or where relevant data could not be abstracted, we obtained further information from the trial authors. We independently assessed articles and abstracted data. We resolved disagreements regarding inclusion/exclusion of studies by consensus.

Assessment of risk of bias in included studies

We independently reviewed the methodological quality of each trial. We assessed each identified trial for methodological quality with respect to a) masking of allocation b) masking of intervention c) completeness of follow-up and d) masking of outcome assessment.This information was to be included in the 'Characteristics of Included Studies' table.

In addition, we completed the Risk of Bias table addressing the following methodological issues:
  1. Sequence generation: Was the allocation sequence adequately generated?
    For each included study, we described the method used to generate the allocation sequence as: adequate (any truly random process e.g. random number table; computer random number generator); inadequate (any nonrandom process e.g. odd or even date of birth; hospital or clinic record number); or unclear.
  2. Allocation concealment: Was allocation adequately concealed?
    For each included study, we described the method used to conceal the allocation sequence as: adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or unclear.
  3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
    For each included study, we described the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We assessed the methods as: adequate, inadequate or unclear for participants; adequate, inadequate or unclear for study personnel; and adequate, inadequate or unclear for outcome assessors and specific outcomes assessed.
  4. Incomplete outcome data: Were incomplete outcome data adequately addressed?
    For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We addressed whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We assessed methods as: adequate (< 20% missing data); inadequate (greater than/or equal to 20% missing data) or unclear.
  5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
    For each included study, we assessed the possibility of selective outcome reporting bias as: adequate (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported); inadequate (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to be reported); or unclear.
  6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?
    For each included study, we noted any important concerns regarding other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We planned to assess whether each study was free of other problems that could put it at risk of bias as: yes; no; or unclear.

Measures of treatment effect

We used RevMan 5.0 for statistical analysis. Planned statistical parameters were relative risk (RR), risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB), number needed to treat for an additional harmful outcome (NNTH) and mean difference (MD) when appropriate. We reported 95% confidence intervals (CI) for estimates of treatment effects.

Unit of analysis issues

We planned to use data from one patient only once even if the patient received intervention more than once to avoid dependency of data. We did not encounter this issue in this review.

Dealing with missing data

We contacted primary trial authors for data not reported in the trial publication. We obtained a full data set and performed analyses for missing outcomes and used them in this review after obtaining the approval of the author.

Assessment of heterogeneity

Tests for between study heterogeneity including the I2 test were to be applied to assess the appropriateness of combining studies; however, we only had one eligible study.

Assessment of reporting biases

We planned to use funnel plots to assess publication bias; however, we only had one included study.

Data synthesis

If multiple studies had been identified, we would have performed meta-analysis using Review Manager software (RevMan 5, The Cochrane Collaboration). For estimates of typical relative risk and risk difference, we planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. We planned to conduct all meta-analyses using the fixed-effect model.

Subgroup analysis and investigation of heterogeneity

We planned to compare the data for the outcomes outlined in the previous section as follows (planned primary and subgroup analyses):

Comparison 1: Propofol versus no treatment/placebo

Category 1: Method of administration

Subgroup:

  1. bolus;
  2. continuous infusion.
Category 2: Type of procedure

Subgroups:

  1. endotracheal intubation;
  2. eye examination;
  3. other procedure.
Category 3: Gestational age

Subgroups:

  1. preterm;
  2. term.

Comparison 2: Propofol versus another regimen (neuromuscular blocking agents with or without the use of sedative or anxiolytics) (different active controls were to be compared separately)

Category 1: Method of administration

Subgroups:

  1. bolus;
  2. continuous infusion.
Category 2: Type of procedure

Subgroups:

  1. endotracheal intubation;
  2. eye examination;
  3. other procedure.
Category 3: Gestational age

Subgroups:

  1. preterm;
  2. term.

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Results

Description of studies

We examined 427 citations to identify eligible studies. We retrieved seven articles for full assessment and identified only one randomised controlled trial (Ghanta 2007) as eligible for inclusion in the review. Two studies (Fabrice 2010; Silva 2008) were identified as ongoing from ClinicalTrials.gov websites. A study by Silva 2008 was reported to have recruitment complete in the year 2009. The authors reported that their manuscript is soon be published.

Ghanta 2007 is described below in the table Characteristics of Included Studies. This study randomised neonates to a propofol group and a morphine-atropine-suxamethonium group. Median gestational age of neonates was 27 weeks in both groups. Time required for successful intubation, heart rate and blood pressure at five minutes were reported outcomes. Data on mean and SD for time taken for intubation, preparation and recovery and rates of metabolic acidosis (defined as base deficit > 2 units) were obtained by contacting Dr Ju Lee Oei (Senior Investigator on this trial).

Risk of bias in included studies

Ghanta 2007 was an open-label randomised controlled trial. The details of risk of bias assessment are described in the table Characteristics of Included Studies below. As this was an open randomised trial, investigators ensured independent outcome assessment. It is unclear whether the person assessing outcome was masked to group allocation or not as this person may be prone to personal bias. It is also not clear whether it was only one person who obtained data on all neonates or whether multiple personnel were involved as this may result in differential coding of outcome. Notwithstanding these points, the study was of good methodological quality.

Effects of interventions

Due to the inclusion of only one study (Ghanta 2007) in this review, we have not provided detailed subgroup analyses at this stage. The study included in this review falls into Comparison 2, Subgroup 1 for all three categories. The study compared propofol with a combination of morphine-atropine-suxamethonium for endotracheal intubation in preterm infants. Thirty-three infants were enrolled in propofol group and 30 infants were in morphine-atropine-suxamethonium group. Most intubations were via nasal route.

Primary outcomes

Success of achievement of proper sedation/anaesthesia as measured by:

  1. Completion of the targeted objective as measured by:
    1. Need for repeated attempts to achieve primary goal: There was no statistically significant difference in the number of infants who required multiple intubation attempts (39% in propofol group versus 57% morphine-atropine-suxamethonium group; RR 1.40, 95% CI 0.85 to 2.29, RD 0.17, 95% CI -0.07 to 0.42, Figure 1). The number of intubation attempts did not differ statistically between groups (median two attempts, interquartile range one to three attempts for morphine-atropine-suxamethonium group versus median one attempt, interquartile range one to two attempts for propofol group; P = 0.082).
    2. Change in heart rate or number of episodes of bradycardia (as defined by investigators): It is reported that there was no difference in the heart rate at and during procedure between two groups. The data were presented in box-whisker plot only. Heart rate decreased in both groups during the procedure; however, according to the study authors there was no statistically significant difference between groups.
    3. Change in oxygen saturation or episode of hypoxaemia requiring intervention (as defined by investigators): Median (interquartile range) intra-procedural oxygen saturations were 80% (67% to 88%) in the propofol group and 60% (43% to 82%) in the morphine-atropine-suxamethonium group (P = 0.019). Median oxygen saturations at recovery were also significantly higher in the propofol group (median (interquartile range) 95% (92% to 98%) compared to 92% (90% to 96%) in morphine-atropine-suxamethonium group (P = 0.008);
    4. Change in blood pressure or hypotension episodes requiring intervention (as defined by investigators): Blood pressure increased during the procedure in both groups. It is reported that there was no difference in the difference of blood pressure at baseline and during procedure between two groups. The data were presented in box-whisker plot only.
  2. Time to complete the procedure as defined by time of administration of the agent to time to complete intubation (time for successful completion of procedures among neonates who had completion of procedure in the first attempt and among those who required more than one attempt):
    1. For all intubation attempts combined: Time was shorter in propofol group (median 120 seconds, interquartile range 60 to 180 seconds) versus morphine-atropine-suxamethonium group median 260 seconds, interquartile range 60 to 435 seconds, P = 0.007).
    2. For intubation successful at first attempt: There was no difference between groups (median 60 seconds, interquartile range 60 to 120 seconds in propofol group versus median 60, interquartile range 52 to 120 seconds in morphine-atropine-suxamethonium group P = 0.641).
    3. For intubation that required mor than one attempt: Time was in propofol group (median 180 seconds, interquartile range 120 to 300 seconds in propofol group versus median 360, interquartile range 300 to 750 seconds in morphine-atropine-suxamethonium group P < 0.001).
  3. Time for preparation of the anaesthetic agents (time from onset of preparation of medication to administration of medication): The time required to prepare drugs for study was shorter in the propofol group (median 180 seconds, interquartile range 180 to 210 seconds in propofol group versus median 960 seconds interquartile range 900 to 1200 seconds in the morphine-atropine-suxamethonium group; P .001).
  4. Time to achieve sleep/muscle relaxation (time from receipt of medication to achievement of sleep/muscle relaxation): There was no statistically significant difference in the time to achieve sleep or muscle relaxation between groups (median 60 seconds, interquartile range 60 to 120 seconds for morphine-atropine-suxamethonium group versus median 60 seconds, interquartile range 30 to 60 seconds in propofol group; P = 0.087)
  5. Time to recovery to prior clinical status (time from completion of procedure to return of clinical status): There was a reduction in time to recover to previous clinical status with propofol compared to control group (median 780 seconds, interquartile range 360 to 1110 seconds versus median 1425 seconds, interquartile range 645 to 2250 seconds, P = 0.002)
  6. Safety of propofol (occurrence of these side effects during or within 24 hours of stoppage of medication) (as defined by investigators):
    1. incidence of sustained hypoxaemia > 1 minute (saturation below target limit): data not collected;
    2. incidence of hypotension (need for fluid bolus or inotropes to maintain blood pressure): data not collected;
    3. incidence of metabolic acidosis (need for correction of acidosis by fluid bolus or sodium bicarbonate): not reported in published paper, but study authors provided data on rates of base deficit > 2 units between groups. There was no difference in the incidence between two groups (RR 1.19, 95% CI 0.95 to 1.48); Figure 2
    4. incidence of lactic acidosis (serum lactate > 2 mmol/l): there was no statistically significant difference between groups in the incidence of lactic acidosis (RR 0.40, 95% CI 0.02 to 9.06 and RD -0.06, 95% CI -0.20 to 0.09); Figure 3
    5. incidence of rhabdomyolysis (myoglobinuria, rising creatinine): data not collected;
    6. incidence of hyperkalaemia (serum potassium > 5.5 mmol/l): data not collected;
    7. incidence of renal failure (serum creatinine > 125 umol/l): data not collected;
    8. incidence of seizures: data not collected;
    9. mortality (all cause mortality assessed at < 28 days of completion of therapy): data not collected.

Discussion

Summary of main results

Only one randomised controlled trial of 63 neonates has evaluated the efficacy and safety of propofol for intubation in neonates. This trial demonstrated the feasibility of giving propofol to neonates with a significant reduction in duration for preparation, procedure time and post-procedural recovery. The study authors did not observe any increased incidence of side effects attributable to propofol. However, it must be recognised that the number of infants enrolled in this trial is too small to detect all but extreme problems with safety and authors did not systematically looked for all adverse effects.Two studies are ongoing, one comparing propofol with sevoflurane and the other comparing propofol and ramifentanil versus midazolam and ramifentanil.

Overall completeness and applicability of evidence

Overall, the data are insufficient to make any practice recommendations. However, the preliminary data on efficacy would suggest that further studies are needed. With a large number of infants receiving one or other form of stressful procedure throughout the world, it is feasible to support a multicentre undertaking.

Quality of the evidence

The only study included in this review was an unblinded study; however, the study authors ascertained outcome in a non-biased way and the overall risk of bias was low. The sample size of this study was small.

Potential biases in the review process

We have obtained certain data from the authors; however, validity of these data is good as we obtained the raw data file and performed analyses.

Agreements and disagreements with other studies or reviews

Recently, the impact of propofol infusion on heart rate, oxygen saturation and blood pressure in neonates has been studied. A transient drop in heart rate and oxygen saturations were observed, but at the same time blood pressure was reduced for approximately one hour (Vanderhaegen 2009). The clearance of propofol was affected by postnatal age, concurrent medication and presence of cardiomyopathy. Propofol metabolism is slower in neonates due to age-dependent maturation of glucuronidation (Allegaert 2008). A recent review of three pharmacokinetic studies on the use of propofol in neonates concluded that a careful approach is necessary as marked inter-individual variability and reduced clearance of propofol is observed in neonates (Allegaert 2009). Repeated administration of boluses or continuous infusion of propofol in the first week after birth was discouraged. No other systematic review has evaluated this comparison. Another important point is that propofol is a hypnotic agent without analgesic effects (Papoff 2008). Their experience with 21 patients who received fentanyl and propofol for neonatal intubation indicated feasibility of combining a hypnotic agent with an analgesic agent. The American Academy of Pediatrics suggests administration of an analgesic or anaesthetic dose of hypnotic for procedural discomfort/pain. Future studies should take this into consideration.

Authors' conclusions

Implications for practice

No practice recommendation can be made based on the available evidence regarding use of propofol in neonates.

Implications for research

Further research is needed in two domains. First, further data on the pharmacokinetics of propofol in neonates are needed. A safe dose of propofol could be identified in neonates undergoing elective intubation who would be given escalating doses of propofol. Blood could be sampled atpredefined times after administrationin order tocorrelatepropofol levelswith clinical findingsincluding depth of relaxation, anaesthesia and ease of procedural completion. Second, once a relatively safe dose is identified, randomised controlled trials assessing the safety and efficacy (successful completion of intended procedure, ease of performance of procedure, etc.) are needed.Itwould be appropriate to compare the safety and efficacy of propofol with other agents (mostly combinations of sedative, anxiolytic and a muscle relaxant).

Acknowledgements

We would like to thank Ms. Elizabeth Uleryk, Chief Librarian, the Hospital for Sick Children, Toronto for her help in the development and execution of the search strategy. We would like to sincerely thank Dr Ju Lee Oei, investigator for the only trial included in this review, for providing certain missing data.

Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

PS Shah:

Writing and editing of the protocol
Development of search strategy
Assessment of eligibility of articles
Data collection, analysis
Writing and editing of review

V Shah:

Editing of the protocol
Article eligibility check
Data entry check
Editing of review

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Ghanta 2007

Methods

Randomised, controlled, open-label study

Participants

Inclusion criteria: Infants requiring elective or semi-elective intubation were eligible if parental consent could be obtained

Exclusion criteria: Major congenital anomaly, parents with limited capability to comprehend due to language barrier, those who required emergency intubation

Propofol group: Median GA 27 weeks (IQR 25-30 weeks, median BW 1020g (IQR 770-1455g)

Morphine-Atropine-Suxamethonium group: Median GA 27 weeks (IQR 25-30 weeks, median BW 1095g (IQR 759-1612g)

Interventions

Propofol group: A single bolus dose of propofol of 2.5 mg/kg was given first. Eyelash reflex was tested every 10 seconds and loss of this reflex determined onset of sleep/hypnotic effect and one more dose was repeated before switching back to morphine-atropine-suxamethonium group

Morphine-Atropine-Suxamethonium group: morphine, 100 µg/kg; atropine, 10 µg/kg; and suxamethonium, 2 mg/kg. Two repeat doses of suxamethonium at 1 mg/kg each (maximum total dose of 4 mg/kg per intubation attempt) were administered if muscle relaxation was not achieved in the space of 3 to 5 minutes.

Outcomes

Time required to achieve successful intubation was determined by adequate chest movement, rising oxygen saturations and bilaterally equal air entry on auscultation

Intraprocedural oxygen saturation, heart rate and blood pressure changes recorded 5 minutes before and 5 minutes after intubation

Notes

An independent personnel (not involved in clinical care and study) recorded the following times:

  1. medication preparation time: time from randomisation until the medications were ready for administration
  2. time to achieve sleep and muscle relaxation: from administration of medications until onset of sleep/hypnosis (defined as loss of eyelash reflex) or muscle relaxation (defined as loss of voluntary muscle activity)
  3. intubation time: from the first insertion of laryngoscope to clinical confirmation of successful intubation after all of the attempts were completed (clinical confirmation of successful intubation is evidenced by adequate chest movement, rising oxygen saturations, and bilaterally equal air entry on auscultation)
  4. recovery time: from onset of sleep and muscle relaxation (above) to return of spontaneous muscle movement
Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Random sequence generated and prepared using envelopes by a nurse not involved in the study and allocated

Allocation concealment? Yes

Sealed opaque envelopes which were consecutively numbered

Blinding? No

Open-label trial

Free of selective reporting? Yes

All clinically important outcomes were reported

Free of other bias? Yes

Except for "open" trial design, no other bias detected

GA = gestational age, IQR = interquartile range

Characteristics of excluded studies

Allegaert 2007

Reason for exclusion

Pharmacokinetic study, no randomisation

Allegaert 2007a

Reason for exclusion

Pharmacokinetic study, no randomisation

Allegaert 2008

Reason for exclusion

Pharmacokinetic study, no randomisation

Allegaert 2009

Reason for exclusion

Pharmacokinetic study, no randomisation

Parke 1992

Reason for exclusion

Case reports, no randomisation

Rigby-Jones 2002

Reason for exclusion

Pharmacokinetic study, no randomisation

Characteristics of ongoing studies

Fabrice 2010

Study name

Sevoflurane versuspropofolfor intubation in neonatal intensive care

Methods

Randomised controlled trial

Participants

Inclusion Criteria:

  • Neonates
  • Hospitalised in neonatal intensive care unit
  • Needing endotracheal intubation

Exclusion Criteria:

  • Emergency state
  • Predictable difficult endotracheal intubation
  • Decrease of blood pressure
  • Neurological disorders
  • Morphinic treatment
Interventions

Sevoflurane: Administration of sevoflurane (SEVORANE) by inhalation until a maximal concentration of 4% of inspired gas.

Propofol: Administration ofpropofol(DIPRIVAN) by intravenous injection (1 mg/kg to turn over twice if necessary)

Outcomes

Recovery time after intubation, facilitation of procedure, tolerance of treatment (mean arterial pressure, apnoea)

Starting date

Not available

Contact information

Fabrice MICHEL fabrice.michel@ap-hm.fr

Notes

Principal Investigator: Fabrice MICHEL

Silva 2008

Study name

Propofol and remifentanil versus midazolam and remifentanil as premedication allowing very early extubation after surfactant treatment in preterm neonates with respiratory distress syndrome

Methods

Randomised controlled trial

Participants

Inclusion Criteria:

  • Gestational age between 28 and 34 weeks
  • Clinical and radiological features compatible with respiratory distress syndrome that required elective tracheal intubation and surfactant therapy
  • Hemodynamic stability before tracheal intubation
  • Signature (parents) consent form

Exclusion Criteria:

  • The presence of major congenital malformations
  • Birth weight less than 1000 g
  • Previous use of opioid or other sedative drug for any reason
  • Previous tracheal intubation
  • Hemodynamic instability before the indication of tracheal intubation
  • Refusal of the parents to enrol the neonate in the study protocol
Interventions

Propofol 2 m/kg IV, other details are not available

Outcomes

Primary Outcome Measures:Time until extubation after bolus dose as premedication for tracheal intubation

Secondary Outcome Measures:Quality of intubation with the combination of drugs used for premedication

Starting date

November 20, 2008

Contact information

Yerkes P Silva, PhD, yerkesps@uol.com.br

Notes

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References to studies

Included studies

Ghanta 2007

Ghanta S, Abdel-Latif ME, Lui K, Ravindranathan H, Awad J, Oei J. Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial. Pediatrics 2007;119(6):e1248-e1255.

Excluded studies

Allegaert 2007

Allegaert K, Peeters MY, Verbesselt R, Tibboel D, Naulaers G, de Hoon JN, et al. Inter-individual variability in propofol pharmacokinetics in preterm and term neonates. British Journal of Anaesthesia 2007;99(6):864-70.

Allegaert 2007a

Allegaert K, de Hoon J, Verbesselt R, Naulaers G, Murat I. Maturational pharmacokinetics of single intravenous bolus of propofol. Paediatric Anaesthesia 2007;17(11):1028-34.

Allegaert 2008

Allegaert K, Vancraeynest J, Rayyan M, de Hoon J, Cossey V, Naulaers G, et al. Urinary propofol metabolites in early life after single intravenous bolus. British Journal of Anaesthesia 2008;10(6):827-31.

Allegaert 2009

Allegaert K. Is propofol the perfect hypnotic agent for procedural sedation in neonates? Current Clinical Pharmacology 2009;4(2):84-6.

Parke 1992

Parke TJ, Stevens JE, Rice AS, Greenaway CL, Bray RJ, Smith PJ, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 1992;305(6854):613-6.

Rigby-Jones 2002

Rigby-Jones AE, Nolan JA, Priston MJ, Wright PM, Sneyd JR, Wolf AR. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002;97(6):1393-400.

Studies awaiting classification

  • None noted.

Ongoing studies

Fabrice 2010

Unpublished data only

Fabrice M. Sevoflurane versuspropofolfor intubation in neonatal intensive care. http://www.clinicaltrials.gov/ct2/show/NCT01006668?term=propofol&type=Intr&age=0&rank=4 May 18, 2010.

Silva 2008

Unpublished data only

Penido M. PropofolVersus Midazolam as Premedication for Preterm Neonates With Respiratory Distress Syndrome (RDS). http://www.clinicaltrials.gov/ct2/show/NCT00797160?term=propofol&type=Intr&age=0&rank=15 (accessed January 2011).

Other references

Additional references

Bacon 1994

Bacon RC, Razis PA. The effect of propofol sedation in pregnancy on neonatal condition. Anaesthesia 1994;49(12):1058-60.

Bray 1998

Bray RJ. Propofol infusion syndrome in children. Paediatric Anaesthesia 1998;8(6):491-9.

Crawford 2003

Crawford MW, Dodgson BG, Holtby HHK, Lawrence Roy W. Propofol infusion in children. Canadian Medical Association Journal 2003;168(6):669.

Gelber 1997

Gelber O, Gal M, Katz Y. Clonic convulsions in a neonate after propofol anaesthesia. Paediatric Anaesthesia 1997;7(1):88.

Golden 2001

Golden S. Combination propofol-ketamine anaesthesia in sick neonates. Paediatric Anaesthesia 2001;11(1):119-22.

Graham 1998

Graham MR, Thiessen DB, Mutch WA. Left ventricular systolic and diastolic function is unaltered during propofol infusion in newborn swine. Anesthesia and Analgesia 1998;86(4):717-23.

Hatch 1999

Hatch DJ. Propofol-infusion syndrome in children. Lancet 1999;353(9159):1117-8.

Lim 2005

Lim EH, Tan S, Lim SL. Anesthesia for a neonate with persistent buccopharyngeal membrane and unilateral choanal atresia. Paediatric Anaesthesia 2005;15(6):509-11.

Mellon 2007

Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesthesia and Analgesia 2007;104(3):509-20.

Oei 2002

Oei J, Hari R, Bhuta T, Lui K. Facilitation of neonatal nasotracheal intubation with premedication: a randomised controlled trial. Journal of Paediatrics and Child Health 2002;38:146-50.

Papoff 2008

Papoff P, Mancuso M, Caresta E, Moretti C. Effectiveness and Safety of Propofol in Newborn Infants. Pediatrics 2008;121:448.

Playfor 2004

Playfor SD, Venkatesh K. Current patterns of propofol use in PICU in the United Kingdom and North America. Pediatric Anesthesia 2004;14:501-4.

Reed 1996

Reed MD, Blumer JL. Propofol bashing: the time to stop is now! Critical Care Medicine 1996;24(1):175-6.

Sanchez-Alcaraz 1998

Sanchez-Alcaraz A, Quintana MB, Laguarda M. Placental transfer and neonatal effects of propofol in caesarean section. Journal of Clinical Pharmacy and Therapeutics 1998;23(1):19-23.

Sloan 2003

Sloan IA. Propofol infusion in children. Canadian Medical Association Journal 2003;168(6):669.

Van de Velde 2004

Van de Velde M, Teunkens A, Kuypers M, Dewinter T, Vandermeersch E. General anaesthesia with target controlled infusion of propofol for planned caesarean section: maternal and neonatal effects of a remifentanil-based technique. International Journal of Obstetric Anesthesia 2004;13(3):153-8.

Vanderhaegen 2009

Vanderhaegen J, Naulaers G, Van Huffel S, Vanhole C, Allegaert K. Cerebral and systemic hemodynamic effects of intravenous bolus administration of propofol in neonates. Neonatology 2009;98(1):57-63.

Vasile 2003

Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Medicine 2003;29(9):1417-25.

Veyckemans 2001

Veyckemans F. Propofol for intubation of the newborn? Paediatric Anaesthesia 2001;11:630-1.

Other published versions of this review

  • None Noted.

Classification pending references

  • None Noted.

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Data and analyses

1 Propofol versus Morphine-Atropine-Suxamethonium group

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Succesful intubation at first attempt 1 63 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [0.85, 2.29]
1.2 Metabolic acidosis 1 63 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.95, 1.48]
1.3 Lactic acidosis 1 33 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.02, 9.06]

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Figures

Figure 1 (Analysis 1.1)

Refer to figure 1 caption below.

Forest plot of comparison: 1 Propofol versus Morphine-Atropine-Suxamethonium group, outcome: 1.1 Succesful intubation at first attempt.

Figure 2 (Analysis 1.2)

Refer to figure 2 caption below.

Forest plot of comparison: 1 Propofol versus Morphine-Atropine-Suxamethonium group, outcome: 1.7 Rates of metabolic acidosis.

Figure 3 (Analysis 1.3)

Refer to figure 3 caption below.

Forest plot of comparison: 1 Propofol versus Morphine-Atropine-Suxamethonium group, outcome: 1.2 Lactic acidosis.

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Sources of support

Internal sources

  • Department of Paediatrics, Mount Sinai Hospital and University of Toronto, Canada

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2011 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.