Propofol is a common and effective sedative/anesthetic for invasive procedures in children with cancer.11,12
Pharmacologic features of propofol include a rapid onset of action, easy titratability, and a smooth and quick recovery. Despite these desirable qualities, adverse cardiopulmonary events are common when propofol is used as a single agent.11,12
Our study demonstrates a distinct advantage of combining propofol with fentanyl to propofol alone for LP sedation in children with acute hematologic malignancies. We have previously described the lower overall incidence of adverse events, faster recovery and family preference with this combination.17
In terms of total propofol requirements and incidence of adverse events, the combination of propofol and fentanyl proved superior to propofol alone. To our knowledge this is the first randomized, controlled study to relate propofol dosing to adverse events in pediatric oncology patients receiving procedural sedation.
The synergy of a propofol-opioid combination has been clearly established in anesthetic practice. Studies consistently show that propofol requirements for anesthetic induction,25,26
airway placement, 27,28
and surgical stimulus29
are less when propofol is combined with an opioid than when propofol is used alone. Similar results have been found in both adults30
undergoing sedation for invasive procedures. We observed the propofol sparing effect of fentanyl as well. Total propofol doses were 34.8% less when the two drugs were given together. Studies show that the magnitude of the propofol-opioid interaction is more pronounced the greater the stimulus.13
Consequently the propofol sparing effect of fentanyl would be expected to be greater for a painful stimulus than it would be for achieving unconsciousness. We found that propofol doses were reduced by 64.5% during the actual procedure, while only 20.3% for induction to loss of consciousness. We believe the lower incidence of adverse events in patients receiving propofol and fentanyl is the direct consequence of requiring lower doses of propofol to successfully complete the procedure.
Fifty percent of patients in our study experienced an adverse event when propofol was given alone in contrast to only 18.2% when given the two drugs together. While no one type of complication was statistically significant between groups, overall, patients were more likely to have some type of adverse occurrence when receiving only propofol. Our results are consistent with a similar study evaluating these two sedative regimens in children undergoing invasive gastrointestinal procedures.14
Disma, et. al.14
compared the combination of propofol and fentanyl to propofol alone in children undergoing oesophagogastroduodenoscopy. Fewer number of patients required supplemental doses of propofol during the procedure and complications were less when patients received the combination of propofol and fentanyl. Five percent of patients receiving propofol with fentanyl experienced an adverse event compared to 19% of patients receiving only propofol. Serious respiratory complications were particularly common in patients receiving propofol as a single agent, with one third of patients experiencing an adverse event requiring bag-and–mask ventilation. No patients receiving the combination of propofol and fentanyl required bag-mask ventilation.
The type and frequency of adverse occurrences in our patients receiving only propofol is comparable to other studies when propofol is used as a single agent for invasive oncology procedures in children.11,12
Hypotension is the most frequently observed adverse event during propofol sedation and may or may not be considered clinically significant enough to require intervention.11,12
Overall, systolic hypotension was the most common adverse event in our study, occurring in six propofol/placebo patients and four propofol/fentanyl patients.
Respiratory complications on the other hand, particularly airway obstruction and moderate oxygen desaturation, are clinically significant and typically require intervention. Our incidence of airway obstruction when propofol was used alone is similar to that found by Hertzog et. al. in children receiving only propofol for invasive oncology procedures.11
In our study, no patients receiving fentanyl/propofol experienced airway complications or moderate oxygen desaturations. One patient receiving fentanyl/propofol was given positive end expiratory pressure for a mild oxygen desaturation during the procedural phase of the sedation. In patients receiving propofol/placebo, however, three children developed airway obstruction and one experienced moderate oxygen desaturation. All incidents of airway obstruction in patients receiving propofol alone occurred during the procedure phase of sedation. Propofol doses were nearly three-fold greater during the procedure when propofol was given alone, implying a relationship between total propofol dose and respiratory complications.
Our study was designed to achieve a common sedation endpoint between the two groups that we believed would be suitable for conducting the LP (CHEOPS score < 8). We chose a common sedation endpoint in order to compare safety at virtually identical sedation depths. To date, the mechanisms conferring an advantage of a propofol-fentanyl combination in terms of safety has not been clearly determined.13
One explanation is based on the findings of several studies showing a differential effect of various sedative drugs on upper airway tone, despite similar depths of sedation. For example, propofol is more prone to causing upper airway collapse than midazolam in spite of similar degrees of sedation.31
In addition, propofol reduces pharyngeal muscle tone and increases the propensity for upper airway collapse in a dose-dependent manner.32
We can only speculate that at similar levels of sedation fentanyl’s effect on upper airway tone is proportionally less than propofol. Another explanation is the frequency in which propofol was bolused during the procedure to maintain a steady sedation state in patients receiving only propofol. Twice as many propofol boluses were required to maintain the desired sedation endpoint during the procedure when propofol was used alone. As a result, the risk of over-sedation and adverse respiratory events would undoubtedly be greater if the patient’s level of sedation was more variable and more propofol boluses were required. We chose not to study propofol by continuous infusion because of how rapidly the LP was performed. In addition, while Klein et al. found that fewer propofol boluses were required when using a propofol infusion versus intermittent dosing for pediatric oncology procedures, the continuous infusion was associated with higher total propofol doses and a greater number of adverse events.33
There were several limitations to our study. Our sample size was small and may not have adequately represented our patient population. In addition, we only studied children older than 2 years of age who were in the consolidation or maintenance phase of chemotherapy and in relatively good health. Consequently, our findings cannot be applied to children younger than 2 years of age or those children in the early stages of chemotherapy. Half way through the study a preliminary analysis was performed that demonstrated a lower incidence of adverse events in patients receiving propofol with fentanyl. Following closer examination, our data revealed a beneficial effect of the drug combination and the study was terminated. At that time the ability to maintain equipoise became increasingly difficult as well. We believe that the crossover nature of our study added power to our analysis and permitted us to reach statistical significance in our primary endpoints, propofol dosing and total adverse events. We chose the crossover design as well because of the lack of drug carry over effect between study periods and to eliminate inter-patient drug variability. Because of our small sample size, however, other endpoints such as comparison of individual adverse events like airway obstruction could not be adequately examined. A larger study would be required to further ascertain the benefits of a propofol/fentanyl regimen in terms of individual safety effects and efficacy.
Being truly blinded to fentanyl or placebo was initially identified as a potential drawback to our design. However, as identified by the m-YPAS score there were no significant differences in anxiety between the two groups. While the m-YPAS score is not meant as a sedation score the lack of any difference between fentanyl and placebo implies few effects on mental status. The probable reason for this is that all children had previously been sedated for procedures in our sedation program and consequently had little pre-procedure anxiety. An additional confounding variable was that the sedating physician was not blinded and may have consciously or unconsciously titrated propofol in an unbiased manner. Fortunately most sedating physicians were not intimately involved with the study and would not be expected to be biased one way or the other.
In 1990, the American Academy of Pediatrics (AAP) specifically addressed the importance of optimizing procedural sedation and pain control in children with cancer. Since that time a number of different sedative regimens have been studied in this patient population. When administered by trained and skilled personnel, propofol is one of the most effective sedative/anesthetic agents for invasive oncology procedures in children with cancer. Our study builds upon the work of others who have studied sedation in this population. We showed that the combination of propofol and fentanyl resulted in fewer adverse sedation events in otherwise healthy children with hematologic malignancies undergoing LPs. We conclude that a fentanyl-propofol combination is a superior sedative regimen to propofol alone in children older than 2 years of age with hematologic malignancies and recommend its use for elective LP sedation.