Abstract
OBJECTIVE
To evaluate adherence to an institutional continuous infusion propofol policy for sedation in mechanically ventilated patients, investigate the rate of propofol-related infusion syndrome (PRIS), and explore areas of improvement to enhance policy compliance and safety.
METHODS
This was a single center, retrospective chart review of patients admitted to a pediatric or cardiac intensive care unit within a large free-standing quaternary care pediatric hospital who received continuous propofol for non-procedural continuous sedation for at least 6 hours between 2014 and 2019. Propofol exposure (dose and duration), laboratory data, and hemodynamic outcomes of patients were evaluated.
RESULTS
A total of 104 patients (108 admissions and 133 treatment courses) met inclusion criteria. Policy adherence to propofol dosing and duration limitations were 70% (93/133 courses) and 68% (91/133 courses), respectively. Adherence to all elements of laboratory and hemodynamic monitoring was 23%. Hypotension and bradycardia were common among patients during propofol treatment courses. Except for hypertriglyceridemia, no significant difference in specific laboratory values were detected between patients exposed to greater than 66 mcg/kg/min (4 mg/kg/hr), compared with those exposed to less than 66 mcg/kg/min of propofol. Patients receiving therapy for longer than 48 hours had the highest rates of laboratory values associated with PRIS. No patient in the study cohort met full criteria for PRIS.
CONCLUSIONS
Adherence to elements of an institutional propofol policy was variable. Improvements in policy adherence may be enhanced by updating policy features, leveraging the electronic medical record order-set, and gaining consensus among key stakeholders.
Keywords: adherence, order-set, PRIS, propofol, safety, sedation
Introduction
Propofol is a short-acting sedative-hypnotic approved by the US Food and Drug Administration for the induction of general anesthesia in children older than 3 years, maintenance of general anesthesia in children older than 2 months, and as a sedative during mechanical ventilation in adults. Common off-label indications for propofol in critically ill children include refractory status epilepticus, rapid sequence intubation, sedation while mechanically ventilated, procedural sedation, and as a bridge to extubation.1,2 Prolonged infusions of propofol in children are generally discouraged owing to the rare, but life-threatening condition termed propofol-related infusion syndrome (PRIS).3,4 In fact, a “Dear Health Care Provider” letter from 2001 was sent by AstraZeneca Pharmaceuticals that stated, “We would like to reemphasize that propofol is currently not approved for sedation in pediatric intensive care unit (ICU) patients in the US and should not be used for this purpose.”5 Nevertheless, many pediatric ICUs (PICUs) continue to use propofol infusions in some capacity despite the lack of guidance since the early 2000s.6
Although some variability exists surrounding the clinical definition of PRIS, most agree this condition is characterized by acute refractory bradycardia that progresses to cardiovascular collapse in patients with 1 or more of the following abnormalities: metabolic acidosis, rhabdomyolysis, hyperlipidemia, and enlarged or fatty liver.3,7,8 The risk of developing PRIS is greatest in children receiving infusions exceeding 66 mcg/kg/min (4 mg/kg/hr) and in those receiving continuous propofol for more than 48 hours.3 In an effort to mitigate the risk of PRIS in critically ill patients receiving propofol infusions for non-procedural sedation, Children's Hospital Colorado developed a clinical practice policy. This policy outlines acceptable dose and duration limits and provides guidance about laboratory surveillance to enhance safety. The purpose of this study was to evaluate adherence to the propofol policy, describe the rate of PRIS, and identify areas of process improvement to enhance policy compliance and safety surrounding propofol use in the critically ill child.
Materials and Methods
This was a single-center, retrospective chart review of patients admitted to either a 32-bed medical/surgical PICU or a 16-bed pediatric cardiac ICU (CICU) in a freestanding, quaternary care, pediatric hospital during a 5-year study period (2014–2019). Patients eligible for inclusion were at least 31 days old postnatal age and had received continuous propofol for sedation during mechanical ventilation for at least 6 continuous hours. Patients could be included more than once if their propofol courses were separated by at least 6 hours. Patients were excluded if they received propofol for procedural sedation or status epilepticus because these indications were not within the scope of the policy. This study protocol was reviewed and approved by the Colorado Multiple Institutional Review Board with a waiver of informed parent/subject consent.
The primary outcome measure was adherence to the institutional policy for continuous propofol in the mechanically ventilated patient. Adherence was divided into 3 domains. The first domain was dose limits (maximum 66 mcg/kg/min). The second domain was duration limits (24 hours or up to 48 hours with anesthesia approval). The third domain was clinical and laboratory surveillance adherence (continuous blood pressure and heart rate monitoring; every-6-hour serum lactate and blood gas; every-12-hour serum triglyceride, creatinine, creatinine kinase, and hepatic enzymes). Secondary outcome measures included rate of PRIS and overall dosing and duration characteristics of propofol. Because age is a clinically important determinant of propofol disposition, patients were categorized into 4 groups (31 days–2 years; 2.1–14 years; 14.1–18 years, and >18 years) to test associations of outcomes with age. Age categories were selected on the basis of expected maturation of drug metabolism and the desire to illustrate specific outcomes in subjects who met the definition of child or adult.
Outcome measures and patient variables were extracted from the electronic medical record (EMR) by using a standardized data collection form. Primary chart review was performed by 2 members of the investigative team and audited by 2 different investigators. Any disputes in chart coding were resolved after agreement by investigators. Data collected included demographic data (age, weight, sex, ICU length of stay, mortality) and variables associated with primary and secondary outcomes (median dose, cumulative dose and duration of propofol, blood pressure, electrocardiogram (ECG), heart rate, serum lactate, specific elements of a blood gas [base deficit and anion gap], triglycerides, serum creatinine, creatinine kinase, and hepatic enzymes). Calculation of median propofol infusion dose (mcg/kg/min) was determined by averaging each individual propofol course and then computing the group median. Any patient experiencing a bradycardic or resuscitation event during propofol therapy underwent a more detailed chart review to explore the possibility of PRIS by reviewing ECG findings, laboratory results, and progress notes.
For the purpose of this study, PRIS was defined as age-appropriate progressive bradycardia (per Pediatric Advanced Life Support criteria) with cardiovascular collapse and at least 1 of the following features: metabolic acidosis (defined as a base deficit greater than 10 mmol/L or an anion gap greater than 12 mmol/L), creatinine kinase greater than 300 units/L, triglycerides greater than 200 mg/dL, serum creatinine greater than 2 times the last recorded serum creatinine prior to propofol initiation, and liver function tests greater than 3 times the upper limit of normal (aspartate transaminase [AST] > 135 units/L, alanine transaminase [ALT] > 78 units/L).9
Statistical analyses were performed by using Statistics Calculators from Social Science Statistics (https://www.socscistatistics.com/tests/) and Microsoft Excel 2010 software. Normality of the data was tested, and data are expressed as mean ± standard deviation, median (IQR), or percentage as appropriate. Chi-square and Kruskal-Wallis tests were used to compare outcomes. Statistical testing was 2-sided and a p value of less than 0.05 was considered statistically significant. After analysis of adherence outcomes, strategies to improve conformity to the propofol policy were explored with input from a consortium of stakeholders. These strategies were assessed for feasibility and impact factor.
Results
A total of 364 critically ill patients received propofol during the study period. After application of exclusion criteria, 260 patients were removed, leaving a total of 104 patients (108 admissions and 133 treatment courses). Characteristics of included patients are described in Table 1. Adherence to propofol dosing and duration limitations were 70% (n = 93/133 courses) and 68% (n = 91/133 courses), respectively. There was no identifiable documentation of approval from anesthesia to exceed a 24-hour treatment course, thus all infusions exceeding 24 hours were considered a deviation. Most duration violations occurred between 24 and 48 hours, with 9.8% of courses exceeding 48 hours in duration. No difference was detected between PICU and CICU adherence. There was, however, a difference in adherence to individual components of the clinical and laboratory guideline (Table 2). Adherence to all elements of the clinical and laboratory surveillance portion of the propofol guideline occurred in 23% of propofol courses. Sixteen of the 133 courses (12%) met complete adherence to dose, duration, and laboratory surveillance monitoring recommendations.
Table 1.
Characteristics of Patients (n = 108) Who Received Continuous Propofol During Mechanical Ventilation
| Characteristic | Result |
|---|---|
| Age, mean ± SD, yr | 7.7 ± 7.5 |
| Sex, male, n (%) | 69 (64) |
| Weight, mean ± SD, kg | 29 ± 24 |
| Number of treatments (n = 133 total), n (%) | |
| Pediatric intensive care unit | 75 (56) |
| Cardiac intensive care unit | 58 (44) |
| Length of intensive care unit stay, median (IQR), days | 12 (5–25) |
| Length of hospital stay, median (IQR), days | 23 (9–43) |
| Overall mortality, n (%) | 9* (7.7) |
* Demonstrator = 104.
Table 2.
Adherence to a Continuous Propofol Monitoring Policy in 108 Mechanically Ventilated Patients (n = 133 Courses)
| Variable | Policy Recommendation | Number of Courses Adherent to Policy, n (%) |
|---|---|---|
| Components of hemodynamic bundle | 133 (100) | |
| Blood pressure | Every 15 min for first hr and then every hr | 133 (100) |
| Heart rate | Continuous | 133 (100) |
|
| ||
| Components of laboratory bundle | 30 (23) | |
| Lactate | Every 6 hr | 37 (28) |
| Blood gas | Every 6 hr | 72 (54) |
| Serum triglyceride | Every 12 hr | 111 (83) |
| Serum creatinine | Every 12 hr | 127 (95) |
| Serum creatinine kinase | Every 12 hr | 117 (88) |
| Serum hepatic enzymes | Every 12 hr | 122 (92) |
Twelve of the 104 patients (11.5%) received a propofol loading dose prior to initiation of the infusion. The mean ± SD loading dose was 1.43 ± 0.53 mg/kg. The median propofol infusion dose was 47 mcg/kg/min (2.8 mg/kg/hr) (IQR, 33–61 mcg/kg/min or 2–3.7 mg/kg/hr) with a duration of 19 hours (IQR, 12–26 hours). To determine the influence of age on the likelihood of dose and duration variances from the policy, comparisons were made between the 4 age groups (Table 3). No significant differences were detected in typical dose, duration, or variances from the policy between the age groups.
Table 3.
Propofol Policy Variances and Median Dose and Duration Between 4 Age Categories of Patients
| Propofol Dose and Duration | Age Category | p value | |||
|---|---|---|---|---|---|
|
| |||||
| 31 days–2 yr (n = 37) | 2.1–14 yr (n = 67) | 14.1–18 yr (n = 23) | >18 yr (n = 6) | ||
| Dose, median (IQR), mcg/kg/min | 54 (45–64) | 46 (25–59) | 43 (29–59) | 51 (32–70) | 0.12* |
| Duration, median (IQR), hr | 19 (15–24) | 19 (10–26) | 19 (13–33) | 18 (14–34) | 0.93* |
| Dose >66 mcg/kg/min (4 mg/kg/hr), n (%) | 10 (27) | 22 (33) | 6 (26) | 2 (33) | 0.89† |
| Duration >24 hr, n (%) | 10 (27) | 22 (33) | 8 (35) | 2 (33) | 0.91† |
* Kruskal-Wallis analysis with significance set at <0.05.
† Two-tailedchi-square.
A large proportion of propofol courses were associated with either hypotension (n = 97/133, 73%) or bradycardia (n = 27/133, 20%). There was no statistical difference in the percentage of patients experiencing these hemodynamic changes between patients in the PICU or CICU. In addition, there did not seem to be a clinical difference in the incidence of hypotension between patients who received a propofol loading dose and those who did not. Of the 97 patients, 27 (n = 27/97, 28%) had hypotension before the initiation of propofol, which decreased in incidence after 2 hours. Bradycardia was unlikely at the initiation of propofol and peaked within 1 hour of starting propofol. No association between bradycardic or resuscitative events was detected between patients receiving more than 66 mcg/kg/min and those receiving less than 66 mcg/kg/min of propofol. The incidence of laboratory values associated with PRIS was based on the total number of times the individual variable was tested and is detailed in Table 4. The most common laboratory value associated with PRIS was hypertriglyceridemia and was experienced by 43% of patients for whom triglyceride concentrations were monitored. To determine if dose and/or duration was associated with laboratory values consistent with PRIS, we compared the presence of an abnormal laboratory value between patients exposed to more than 66 mcg/kg/min and those with durations exceeding 24 and 48 hours. No difference in the incidence of acidosis, hyperlactatemia, elevated serum creatinine, or elevated hepatic enzymes was detected between patients who received greater than 66 mcg/kg/min and those who received less than 66 mcg/kg/min. There was, however, a significantly higher rate of hypertriglyceridemia among patients who received more than 66 mcg/kg/min (65% vs 35%, p = 0.008) and there were fewer patients with a creatinine kinase level above 300 units/L (19% vs 39%, p = 0.0445). Laboratory values associated with PRIS were more likely in those patients receiving greater than 48 hours of therapy (Table 5).
Table 4.
Laboratory Values Consistent With PRIS Among 108 Patients Receiving 133 Continuous Propofol Courses for Sedation While Mechanically Ventilated
| Variable | Values Consistent With the Definition of PRIS* |
|---|---|
| Metabolic acidosis (base deficit > 10 mmol/L or anion gap > 12 mmol/L), n/total (%) | 20/115 (17) |
| Hypertriglyceridemia > 200 mg/dL, n/total (%) | 44/102 (43) |
| Elevation in serum creatinine > 2× baseline, n/total (%) | 2/121 (1.7) |
| Elevation in creatinine kinase > 300 U/L, n/total (%) | 31/96 (32) |
| Elevation in LFTs >3 × upper limit of normal | |
| AST > 135 U/L, n/total (%) | 21/103 (20) |
| ALT > 78 U/L, n/total (%) | 27/106 (25) |
| Lactate > 1.5 mmol/L, n/total (%) | 43/121 (36) |
ALT, alanine transaminase; AST, aspartate transaminase; LFTs, liver function tests; PRIS, propofol-related infusion syndrome
Table 5.
Laboratory Abnormalities Based on Variance in Propofol Duration During Treatment Courses of Propofol in Critically Ill Patients
| Variable | Propofol Courses With Specific Variable Collected, n | Duration, n/total (%) | p value* | ||
|---|---|---|---|---|---|
|
| |||||
| 6–24 hr | 24–48 hr | >48 hr | |||
| Metabolic acidosis (base deficit > 10 mmol/L or anion gap > 12 mmol/L) | 115 | 9/76 (12) | 7/27 (26) | 4/12 (33) | 0.08 |
| Hypertriglyceridemia > 200 mg/dL | 102 | 21/62 (34) | 12/27 (44) | 11/13 (85) | 0.004 |
| Elevation in serum creatinine > 2× baseline | 121 | 0/78 (0) | 0/30 (0) | 2/13 (15) | NA |
| Elevation in creatinine kinase > 300 U/L | 96 | 21/54 (39) | 7/30 (23) | 3/12 (25) | 0.29 |
| Elevation in LFTs (greater than 3 × upper limit of normal) | |||||
| AST > 135 U/L | 103 | 11/62 (18) | 4/28 (14) | 6/13 (46) | 0.044 |
| ALT > 78 U/L | 106 | 12/65 (18) | 8/28 (29) | 7/13 (54) | 0.026 |
| Lactate > 1.5 mmol/L | 121 | 22/80 (28) | 13/29 (45) | 8/12 (67) | 0.015 |
ALT, alanine transaminase; AST, aspartate transaminase; LFTs, liver function tests; NA, not applicable
* Two-tailed chi-square analysis with significance set at <0.05.
The presence of PRIS was explored in all 133 courses of propofol (Figure). The initial criteria of bradycardia and/or a resuscitative event occurred in 22% (n = 29) of propofol courses. These events were further examined for the progression to cardiovascular collapse and the presence of laboratory abnormalities. In the end, no patient fulfilled the complete definition of PRIS.
Figure.
Exploration of propofol infusion syndrome among 133 propofol courses in critically ill children requiring sedation during mechanical ventilation.
The consortium of physician and pharmacy representatives from the PICU, CICU, and anesthesia, who were tasked with identifying barriers to policy adherence, prioritized 3 areas of improvement: 1) increased functionality of the EMR order-set with embedded clinical decision support; 2) creation of an age-based pathway—one for patients younger than 14 years and a second for patients older than 14 years; and 3) extension of the duration limits from 24 hours to 48 hours with removal of the anesthesia consult. These improvement suggestions were presented to the medication safety and pharmacy and therapeutics committees at the institution. Following approval from these committees, consultation with the clinical application services to build a new pathway and order-set was initiated.
Discussion
The primary finding of this single center, retrospective study was that adherence to all elements of an institutional propofol policy for critically ill patients requiring continuous propofol sedation during mechanical ventilation was low and could be improved. Approximately one-third of patients receiving continuous propofol in the PICU and CICU exceeded the current dose and duration limitations of 66 mcg/kg/min and 24 hours, respectively. Adherence to all components of the policy was low at 12%.
Barriers to policy adherence were considered by a multidisciplinary team of stakeholders and were supported by analyzing the dosing and safety outcomes demonstrated by the current study cohort. Because most duration variances in the current study occurred between 24 and 48 hours, the first consideration was to examine the safety of extending the duration of propofol from 24 hours to 48 hours. The original restriction of 24 hours was intentionally short and represented a conservative approach. Although the current study did not detect any cases of PRIS, laboratory abnormalities associated with PRIS were observed more often in patients exposed to propofol for greater than 48 hours than those exposed for 24 to 48 hours. Data from this cohort, along with information from a survey of 50 PICUs across North America, suggest that extension to 48 hours is acceptable.6 A 48-hour duration limit would still represent a more conservative approach compared with the 72-hour limit that most respondents in the survey follow.6
The next domain within the policy that exhibited variances was the dose limitation of 66 mcg/kg/min. Apart from serum triglyceride concentrations, the current study did not detect any laboratory safety concerns when greater than 66 mcg/kg/min was administered. Most propofol treatments in the current study were in patients younger than 14 years (n = 104, 78%), with 29 courses (22%) administered to patients older than 14 years. The stakeholder team acknowledged that age-based dose thresholds could be applied that may result in improved dose-limit adherence. Propofol infusions up to 83 mcg/kg/min (5 mg/kg/hr) are acceptable for adolescents and adults, and some institutions allow up to 200 mcg/kg/min (12 mg/kg/hr).6, 10–12 These findings support the consideration of allowing up to 83 mcg/kg/min in patients older than 14 years.
Lastly, there was consensus that adding laboratory orders to the propofol order-set would aid providers and bedside nurses with proper safety surveillance measures. It was recognized that consultation with anesthesiology was an unused and unnecessary step in the care of these patients, and thus this expectation was eliminated. In the end, the policy was amended and a new propofol order-set that included updated dosing, duration, and compulsory laboratory orders was created.
The use of electronic order-sets to guide therapy decisions is not new. The Institute for Safe Medication Practices and the Joint Commission recommend drug protocols, clinical pathways, and order-sets within the EMR to guide drug therapy and promote monitoring.13,14 Pediatric institutions, in particular, can benefit from a standardized dosing and monitoring approach to mitigate adverse events in a vulnerable population. The use of an order-set has the potential to include specific monitoring parameters (e.g., laboratory and clinical surveillance) to enhance safe administration of high-risk medications.13,14 Order-sets can save time, are convenient, and can improve communication with and expectations of the bedside nurse.15
Not surprisingly, this study failed to detect any confirmed cases of PRIS. This is consistent with published reviews from other pediatric institutions.6,16,17 The authors do believe, however, that the propofol policy adopted at the institution helped limit the use of prolonged and high-dose propofol infusions and may have attenuated the rates of laboratory values associated with PRIS. We did observe an increase in the number and degree of abnormal laboratory findings as the duration of propofol increased. This finding is in line with other studies that noted a dose- and duration-dependent relationship between propofol infusions and PRIS.3 With propofol use persisting in pediatric institutions across the country, the current study underscores the benefits of using an institutional policy and order-set to guide safe propofol therapy.
There were limitations to this study that must be acknowledged. First, the retrospective nature of the study design did not allow for control of factors that may have impacted patient outcomes. It is possible that undocumented approval for extended propofol durations was obtained from anesthesiology. This may have influenced overall adherence to duration limitations. Collection of baseline laboratory values was not part of the current propofol policy and thus it is possible that some patients may have had abnormal values prior to the initiation of propofol. In addition, we did not collect or analyze the influence of disease conditions or other drug therapy (e.g., intravenous fat emulsion) that may have influenced outcomes. Nevertheless, this study does demonstrate that most providers can follow limitations set forth within a propofol policy and order-set. However, this study also highlights the importance of including monitoring directives as part of the EMR order-set.
Conclusion
Adherence to an institutional propofol policy that outlines dose and duration limits along with safety monitoring was low and suggests routine reevaluation is important. Improvements to a policy can be achieved by gaining consensus among stakeholders, analyzing current patient outcomes, and adopting new evidenced-based policies. Including laboratory and hemodynamic monitoring expectations within the EMR order-set can aid in overall safety and policy adherence.
Acknowledgments
We would like to acknowledge the Pediatric Critical Care and Heart Institute physicians, pharmacists, medical teams, and nurses at Children's Hospital Colorado for their assistance.
ABBREVIATIONS
- ALT
alanine transaminase
- AST
aspartate transaminase
- CICU
cardiac intensive care unit
- ECG
electrocardiogram
- EMR
electronic medical record
- ICU
intensive care unit
- IQR
interquartile range
- PICU
pediatric intensive care unit
- PRIS
propofol-related infusion syndrome
Footnotes
Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Ethical Approval and Informed Consent. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and have been approved by the appropriate committees at our institution. This study was reviewed and approved by the Colorado Multiple Institutional Review Board with a waiver of informed parent/subject consent.
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