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Safety of Propofol for Oxygenator Exchange in Extracorporeal Membrane Oxygenation

Hohlfelder, Benjamin; Szumita, Paul M.; Lagambina, Susan; Weinhouse, Gerald; Degrado, Jeremy R.

doi: 10.1097/MAT.0000000000000461
Clinical Critical Care
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The purpose of this analysis is to describe the safety of propofol administration in adult extracorporeal membrane oxygenation (ECMO) patients. We performed a prospective cohort analysis of patients using ECMO at Brigham and Women's Hospital between February 2013 and October 2015. Patients were included if they used ECMO for at least 48 hours. The major end-point of the analysis was the median oxygenator lifespan. Oxygenator exchanges were analyzed by the number of patients requiring an oxygenator exchange and the number of oxygenator exchanges per ECMO day. A priori analysis was performed by comparing the outcomes between patients who did and did not receive propofol during their ECMO course. During the study, 43 patients were included in the analysis. Sixteen patients used propofol during their ECMO course. There were 12 oxygenator exchanges during therapy. Oxygenator exchange occurred on 1.8% of ECMO days. The median oxygenator lifespan was 7 days. Patients who used propofol had a significantly longer oxygenator lifespan (p = 0.02). Among patients who received propofol, patients who required oxygenator exchange used a significantly lower median daily dose of propofol (p < 0.001). The use of propofol appears safe in ECMO with regards to oxygenator viability. Contrary to expected, oxygenator lifespan was significantly longer among patients who received propofol.

From the *Department of Pharmacy Services, Brigham and Women’s Hospital, Boston, Massachusetts; Department of Respiratory Therapy, Brigham and Women’s Hospital, Boston, Massachusetts; and Department of Pulmonary Medicine, Brigham and Women’s Hospital, Boston, Massachusetts.

Submitted for consideration June 2016; accepted for publication in revised form October 2016.

Disclosures: The authors have no conflicts of interest to report.

Correspondence: Benjamin Hohlfelder, Department of Pharmacy Services, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Email: benhohlfelder@gmail.com.

The utilization of extracorporeal membrane oxygenation (ECMO) has increased significantly in the past decade, spurred by new evidence and experience in the treatment of patients with acute respiratory distress syndrome (ARDS).1 The use of ECMO also includes several other indications, including as a bridge to lung transplant,2,3 posttransplant rescue,4 and cardiogenic shock.5 The management of pain, agitation, and delirium (PAD) is complex in patients on ECMO.6–8 The ECMO circuit introduces several pharmacokinetic changes, notably an increased volume of distribution, and sequestration of medications in the circuit.6,9–11 Many of the first line agents for the management of PAD are highly lipophilic,12,13 and may bind to plasticized ECMO cannulae and silicone or polymethylpentene oxygenators.14 Clinically, significantly higher doses of opioids and benzodiazepines have been required to adequately sedate patients requiring ECMO, with increasing requirements over the course of therapy with ECMO.7,8

Despite being recommended as a first-line sedative agent in the management of PAD by the 2013 Society of Critical Care Medicine Guidelines,15 the use of propofol in adult ECMO patients is relatively limited. Propofol, a 10% lipid emulsion, has previously been implicated in the occlusion of membrane oxygenators.16 For many, the fear of oxygenator failure precludes the use of propofol in patients receiving ECMO. In addition, propofol-related infusion syndrome is a concern, particularly in an ECMO patient population that may require higher doses of propofol for an extended duration of therapy.17 An international survey conducted in collaboration with the Extracorporeal Life Support Organization found that propofol was used in just 36% of patients,18 whereas some institutions have limited its role to being used as a rescue agent.7

At our institution, propofol has been used judiciously because of the fear of oxygenator failure. Although the fear of oxygenator failure has limited the use of propofol in adult ECMO patients, no data exist to our knowledge that describe or demonstrate this adverse event in contemporary ECMO circuits.18 The objective of this analysis is to describe the safety of propofol in adult ECMO patients with regards to oxygenator function.

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Methods

Brigham and Women’s Hospital is a 793 bed tertiary, academic medical center. The ECMO program was established in February 2013, and is a multidisciplinary collaboration with members from Cardiac Surgery, Thoracic Surgery, Pulmonary Medicine, Anesthesiology, Hematology, Respiratory Therapy, Physical Therapy, Pharmacy, Perfusion, and Nursing. ECMO is primarily used as a bridge to solid-organ transplant, management of ARDS, and cardiogenic shock.

Brigham and Women's Hospital Institutional IRB approval was obtained before the beginning of this study (IRB Protocol #2013P001049). We performed a single-center, prospective, observational cohort analysis of patients who were supported on ECMO at our institution between February 1, 2013 and October 31, 2015. An institution-specific database to track and monitor patients requiring extracorporeal life support was used to identify patients. Patients requiring ECMO support for more than 48 hours were included in the analysis. Patients cannulated at an outside hospital more than 24 hours before transfer to our institution, or those with an incomplete medical record were excluded.

Baseline patient demographics and laboratory data were collected on inclusion in the analysis. The indication for ECMO and initial ECMO settings were recorded. Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation II scores were calculated for each patient.

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Outcomes

The major outcome of the analysis was the duration of oxygenator viability as a function of propofol use. Oxygenator exchanges were analyzed by the total number of exchanges, the number of patients requiring an oxygenator exchange during therapy, the number of patients requiring multiple oxygenator exchanges during therapy, and the number of oxygenator exchanges per ECMO day. Oxygenator lifespan was calculated in days. For patients who did not require oxygenator exchange during therapy, the total duration of ECMO support was considered to be the oxygenator lifespan.

For each oxygenator exchange, several factors that may have influenced circuit integrity were evaluated. Cumulative propofol administration throughout the ECMO course and before oxygenator exchange was recorded. The propofol dose administered in the 24 hour period before oxygenator failure was also documented. The mean activated partial thromboplastin time (aPTT) or activated clotting time (ACT) while on ECMO was calculated. Mean ACT and aPTT were also calculated for the 24 hours before oxygenator exchange. Platelet administration was analyzed, including the total number of units of platelets administered while receiving ECMO support and in the 24 hours before oxygenator exchange. Hemostatic agent administration was recorded. Hemostatic agents included fresh frozen plasma, cryoprecipitate, platelets, and concentrated coagulation factors. Total doses of hemostatic agents were also recorded.

Other minor end-points evaluated included propofol and pharmacotherapy utilization data. The total number of days of propofol exposure was recorded. For each patient who was administered propofol, the duration of therapy with propofol was evaluated. In addition, the median daily dose of propofol was recorded. Outcomes regarding propofol utilization were compared between those patients who required oxygenator exchange and those who did not.

Administrations of benzodiazepines and opioids were assessed. For each day, these medications were administered, the total daily dose administered was recorded. All benzodiazepines were converted to midazolam equivalents (1 mg intravenous [IV] lorazepam = 1 mg oral [PO] lorazepam = 3 mg IV midazolam = 5 mg IV diazepam = 5 mg PO diazepam).12 All opioids were converted to fentanyl equivalents (200 mcg IV fentanyl = 1.5 mg IV hydromorphone = 7.5 mg PO hydromorphone = 10 mg IV morphine = 40 mg PO morphine = 10 mg IV methadone = 20 mg PO methadone = 100 mcg IV meperidine = 20 mg PO oxycodone).12

Clinical outcomes assessed included hospital length of stay, intensive care unit (ICU) length of stay, duration of ECMO support, mortality status, and discharge disposition. Mortality status was assessed on ICU discharge and hospital discharge. The location where patients were discharged and the patient’s ventilatory status were assessed on hospital discharge.

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Statistical Analysis

Descriptive statistics including baseline characteristics, variables related to the use of propofol and oxygenator data and those pertaining to clinical outcomes were stratified as continuous or binary. Continuous variables were presented as means with standard deviations or medians with interquartile ranges. Binary variables were presented as numbers and proportions.

We also performed an a priori subgroup analysis comparing patients who used propofol, and those who did not. Outcomes assessed between these two groups were performed using the χ2 analysis for binary data, Student’s t test for parametric continuous data, and Mann–Whitney U test for nonparametric continuous data. Assuming a β of 0.80, an α of 0.05 was considered to be statistically significant.

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Results

Of the 57 patients that received ECMO support at the institution, 43 patients were included in the analysis (Table 1). Notable exclusion criteria included ECMO support less than 48 hours (n = 9, 16%) and ECMO support initiated more than 24 hours before transfer to the institution (n = 4, 7%). In total, 16 (37%) patients received propofol during the course of ECMO therapy. There were no notable differences in baseline demographics between patients who received propofol and those who did not.

Table 1

Table 1

Overall, there were 12 total oxygenator exchanges during the course of ECMO therapy (Table 2). Factors that may have influenced oxygenator function are described in Table 3. In total, eight patients (19%) required oxygenator exchanges during the course of ECMO therapy. Four patients required multiple oxygenator exchanges. Oxygenators were exchanged on 1.8% of ECMO days. The median oxygenator life span was 7 days.

Table 2

Table 2

Table 3

Table 3

Sixteen (37%) patients used propofol during their course of ECMO (Table 4). These patients were exposed to propofol on 137 ECMO days, representing 36% of their total days of ECMO support. The median duration of propofol therapy was 4 days, with a median daily dose of propofol of 1013 mg.

Table 4

Table 4

Among the 16 patients who received propofol, five (31%) required oxygenator exchange, including two patients who required two oxygenator exchanges. However, two of these patients required device exchange before the administration of propofol. Of the 27 patients who did not receive propofol, three (11%) required oxygenator exchange, including two patients who required two oxygenator exchanges. There was no difference in the percentage of patients requiring oxygenator exchange between the groups (p = 0.10). There was no significant difference in the percentage of patients requiring multiple oxygenator exchanges (13% vs. 8%, p = 0.58) or the percentage of ECMO days requiring oxygenator exchange (1.9% vs. 1.7%, p = 0.91). Contrary to our expectation, oxygenator life span was significantly longer in the propofol group (9 days vs. 5 days, p = 0.02).

There was a trend toward a longer median duration of ECMO among propofol patients who required oxygenator exchange (30 vs. 9 days, p = 0.09). Propofol patients who required an oxygenator exchange used propofol on a higher percentage of ECMO days (47% vs. 24%, p < 0.001), and had a trend toward a longer duration of propofol therapy (8 days vs. 2 days, p = 0.14). However, patients who did not require oxygenator exchange had a significantly higher median daily dose of propofol (3196 vs. 739 mg, p < 0.001).

Benzodiazepines were used on 62% of ECMO days, with a median daily dose of 30 mg of midazolam equivalents. Patients who were administered propofol during their ECMO course used benzodiazepines less frequently (44% vs. 85%, p < 0.001). However, on days where these patients received benzodiazepines, they received a higher median dose than those who did not receive propofol during their ECMO course (49 vs. 24 mg, p < 0.001).

For the entire cohort, opioids were administered on 93% of ECMO days. The median opioid requirement for patients was 3780 mcg of fentanyl equivalents. As with benzodiazepines, patients receiving propofol received opioids less frequently than those not receiving propofol (88% vs. 99%, p < 0.001). They were also administered a lower median daily dose of opioid (3657 vs. 4025 mcg, p = 0.004).

The median ICU and hospital length of stay was 25 days and 30 days, respectively. The median duration of ECMO support was 9 days. Patients who received propofol had a longer duration of ECMO support than those who did not receive propofol (14 vs. 6.5 days, p = 0.004). Survival to ICU and hospital discharge was seen in greater than 50% of patients, and did not differ between patients who were administered propofol and those who did not.

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Discussion

We describe the rates of ECMO oxygenator exchange at a tertiary medical center and the possible influence of propofol on oxygenator patency. Overall, oxygenator exchanges during ECMO therapy were relatively rare, and the administration of propofol did not appear to significantly increase the risk of oxygenator failure during the course of ECMO. Contrary to previous hypotheses, oxygenator life span was longer in the propofol group. Longer duration, but not dose, of propofol may be associated with an increased risk of oxygenator failure.

The fear of oxygenator failure with the administration of propofol is largely gathered from literature describing the impact of propofol of cardiopulmonary bypass circuits.16,19,20 Sequestration of propofol in an extracorporeal circuit has been well described and partially attributed to the use of lipophilic, silicone membrane oxygenators.16,19–23 At our institution, two primary ECMO circuits are used: the CARDIOHELP system and Sorin ECMO system. Both are equipped with polymethylpentene oxygenators made by Maquet. Propofol, formulated as a 10% lipid emulsion, de-emulsifies to its hydrophilic form when administered intravenously. When administered before a membrane oxygenator in circuit, there may be a higher likelihood of lipid accumulation at the oxygenator.24 However, when administered intravenously beyond the oxygenator, the risk of oxygenator failure may be attenuated.19,24 At our institution, with the exception of heparin, propofol and other medications are administered intravenously into systemic circulation.

In our cohort, we did not observe an increase in the rates of oxygenator failure among patients who received propofol. In fact, the oxygenator life span was significantly longer in patients who received propofol. It is important to note baseline differences between the patients who received propofol and those who did not. A higher percentage of patients used ECMO as a bridge to transplant in the propofol group, whereas treatment of cardiogenic shock was more common in the nonpropofol group. Although severity of illness did not differ between the groups, differences in physiology between the groups may have led to variations in patients’ inflammatory, hemolytic, and prothrombotic states. The frequency of oxygenator exchange may also be related to the age of the circuit, as has been previously described.21,25

Propofol has been used at our institution during the course of ECMO therapy primarily as a benzodiazepine sparing agent. This has manifested itself in two patient populations: patients in whom traditional strategies for management of PAD have been unsuccessful, and patients who have had a prolonged ECMO course, or expected to have a prolonged ECMO course.

Utilization of propofol as an alternative to a benzodiazepine-based regimen may present an attractive option, particularly among those with delirium or those with organ failure in whom there is a significant risk of drug accumulation. In the general critical care population, the use of propofol in mechanically-ventilated patients has been demonstrated to decrease the duration of mechanical ventilation and ventilator-associated adverse events in comparison with benzodiazepines.26 Propofol also represents a significantly cheaper option than dexmedetomidine.27 It may be prudent; however, to limit the duration of therapy with propofol, as this was significantly higher among patients receiving propofol who required oxygenator exchange. The median duration of propofol before oxygenator exchange was 3 days. This may represent the amount of time needed for propofol to saturate the ECMO circuit before influencing the oxygenator.

The importance of other factors that could influence circuit patency should not be overlooked. In an analysis of technical complications during venovenous ECMO, a high percentage of oxygenator exchanges were caused by coagulation abnormalities.21 Administration of platelets, concentrated clotting factors, and the degree of anticoagulation achieved during ECMO may all play a role in oxygenator patency. In our cohort, patients requiring oxygenator exchange had a high rate of platelet and concentrated clotting factor administration.

The results of our analysis must be interpreted within the context of our study design. First, this was a single-center analysis with a limited patient population. As data in adult ECMO patients are often limited, there were only 43 patients included in our cohort. Subgroup analyses that were performed took place in a small number of patients, and may not have been able to detect significant differences between groups. In addition, the results of this analysis are purely observational. The decision to use propofol was made by the primary team, and there was a significant variance in the doses, duration, and reasons for propofol selection. The choice to use propofol as opposed to an alternative sedative agent was left to the discretion of the attending provider and multidisciplinary team. Lastly, it is difficult to assess and control for all possible variables that may have influenced oxygenator patency. Endogenous markers of possible coagulation disorders or hemolysis, including but not limited to fibrinogen and d-dimer, were not recorded. It is possible that variables contributing to oxygenator failure may not have been analyzed. Because of the retrospective design of the study, the exact rationale for oxygenator exchange was unable to be elicited via chart review, and information regarding the patients’ oxygenation status was not obtained.

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Conclusion

To our knowledge, this is the first analysis describing the real-life utilization of propofol in ECMO, with a focus on the need for oxygenator exchange. In total, nearly 40% of patients in our cohort used propofol during their course of ECMO, with no significant impact on the need for oxygenator exchange. Longer duration of therapy with propofol, but not the dose of propofol may be associated with an increased risk of oxygenator failure. A future analysis describing multicenter experiences with propofol in ECMO is warranted.

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Keywords:

extracorporeal membrane oxygenation; propofol; membrane oxygenator; sedation

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