Safety of Propofol for Oxygenator Exchange in Extracorporeal Membrane Oxygenation

Transcription

1 ASAIO Journal 2017 Clinical Critical Care Safety of Propofol for Oxygenator Exchange in Extracorporeal Membrane Oxygenation Benjamin Hohlfelder,* Paul M. Szumita,* Susan Lagambina, Gerald Weinhouse, and Jeremy R. Degrado* 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 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. ASAIO Journal 2017; 63: Key Words: extracorporeal membrane oxygenation, propofol, membrane oxygenator, sedation 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 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 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 benhohlfelder@gmail.com. Copyright 2017 by the ASAIO DOI: /MAT 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. 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, 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. 179

2 180 HOHLFELDER et al. 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. 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. 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 χ 2 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. 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. 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. 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. 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,

3 SAFETY OF PROPOFOL IN ECMO 181 Table 1. Patient Demographics Characteristic All Patients (N = 43) Propofol Patients (N = 16) Nonpropofol Patients (N = 27) p Age* 46 ( ) 47 ( ) 46 ( ) 0.81 Male gender, n (%) 28 (65) 13 (81) 15 (56) 0.09 SOFA score* 11 (8 13) 11 (8 13) 11 (8.5 13) 0.96 APACHE II score* 28 ( ) 29 ( ) 28 (24 31) 0.22 Indication for ECMO, n (%) Cardiogenic shock 16 (37) 4 (25) 12 (44) 0.17 Bridge-to-transplant 13 (30) 8 (50) 5 (19) ARDS 9 (21) 3 (19) 6 (22) Posttransplant complication 5 (12) 1 (6) 4 (15) ECMO cannulation mode, n (%) VA 19 (44) 6 (37) 13 (48) 0.50 VV 24 (56) 10 (63) 14 (52) Benzodiazepine use, n (%) 409 (62) 167 (44) 242 (85) <0.001 Benzodiazepine daily dose* (midazolam 30 (9 78) 49 ( ) 24 (9 51.8) <0.001 equivalents) Opioid use, n (%) 613 (93) 329 (88) 284 (99) <0.001 Opioid daily dose* (fentanyl equivalents) 3780 ( ) 3657 ( ) 4025 ( ) ICU length of stay* (days) 25 ( ) 35 ( ) 24 (9.5 33) 0.05 Hospital length of stay* (days) 30 ( ) 35 ( ) 25 (16 52) 0.35 Duration of ECMO* (days) 9 (5 16.5) 14 (8.5 28) 6.5 (4 12.5) ICU mortality, n (%) 20 (47) 10 (63) 10 (37) 0.11 Hospital mortality, n (%) 20 (47) 10 (63) 10 (37) 0.11 *Median (interquartile range). Based on the total number of ECMO days (all patients 662, propofol 376, nonpropofol 286). APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; SOFA, Sequential Organ Failure Assessment; VA, venoarterial; VV, venovenous. 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 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. 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 Table 2. Oxygenator Exchange Data Outcome All Patients (N = 43) Propofol Patients (N = 16) Nonpropofol Patients (N = 27) p Median duration of ECMO* (days) 9 (5 16.5) 14 (8.5 28) 6.5 (4 12.5) Required oxygenator exchange, n (%) 8 (19) 5 (31) 3 (11) 0.10 Required multiple oxygenator exchanges, n (%) 4 (9) 2 (13) 2 (8) 0.58 Total oxygenator exchanges N/A Oxygenator exchanges per ECMO day Median oxygenator lifespan* (days) 7 (4 13) 9 (7 18) 5 (4 10) 0.02 *Median (interquartile range). ECMO, extracorporeal membrane oxygenation.

4 182 HOHLFELDER et al. Table 3. Evaluation of Variables Associated with Oxygenator Failure Hemostatic Agent Administration (Agent, Dosage) Platelet Administration in the 24 Hours Before Oxygenator Exchange (units) Cumulative Platelet Administration (units) Mean aptt and ACT in the 24 Hours Before Oxygenator Exchange (sec) Mean aptt and ACT During ECMO (sec) Propofol dose in the 24 Hours Before Oxygenator Exchange (mg) Cumulative Propofol Dose Before Oxygenator Exchange (mg) Cumulative Propofol Dose (mg) Days of Propofol Use (Days Before Oxygenator Failure) Total Oxygenator Failures Patient N/A 46 Device 1: 0 Device 2: 6 65, 177 Device 1: 132, 201 Device 2: 57, 174 Device 1: 50 Device 2: (1, 0) 50 Device 1: 50 Device 2: (3) 88, , , N/A (6) , , KCentra 1671 units (0) , , N/A N/A 6 Device 1: 0 Device 2: 2 87, 194 Device 1: 85, 156 Device 2: 76, 166 Device 1: 5650 Device 2: (5, 4) 40,220 Device 1: 30,200 Device 2: 10, N/A N/A N/A 74, , Riastap 3 g Profilnine 2190 units DDAVP 20 mcg Aminocaproic acid 5 g KCentra 2072 units x1, 1601 units x1 85 Device 1: 0 Device 2: N/A N/A N/A 56, 162 Device 1: 71, 171 Device 2: 57, 174 Aminocaproic acid g KCentra 2840 units DDAVP 20 mcg Aminocaproic acid 5 g 16 Device 1: 3 Device 2: N/A N/A N/A 74, 168 Device 1: 103, 176 Device 2: 38, 150 ACT, activated clotting time; aptt, activated partial thromboplastin time; DDAVP, desmopressin; ECMO, extracorporeal membrane oxygenation. 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 ventilatorassociated 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

5 SAFETY OF PROPOFOL IN ECMO 183 Table 4. Propofol Data Outcome All Propofol Patients (N = 16) Requiring Oxygenator Exchange (N = 5) No Oxygenator Exchange (N = 11) p Total duration of ECMO support (days) N/A Median duration of ECMO support (days) 14 (8.5 28) 30 (27 49) 9 ( ) 0.09 Total days of propofol exposure, n (%) 137 (36) 96 (47) 41 (24) <0.001 Duration of propofol therapy per patient* (days) 4 (1 8) 8 (6 10) 2 (1 6) 0.14 Median daily propofol dose* (mg) 1013 ( ) 739 ( ) 3196 ( ) <0.001 Median cumulative propofol dose before N/A 1220 ( ) N/A N/A oxygenator exchange (mg) Median propofol dose in the 24 hours before oxygenator exchange (mg) N/A 50 (0 1555) N/A N/A *Median (IQR). ECMO, extracorporeal membrane oxygenation; IQR, interquartile range. 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. 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. References 1. Peek GJ, Mugford M, Tiruvoipati R, et al: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicentre randomised controlled trial. Lancet 374: , Lehr CJ, Zaas DW, Cheifetz IM, Turner DA: Ambulatory extracorporeal membrane oxygenation as a bridge to lung transplantation: Walking while waiting. Chest 147: , Mohite PN, Sabashnikov A, Reed A, et al: Extracorporeal life support in awake patients as a bridge to lung transplant. Thorac Cardiovasc Surg 63: , Gulack BC, Hirji SA, Hartwig MG. Bridge to lung transplantation and rescue post-transplant: The expanding role of extracorporeal membrane oxygenation. J Thorac Dis 6: , Bartlett RH, Gattinoni L: Current status of extracorporeal life support (ECMO) for cardiopulmonary failure. Minerva Anestesiol 76: , Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care 27: 741.e e718, Shekar K, Roberts JA, Mullany DV, et al: Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth Intensive Care 40: , Nigoghossian CD, Dzierba AL, Etheridge J, et al: Effect of extracorporeal membrane oxygenation use on sedative requirements in patients with severe acute respiratory distress syndrome. Pharmacotherapy 36: , Shekar K, Roberts JA, McDonald CI, et al: Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care 16: R194, Shekar K, Roberts JA, Ghassabian S, et al: Sedation during extracorporeal membrane oxygenation why more is less. Anaesth Intensive Care 40: , Shekar K, Roberts JA, McDonald CI, et al: Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: Results from an ex vivo study. Crit Care 19: 164, Devlin JW, Roberts RJ. Pharmacology of commonly used analgesics and sedatives in the ICU: Benzodiazepines, propofol, and opioids. Crit Care Clin 25: , Choi L, Ferrell BA, Vasilevskis EE, et al: Population pharmacokinetics of fentanyl in the critically ill. Crit Care Med 44: 64 72, Harthan AA, Buckley KW, Heger ML, Fortuna RS, Mays K. Medication adsorption into contemporary extracorporeal membrane oxygenator circuits. J Pediatr Pharmacol Ther 19: , Barr J, Fraser GL, Puntillo K, et al: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 41: , Myers GJ, Voorhees C, Eke B, Johnstone R: The effect of Diprivan (propofol) on phosphorylcholine surfaces during cardiopulmonary bypass An in vitro investigation. Perfusion 24: , Krajčová A, Waldauf P, Anděl M, Duška F: Propofol infusion syndrome: A structured review of experimental studies and 153 published case reports. Crit Care 19: 398, Buscher H, Vaidiyanathan S, Al-Soufi S, et al: Sedation practice in veno-venous extracorporeal membrane oxygenation: An international survey. ASAIO J 59: , Arya VK, Kumar A, Thingnam SK. Propofol infusion into the pump during cardiopulmonary bypass: Is it safe and effective? J Cardiothorac Vasc Anesth 18: , Hickey S, Quasim I, Gaylor JD. In vitro variability in propofol absorption by different membrane oxygenators. Crit Care 5: 8, Lubnow M, Philipp A, Foltan M, et al: Technical complications during veno-venous extracorporeal membrane oxygenation

6 184 HOHLFELDER et al. and their relevance predicting a system-exchange Retrospective analysis of 265 cases. PLoS One 9: e112316, Hynynen M, Hammarén E, Rosenberg PH: Propofol sequestration within the extracorporeal circuit. Can J Anaesth 41: , Hammaren E, Rosenberg PH, Hynynen M. Coating of extracorporeal circuit with heparin does not prevet sequestration of propofol in vitro. Br J Anesth 82: 38 40, Nader-Djalal N, Khadra WZ, Spaulding W, Panos AL. Does propofol alter the gas exchange in membrane oxygenators? Ann Thorac Surg 66: , Muensterer OJ, Laney D, Georgeson KE: Survival time of ECMO circuits on and off bleeding protocol: is there a higher risk of circuit clotting? Eur J Pediatr Surg 21: 30 32, Klompas M, Li L, Szumita P, Kleinman K, Murphy MV. Associations between different sedatives and ventilator-associated events, length of stay, and mortality in patients who were mechanically ventilated. Chest 149: , Patanwala AE, Erstad BL. Comparison of dexmedetomidine versus propofol on hospital costs and length of stay. J Intensive Care Med 31: , 2016.