Abstract
This study aimed to identify drug administration patterns in patients of all ages supported with extracorporeal membrane oxygenation (ECMO) across multiple institutions and determine which of the most commonly administered drugs lack published dosing guidance.
We conducted a retrospective, multicenter database study using the TriNetX data network and the Pediatric Health Information Systems database. All adults and children supported with ECMO were included for analysis. Drug exposure and days of use were described according to age category (Infants [<2 years], Children [≥2 and <18 years], and Adults [≥18 years]). The literature was reviewed for the top 50 most commonly administered drugs in all ages; all pharmacokinetic and ex vivo studies were included. A total of 17,909 patients were analyzed. The patient population comprised 24% adults (n = 4,253), 18% children (n = 3266), and 58% infants (n = 10,390). The 10 most commonly administered drugs, by days of use, were heparin, furosemide, midazolam, morphine, fentanyl, vancomycin, milrinone, hydrocortisone, epinephrine, and lorazepam. Published literature comprised 86 studies, including 66 pharmacokinetic studies (77%) and 20 ex vivo studies (23%). Of these, 29% (n = 19) were conducted in adults, 14% (n = 9) were conducted in children, and 60% (n = 39) were performed in infants. ECMO-specific dosing guidance for any age was available for only 28% (n = 14) of the top 50 most commonly administered drugs.
Sedatives, antimicrobials, and cardiovascular agents are among the most commonly administered drugs in patients supported with ECMO. This study highlights an urgent need for evidence-based dosing guidance in this patient population.
Keywords: extracorporeal membrane oxygenation, pharmacology, pharmacokinetics, database, critical illness, intensive care units
Introduction
Extracorporeal membrane oxygenation (ECMO) is a mode of advanced life support used in patients with refractory respiratory and/or cardiac failure. Mechanistically, it consists of a drainage cannula that removes blood from a patient, a pump that moves blood forward through the system, an oxygenator that adds oxygen and removes carbon dioxide from the blood, and a return cannula that returns blood to the patient. Although this mechanical support can be life-saving, mortality often exceeds 40%.1,2 The high mortality is multifactorial, but is suspected to be due, in part, to significantly altered drug disposition by the ECMO circuit, resulting in suboptimal dosing.3 Inappropriate dosing places these patients at risk of treatment failure and toxicities.
Drug dosing in patients on ECMO is unique due to a combination of circuit-, patient-, and disease-related alterations of drug pharmacokinetics (PK). The circuit can directly extract drugs by nonspecific adsorption of drug to circuit components, resulting in reduced drug concentration.4–8 Additionally, the large volume of exogenous blood and crystalloid required to prime the circuit and maintain flows results in hemodilution and increased volume of distribution.9 Critical illness (e.g., renal dysfunction) and inflammation are common disease-related alterations in ECMO patients and result in decreased drug clearance.10,11 Patient-specific factors include developmental changes in body composition and organ function, resulting in age-related variation in drug distribution, metabolism, and elimination.12,13 As a result of these PK alterations, adjustments in standard dosing are likely needed for most drugs commonly used in this population.
Most of the drugs used in patients on ECMO lack specific dosing guidance.14,15 To prioritize drugs for study, it is important to identify commonly used drugs in ECMO. Unfortunately, these data are scarce and limited to single-center studies. A recent study from a large children’s hospital provided excellent insight into commonly used drugs in ECMO. However, this study was limited to a single center and may lack generalizability, especially to the adult population.16 The purpose of this current study is to identify drug administration patterns in patients of all ages supported with ECMO across multiple institutions and determine which of the most commonly administered drugs lack published dosing guidance.
Materials and Methods
Study Population
This was a retrospective study analyzing drug administration patterns in patients supported with ECMO. Patients were identified by querying the TriNetX data network and Pediatric Health Information System (PHIS) database. TriNetX is a global health research network that contains electronic medical record data provided by 25 participating health care organizations. PHIS is an administrative and resource utilization database consisting of de-identified medical record information from inpatient, ambulatory surgery, emergency department, and observation unit patient encounters from 49 children’s hospitals in North America. TriNetX data were downloaded in February 2020 and included encounters from December 30, 2001, through February 13, 2020. The PHIS data were downloaded in September 2020 and included encounters from March 6, 2003, to December 29, 2019.
Patients with the following International Classification of Diseases, 9th Revision (ICD-9), ICD-10, and/or Current Procedural Terminology (CPT) ECMO codes were included for analysis: 39.65, 5A15223, 5A1522F, 5A1522G, 5A1522H, 5A15A2F, 5A15A2G, 5A15A2H, 521180, 521181, 521182, 1022227, 1021846, 33946, 33947, 33948, 33949, 33951, 33952, 33953, 33954, 33955, 33956, 33957, 33958, 33959, 33962, 33963, 33964, 33965, 33966, 33969, 33984, 33985, 33986. Eight institutions contribute patient data to both TriNetX and PHIS. Patients from these institutions were excluded from the PHIS dataset to prevent duplications. We collected the following data elements: (1) patient demographics including date of birth, race/ethnicity, sex, death during study period; (2) date(s) of ICD/CPT code(s) for ECMO; (3) drug names; (4) drug administration dates. Intravenous fluids, vitamins (except vitamin K), electrolyte and nutritional supplements, ophthalmic drops, ointments, and topical drugs were not included for analysis. If a patient was supported with ECMO more than once, we only included drugs administered during the first ECMO run.
Regulatory
TriNetX, LLC, is compliant with the Health Insurance Portability and Accountability Act (HIPAA), the U.S. federal law which protects the privacy and security of health care data, and any additional data privacy regulations applicable to the contributing Health Care Organization. TriNetX is certified to the ISO 27001:2013 standard and maintains an Information Security Management System to ensure the protection of the health care data it has access to and to meet the requirements of the HIPAA Security Rule. Any data displayed on the TriNetX Platform in aggregate form, or any patient level data provided in a dataset generated by the TriNetX Platform, only contain de-identified data as per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The process by which the data are de-identified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule. No Institutional Review Board approval was necessary because this study used only de-identified patient records and did not involve the collection, use, or transmittal of individually identifiable data, and thus this study did not fall under the board’s guidelines as human subjects research.
Definitions
Patients were divided into the following age categories based upon age at time of ECMO cannulation: Infants (<2 years), Children (≥2 and <18 years), and Adults (≥18 years). Only the year of birth was available for patients in the TriNetX dataset. Therefore, we assigned the month and day of birth as July 1 to determine age category for these patients. For patients in the PHIS dataset, complete birth dates (day, month, year) were available and used to determine age category.
ECMO day 0 was defined for each patient as the earliest date with an ECMO ICD-9, ICD-10, and/or CPT code. We excluded all drugs administered on ECMO day 0 to prevent the inclusion of drugs administered prior to ECMO cannulation. Due to database limitations, we were unable to reliably determine the dates of decannulation. Therefore, we defined the ECMO run duration as 8 days for all patients. This duration was chosen based on the average ECMO run time from 2015 to 2019 as reported in the Extracorporeal Life Support Organization’s Extracorporeal Life Support Registry Report International Summary 2020.1
Analysis
We described drug use using two different methods, similar to those described by Hsieh et al in an analysis of commonly used drugs in neonates.17 Days of use was defined as the total number of days a unique drug was administered. Exposure was defined as the number of unique patients who received a drug. For example, if azithromycin was administered to two patients for 1 day and one patient for 3 days, azithromycin would be reported as: days of use = 1 + 1 + 3 = 5, exposure = 1 + 1 + 1 = 3. Percent days of use was calculated by dividing days of use by the total number of ECMO days per age group (i.e., number of patients in age group × 8 days). Percent exposure was calculated by dividing exposure by the total number of patients per age group.
We classified the top 50 most commonly administered drugs into anatomical/pharmacological groups according to the World Health Organization’s Anatomical Therapeutic Chemical (ATC) Classification system.18 Days of use was defined as the total number of days a drug within an ATC class was administered. Percent days of use was calculated by dividing days of use per ATC class by the total number of ECMO days per age group. Individual drugs were counted in more than one class when indicated. For example, the ATC system classifies aspirin within both nervous system and blood and blood forming organs; therefore, aspirin days of use were counted in both the classes.
Dosing Guidance
To understand which commonly administered drugs have published dosing guidance, we reviewed the literature for pharmacokinetic studies supporting ECMO-specific dosing regimens for the top 50 most commonly administered drugs in all ages. The literature search was performed in May 2021 using the PubMed database. Animal studies and studies published in a language other than English were excluded. Search terms included the generic drug name AND “pharmacokinetics” AND “ECMO OR extracorporeal membrane oxygenation OR extracorporeal life support.” Studies were included if they contained in vivo PK data from any age patient(s) or concentration data from an ex vivo system.
Results
Data from 25,586 patients were downloaded from the TriNetX (n = 5,222) and PHIS (n = 20,364) databases. A total of 7,677 patients were excluded: 1,715 patients (1,070 TriNetX, 645 PHIS) due to lack of information about medication administration and 5,962 PHIS patients from institutions contributing to both databases. This resulted in a final cohort of 17,909 patients for analysis.
Table 1 describes the characteristics of the final cohort. The majority were male (57%, n = 10,224), White (48%, n = 8,609), and alive at the end of the study period (60%, n = 10,664). The age group distribution of the cohort was as follows: 24% adults (n = 4,253), 18% children (n = 3,266), 58% infants (n = 10,390).
Table 1.
Patient characteristics stratified by data source
| Patient characteristic | PHIS (n = 13,757) | TriNetX (n = 4,152) | All (n = 17,909) |
|---|---|---|---|
| Age category, n (%) | |||
| Adults (≥18 years) | 355 (3) | 3,898 (94) | 4,253 (24) |
| Children (≥2 and <18 years) | 3,134 (23) | 132 (3) | 3,266 (18) |
| Infants (<2 years) | 10,268 (75) | 122 (3) | 10,390 (58) |
| Sex, n (%) | |||
| Male | 7,563 (55) | 2,661 (64) | 10,224 (57) |
| Female | 6,188 (45) | 1,491 (36) | 7,679 (43) |
| Ethnicity, n (%) | |||
| White, non-Hispanic | 6,831 (50) | 1,778 (43) | 8,609 (48) |
| Black, non-Hispanic | 2,233 (16) | 439 (11) | 2,672 (15) |
| Other, non-Hispanic | 1,724 (13) | 282 (7) | 2,006 (11) |
| Hispanic | 1,485 (11) | 303 (7) | 1,788 (10) |
| Unknown | 824 (6) | 1,350 (33) | 2,174 (12) |
| Multiple | 660 (5) | 0 (0) | 660 (4) |
| Died during study period, n (%) | |||
| Yes | 5,388 (39) | 1,857 (45) | 7,245 (41) |
| No | 8,369 (61) | 2,295 (55) | 10,664 (60) |
Abbreviation: PHIS, Pediatric Health Information System.
The 10 most commonly administered drugs, by days of use, were heparin, furosemide, midazolam, morphine, fentanyl, vancomycin, milrinone, hydrocortisone, epinephrine, and lorazepam (Table 2). When stratified by age, heparin, fentanyl, furosemide, vancomycin, and midazolam were in the top 10 most commonly administered drugs for all age groups. Insulin, docusate, propofol, and amiodarone were in the top 10 most commonly administered drugs for adult patients (Table 3). Children were more likely to receive dexmedetomidine (Table 4) than adults (48 vs. 32% exposure) or infants (48 vs. 27% exposure). Hydrocortisone was more commonly administered to infants (Table 5) than adults (52 vs. 23% exposure) or children (52 vs. 37% exposure).
Table 2.
Most commonly administered drugs, all ages
| Rank | Drug | Days of usea, n (%) | Drug | Exposureb, n (%) |
|---|---|---|---|---|
| 1 | Heparin | 97,127 (78) | Heparin | 17,090 (95) |
| 2 | Furosemide | 66,858 (53) | Fentanyl | 12,866 (72) |
| 3 | Midazolam | 63,442 (51) | Furosemide | 11,683 (65) |
| 4 | Morphine | 53,789 (43) | Vancomycin | 10,760 (60) |
| 5 | Fentanyl | 53,613 (43) | Propofol | 8,079 (45) |
| 6 | Vancomycin | 46,269 (37) | Docusate | 7,970 (45) |
| 7 | Milrinonec | 40,611 (32) | Midazolam | 7,904 (44) |
| 8 | Hydrocortisone | 37,480 (30) | Insulin lispro | 7,420 (41) |
| 9 | Epinephrine | 34,296 (27) | Pantoprazole | 7,327 (41) |
| 10 | Lorazepam | 28,355 (23) | Amiodarone | 6,268 (35) |
| 11 | Vecuroniumc | 25,460 (20) | Sennosides | 6,139 (34) |
| 12 | Dexmedetomidine | 24,941 (20) | Insulin regular | 6,096 (34) |
| 13 | Pantoprazolec | 24,590 (20) | Epinephrine | 6,070 (34) |
| 14 | Ranitidine | 24,402 (20) | Acetaminophen | 5,931 (33) |
| 15 | Dopamine | 21,587 (17) | Aspirin | 5,546 (31) |
| 16 | Famotidinec | 19,635 (16) | Piperacillin–Tazobactam | 5,404 (30) |
| 17 | Cefazolin | 19,115 (15) | Lidocaine | 5,258 (29) |
| 18 | Piperacillin–Tazobactam | 17,508 (14) | Dexmedetomidine | 4,901 (27) |
| 19 | Ampicillin | 17,486 (14) | Milrinone | 4,753 (27) |
| 20 | Acetaminophen | 16,630 (13) | Polyethylene glycol | 4,340 (24) |
| 21 | Chlorothiazidec | 15,862 (13) | Dobutamine | 4,340 (24) |
| 22 | Cefepime | 15,476 (12) | Albuterol | 4,249 (24) |
| 23 | Methylprednisolonec | 14,867 (12) | Insulin aspart | 4,118 (23) |
| 24 | Gentamicin | 14,049 (11) | Methylprednisolone | 3,979 (22) |
| 25 | Rocuroniumc | 13,927 (11) | Oxycodone | 3,871 (22) |
| 26 | Albuterolc | 13,910 (11) | Rocuronium | 3,834 (21) |
| 27 | Antithrombinc | 13,510 (11) | Famotidine | 3,488 (20) |
| 28 | Insulin regularc | 12,964 (10) | Hydromorphone | 3,427 (19) |
| 29 | Fluconazole | 11,940 (10) | Hydrocortisone | 3,349 (19) |
| 30 | Docusatec | 11,451 (9) | Norepinephrine | 3,328 (19) |
| 31 | Amiodarone | 11,405 (9) | Vasopressin | 3,154 (18) |
| 32 | Lidocainec | 11,393 (9) | Insulin glargine | 2,948 (17) |
| 33 | Vasopressinc | 10,720 (9) | Ipratropium | 2,909 (16) |
| 34 | Cefotaxime | 10,342 (8) | Cefazolin | 2,858 (16) |
| 35 | Nicardipinec | 10,271 (8) | Atorvastatin | 2,797 (16) |
| 36 | Nitroprussidec | 10,155 (8) | Lorazepam | 2,768 (16) |
| 37 | Cisatracuriumc | 9,787 (8) | Cefepime | 2,626 (15) |
| 38 | Meropenem | 9,580 (8) | Insulin isophane | 2,533 (14) |
| 39 | Aspirinc | 9,091 (7) | Hydralazine | 2,483 (14) |
| 40 | Hydromorphone | 8,932 (7) | Esomeprazole | 2,356 (13) |
| 41 | Phenobarbital | 8,120 (7) | Nicardipine | 2,294 (13) |
| 42 | Propofol | 7,945 (6) | Fluconazole | 2,268 (13) |
| 43 | Insulin lisproc | 7,721 (6) | Metoprolol | 2,224 (12) |
| 44 | Polyethylene glycolc | 7,395 (6) | Morphine | 2,117 (12) |
| 45 | Levetiracetam | 7,384 (6) | Bisacodyl | 2,058 (12) |
| 46 | Norepinephrinec | 6,984 (6) | Ondansetron | 2,036 (11) |
| 47 | Sennosidesc | 6,284 (5) | Insulin detemir | 2,011 (11) |
| 48 | Hydralazinec | 6,101 (5) | Insulin glulisine | 1,973 (11) |
| 49 | Ketamine | 6,085 (5) | Bivalirudin | 1,935 (11) |
| 50 | Bumetanide | 5,937 (5) | Meropenem | 1,917 (11) |
Days of use was defined as the total number of days a unique drug was administered.
Exposure was defined as the number of unique patients who received a drug.
No pharmacokinetic studies on extracorporeal membrane oxygenation.
Table 3.
Most commonly administered drugs, adults
| Rank | Drug | Days of usea, n (%) | Drug | Exposureb, n (%) |
|---|---|---|---|---|
| 1 | Heparin | 17,090 (57) | Heparin | 3,593 (85) |
| 2 | Fentanyl | 12,866 (43) | Fentanyl | 2,838 (67) |
| 3 | Furosemide | 11,683 (39) | Vancomycin | 2,709 (64) |
| 4 | Vancomycin | 10,760 (36) | Insulin regular | 2,572 (61) |
| 5 | Propofol | 8,079 (27) | Furosemide | 2,531 (60) |
| 6 | Docusate | 7,970 (27) | Midazolam | 2,476 (58) |
| 7 | Midazolam | 7,904 (27) | Insulin lispro | 2,165 (51) |
| 8 | Insulin lispro | 7,420 (25) | Epinephrine | 2,162 (51) |
| 9 | Pantoprazole | 7,327 (25) | Propofol | 2,112 (50) |
| 10 | Amiodarone | 6,268 (21) | Docusate | 2,013 (47) |
| 11 | Sennosides | 6,139 (21) | Acetaminophen | 1,871 (44) |
| 12 | Insulin regular | 6,096 (20) | Lidocaine | 1,717 (40) |
| 13 | Epinephrine | 6,070 (20) | Sennosides | 1,715 (40) |
| 14 | Acetaminophen | 5,931 (20) | Pantoprazole | 1,688 (40) |
| 15 | Aspirin | 5,546 (19) | Piperacillin–Tazobactam | 1,615 (38) |
| 16 | Piperacillin–Tazobactam | 5,404 (18) | Amiodarone | 1,568 (37) |
| 17 | Lidocaine | 5,258 (18) | Rocuronium | 1,504 (35) |
| 18 | Dexmedetomidine | 4,901 (16) | Vasopressin | 1,474 (35) |
| 19 | Milrinone | 4,753 (16) | Polyethylene glycol | 1,446 (34) |
| 20 | Polyethylene glycol | 4,340 (15) | Dexmedetomidine | 1,355 (32) |
| 21 | Dobutamine | 4,340 (15) | Norepinephrine | 1,353 (32) |
| 22 | Albuterol | 4,249 (14) | Aspirin | 1,351 (32) |
| 23 | Insulin aspart | 4,118 (14) | Insulin aspart | 1,289 (30) |
| 24 | Methylprednisolone | 3,979 (13) | Albuterol | 1,275 (30) |
| 25 | Oxycodone | 3,871 (13) | Milrinone | 1,115 (26) |
| 26 | Rocuronium | 3,834 (13) | Cefazolin | 1,112 (26) |
| 27 | Famotidine | 3,488 (12) | Phenylephrine | 1,021 (24) |
| 28 | Hydromorphone | 3,427 (12) | Hydrocortisone | 977 (23) |
| 29 | Hydrocortisone | 3,349 (11) | Dobutamine | 968 (23) |
| 30 | Norepinephrine | 3,328 (11) | Famotidine | 962 (23) |
| 31 | Vasopressin | 3,154 (11) | Lorazepam | 952 (22) |
| 32 | Insulin glargine | 2,948 (10) | Methylprednisolone | 939 (22) |
| 33 | Ipratropium | 2,909 (10) | Hydromorphone | 925 (22) |
| 34 | Cefazolin | 2,858 (10) | Bisacodyl | 915 (22) |
| 35 | Atorvastatin | 2,797 (9) | Ondansetron | 899 (21) |
| 36 | Lorazepam | 2,768 (9) | Insulin glargine | 892 (21) |
| 37 | Cefepime | 2,626 (9) | Oxycodone | 856 (20) |
| 38 | Insulin isophane | 2,533 (9) | Hydralazine | 853 (20) |
| 39 | Hydralazine | 2,483 (8) | Ipratropium | 840 (20) |
| 40 | Esomeprazole | 2,356 (8) | Insulin isophane | 786 (19) |
| 41 | Nicardipine | 2,294 (8) | Cefepime | 757 (18) |
| 42 | Fluconazole | 2,268 (8) | Morphine | 746 (18) |
| 43 | Metoprolol | 2,224 (7) | Nicardipine | 746 (18) |
| 44 | Morphine | 2,117 (7) | Metoclopramide | 729 (17) |
| 45 | Bisacodyl | 2,058 (7) | Protamine | 719 (17) |
| 46 | Ondansetron | 2,036 (7) | Metoprolol | 702 (17) |
| 47 | Insulin detemir | 2,011 (7) | Fluconazole | 701 (17) |
| 48 | Insulin glulisine | 1,973 (7) | Acetazolamide | 654 (15) |
| 49 | Bivalirudin | 1,935 (6) | Vecuronium | 617 (15) |
| 50 | Meropenem | 1,917 (6) | Cisatracurium | 609 (14) |
Days of use was defined as the total number of days a unique drug was administered.
Exposure was defined as the number of unique patients who received a drug.
Table 4.
Most commonly administered drugs, children
| Rank | Drug | Days of usea, n (%) | Drug | Exposureb, n (%) |
|---|---|---|---|---|
| 1 | Heparin | 17,434 (76) | Heparin | 3,014 (92) |
| 2 | Midazolam | 13,527 (59) | Midazolam | 2,577 (79) |
| 3 | Furosemide | 10,955 (48) | Fentanyl | 2,370 (73) |
| 4 | Morphine | 10,311 (45) | Vancomycin | 2,333 (71) |
| 5 | Vancomycin | 9,769 (43) | Furosemide | 2,326 (71) |
| 6 | Fentanyl | 9,361 (41) | Epinephrine | 2,320 (71) |
| 7 | Milrinone | 8,821 (39) | Morphine | 2,078 (64) |
| 8 | Dexmedetomidine | 7,506 (33) | Milrinone | 1,824 (56) |
| 9 | Pantoprazole | 7,067 (31) | Vecuronium | 1,793 (55) |
| 10 | Epinephrine | 6,963 (31) | Dexmedetomidine | 1,571 (48) |
| 11 | Vecuronium | 6,346 (28) | Lorazepam | 1,522 (47) |
| 12 | Methylprednisolone | 5,948 (26) | Acetaminophen | 1,514 (46) |
| 13 | Lorazepam | 5,935 (26) | Methylprednisolone | 1,250 (38) |
| 14 | Hydrocortisone | 5,488 (24) | Pantoprazole | 1,246 (38) |
| 15 | Ranitidine | 5,087 (22) | Hydrocortisone | 1,217 (37) |
| 16 | Famotidine | 4,548 (20) | Ranitidine | 1,137 (35) |
| 17 | Acetaminophen | 4,507 (20) | Rocuronium | 1,133 (35) |
| 18 | Piperacillin–Tazobactam | 3,843 (17) | Cefazolin | 1,114 (34) |
| 19 | Insulin regular | 3,815 (17) | Insulin regular | 1,099 (34) |
| 20 | Albuterol | 3,713 (16) | Lidocaine | 1,082 (33) |
| 21 | Nicardipine | 3,471 (15) | Dopamine | 1,050 (32) |
| 22 | Cefepime | 3,450 (15) | Antithrombin | 1,006 (31) |
| 23 | Cefazolin | 3,328 (15) | Albuterol | 990 (30) |
| 24 | Dopamine | 3,200 (14) | Nitroprusside | 983 (30) |
| 25 | Nitroprusside | 3,059 (13) | Diphenhydramine | 969 (30) |
| 26 | Cisatracurium | 2,953 (13) | Ketamine | 929 (28) |
| 27 | Meropenem | 2,944 (13) | Nicardipine | 925 (28) |
| 28 | Fluconazole | 2,824 (12) | Famotidine | 891 (27) |
| 29 | Diphenhydramine | 2,660 (12) | Piperacillin–Tazobactam | 879 (27) |
| 30 | Rocuronium | 2,626 (12) | Chlorothiazide | 870 (27) |
| 31 | Chlorothiazide | 2,610 (11) | Vasopressin | 819 (25) |
| 32 | Hydromorphone | 2,518 (11) | Cefepime | 795 (24) |
| 33 | Clindamycin | 2,327 (10) | Cisatracurium | 775 (24) |
| 34 | Antithrombin | 2,234 (10) | Thrombin | 755 (23) |
| 35 | Polyethylene glycol | 2,194 (10) | Polyethylene glycol | 699 (21) |
| 36 | Docusate | 2,166 (10) | Norepinephrine | 693 (21) |
| 37 | Ketamine | 2,151 (9) | Fluconazole | 690 (21) |
| 38 | Lidocaine | 2,123 (9) | Meropenem | 652 (20) |
| 39 | Ceftriaxone | 2,078 (9) | Propofol | 623 (19) |
| 40 | Levetiracetam | 1,966 (9) | Hydromorphone | 590 (18) |
| 41 | Vasopressin | 1,862 (8) | Docusate | 566 (17) |
| 42 | Dornase alfa | 1,582 (7) | Immunoglobulin | 530 (16) |
| 43 | Sennosides | 1,571 (7) | Ceftriaxone | 529 (16) |
| 44 | Norepinephrine | 1,531 (7) | Ondansetron | 521 (16) |
| 45 | Amiodarone | 1,477 (7) | Clindamycin | 517 (16) |
| 46 | Methadone | 1,466 (6) | Atropine | 486 (15) |
| 47 | Mycophenolate | 1,414 (6) | Methadone | 454 (14) |
| 48 | Azithromycin | 1,322 (6) | Sennosides | 446 (14) |
| 49 | Esomeprazole | 1,250 (6) | Dornase alfa | 441 (14) |
| 50 | Bumetanide | 1,203 (5) | Vitamin K | 422 (13) |
Days of use was defined as the total number of days a unique drug was administered.
Exposure was defined as the number of unique patients who received a drug.
Table 5.
Most commonly administered drugs, infants
| Rank | Drug | Days of usea, n (%) | Drug | Exposureb, n (%) |
|---|---|---|---|---|
| 1 | Heparin | 59,804 (82) | Heparin | 9,952 (96) |
| 2 | Furosemide | 44,220 (61) | Furosemide | 8,719 (84) |
| 3 | Midazolam | 42,011 (58) | Midazolam | 8,021 (77) |
| 4 | Morphine | 41,361 (57) | Fentanyl | 7,911 (76) |
| 5 | Fentanyl | 31,386 (43) | Morphine | 7,356 (71) |
| 6 | Hydrocortisone | 28,643 (39) | Epinephrine | 6,506 (63) |
| 7 | Milrinone | 27,037 (37) | Vecuronium | 6,298 (61) |
| 8 | Vancomycin | 25,740 (35) | Vancomycin | 6,027 (58) |
| 9 | Epinephrine | 21,263 (29) | Milrinone | 6,013 (58) |
| 10 | Lorazepam | 19,652 (27) | Dopamine | 5,465 (53) |
| 11 | Ranitidine | 18,755 (26) | Hydrocortisone | 5,398 (52) |
| 12 | Vecuronium | 18,734 (26) | Lorazepam | 4,495 (43) |
| 13 | Dopamine | 18,247 (25) | Cefazolin | 4,334 (42) |
| 14 | Ampicillin | 17,254 (24) | Antithrombin | 4,099 (40) |
| 15 | Cefazolin | 15,600 (21) | Ranitidine | 3,956 (38) |
| 16 | Chlorothiazide | 13,206 (18) | Ampicillin | 3,752 (36) |
| 17 | Gentamicin | 12,949 (18) | Chlorothiazide | 3,573 (34) |
| 18 | Dexmedetomidine | 12,534 (17) | Gentamicin | 3,355 (32) |
| 19 | Famotidine | 11,599 (16) | Rocuronium | 3,136 (30) |
| 20 | Antithrombin | 11,126 (15) | Dexmedetomidine | 2,839 (27) |
| 21 | Pantoprazole | 10,196 (14) | Nitroprusside | 2,550 (25) |
| 22 | Cefepime | 9,400 (13) | Acetaminophen | 2,435 (23) |
| 23 | Cefotaxime | 9,320 (13) | Thrombin | 2,218 (21) |
| 24 | Phenobarbital | 7,752 (11) | Famotidine | 2,202 (21) |
| 25 | Piperacillin–Tazobactam | 7,678 (11) | Cefepime | 2,109 (20) |
| 26 | Rocuronium | 7,467 (10) | Lidocaine | 2,106 (20) |
| 27 | Nitroprusside | 6,886 (10) | Vasopressin | 2,066 (20) |
| 28 | Fluconazole | 6,848 (9) | Albuterol | 1,956 (19) |
| 29 | Acetaminophen | 6,192 (9) | Piperacillin–Tazobactam | 1,917 (19) |
| 30 | Albuterol | 5,948 (8) | Cefotaxime | 1,910 (18) |
| 31 | Cisatracurium | 5,363 (7) | Pantoprazole | 1,808 (17) |
| 32 | Vasopressin | 5,352 (7) | Fluconazole | 1,771 (17) |
| 33 | Methylprednisolone | 4,940 (7) | Trimethoprim–Sulfamethoxazole | 1,737 (17) |
| 34 | Meropenem | 4,719 (7) | Methylprednisolone | 1,639 (16) |
| 35 | Bumetanide | 4,678 (6) | Phenobarbital | 1,630 (16) |
| 36 | Nicardipine | 4,480 (6) | Cisatracurium | 1,613 (16) |
| 37 | Levetiracetam | 4,351 (6) | Nicardipine | 1,522 (15) |
| 38 | Lidocaine | 4,012 (6) | Dexamethasone | 1,475 (14) |
| 39 | Amiodarone | 3,660 (5) | Atropine | 1,416 (14) |
| 40 | Ceftazidime | 3,467 (5) | Ketamine | 1,401 (14) |
| 41 | Sildenafil | 3,395 (5) | Acetazolamide | 1,368 (13) |
| 42 | Dexamethasone | 3,320 (5) | Aminocaproic acid | 1,340 (13) |
| 43 | Methadone | 3,264 (5) | Insulin regular | 1,312 (13) |
| 44 | Insulin regular | 3,053 (4) | Hydralazine | 1,308 (13) |
| 45 | Aminocaproic acid | 3,051 (4) | Bumetanide | 1,252 (12) |
| 46 | Thrombin | 3,027 (4) | Protamine | 1,128 (11) |
| 47 | Hydromorphone | 2,987 (4) | Vitamin K | 1,110 (11) |
| 48 | Dornase alfa | 2,973 (4) | Meropenem | 1,083 (10) |
| 49 | Acetazolamide | 2,953 (4) | Mannitol | 1,062 (10) |
| 50 | Hydralazine | 2,830 (4) | Methadone | 1,000 (10) |
Days of use was defined as the total number of days a unique drug was administered.
Exposure was defined as the number of unique patients who received a drug.
Supplementary Table S1 (available in the online version only) describes the ATC Classifications of the top 50 most commonly administered drugs. Overall, administration patterns by ATC classification were similar between age groups. Drugs within the nervous system class were the most frequently administered (28% days of use), followed by those within the cardiovascular system class (23% days of use).
The PK literature for the top 50 most commonly administered drugs is summarized in Supplementary Table S2 (available in the online version only). A total of 86 studies were reviewed including 66 PK studies (77%) and 20 ex vivo studies (23%). Of the PK studies, 29% (n = 19) were conducted in adults, 14% (n = 9) were conducted in children, and 60% (n = 39) were performed in infants. One PK study included both adults and children. Dosing guidance in any age was provided for 28% (n = 14) of the top 50 most common drugs. No ECMO PK or ex vivo studies were found for the following 22 drugs: milrinone, vecuronium, pantoprazole, famotidine, chlorothiazide, methylprednisolone, rocuronium, albuterol, antithrombin, regular insulin, docusate, lidocaine, vasopressin, nicardipine, nitroprusside, cisatracurium, and aspirin.
Discussion
Using two large multicenter databases, this study identifies the drugs most commonly administered to patients on ECMO across the age spectrum. It also emphasizes a lack of available dosing recommendations in this critically ill patient population.
Therapeutic categories exhibit wide variation in the number of existing pharmacokinetic studies and robustness of dosing guidelines. Sedatives and analgesics are among the most well-studied agents, presumably due to their ubiquitous use in this patient population.19–22 In contrast, cardiovascular, gastrointestinal, and hematologic agents have a paucity of data to guide dosing. Cardiovascular agents, including inotropes, chronotropes, vasoconstrictors, vasodilators, diuretics, and antiarrhythmics, were among the most commonly administered and least well-studied drugs in all ages in our cohort. The existing data are limited to small PK trials and ex vivo studies that, with the exception of a case report on amiodarone, lack any specific dosing recommendations. Antibiotics are variable in the amount of published PK data available. Some antibiotics, such as vancomycin and meropenem, have fairly robust PK literature to guide dosing. Others, such as cefazolin, ampicillin, and cefepime, have little to no dosing data in ECMO. Appropriate antibiotic dosing is critical in the ECMO population because infectious complications of ECMO are common and can increase mortality by 38 to 63%.23,24 Treatment of these life-threatening infections requires adequate drug exposure while limiting toxicities. While therapeutic drug monitoring is routinely used for agents with an exceedingly narrow therapeutic window (e.g., vancomycin and gentamicin), this is not considered standard of care for the majority of antibiotics.25 Overall, there is an urgent need for evidence-based dosing guidance, especially for drugs that (1) are commonly used in patients on ECMO but lack any PK data, (2) have a narrow therapeutic index, (3) lack readily available methods of therapeutic drug monitoring, or (4) do not have a rapidly measurable clinical effect.
Drug disposition during ECMO support has primarily been studied using ex vivo experiments and clinical PK trials. In ex vivo experiments, drug is administered to isolated, closed-loop ECMO circuits and concentrations are measured over time.26–29 There is no contribution from corporeal pharmacokinetic processes; thus, any drug loss over time is due to circuit extraction or drug degradation. Ex vivo experiments are faster and less expensive than PK trials. However, in isolation, ex vivo study data are inadequate to establish dosing recommendations. Clinical PK trials, in contrast, can effectively determine a safe and efficacious dosing regimen in a population of interest. There are, however, two important limitations to PK trials in the ECMO population. First, the impact of ECMO on drug disposition is drug- and age-specific, thus necessitating a trial for each drug of interest across all ages. Second, the impact of ECMO is also component-specific. Consequently, as new ECMO circuit equipment is developed, PK trials need to be repeated to quantify the impact of the new equipment on drug disposition. Importantly, many of the published ex vivo experiments and PK trials reviewed for our study were performed using older technology; it is not known whether dosing recommendations derived from these trials can be extrapolated to patients supported with modern ECMO circuits.
The amount of available dosing guidance in ECMO varies by age group. The majority of PK studies in ECMO were performed in neonates and infants. PK data from neonates and infants cannot always be extrapolated to older children and adults due to several patient- and circuit-related factors. First, the size of the membrane oxygenator may affect extraction for some drugs with larger oxygenators extracting more drug.30,31 Second, the circuit priming volume can have a variable impact on hemodilution and thus volume of distribution depending on the size of the patient. For example, for a 3-kg neonate, the ECMO prime volume may effectively double the total circulating blood volume, while for a 75-kg adult, the prime volume likely represents <10% of the circulating blood volume.3 Third, the influence of ontogeny on drug absorption, distribution, metabolism, and excretion necessitates age-specific dosing regimens for most drugs.12 Our study highlights the need for further research into drug dosing in ECMO across the age spectrum with particular focus on children and adults.
Efforts are currently underway to fill the knowledge gaps in drug dosing in patients supported with ECMO. Antibiotic, Sedative and Analgesic Pharmacokinetics during Extracorporeal Membrane Oxygenation (ACTRN12612000559819) is a multicenter, open-label, PK study sponsored by the Critical Care Research Group at the Prince Charles Hospital in Brisbane, Australia. This study is part of a larger research platform that combines ex vivo and animal experiments, clinical PK trials, and population PK modeling to develop evidence-based dosing recommendations.32 Our group is utilizing Physiologically Based Pharmacokinetic (PBPK) modeling to translate ex vivo data into clinical dosing guidelines.33 PBPK models differ from traditional PK models in that they are structured in a physiologically relevant manner with virtual organ compartments for each organ and connected by blood flow. Each organ compartment (e.g., liver) is parameterized with a mathematical equation describing drug disposition within the compartment. In patients on ECMO, an ECMO “organ” can be added to the model and parameterized using data obtained from ex vivo experiments. PBPK models can account for age- and critical illness-related physiologic changes, allowing dose predictions across the age and disease spectra.34–36
Our study has several limitations. It is a retrospective database study and thus there is potential for misclassification in ICD coding. Given that the dates of decannulation are estimated, our list of most commonly administered drugs may include drugs that were administered to patients after decannulation. The ages of patients from the TriNetX database were estimated based on a July 1 birthdate; thus, these patients are subject to possible age group misclassification. Because the ages were estimated, we were unable to accurately separate neonates from infants. Lastly, while our study describes the prevalence of medication administration in a large patient population over a nearly 20-year period, we recognize that our data do not adequately capture the changes in medication prescribing practices over time (i.e., increasing use of bivalirudin for anticoagulation).
It is worth noting that our systematic literature review did not include PK studies performed in cardiopulmonary bypass. Generally, the factors that alter drug PK are similar in both extracorporeal modalities.37 Additionally, several drugs commonly administered in the ECMO population have been studied in cardiopulmonary bypass.38–47 However, several key differences between the two modalities exist including patient population, duration of support provided, anticoagulation strategy, and circuit mechanics (open vs. closed system).48,49 Because of these differences, it is not known whether the findings from PK studies in cardiopulmonary bypass can be extrapolated to ECMO. Further research in this area is warranted.
Conclusion
Sedatives, antimicrobials, and cardiovascular agents are among the most commonly administered drugs in patients supported with ECMO. ECMO can substantially alter drug exposure. However, there is a critical lack of dosing guidance for the most commonly administered drugs in patients on ECMO.
Supplementary Material
Acknowledgments
We acknowledge the TriNetX and PHIS data management teams for their support of this study. We would like to thank Jacob Wilkes (Intermountain Healthcare, Salt Lake City) for his help with data extraction.
Funding
D.J.G. receives support for critical care research from the National Heart, Lung, and Blood Institute (2T32HL105321). A.M. receives support for pediatric pharmacology research from the National Institute of Diabetes and Digestive and Kidney Diseases (1F311DK130542). K.M.W. receives support for pediatric research from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD097775).
Footnotes
Conflict of Interest
None declared.
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