A Narrative Review of the Impact of Extracorporeal Membrane Oxygenation on the Pharmacokinetics and Pharmacodynamics of Critical Care Therapies.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) utilization is increasing on a global scale, and despite technological advances, minimal standardized approaches to pharmacotherapeutic management exist. This objective was to create a comprehensive review for medication dosing in ECMO based on the most current evidence. DATA SOURCES: A literature search of PubMed was performed for all pertinent articles prior to 2022. The following search terms were utilized: ECMO, pharmacokinetics, pharmacodynamics, sedation, analgesia, antiepileptic, anticoagulation, antimicrobial, antifungal, nutrition. Retrospective cohort studies, case-control studies, case series, case reports, and ex vivo investigations were reviewed. STUDY SELECTION AND DATA EXTRACTION: PubMed (1975 through July 2022) was the database used in the literature search. Non-English studies were excluded. Search terms included both drug class categories, specific drug names, ECMO, and pharmacokinetics. DATA SYNTHESIS: Medications with high protein binding (>70%) and high lipophilicity (logP > 2) are associated with circuit sequestration and the potential need for dose adjustment. Volume of distribution changes with ECMO may also impact dosing requirements of common critical care medications. Lighter sedation targets and analgosedation may help reduce sedative and analgesia requirements, whereas higher antiepileptic dosing is recommended. Vancomycin is minimally affected by the ECMO circuit and recommendations for dosing in critically ill adults are reasonable. Anticoagulation remains challenging as optimal aPTT goals have not been established. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review describes the anticipated impacts of ECMO circuitry on sedatives, analgesics, anticoagulation, antiepileptics, antimicrobials, antifungals, and nutrition support and provides recommendations for drug therapy management. CONCLUSIONS: Medication pharmacokinetic/pharmacodynamic parameters should be considered when determining the potential impact of the ECMO circuit on attainment of therapeutic effect and target serum drug concentrations, and should guide therapy choices and/or dose adjustments when data are not available.

Comparison of 4-factor prothrombin complex concentrate and andexanet alfa for reversal of apixaban and rivaroxaban in the setting of intracranial hemorrhage.

The purpose of this study was to evaluate and compare clinical outcomes in patients who experienced intracranial hemorrhage (ICH) while taking apixaban or rivaroxaban and were reversed with four-factor prothrombin complex concentrates (4F-PCC) or andexanet alfa (AA). This retrospective cohort included adult patients that received 4F-PCC or AA for the initial management of an apixaban- or rivaroxaban-associated ICH. A primary outcome of excellent or good hemostatic efficacy at 12 h post-reversal was assessed. Secondary outcomes evaluated were change in hematoma volume size at 12 h, functional status at discharge, need for surgical intervention or additional hemostatic agents post-reversal, new thrombotic event within 28 days, 28-day all-cause mortality, discharge disposition, and hospital and intensive care unit lengths of stay. A total of 70 patients were included (4F-PCC, n = 47; AA, n = 23). For the primary outcome analysis, 21 patients were included in the 4F-PCC group and 12 in the AA group. The rate of effective hemostasis was similar between the 4F-PCC and AA groups (66.7% vs 75%, p = 0.62). There were no statistically significant differences between the groups for secondary outcomes, including 28-day mortality (40.4% vs 39.1%, p = 0.92) and thrombotic complications within 28 days of reversal (17.0% vs 21.7%, p = 0.63). In patients who experienced an ICH while taking apixaban or rivaroxaban, 4F-PCC and AA were found to have similar rates of excellent or good hemostatic efficacy.

Comparison of 4-factor PCC reversal of apixaban and rivaroxaban versus warfarin for intracranial hemorrhage.

The purpose of this study is to assess efficacy of 4-factor prothrombin complex concentrates (4F-PCC) for direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) as compared to its use in warfarin-associated ICH. A retrospective cohort study was performed to compare the efficacy of 4F-PCC for reversal of apixaban and rivaroxaban versus warfarin for ICH at Cooper University Health Care from January 2015 to December 2019. Patients included were ≥ 18 years of age who developed an ICH while on apixaban, rivaroxaban, or warfarin. The primary outcome was to compare the percentage of patients with Excellent or Good hemostatic efficacy after 4F-PCC administration. Secondary outcomes were to describe functional outcomes at discharge, in-hospital mortality, and thrombotic complications after 4F-PCC administration. A total of 159 patients were included; 115 patients received warfarin and 44 patients received a DOAC (apixaban, n = 22; rivaroxaban, n = 22). 70 patients were evaluable for the primary endpoint. Thirty-four (66.7%) patients in the warfarin group versus 14 (73.7%) patients in the DOAC group were determined to have excellent or good hemostatic efficacy (p = 0.57). In-hospital mortality (30.4% vs. 40.9%, p = 0.21) and thrombotic complications (9.6% vs. 11.4%, p = 0.67) were comparable between the warfarin vs. DOAC groups, respectively. This small, retrospective study found no difference in patients with excellent/good hemostatic efficacy after reversal with 4F-PCC for DOAC-associated ICH compared to warfarin-associated ICH. This study is limited by its retrospective nature and sample size. Larger, prospective studies are needed to further determine the efficacy of 4F-PCC in reversing DOAC-associated ICH.

Heparin Resistance in SARS-CoV-2 Infected Patients with Venous Thromboembolism.

Introduction: Heparin resistance has been reported in coronavirus disease 2019 (COVID-19) patients receiving intravenous unfractionated heparin (IV UFH). Anti-Xa monitoring of IV UFH has been suggested over activated partial thromboplastin times due to laboratory interference from elevated factor VIII and fibrinogen levels in COVID-19 patients. Information on heparin resistance with anti-Xa monitoring in COVID-19 patients with confirmed venous thromboembolism (VTE) is lacking. Methods: In this retrospective cohort study of patients with radiographically confirmed VTE, IV UFH dosage requirements in COVID-19 positive patients were compared with COVID-19 negative patients. The primary endpoint was the IV UFH dose needed to achieve a therapeutic anti-Xa level. Secondary endpoints included time to therapeutic anti-Xa, number of dose adjustments to achieve therapeutic anti-Xa, and bleeding. Results: Sixty-four patients with confirmed VTE were included (20 patients COVID-19 positive, 44 patients COVID-19 negative). Eighty-five percent (17 of 20) of COVID-19 positive patients achieved anti-Xa ≥ 0.3 units/mL with the first anti-Xa level drawn post-IV UFH infusion initiation. The median UFH dose needed to achieve first therapeutic anti-Xa was similar between COVID-19 positive and COVID-19 negative patients (median [IQR]: 18 units/kg/hour [18-18] vs 18 units/kg/hour [18-18], P = .423). The median number of dose adjustments and time to achieve therapeutic anti-Xa were also similar between the 2 groups. The frequency of patients receiving IV UFH of more 35 000 units/day did not differ between the 2 groups. Two cases of clinically significant heparin resistance in the COVID-19 positive group were identified. Conclusions: During the first wave of COVID-19, heparin dose and time to therapeutic anticoagulation appeared to be similar between COVID-19 positive and COVID-19 negative patients monitored by anti-Xa at our institution. More studies are required to evaluate clinically significant heparin resistance in the context of the wide range of viral variants which developed, and beyond the population observed in this single center retrospective study.

Infectious Pulmonary Diseases.

Pneumonia is a lower respiratory tract infection caused by the inability to clear pathogens from the lower airway and alveoli. Cytokines and local inflammatory markers are released, causing further damage to the lungs through the accumulation of white blood cells and fluid congestion, leading to pus in the parenchyma. The Infectious Diseases Society of America defines pneumonia as the presence of new lung infiltrate with other clinical evidence supporting infection, including new fever, purulent sputum, leukocytosis, and decline in oxygenation. Importantly, lower respiratory infections remain the most deadly communicable disease. Pneumonia is subdivided into three categories: (1) community acquired, (2) hospital acquired, and (3) ventilator associated. Therapy for each differs based on the severity of the disease and the presence of risk factors for methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa.

Infectious Pulmonary Diseases.

Pneumonia is a lower respiratory tract infection caused by the inability to clear pathogens from the lower airway and alveoli. Cytokines and local inflammatory markers are released, causing further damage to the lungs through the accumulation of white blood cells and fluid congestion, leading to pus in the parenchyma. The Infectious Diseases Society of America defines pneumonia as the presence of new lung infiltrate with other clinical evidence supporting infection, including new fever, purulent sputum, leukocytosis, and decline in oxygenation. Importantly, lower respiratory infections remain the most deadly communicable disease. Pneumonia is subdivided into three categories: (1) community acquired, (2) hospital acquired, and (3) ventilator associated. Therapy for each differs based on the severity of the disease and the presence of risk factors for methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa.

Systemic Thrombolytic Therapy for Massive and Submassive Pulmonary Embolism.

OBJECTIVE: To critically evaluate the published literature assessing the safety and efficacy of thrombolytic therapy for massive and submassive pulmonary embolism (PE). METHODS: A search of human trials in the English-language (September 2017) was conducted through the MEDLINE database using the following terms: PE, tissue plasminogen activator, tenecteplase, and alteplase. 67 unique articles were identified, of which 24 clinical trials discussing clinical outcomes related to administration of either intravenous tenecteplase or alteplase were included. RESULTS: Thrombolytic therapy with anticoagulation significantly reduced mortality compared to anticoagulation alone in massive PE. In submassive PE, thrombolytics reduced the rate of right ventricular dysfunction and hemodynamic collapse; however, there is an increased risk of major and minor bleeding with no benefit on long-term functional outcomes. CONCLUSIONS: Patients with massive PE should receive thrombolytics when no major contraindications to therapy exist. Patients with submassive PE at highest risk for progression to hemodynamic instability should receive anticoagulation and be monitored for clinical deterioration. If an imminent risk of hemodynamic instability or cardiac arrest occurs, thrombolytics should be administered if no contraindications exist. Net mortality benefit and risk of bleeding must be considered when deciding to administer thrombolytic therapy in massive or submassive PE.

Methylprednisolone sodium succinate-associated macroglossia in a critically ill patient.

Allergic hypersensitivity reactions are a rare adverse effect of corticosteroids. Previous reports have identified patients who developed symptoms of urticaria, dyspnea, hypotension, bronchospasm, and angioedema occurring within minutes to an hour after corticosteroid administration. A 35-year-old woman is described who developed an atypical reaction of isolated macroglossia after receiving intravenous methylprednisolone sodium succinate for myasthenic crisis. Macroglossia was identified on day 2 of therapy and worsened through day 5. On day 5, she was transitioned to prednisone 50 mg daily administered by feeding tube. Tongue swelling improved by day 7 and on day 10, the patient was extubated. The patient required reintubation due to stridor, but received a tracheostomy and was weaned off mechanical ventilation by day 15. The reaction was not confirmed with skin-prick tests, intradermal tests, or a drug rechallenge; however, she had previously received and tolerated all other drugs administered during this time. Due to the timing of administration and onset of symptoms, we feel this adverse drug reaction was likely due to administration of methylprednisolone. Applying the Naranjo adverse drug reaction probability scale to this case, a score of six was obtained, indicating a probable association between the administration of methylprednisolone and the development of macroglossia. As intravenous corticosteroids are often used in the treatment of allergic reactions, they may be overlooked as a cause of macroglossia and other allergic reactions; therefore, practitioners need to be aware of the possibility of this adverse effect secondary to corticosteroid administration. In the event of methylprednisolone sodium succinate-induced macroglossia, alternative nonesterified corticosteroids, such as dexamethasone or prednisone, should be considered if continuation of therapy is required.