Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype.

BACKGROUND: Tacrolimus extended-release tablets have been Food and Drug Administration-approved for use in the de novo kidney transplant population. Dosing requi rements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression. Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus, but this has not been established for tacrolimus extended-release tablets in the de novo setting. AIM: To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype. METHODS: Single-arm, prospective, single-center, open-label, observational study (ClinicalTrials.gov: NCT037 13645). Life cycle pharma tacrolimus (LCPT) orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight. If weight is more than 120% of ideal body weight, an adjusted body weight was used. LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL. Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion. RESULTS: Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (6 d vs 13.5 d vs 4.5 d; P = 0.025). Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (16 mg vs 16 mg vs 12 mg; P = 0.010) (0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg; P = 0.018). CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers (7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL; P = 0 0.008). No differences were identified with regards to kidney graft function at 30-d post-transplant. Serious adverse events were reported for 13 (36%) patients. CONCLUSION: Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacro limus to achieve target trough concentrations. We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

Contemporary practice patterns and outcomes of systemic thrombolysis in acute pulmonary embolism.

OBJECTIVE: Although systemic thrombolysis (ST) is the standard of care in the treatment of high-risk pulmonary embolism (PE), large variations in real-world usage exist, including its use to treat intermediate-risk PE. A paucity of data is available to define the outcomes and practice patterns of the ST dose, duration, and treatment of presumed and imaging-confirmed PE. METHODS: We performed a multicenter retrospective study to evaluate the real-world practice patterns of ST use in the setting of acute PE (presumed vs imaging-confirmed intermediate- and high-risk PE). Patients who had received tissue plasminogen activator for PE between 2017 and 2019 were included. We compared the baseline clinical characteristics, tissue plasminogen activator practice patterns, and outcomes for patients with confirmed vs presumed PE. RESULTS: A total of 104 patients had received ST for PE: 52 with confirmed PE and 52 with presumed PE. Significantly more patients who had been treated for presumed PE had experienced cardiac arrest (n = 47; 90%) compared with those with confirmed PE (n = 23; 44%; P < .01). Survival to hospital discharge was 65% for the patients with confirmed PE vs 6% for those with presumed PE (P < .01). The use of ST was contraindicated for 56% of the patients with confirmed PE, with major bleeding in 26% but no intracranial hemorrhage. CONCLUSIONS: The in-hospital mortality of patients with confirmed acute PE has remained high (35%) in contemporary practice for those treated with ST. A large proportion of these patients had had contraindications to ST, and the rates of major bleeding were significant. Those with confirmed PE had had a higher survival rate compared with those with presumed PE, including those with cardiac arrest. This observation suggests a limited role for empiric thrombolysis in cardiac arrest situations.

Safety of Propofol When Used for Rapid Sequence Intubation in Septic Patients: A Multicenter Cohort Study.

Purpose: Septic patients are at risk for hypotension, and this risk may increase during rapid sequence intubation (RSI). Sedatives such as propofol must be used carefully due to its ability to reduce vascular sympathetic tone. Since the safety of propofol for RSI is not well described in sepsis, this was a study evaluating propofol and its effects on hemodynamics when used for RSI in a septic population. Materials and methods: We conducted a multicenter, retrospective, cohort study of patients with sepsis or severe sepsis requiring sedation for RSI. Patients receiving a propofol bolus for RSI were compared to patients undergoing RSI without a propofol bolus. The safety profile of propofol was evaluated according to the rates of post-intubation hypotension and vasopressor utilization between groups. Results: A total of 179 patients (79 propofol, 100 non-propofol) were evaluated. There were no differences in hypotension (81% vs 78%; P = .62) or vasopressor utilization between the propofol and non-propofol groups (43% vs 49%; P = .43). Patients in the non-propofol group had increased APACHE II scores and healthcare-associated infections. Conclusions: In this cohort study, administration of propofol for RSI in patients with sepsis and severe sepsis did not increase incidence of hypotension or vasopressor use, but acute illness may have introduced provider selection bias causing less propofol use in the non-propofol group. Larger prospective studies are needed to better characterize the adverse hemodynamic effects of propofol, before propofol bolus doses for RSI can be considered for safe use in this population.

Decreased isavuconazole trough concentrations in the treatment of invasive aspergillosis in an adult patient receiving extracorporeal membrane oxygenation support.

PURPOSE: We present the case of a 56-year-old man with stage IV sarcoidosis on veno-venous extracorporeal membrane oxygenation (VV-ECMO) support for the management of respiratory failure receiving treatment with isavuconazole for invasive aspergillosis. SUMMARY: VV-ECMO is an increasingly utilized life support therapy for patients with cardiac and/or respiratory failure, but its impact on medication dosing is poorly understood. In our patient with invasive Aspergillus infection receiving VV-ECMO, because of difficulty achieving therapeutic serum concentrations of voriconazole, we administered isavuconazole 372 mg intravenously (IV) every 8 hours for 6 doses followed by 372 mg IV once daily. Isavuconazole has a favorable pharmacokinetic and safety profile compared to other azole antifungal agents, but its high protein binding and lipophilicity raise concerns about drug sequestration in the VV-ECMO circuit. To optimize the efficacy and safety of this treatment, the isavuconazole trough concentration was measured at days 5 and 17, at which time it was 1.7 and 0.7 µg/mL, respectively. The dose was subsequently increased to 744 mg IV once daily, and serum trough concentrations were measured 5 and 8 days after dose adjustment, corresponding to 3.7 and 2.9 µg/mL, respectively. To our knowledge, this is the third report to describe inadequate isavuconazole trough concentrations during VV-ECMO support when utilizing standard doses. CONCLUSION: In the case described here, standard-dose isavuconazole (372 mg every 8 hours for 6 doses followed by 372 mg daily) did not achieve target trough concentrations in a patient receiving concomitant ECMO support.

Safety and efficacy of catheter directed thrombolysis (CDT) in elderly with pulmonary embolism (PE).

INTRODUCTION: Acute pulmonary embolism (PE) remains a common cause for morbidity and mortality in patients over 65 years. Given the increased risk of bleeding in the elderly population with the use of systemic thrombolysis, catheter-directed therapy (CDT) is being increasingly used for the treatment of submassive PE. Nevertheless, the safety of CDT in the elderly population is not well studied. We, therefore, aimed to evaluate the safety of CDT in our elderly patients. METHODS: We conducted a retrospective observational study of consecutive patients aged >65 years with a diagnosis of PE from our Pulmonary Embolism Response Team database. We compared the treatment outcomes of CDT versus anticoagulation (AC) in elderly. Propensity score matching was used to construct two matched cohorts for final outcomes analysis. RESULTS: Of 346 patients with acute PE, 138 were >65 years, and of these, 18 were treated with CDT. Unmatched comparison between CDT and AC cohorts demonstrated similar in-hospital mortality (11.1% vs 5.6%, p=0.37) and length of stay (LOS) (3.81 vs 5.02 days, p=0.5395), respectively. The results from the propensity-matched cohort mirrored results of the unmatched cohort with no significant difference between CDT and AC in-hospital mortality (11.8% vs 5.9%, p=0.545) or median LOS (3.76 vs 4.21 days, p=0.77), respectively. CONCLUSION: In this observational study using propensity score-matched analysis, we found that patients >65 years who were treated with CDT for management of acute PE had similar mortality and LOS compared with those treated with AC. Further studies are required to confirm these findings.

Pharmacokinetics of linezolid for methicillin-resistant Staphylococcus aureus pneumonia in an adult receiving extracorporeal membrane oxygenation.

PURPOSE: We present a case of a 55-year-old man post right lung transplantation receiving ECMO for treatment of respiratory failure secondary to methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. SUMMARY: Extracorporeal membrane oxygenation (ECMO) is a frequently utilized support therapy for patients with cardiac and/or respiratory failure. Dosing of medications during ECMO can be challenging due to several factors, including sequestration of medications within ECMO circuits, alterations in volume of distribution, and changes in drug clearance. The patient was initiated on empiric antibiotics, then switched to linezolid at a dose of 600 mg every 8 hours. Linezolid plasma concentrations were collected 30 minutes prior to the sixth administered dose and 30 minutes following the 1-hour infusion of the sixth dose, which resulted in values of 0.4 and 1.7 µg/mL, respectively. The ratio of 24-hour area under the curve (AUC0-24) to minimum inhibitory concentration (MIC), assuming a MIC of 2 µg/mL, was calculated using the extrapolated maximum concentration (1.9 µg/mL) and minimum concentration (0.35 µg/mL), resulting in an AUC0-24/MIC value of 10.8. Due to subtherapeutic linezolid plasma concentrations, ceftaroline was initiated and continued for a total of 18 days. To our knowledge, this is the second report to describe inadequate plasma concentrations of linezolid during ECMO. CONCLUSION: In the case described here, linezolid at a dose of 600 mg every 8 hours did not achieve target plasma concentrations in a patient receiving concomitant venovenous ECMO support.

Impact of an Antiretroviral Stewardship Team on the Care of Patients With Human Immunodeficiency Virus Infection Admitted to an Academic Medical Center.

BACKGROUND: Interdisciplinary antiretroviral stewardship teams, comprising a human immunodeficiency virus pharmacist specialist, an infectious diseases physician, and associated learners, have the ability to assist in identification and correction of inpatient antiretroviral-related errors. METHODS: Electronic medical records of patients with antiretroviral orders admitted to our hospital were evaluated for the number of interventions made by the stewardship team, number of admissions with errors identified, risk factors for occurrence of errors, and cost savings. Risk factors were analyzed by means of multivariable logistic regression. Cost savings were estimated by the documentation system Clinical Measures. RESULTS: A total of 567 admissions were included for analysis in a 1-year study period. Forty-three percent of admissions (245 of 567) had ≥1 intervention, with 336 interventions in total. The following were identified as risk factors for error: multitablet inpatient regimen (odds ratio, 1.834; 95% confidence interval, 1.160-2.899; P = .009), admission to the intensive care unit (2.803; 1.280-6.136; P = .01), care provided by a surgery service (1.762; 1.082-2.868; P = .02), increased number of days reviewed (1.061; 1.008-1.117; P = .02), and noninstitutional outpatient provider (1.375; .972-1.946; P = .07). The 1-year cost savings were estimated to be $263 428. CONCLUSIONS: Antiretroviral stewardship teams optimize patient care through identification and correction of antiretroviral-related errors. Errors may be more common in patients with multitablet inpatient regimens, admission to the intensive care unit, care provided by a surgery service, and increased number of hospital days reviewed. Once antiretroviral-related errors are identified, the ability to correct them provides cost savings.

Diagnosis, Treatment and Follow Up of Acute Pulmonary Embolism: Consensus Practice from the PERT Consortium.

Pulmonary embolism (PE) is a life-threatening condition and a leading cause of morbidity and mortality. There have been many advances in the field of PE in the last few years, requiring a careful assessment of their impact on patient care. However, variations in recommendations by different clinical guidelines, as well as lack of robust clinical trials, make clinical decisions challenging. The Pulmonary Embolism Response Team Consortium is an international association created to advance the diagnosis, treatment, and outcomes of patients with PE. In this consensus practice document, we provide a comprehensive review of the diagnosis, treatment, and follow-up of acute PE, including both clinical data and consensus opinion to provide guidance for clinicians caring for these patients.

Direct-Acting Oral Anticoagulants in Critically Ill Patients.

The direct-acting oral anticoagulants (DOACs) have been increasingly used over vitamin K antagonists in recent years because they do not require monitoring and have an immediate anticoagulation effect. In general, DOACs have exhibited a better safety profile and noninferiority for prophylaxis and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation compared with vitamin K antagonists in the non-ICU population; whether this finding holds true in patients who are critically ill remains unknown. The current review addresses the role of DOACs in special ICU populations, use of these agents for VTE prophylaxis, perioperative management of DOACs, drug monitoring, and potential drug interactions of DOACs in critically ill patients. Adverse events and available reversal agents for DOACs are also discussed.

Effects of propofol on vasopressor use in patients with sepsis and severe sepsis: A pilot study.

PURPOSE: Propofol is one of the most commonly used sedatives in the intensive care unit (ICU) despite its undesirable hypotensive effects. The purpose of this study was to determine the effects of continuous intravenous (CIV) propofol on vasopressor requirements in mechanically ventilated patients with sepsis. MATERIALS AND METHODS: A multicenter, retrospective, propensity-matched pilot study was conducted comparing patients with sepsis or severe sepsis who received CIV propofol for sedation to those who did not. The primary outcome was incidence of vasopressor support. Secondary outcomes included change in mean arterial pressure, mortality, and length of stay. RESULTS: A total of 279 patients (149 CIV propofol, 130 non-CIV propofol) were evaluated, with 174 patients matched 1:1 based on propensity score. There was no difference in vasopressor support requirements (49.4% vs 54%; P= .65) or in those experiencing a greater than 20% decrease in mean arterial pressure from baseline (58.6% vs 63.2%; P= .53) in the CIV propofol and non-CIV propofol groups. Furthermore, there were no differences in any secondary outcomes including hospital mortality (32.2% vs 33.3%; P= .87). CONCLUSIONS: Continuous intravenous propofol for sedation did not increase vasopressor requirements in this septic population. Furthermore, CIV propofol was not associated with significant differences in the use of multiple vasopressors, change in mean arterial pressure, length of stay, or mortality.

3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe Bleeding: A Multicenter, Retrospective, Propensity-Matched Pilot Study.

Current guidelines recommend 4-factor prothrombin complex concentrate (4PCC) for emergent reversal of bleeding secondary to warfarin. While current research has demonstrated superiority of 4PCC over plasma, direct comparisons with 3-factor PCC (3PCC) are lacking. The purpose of this study is to compare the efficacy and safety of 3PCC and 4PCC. We conducted a retrospective analysis of patients who received PCC at one of four medical centers. All patients in the 3PCC group were treated at one center that utilizes a fixed, weight-based dosing protocol. After evaluation of all patients meeting inclusion criteria, propensity-score matching was used to adjust for differences in treatment characteristics. There was no difference in the primary outcome of INR ≤ 1.4 between 3PCC and 4PCC in both the unmatched (85.7 vs. 90.6 %; p = 0.37) and matched (84.2 vs. 92.1 %; p = 0.48) analyses. There was a significant difference in goal INR achieved favoring 4PCC (56.3 vs 90.0 %; p < 0.02) when baseline INR > 4.0. A total of three thrombotic events were documented, all in the 4PCC group. We found no difference in the rate of INR reversal in those treated with 3PCC and 4PCC. However, those with a baseline INR > 4.0 may experience more successful INR reversal with 4PCC.

Continuous intravenous antiarrhythmic agents in the intensive care unit: strategies for safe and effective use of amiodarone, lidocaine, and procainamide.

The development of cardiac arrhythmias in the intensive care unit is common and associated with poor prognoses and outcomes. Because of the complexity of patients admitted to the intensive care unit, the management of arrhythmias is often difficult and may require multiple therapeutic interventions. In order for clinicians to appropriately manage arrhythmias, a thorough understanding of all available therapies, including intravenous antiarrhythmic agents, is essential. Suitable antiarrhythmic agents for use in the critical care setting include amiodarone, lidocaine, and procainamide. While these agents can be effective in managing cardiac arrhythmias, they also possess significant disadvantages and require additional monitoring during use. Therapy with these agents is often complicated because of the presence of significant associated adverse effects, clinician unfamiliarity, variable dosing strategies, and the potential for drug-drug interactions. The purpose of this review is to discuss indications and strategies for safe and effective use of amiodarone, lidocaine, and procainamide.

Intensive blood pressure control during the hyperacute phase of intracerebral hemorrhage in patients at risk for resistant hypertension: a retrospective cohort study.

INTRODUCTION: There are limited data evaluating intensive systolic blood pressure (SBP) control during the hyperacute phase of intracerebral hemorrhage (ICH) in patients with multiple risk factors for resistant hypertension. We evaluated the feasibility and safety of this intervention in a primary population that includes patients with multiple risk factors for resistant hypertension. MATERIALS AND METHODS: We conducted a retrospective analysis of ICH patients for which intensive SBP control (<140 mm Hg)- i.e. less than or equal to 140 was targeted. All patients possessed at least 2 risk factors that have been associated with resistant hypertension. Our primary objective was to determine the percentage of patients who achieved goal SBP within 1 hour of ICH diagnosis. Secondary objectives included identifying predictors of achieving goal SBP within 6 hours. RESULTS: Goal SBP within 1 hour was achieved in 8.1% of patients. The total number of risk factors a patient possessed was found to negatively predict ability to achieve goal SBP. For each risk factor possessed, the odds of achieving goal SBP within 6 hours are reduced by 31% (odds ratio, 0.69 [95% confidence interval, 0.54-0.89]). CONCLUSION: Intensive SBP control after ICH was difficult to achieve within 1 hour in those with risk factors for resistant hypertension. Patients' total risk factors were found to reduce the odds of achieving goal SBP within 6 hours.

Evaluation of a fixed, weight-based dose of 3-factor prothrombin complex concentrate without adjunctive plasma following warfarin-associated intracranial hemorrhage.

INTRODUCTION: Data regarding use of prothrombin complex concentrate (PCC) for international normalization ratio (INR) reversal in warfarin-associated intracranial hemorrhage (wICH) is variable with regards to dosages, adjunctive agents, and product choice. In 2012, we implemented a fixed, weight-based [30 IU/kg] dosing protocol of 3-factor PCC (3PCC) utilizing a rapid infusion rate and no requirement for fresh frozen plasma (FFP) following factor product administration. We aimed to evaluate the impact of this protocol on immediate and delayed INR reversal in patients admitted with wICH in the absence of FFP co-administration. METHODS: We conducted a retrospective review of patients receiving 3PCC following wICH between January 1, 2012 and December 10, 2013. The primary objective was to determine the percentage of patients achieving goal INR (≤1.4) following 3PCC administration. Patients were excluded if their bleed was not intracranial in origin, received a dose outside of the specified protocol, or were given FFP as an adjunctive agent. RESULTS: We included 35 patients with a mean presenting INR of 3.2 ± 1.3. Thirty patients (85.7%) achieved goal INR (≤1.4) following one dose of 3PCC. The mean INR after infusion of 3PCC was 1.3 ± 0.2. The median duration between 3PCC infusion and subsequent INR was 48.0 min (30-70.1 min). Vitamin K was utilized in 33 (94.3%) patients. No patient experienced a thromboembolic event within 7 days of 3PCC administration. CONCLUSIONS: Fixed, weight-based dosing of 3PCC without adjunctive FFP resulted in high rates of complete INR reversal without significant adverse events.

Remifentanil, ketamine, and fospropofol: a review of alterative continuous infusion agents for sedation in the critically ill.

Sedation and analgesia are integral aspects in the care of critically ill patients admitted to the intensive care unit. In recent years, many of the commonly used sedative agents in the United States have experienced manufacturing and sterility issues leading to decreased availability. In addition, current practice has shifted to providing lighter levels of sedation as clinicians have gained a better understanding of the consequences of prolonged deep sedation. Benzodiazepines have fallen out of favor due to findings including increased delirium and duration of mechanical ventilation. Alterations in end-organ function in critically ill patients may also lead to varied responses to commonly used sedatives. With numerous factors impacting choice of sedation in the intensive care unit, fospropofol, ketamine, and remifentanil have been considered potential alternatives to standard therapy. The purpose of this review was to discuss strategies for the safe and effective use of fospropofol, ketamine, and remifentanil for continuous intravenous sedation in critically ill patients.