Continuous Renal Replacement Therapy

TANGO II was a Phase 3, randomized, prospective, multicenter, multinational, open-label, active-controlled trial of adults with infections due to confirmed/suspected CRE. The trial enrolled patients from 27 hospital sites in 8 countries (Argentina, Brazil, Colombia, Greece, Israel, Italy, United Kingdom, United States) with known prevalence of KPC-producing CRE between November 2014 and June 2017. Protocol and informed consent form were approved by the sites’ Institutional Review Boards/Independent Ethics Committees. The trial was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guideline and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Prior to initiation of study-related procedures, an informed consent form was signed by the patient or guardian/legal representative.
Prior to initiation of study-related procedures, an informed consent form was signed by the patient or guardian/legal representative. An independent Data Safety Monitoring Board (DSMB) reviewed accumulated safety data at scheduled intervals and serious adverse events on an ongoing basis. Once 72 patients were included in the safety and efficacy analysis, the DSMB determined the study met its stated objectives and advised discontinuing the study in its current form, as the risk/benefit analysis did not support ongoing randomization of patients to the BAT arm and would not be in the best interest of patients.
Eligible patients were age ≥ 18 years with cUTI/AP, hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), bacteremia, or complicated intra-abdominal infection (cIAI), and confirmed or suspected (evidence in culture or molecular testing within past 90 days) CRE pathogen, requiring ≥ 7 days of intravenous (IV) therapy (eTable 1). Patients with confirmed CRE infection were eligible if the baseline CRE pathogen was not susceptible to the current antimicrobial therapy (or the patient was not on antimicrobial therapy). If susceptible, patients were eligible if they had received ≤ 24 h of therapy before enrollment or had clinical deterioration/failure to improve after ≥ 48 h of therapy. Patients with suspected CRE infection who received ≤ 24 h of empirical Gram-negative antimicrobial therapy before enrollment were also eligible.
Key exclusion criteria included: history of significant hypersensitivity to beta-lactam antibiotics; confirmed infection with CRE-producing New Delhi metallo (NDM)-, Verona integron-encoded metallo-, imipenemase-metallo-, or oxacillinase-encoded beta-lactamases (based on local microbiology laboratory results); Acute Physiology and Chronic Health Evaluation II [21 (link)] score > 30; or immediately life-threatening disease. Patients with impaired renal function, including hemodialysis, were eligible; those receiving continuous renal replacement therapy were not. Immunocompromised patients—leukemia or lymphoma (not in remission), prior solid organ/stem cell transplantation, neutropenia, or active receipt of immunosuppressive medications (including high-dose systemic steroids for ≥ 2 weeks)—were eligible (NCT02168946).

A propensity score–matched cohort of patients with and without a history of delirium was created. Propensity scores were based on age, sex, admission type (no surgery, elective surgery, or emergent surgery), the presence or absence of each of the individual Charlson comorbidities (diabetes, chronic lung disease, chronic kidney disease, liver disease, cancer, chronic heart or peripheral vascular disease, or neurological disease), admission APACHE II score, use of invasive mechanical ventilation (yes/no), use of vasoactive medications (yes/no), use of continuous renal replacement therapy (yes/no), and ICU LOS (<3, 3 to <7, or ⩾7 d). The cohort was based on 1:1 nearest-neighbor matching without replacement by using the logit of the propensity score and a specified caliper width equal to 0.05 of the SD of the logit of the propensity score. The analyses were repeated for the overall sample (i.e., non–propensity score–matched cohort). The time to mortality from hospital discharge among the overall cohort was compared among patients with and without a history of delirium by using the Kaplan-Meier method to determine the cumulative incidence. Because mortality is a competing risk for emergency department visits and hospital readmission, we considered a composite measure of the time to the first hospital readmission, the first emergency department visit, or mortality. Follow-up was 2.5 years or until death, with censoring for loss to follow-up (n = 1). Because of the proportional hazard assumption not being satisfied for the overall cohort, mortality analyses were stratified by specified time intervals (0 to 30 d, >30 to 90 d, and >90 d), which were selected on the basis of a review of spline plots (see Figures E1 and E2 in the online supplement), with nonproportionality being shown early after hospital discharge (see the online supplement for further details). Cox proportional hazard regression models accounting for clustering of patients within ICUs (by using robust sandwich variance estimators) were used to examine the association between delirium and the time to the first hospital readmission, the first emergency department visit, or mortality. All analyses were adjusted for the same variables included in the propensity score, with the addition of hospital LOS (<7, 7 to <14, ⩾14 d) and the hospital discharge disposition. A two-sided P value of <0.05 was considered to indicate statistical significance. Analyses used R (version 3.5.1, R Foundation for Statistical Computing) and the R packages “survival” (version 2.44–1.1), “cmprsk” (version 2.2–7), and “survRM2” (version 1.0–3). Propensity score matching was performed using the R package “MatchIt” (version 3.0.2) (30 ). Additional details on the methods and data analysis are provided in the online supplement.

Clinical information was extracted from the electronic medical records using a standardised data collection form, which included demographic information, clinical data, laboratory findings, CT of the chest, antifungal treatments and outcomes. All the data were reviewed by two investigators independently to verify data accuracy. The 7-category ordinal scale13 (link) was modified based on the study design, which consisted of mutually exclusive categories as follows: category 7, death; category 6, requiring invasive ventilation and additional organ support (eg, continuous renal replacement therapy or extracorporeal membrane oxygenation); category 5, requiring invasive mechanical ventilation; category 4, requiring non-invasive ventilation or high-flow oxygen; category 3, requiring supplemental oxygen by mask or nasal prongs; category 2, hospitalised, no oxygen; category 1, discharged. Improvement in clinical status was defined as a decline of 2 categories assessed by the 7-level ordinal scale at fixed time points (day 1, 7, 14, 21 and 28).
Testing for GM antigen in serum and GM in BALF is generally performed in all enrolled patients. A result was considered positive when optical index values were≥1.0 in serum or ≥1.0 in BALF or ≥0.7 in serum and ≥0.8 in BALF. BALF specimens were subjected to mNGS, smear by microscopy and ordinary fungal culture.