Lal, Amos

Abstract Rationale Mechanically ventilated intensive care unit patients receive sedatives based on clinician observations of arousal and motor activity with potential for negative consequences and poor mitigation of symptoms. Objectives To test the preliminary efficacy of patient self-managed sedative therapy compared to usual care of nurse-administered sedation on self-reported anxiety, duration of mechanical ventilation, and delirium incidence (CAM-ICU). Methods A two-group, open-label, randomized, multicenter clinical trial in 5 Midwestern hospitals enrolled 161 patients receiving invasive mechanical ventilation who were willing and able to use a push-button device to self-administer sedation for up to 7 days. Patients were randomized 1:1 using center-stratified blocks to usual care (n = 81) or intervention (n = 80) with self-administered dexmedetomidine. Intervention patients were allowed 3 self-administered dexmedetomidine boluses per hour (0.25 mcg/kg) with 20-minute lock-outs. The initial basal infusion (0.2 mcg/kg/hr) was adjusted by nurses between 0.1-0.7 mcg/kg/hr based on patient-delivered boluses in the prior 2 hours. Analysis consisted of linear mixed-effects model for comparisons of anxiety ratings over time and duration of mechanical ventilation. Incidence of delirium was analyzed using generalized estimating equations. Measurement and Main Results Sample characteristics had a female (54.7%) and Caucasian preponderance (92.5%) with a median age of 62 years on protocol for a median of 88 hours. Nine intervention patients were extubated prior to protocol initiation. Patient self-reported three times daily anxiety ratings with a visual analog scale (VAS) ranged from 0-100 over time but were not significantly different between groups in either an intention-to-treat (ITT) or per protocol (PP) analysis (p = 0.94, p = 0.30 respectively). While intervention patients had shorter duration of MV [(mean 50.8(52.8) vs. usual care 68.7(58.2) hours), p = 0.02 ITT], PP analysis resulted in no difference between groups (mean 56.4 (53.0) vs. 68.7(58.2), p = 0.23). 10.2% of intervention patients developed new incidence of delirium vs. 8.5% of usual care which was not significantly different between groups by either ITT (p = 0.65) or PP analyses (p = 0.58). Conclusions Intervention patients had similar outcomes compared to usual care patients. Self-administration of sedative therapy is a safe, novel patient-centered intervention warranting further rigorous investigation for anxiety self-management.

Introduction Community-acquired pneumonia (CAP) is common and remains the leading infectious cause of death worldwide. Antibiotics remain the mainstay of treatment, but organisms are often not identified, necessitating empirical treatment. Current treatment guidelines recommend combination therapy with beta-lactams and macrolides or monotherapy with fluoroquinolones for non-severe CAP. However, rising antibiotic resistance and safety concerns have led to increased doxycycline use, despite limited evidence supporting its efficacy. Our goal is to conduct a pragmatic, open-label, randomised clinical trial comparing the effectiveness of azithromycin with that of doxycycline in combination with beta-lactam therapy in adult patients hospitalised for CAP. Methods and analysis Patients presenting to the emergency department or directly referred to the hospital with a clinical presentation concerning for CAP and need for hospitalisation are eligible. We plan to enrol 1120 adults hospitalised at six hospitals across four states, including rural, suburban and urban settings and academic and community hospitals. Randomisation will be 1:1 using an electronic health record (EHR)-embedded screening and randomisation tool triggered by the treating clinician’s orders for azithromycin or doxycycline. Outcomes will be ascertained pragmatically via EHR-based data retrieval and will not require additional study visits. Our primary outcome is days alive and out of the hospital through day 28. Secondary outcomes include oxygen-free days; a composite of a need for advanced respiratory support or in-hospital mortality with analyses of each component separately; an ordinal measure of clinical deterioration defined by a prespecified severity scale; and 60-day and 180-day mortality. Safety outcomes are the incidence of Clostridioides difficile infection and QT prolongation. Analyses will follow an intention-to-treat framework, with per-protocol analyses for sensitivity. The primary endpoint will be compared between groups using a stratified van Elteren test, with supportive analyses using proportional odds regression and analysis of covariance adjusted for key covariates. Ethics and dissemination The Mayo Clinic Institutional Review Board reviewed and approved this protocol with a waiver of written consent, requiring verbal consent to be obtained by the clinician initiating the antibiotics (IRB# 24–0 06 503). Findings will be disseminated through peer-reviewed publications and international conference presentations. Trial registration number NCT07164131 .

Introduction Sepsis is a global health priority with nearly 50 million cases annually. Cardiovascular dysfunction is common, frequently manifesting as hypotension that persists despite fluid resuscitation. Most affected patients require the use of intravenous (IV) vasoactive agents, typically necessitating intensive care unit (ICU)-level monitoring, invasive interventions and contributing substantially to healthcare costs. Midodrine, an oral alpha-1 agonist approved for orthostatic hypotension, has increasingly been used off-label as a vasopressor-sparing (reducing IV vasopressor use) strategy in sepsis, despite limited and inconsistent evidence. This pragmatic, randomised, open-label trial evaluates the efficacy and safety of midodrine in patients with sepsis-associated hypotension. We hypothesise that, compared with standard care, midodrine administration will reduce the duration of IV vasopressor use. Methods and analysis A total of 308 adult patients with sepsis-associated hypotension will be enrolled (154 per arm). The intervention group will, in addition to standard of care, receive enteral midodrine 10 mg three times daily. Outcomes will be ascertained pragmatically via electronic health record-based data retrieval and adjudicated by research coordinators blinded to treatment assignment. The primary outcome is time alive and off IV vasopressors in the first 28 days (in hours) after randomisation. Secondary outcomes include cumulative vasopressor exposure; use and duration of central venous access; cumulative fluid balance over the first 48 hours and up to 7 days of ICU stay; ICU and hospital length of stay; and ICU-, hospital-, and organ support-free days through day 28. Safety outcomes include adverse events potentially attributable to midodrine during hospitalisation including acute kidney injury. Primary analyses will follow an intention-to-treat framework, including all randomised participants according to their assigned treatment groups. Primary and secondary outcomes will be compared using a van Elteren test stratified by randomisation factors. A predefined secondary Bayesian analysis of the primary outcome will provide complementary estimates of treatment effect. Safety outcomes will be summarised descriptively without formal between-arm hypothesis testing. Ethics and dissemination The Mayo Clinic Institutional Review Board approved this protocol and required written informed consent from all participants (IRB# 24–0 00 121). Findings will be disseminated through peer-reviewed publications and international conference presentations. Trial registration number NCT06319248 .

Abstract Background Cardiac dysfunction is a common complication in septic population. Though traditionally considered an acute and reversible phenomenon, the true prevalence of reversible cardiac dysfunction and its long-term prognostic implications remain unclear. Purpose Using serial echocardiographic assessments, this study aimed to investigate the prevalence and reversibility of cardiac dysfunction in septic patients, and to determine whether the recovery of cardiac function is associated with improved 5-year mortality. Methods We retrospectively screened 16,041 septic patients who underwent transthoracic echocardiography during their ICU stay. After excluding patients with a history of heart failure, pre-existing cardiac dysfunction, or lacking follow-up echocardiographic assessments post-ICU discharge, 3,112 patients were enrolled for analysis. To assess the reversibility of cardiac dysfunction, paired-sample t-tests were used to evaluate changes in echocardiographic parameters between in-ICU and post-ICU measurements. Furthermore, 5-year mortality were compared among controls and patients with or without recovery of echocardiographic abnormalities. Results Totally 1,604 patients (51.5%) were found to have newly recognized cardiac dysfunction during ICU stay. The mean interval between ICU admission and follow-up echocardiography was 425 days. Most in-ICU echocardiographic abnormalities demonstrated partial recovery over time, with the exception of left atrial volume index (LAVi) and right ventricular fractional area change (RV FAC) (Figure 1). Recovery of left ventricular ejection fraction (LVEF), average E/e', and tricuspid regurgitation (TR) velocity was significantly associated with reduced 5-year mortality (Figure 2). Older age [adjusted hazard ratio (aHR) 0.99, p=0.034], male gender (aHR 0.54, p=0.003), and elevated troponins (aHR 0.87, p=0.006) were negative predictors for LVEF recovery; while older age (aHR 0.099, p=0.043), higher APACHE III scores (aHR 0.99, p=0.018), atrial fibrillation (aHR 0.59, p=0.046), and chronic pulmonary disease (aHR 0.68, p=0.042) were negative predictors for TR velocity recovery. Conclusions Both the presence and recovery of newly recognized echocardiographic abnormalities during ICU stay were significantly associated with long-term mortality. Certain abnormalities, such as increased LAVi, persisted despite resolution of sepsis.Figure 1 Figure 2

This systematic review examined multicenter randomized controlled trials (RCTs) conducted during the Sepsis-3 era that evaluated pharmaceutical and mechanistic interventions in adult patients with sepsis or septic shock, with a focus on identifying interventions that demonstrated mortality benefit. A comprehensive search was performed across Ovid MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, WHO ICTRP, and Web of Science for trials published since 2016. Studies were included if they enrolled adult patients with sepsis or septic shock using Sepsis-3 criteria and reported mortality as either a primary or secondary outcome. Data were extracted by two independent reviewers and included trial design characteristics, funding source, randomization methods, and reported outcomes. Among the 31 eligible multicenter RCTs enrolling over 7,000 patients across 550 centers, only four trials showed a mortality benefit. These included three studies from China—two evaluating herbal anti-inflammatory compounds and one evaluating aminophylline—and one European study assessing corticosteroid therapy in vasopressor-dependent septic shock. The remaining 27 trials reported no mortality benefit, and substantial heterogeneity was observed in patient populations, sepsis definitions, and outcome reporting. Median mortality in control arms was 31.6% (IQR 24.1–45.5), and 35.4% (IQR 25.7–49.6) in intervention arms. These findings suggest that despite extensive efforts, most interventions have not reduced mortality in multicenter sepsis trials. Future research should focus on optimizing trial design, refining patient selection, and incorporating patient-centered outcomes beyond mortality.

Abstract RATIONALE: Clinical practice guidelines recommend that mechanically ventilated patients (MVPs) receiving sedative therapy achieve a target goal of ‘awake and calm’ when medically possible. However, ICU sedation practices rely on clinicians’ administration of medications based on observations of patients’ arousal/motor activity that are not consistently based on symptom assessments nor consider patients’ preferences. We hypothesized that MVPs would safely self-manage sedative therapy (SMST) base on individual needs and perceived anxiety while experiencing less sedative exposure and delirium. METHODS: A two-group randomized clinical trial conducted in two Midwestern academic medical centers enrolled 161 MVPs willing and able to depress a medication delivery push-button device who remained on protocol for 7 days or until extubated, withdrew or died. Control group (CG) patients (n=81) received sedative medications administered by ICU nurses per unit protocols. Experimental SMST group patients (n=80) received a basal infusion of dexmedetomidine (0.2 mcg/kg/hr titrated per algorithm) + self-administered bolus doses (0.25 mcg/kg up to 3/hour). Primary outcomes were anxiety ratings using a 100-mm visual analog scale (VAS-A), sedation intensity score (aggregate summary of 9 intravenous sedative/opioid medications received range 0-36), and incidence of delirium using the CAM-ICU. Analyses were descriptive and parametric statistics and Generalized Estimating Equations. RESULTS: Patients were predominantly White (93%) females (55%), mean age 58.9+15.1 years receiving mechanical ventilation for respiratory failure (60%) with mean APACHE III of 84.5 + 32.5. Anxiety was highly variable over time wherein patients in both groups endorsed the full range from 0-100. VAS-A over time between groups was -0.06 (p=0.98) indicating that anxiety was 0.06 units lower for SMST patients versus CG. Median sedation intensity in SMST group 11.8 + 9.6, compared to CG 12.7 + 9.6 (p = 0.55) over 7 days. 10.2% of SMST patients had one or more incident delirium events compared to 8.5% of CG (p =.97). Hypotension was experienced equally between groups: 22 in SMST, 23 in CG (p = 1.0) as were device disruptions: 2 in SMST versus 3 in CG (p = 1.0). 82% of SMST were satisfied/very satisfied with ability to self-administer dexmedetomidine; 70% were satisfied/very satisfied with ability to control anxiety; 68% were satisfied/very satisfied with the level of relaxation experienced. CONCLUSIONS: Although there were no significant differences between groups on the primary outcomes, the experimental SMST intervention was safe with high patient-reported satisfaction. SMST may be a viable new paradigm for sedative therapy administration among select ICU patients.