Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial

 

Intensive Care Medicine: Published: 01 February 2022

 

Purpose

Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.

Methods

Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.

Results

Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1–8.7) and without TDM (8.2 points; 95% CI 7.5–9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5–1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5–6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7–7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9–6.9, p < 0.001).

Conclusion

TDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.

 

Reporting of Organ Support Outcomes in Septic Shock Randomized Controlled Trials: A Methodologic Review—The Sepsis Organ Support Study

Reporting of Organ Support Outcomes in Septic Shock Randomized Controlled Trials: A Methodologic Review—The Sepsis Organ Support Study

by Bourcier, Simon; Hindlet, Patrick; Guidet, Bertrand; Dechartres, Agnès 

Objectives: Many recent randomized controlled trials in the field of septic shock failed to demonstrate a benefit on mortality. Randomized controlled trials increasingly report organ support duration and organ support-free days as primary or secondary outcomes. We conducted a methodologic systematic review to assess how organ support outcomes were defined and reported in septic shock randomized controlled trials.

Data Sources: MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science.

Study Selection: We included randomized controlled trials published between January 2004 and March 2018 that involved septic shock adults and assessed organ support duration and/or organ support-free days for hemodynamic support, respiratory support, or renal replacement therapy. 

Data Extraction: For each randomized controlled trial, we extracted the definitions of organ support duration and organ support-free days. We particularly evaluated how nonsurvivors were accounted for. Study authors were contacted to provide any missing information regarding these definitions. Data Synthesis: We included 28 randomized controlled trials. Organ support duration and organ support-free days outcomes were reported in 17 and 15 randomized controlled trials, respectively, for hemodynamic support, 15 and 15 for respiratory support, and five and nine for renal replacement therapy. Nonsurvivors were included in the organ support duration calculation in 13 of 14 randomized controlled trials (93%) for hemodynamic support and nine of 10 (90%) for respiratory support. The organ support-free days definition for hemodynamic support, respiratory support, and renal replacement therapy was reported in six of 15 randomized controlled trials (40%), eight of 15 randomized controlled trials (53%), and six of nine randomized controlled trials (67%) reporting an organ support-free days outcome, respectively. Of these, one half assigned “0” to nonsurvivors, and the other half attributed one point per day alive free of organ support up to a predefined time point. Conclusions: This study highlights the heterogeneity and infrequency of organ support duration/organ support-free days outcome reporting in septic shock trials. When reported, the definitions of these outcome measures and methods of calculation are also infrequently reported, in particular how nonsurvivors were accounted for, which may have an important impact on interpretation.

An overview of positive cultures and clinical outcomes in septic patients: a sub-analysis of the Prehospital Antibiotics Against Sepsis (PHANTASi) trial

An overview of positive cultures and clinical outcomes in septic patients: a sub-analysis of the Prehospital Antibiotics Against Sepsis (PHANTASi) trial

Critical Care  2019  23:182 - Published: 21 May 2019

Background

Sepsis remains one of the most important causes of morbidity and mortality worldwide. In approximately 30–50% of cases of suspected sepsis, no pathogen is isolated, disabling the clinician to treat the patient with targeted antimicrobial therapy. Studies investigating the differences in the patient outcomes between culture-positive and culture-negative sepsis patients have only been conducted in subgroups of sepsis patients and results are ambiguous.

Methods

This is a sub-analysis of the PHANTASi (Prehospital Antibiotics Against Sepsis trial), a randomized controlled trial that focused on the effect of prehospital antibiotics in sepsis patients. We evaluated the outcome of cultures from different sources and determined what the clinical implications of having a positive culture compared to negative cultures were for patient outcomes. Furthermore, we looked at the effect of antibiotics on culture outcomes.

Results

1133 patients (42.6%) with culture-positive sepsis were identified, compared to 1526 (56.4%) patients with culture-negative sepsis.

28-day mortality (RR 1.43 [95% CI 1.11–1.83]) and 90-day mortality (RR 1.41 [95% CI 1.15–1.71]) were significantly higher in culture-positive patients compared to culture-negative patients.

Culture-positive sepsis was also associated with ≥ 3 organ systems affected during the sepsis episode (RR 4.27 [95% CI 2.78–6.60]). Patients who received antibiotics at home more often had negative blood cultures (85.9% vs. 78%) than those who did not (p < 0.001).

Conclusions

Our results show that culture-positive sepsis is associated with a higher mortality rate and culture-positive patients more often have multiple organ systems affected during the sepsis episode.

Trial registration

The PHANTASi trial is registered at ClinicalTrials.gov, number NCT01988428. Date of registration: November 20, 2013.

Variation in Identifying Sepsis and Organ Dysfunction Using Administrative Versus Electronic Clinical Data and Impact on Hospital Outcome Comparisons*

Variation in Identifying Sepsis and Organ Dysfunction Using Administrative Versus Electronic Clinical Data and Impact on Hospital Outcome Comparisons*

by Rhee, Chanu; Jentzsch, Maximilian S.; Kadri, Sameer S.; Seymour, Christopher W.; Angus, Derek C.; Murphy, David J.; Martin, Greg S.; Dantes, Raymund B.; Epstein, Lauren; Fiore, Anthony E.; Jernigan, John A.; Danner, Robert L.; Warren, David K.; Septimus, Edward J.; Hickok, Jason; Poland, Russell E.; Jin, Robert; Fram, David; Schaaf, Richard; Wang, Rui; Klompas, Michael; for the Centers for Disease Control and Prevention (CDC) Prevention Epicenters Program  

Critical Care Medicine: April 2019 - Volume 47 - Issue 4 - p 493–500

Objectives: Administrative claims data are commonly used for sepsis surveillance, research, and quality improvement. However, variations in diagnosis, documentation, and coding practices for sepsis and organ dysfunction may confound efforts to estimate sepsis rates, compare outcomes, and perform risk adjustment. We evaluated hospital variation in the sensitivity of claims data relative to clinical data from electronic health records and its impact on outcome comparisons.

Design, Setting, and Patients: Retrospective cohort study of 4.3 million adult encounters at 193 U.S. hospitals in 2013–2014.

Interventions: None.

Measurements and Main Results: Sepsis was defined using electronic health record–derived clinical indicators of presumed infection (blood culture draws and antibiotic administrations) and concurrent organ dysfunction (vasopressors, mechanical ventilation, doubling in creatinine, doubling in bilirubin to ≥ 2.0 mg/dL, decrease in platelets to < 100 cells/µL, or lactate ≥ 2.0 mmol/L). We compared claims for sepsis prevalence and mortality rates between both methods. All estimates were reliability adjusted to account for random variation using hierarchical logistic regression modeling. The sensitivity of hospitals’ claims data was low and variable: median 30% (range, 5–54%) for sepsis, 66% (range, 26–84%) for acute kidney injury, 39% (range, 16–60%) for thrombocytopenia, 36% (range, 29–44%) for hepatic injury, and 66% (range, 29–84%) for shock. Correlation between claims and clinical data was moderate for sepsis prevalence (Pearson coefficient, 0.64) and mortality (0.61). Among hospitals in the lowest sepsis mortality quartile by claims, 46% shifted to higher mortality quartiles using clinical data. Using implicit sepsis criteria based on infection and organ dysfunction codes also yielded major differences versus clinical data.

Conclusions: Variation in the accuracy of claims data for identifying sepsis and organ dysfunction limits their use for comparing hospitals’ sepsis rates and outcomes. Using objective clinical data may facilitate more meaningful hospital comparisons.

Multiple Organ Dysfunction Score Is Superior to the Obstetric-Specific Sepsis in Obstetrics Score in Predicting Mortality in Septic Obstetric Patients

Multiple Organ Dysfunction Score Is Superior to the Obstetric-Specific Sepsis in Obstetrics Score in Predicting Mortality in Septic Obstetric Patients
Critical Care Medicine:January 2017 - Volume 45 - Issue 1 - p e49–e57
Aarvold, A et al

Objectives: Mortality prediction scores have been used for a long time in ICUs; however, numerous studies have shown that they over-predict mortality in the obstetric population. With sepsis remaining a major cause of obstetric mortality, we aimed to look at five mortality prediction scores (one obstetric-based and four general) in the septic obstetric population and compare them to a nonobstetric septic control group. 
Subject and Design: Women in the age group of 16–50 years with an admission diagnosis or suspicion of sepsis were included. In a multicenter obstetric population (n = 797), these included all pregnant and postpartum patients up to 6 weeks postpartum. An age- and gender-matched control nonobstetric population was drawn from a single-center general critical care population (n = 2,461). Sepsis in Obstetric Score, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction Scores were all applied to patients meeting inclusion criteria in both cohorts, and their area under the receiver-operator characteristic curves was calculated to find the most accurate predictor. Measurements and Main Results: A total of 146 septic patients were found for the obstetric cohort and 299 patients for the nonobstetric control cohort. The Sepsis in Obstetric Score, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction Scores gave area under the receiver-operator characteristic curves of 0.67, 0.68, 0.72, 0.79, and 0.84 in the obstetric cohort, respectively, and 0.64, 0.72, 0.61, 0.78, and 0.74 in the nonobstetric cohort, respectively. The Sepsis in Obstetric Score performed similarly to all the other scores with the exception of the Multiple Organ Dysfunction Score, which was significantly better (p < 0.05). 
Conclusion: The Sepsis in Obstetric Score, designed specifically for sepsis in obstetric populations, was not better than general severity of illness scoring systems. Furthermore, the Sepsis in Obstetric Score performance was no different in an obstetric sepsis population compared to a nonobstetric sepsis population. The Multiple Organ Dysfunction Score is a simple organ-based score, and this result supports the use of organ-based outcome predictors in ICU even in an obstetric sepsis population.

Daily laxative therapy reduces organ dysfunction in mechanically ventilated patients:a phase II randomized controlled trial

Critical Care 2015, 19:329

Palacio de Azevedo R et al

Introduction Constipation is a common problem in intensive care units. We assessed the efficacy and safety of laxative therapy aiming to promote daily defecation in reducing organ dysfunction in mechanically ventilated patients. 

Methods: We conducted a prospective, randomized, controlled, nonblinded phase II clinical trial at two general intensive care units. Patients expected to remain ventilated for over 3 days were randomly assigned to daily defecation or control groups. The intervention group received lactulose and enemas to produce 1–2 defecations per day. In the control group, absence of defecation was tolerated up to 5 days. Primary outcome was the change in Sequential Organ Failure Assessment (SOFA) score between the date of enrollment and intensive care unit discharge, death or day 14.
Results: We included 88 patients. Patients in the treatment group had a higher number of defecations per day (1.3 ± 0.42 versus 0.7 ± 0.56, p < 0.0001) and lower percentage of days without defecation (33.1 ± 15.7 % versus 62.3 ±24.5 %, p < 0.0001). Patients in the intervention group had a greater reduction in SOFA score (–4.0 (–6.0 to 0) versus –1.0 (–4.0 to 1.0), p = 0.036) with no difference in mortality rates or in survival time. Adverse events were more frequent in the treatment group (4.5 (3.0–8.0) versus 3.0 (1.0–5.7), p = 0.016), including more days with diarrhea (2.0 (1.0–4.0) versus 1.0 (0–2.0) days, p < 0.0001). Serious adverse events were rare and did not significantly differ between groups.
Conclusions: Laxative therapy improved daily defecation in ventilated patients and was associated with a greater reduction in SOFA score.

Daily estimation of the severity of organ dysfunctions in critically ill children by using the PELOD-2 scor

Daily estimation of the severity of organ dysfunctions in critically ill children by using the PELOD-2 score

Critical Care 2015, 19:324

Leteurtre S et al

Introduction: Daily or serial evaluation of multiple organ dysfunction syndrome (MODS) scores may provide useful information. We aimed to validate the daily (d) PELOD-2 score using the set of seven days proposed with the previous version of the score.
Methods: In all consecutive patients admitted to nine pediatric intensive care units (PICUs) we prospectively measured the dPELOD-2 score at day 1, 2, 5, 8, 12, 16, and 18. PICU mortality was used as the outcome dependent variable. The discriminant power of the dPELOD-2 scores was estimated using the area under the ROC curve and the calibration using the Hosmer-Lemeshow chi-square test. We used a logistic regression to investigate the relationship between the dPELOD-2 scores and outcome, and between the change in PELOD-2 score from day1 and outcome. Results: We included 3669 patients (median age 15.5 months, mortality rate 6.1 %, median length of PICU stay 3 days). Median dPELOD-2 scores were significantly higher in nonsurvivors than in survivors (p < 0.0001). The dPELOD-2 score was available at least at day 2 in 2057 patients: among the 796 patients without MODS on day1, 186 (23.3 %) acquired the syndrome during their PICU stay (mortality 4.9 % vs. 0.3 % among the 610 who did not; p < 0.0001). Among the1261 patients with MODS on day1, the syndrome worsened in 157 (12.4 %) and remained unchanged or improved in 1104 (87.6 %) (mortality 22.9 % vs. 6.6 %; p < 0.0001). The AUC of the dPELOD-2 scores ranged from 0.75 (95 % CI: 0.67-0.83) to 0.89 (95 % CI: 0.86-0.91). The calibration was good with a chi-square test between 13.5 (p = 0.06) and 0.9 (p = 0.99). The PELOD-2 score on day1 was a significant prognostic factor; the serial evaluation of the change in the dPELOD-2 score from day1, adjusted for baseline value, demonstrated a significant odds ratio of death for each of the 7 days. Conclusion: This study suggests that the progression of the severity of organ dysfunctions can be evaluated by measuring the dPELOD-2 score during a set of 7 days in PICU, providing useful information on outcome in critically ill children. Its external validation would be useful

Intra-abdominal hypertension: incidence and association with organ dysfunction during early septic shock.

Intra-abdominal hypertension: incidence and association with organ dysfunction during early septic shock.
Regueira T, Bruhn A, Hasbun P, Aguirre M, Romero C, Llanos O, Castro R, Bugedo G, Hernandez G.J Crit Care. 2008 Dec;23(4):461-7. Epub 2008 Apr 18.
PMID: 19056007 [PubMed - in process]
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