Fredrik Sjövall

Intensive care doctors' preferences for arterial oxygen tension levels in mechanically ventilated patients.

Publisher: Wiley

Date: 21-06-2018

DOI: 10.1111/AAS.13171

Abstract: Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors' preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors' preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. In April to August 2016, an online multiple-choice 17-part-questionnaire was distributed to 1080 ICU doctors in seven Northern European countries. Repeated reminder e-mails were sent. The study ended in October 2016. The response rate was 63%. When evaluating oxygenation 52% of respondents rated arterial oxygen tension (PaO Intensive care unit doctors preferred PaO

A new tool to assess Clinical Diversity In Meta‐analyses (CDIM) of interventions

Publisher: Elsevier BV

Date: 07-2021

DOI: 10.1016/J.JCLINEPI.2021.01.023

Abstract: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical ersity between trials in meta-analyses of interventions. The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups. CDIM measures clinical ersity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type) population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities) interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions) and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical ersity in the four domains. Second, after agreeing upon scores of in idual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters. CDIM is the first tool developed for assessing clinical ersity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical ersity among trials in meta-analysis.

Empirical mono- versus combination antibiotic therapy in adult intensive care patients with severe sepsis – A systematic review with meta-analysis and trial sequential analysis

Publisher: Elsevier BV

Date: 04-2017

DOI: 10.1016/J.JINF.2016.11.013

Abstract: To assess benefits and harms of empirical mono- vs. combination antibiotic therapy in adult patients with severe sepsis in the intensive care unit (ICU). We performed a systematic review according to the Cochrane Collaboration methodology, including meta-analysis, risk of bias assessment and trial sequential analysis (TSA). We included randomised clinical trials (RCT) assessing empirical mono-antibiotic therapy versus a combination of two or more antibiotics in adult ICU patients with severe sepsis. We exclusively assessed patient-important outcomes, including mortality. Two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated and the risk of random errors was assessed by TSA. Thirteen RCTs (n = 2633) were included all were judged as having high risk of bias. Carbapenems were the most frequently used mono-antibiotic (8 of 13 trials). There was no difference in mortality (RR 1.11, 95% CI 0.95-1.29 p = 0.19) or in any other patient-important outcomes between mono- vs. combination therapy. In TSA of mortality, the Z-curve reached the futility area, indicating that a 20% relative risk difference in mortality may be excluded between the two groups. For the other outcomes, TSA indicated lack of data and high risk of random errors. This systematic review of RCTs with meta-analysis and TSA demonstrated no differences in mortality or other patient-important outcomes between empirical mono- vs. combination antibiotic therapy in adult ICU patients with severe sepsis. The quantity and quality of data was low without firm evidence for benefit or harm of combination therapy.

Defining optimal dosing of ciprofloxacin in patients with septic shock

Publisher: Oxford University Press (OUP)

Date: 26-02-2019

DOI: 10.1093/JAC/DKZ069

Abstract: Patients with septic shock may undergo extensive physiological alterations that can alter antibiotic pharmacokinetics. To describe the population pharmacokinetics of ciprofloxacin in septic shock and to define recommendations for effective ciprofloxacin dosing in these patients. Adult patients with septic shock treated with ciprofloxacin were eligible for inclusion. Concentrations were measured by HPLC-MS/MS. Population pharmacokinetic modelling was performed with Monte Carlo simulations then used to define dosing regimens that optimize the PTA of an AUC/MIC ratio >125 for different MICs and fractional target attainment (FTA) of empirical and targeted therapy against Pseudomonas aeruginosa. We included 48 patients with median Simplified Acute Physiology Score (SAPS) II of 49 and 90 day mortality of 33%. Ciprofloxacin pharmacokinetics was best described by a two-compartment linear model including CLCR and body weight as covariates on CL and central volume respectively. With a dose of 400 mg q8h and CLCR of 80 mL/min, >95% PTA was achieved for bacteria with MICs ≤0.25 mg/L. For empirical treatment of P. aeruginosa, 600 mg q8h only reached a maximum of 68% FTA. For directed therapy against P. aeruginosa, a dose of 600 mg q8h was needed to achieve sufficient AUC/MIC ratios. In patients with septic shock, standard ciprofloxacin dosing achieved concentrations to successfully treat bacteria with MICs ≤0.25 mg/L and then only in patients with normal or reduced CLCR. To cover pathogens with higher MICs or in patients with augmented renal CL, doses may have to be increased.

Piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections: A systematic review with meta‐analysis

Publisher: Wiley

Date: 28-03-2023

DOI: 10.1111/AAS.14239

Abstract: Piperacillin/tazobactam or meropenem are often used to treat patients with severe bacterial infections. We aimed to compare the desirable and undesirable effects of empirical and/or definitive piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections. We searched PubMed, Embase, CENTRAL, Epistemonikos, and trial registers for randomised clinical trials of empirical and/or definitive piperacillin/tazobactam versus carbapenems in adult patients with severe bacterial infection (i.e., any bacterial infection requiring hospitalisation). The primary outcome was all‐cause short‐term mortality within 90 days. Secondary outcomes were all‐cause long‐term mortality, adverse events, quality of life, days alive without or duration of life support, secondary infections, selection of fungi or resistant bacteria, and days alive and out of hospital or hospital length of stay. We calculated relative risks (RRs) using random effects and fixed effect meta‐analyses along with trial sequential analyses. We included 31 trials ( n = 8790 patients) with overall high risk of bias. The RR for all‐cause short‐term mortality was 1.16 (95% confidence interval [CI]: 0.94–1.43, low certainty evidence), for adverse events 1.00 (98% CI: 0.96–1.04, moderate certainty evidence), for secondary infections 1.13 (98% CI: 0.76–1.68, very low certainty evidence), and for selection of fungi or resistant bacteria 1.61 (98% CI: 0.89–2.89, very low certainty evidence). There were no or limited data for the remaining outcomes. Based on very low or low certainty evidence, piperacillin/tazobactam may be associated with less favourable outcomes in patients with severe bacterial infections as compared with carbapenems, but the information size for a robust conclusion has not been reached.

Empirical metronidazole for patients with severe bacterial infection: A systematic review with meta‐analysis and trial sequential analysis

Publisher: Wiley

Date: 06-02-2019

DOI: 10.1111/AAS.13327

Abstract: Metronidazole is the preferred empirical anti-anaerobic agent for patients with suspected anaerobic infection. The balance between benefits and harms of empirical metronidazole is unclear. We aimed to assess patient-important benefits and harms of empirical metronidazole vs placebo/no treatment in adult patients with severe bacterial infection of any origin. We conducted a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing empirical metronidazole vs placebo/no treatment in adult hospitalized patients with severe bacterial infection. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. A protocol and statistical analysis plan was published prior to conducting the review. We included a total of nine trials (n = 1753 patients), all of which were adjudicated as having high risk of bias. We found no difference in the primary outcome mortality within 90 days (relative risk 1.56, 95% confidence interval 0.39-6.25). Fewer patients receiving metronidazole had secondary infections (relative risk 0.43, 95% CI: 0.27-0.68). Trial sequential analysis indicated high risk of random errors due to lack of data, and the quality of evidence was very low for all outcomes. There is low quantity and quality of evidence supporting the use of empirical metronidazole in adult patients with severe bacterial infections of any origin, and no firm evidence for benefit or harm.

Use of the Hollow-Fiber Infection Model to Measure the Effect of Combination Therapy of Septic Shock Exposures of Meropenem and Ciprofloxacin against Intermediate and Resistant Pseudomonas aeruginosa

Publisher: American Society for Microbiology

Date: 17-05-2022

DOI: 10.1128/AAC.02140-21

Abstract: Meropenem-ciprofloxacin combination therapy was compared to the respective monotherapy in a Hollow-Fiber Infection Model against two Pseudomonas aeruginosa isolates. Following initial kill of ∼ 5-logs by each monotherapy, rapid regrowth occurred within 24 h, reaching 10 8 – 10 10 CFU/mL at 120 h.

Maximally effective dosing regimens of meropenem in patients with septic shock

Publisher: Oxford University Press (OUP)

Date: 12-09-2017

DOI: 10.1093/JAC/DKX330

Abstract: To use a population pharmacokinetic approach to define maximally effective meropenem dosing recommendations for treatment of Acinetobacter baumannii and Pseudomonas aeruginosa infections in a large cohort of patients with septic shock. Adult patients with septic shock and conserved renal function, treated with meropenem, were eligible for inclusion. Seven blood s les were collected during a single dosing interval and meropenem concentrations were measured by a validated HPLC-MS/MS method. Monte Carlo simulations were employed to define optimum dosing regimens for treatment of empirical or targeted therapy of A. baumannii and P. aeruginosa. EudraCT-no. 2014-002555-26 and NCT02240277. Fifty patients were included, 26 male and 24 female, with a median age of 64 years with an all-cause 90 day mortality of 34%. A two-compartment linear model including creatinine clearance (CLCR) as a covariate best described meropenem pharmacokinetics. For empirical treatment of A. baumannii, 2000 mg/6 h was required by intermittent (30 min) or prolonged (3 h) infusion, whereas 6000 mg/day was required with continuous infusion. For P. aeruginosa, 2000 mg/8 h or 1000 mg/6 h was required for both empirical and targeted treatment. In patients with a CLCR of ≤ 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h. In patients with septic shock and possible augmented renal clearance, doses should be increased and/or administration should be performed by prolonged or continuous infusion to increase the likelihood of achieving therapeutic drug concentrations. In patients with normal renal function, however, standard dosing seems to be sufficient.

Empirical metronidazole for patients with severe bacterial infection: protocol for a systematic review

Publisher: Wiley

Date: 08-03-2018

DOI: 10.1111/AAS.13101

Abstract: Anaerobic bacteria are believed to be common pathogens in severe infections. Yet, they are difficult to culture and consequently often unrecognised in clinical infections. Metronidazole is often used empirically for potential anaerobic infections, as the resistance to metronidazole is low. However, disadvantages of metronidazole use exist, including drug interactions, side effects and economical expenses. Currently, the balance between the benefits and harms of empirical metronidazole for severe bacterial infections is unknown. We aim to assess patient-important benefits and harms of empirical metronidazole vs. placebo or no treatment in adult patients with severe bacterial infection of any origin in a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. This protocol provides details on the planned systematic review, which will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. The primary outcome is all-cause mortality. Secondary outcomes include adverse events, secondary infections, use of life support, antibiotic resistance and hospital length of stay. We will conduct conventional meta-analyses, including predefined subgroup- and sensitivity analyses. Additionally, we will assess the risk of random errors by trial sequential analysis. Ethical approval is not needed, as the outlined review exclusively will include previously published data. We aim to publish in an international, peer-reviewed journal.

Protocol for an international, multicentre, prospective, observational study of nosocomial pneumonia in intensive care units: the PneumoINSPIRE study

Publisher: Elsevier BV

Date: 03-2021

DOI: 10.51893/2021.1.OA5

Abstract: Background: Nosocomial pneumonia in the critical care setting is associated with increased morbidity, significant crude mortality rates and high health care costs. Ventilator-associated pneumonia represents about 80% of nosocomial pneumonia cases in intensive care units (ICUs). Wide variance in incidence of nosocomial pneumonia and diagnostic techniques used has been reported, while successful treatment remains complex and a matter of debate. Objective: To describe the epidemiology, diagnostic strategies and treatment modalities for nosocomial pneumonia in contemporary ICU settings across multiple countries around the world. Design, setting and patients: PneumoINSPIRE is a large, multinational, prospective cohort study of adult ICU patients diagnosed with nosocomial pneumonia. Participating ICUs from at least 20 countries will collect data on 10 or more consecutive ICU patients with nosocomial pneumonia. Site-specific information, including hospital policies on antibiotic therapy, will be recorded along with patient-specific data. Variables that will be explored include: aetiology and antimicrobial resistance patterns, treatment-related parameters (including time to initiation of antibiotic therapy, and empirical antibiotic choice, dose and escalation or de-escalation), pneumonia resolution, ICU and hospital mortality, and risk factors for unfavourable outcomes. The concordance of ventilator-associated pneumonia diagnosis with accepted definitions will also be assessed. Results and conclusions: PneumoINSPIRE will provide valuable information on current diagnostic and management practices relating to ICU nosocomial pneumonia, and identify research priorities in the field. Trial registration: ClinicalTrials.gov identifier NCT02793141.

Untargeted antifungal therapy in adult patients with complicated intra‐abdominal infection: a systematic review

Publisher: Wiley

Date: 09-11-2017

DOI: 10.1111/AAS.13031

Abstract: Systematic reviews comparing untargeted antifungal treatment with placebo or no treatment in critically ill patients have provided conflicting results. We aimed to assess patient-important benefits and harms of untargeted antifungal therapy vs. placebo or no treatment in adult patients with complicated intra-abdominal infection. We conducted a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials assessing untargeted antifungal therapy compared to placebo or no treatment in adults with complicated intra-abdominal infection. We used the Cochrane and GRADE methodologies and exclusively assessed patient-important outcomes. Two independent authors screened trials for eligibility, extracted data and assessed risk of bias. We performed conventional meta-analyses, including sensitivity and subgroup analyses, and trial sequential analysis to assess the risk of random errors and to estimate trial sequential analysis adjusted confidence intervals. We included six trials (1,067 patients) in the review, and four trials reported data on the predefined outcome measures and were included in the meta-analysis. Three of the four trials had high risk of bias. We observed no statistically significant difference in mortality (relative risk 0.58, 95% confidence interval 0.24-1.39) or in any of the other patient-important outcomes between untargeted antifungal treatment and placebo or no treatment (low/very low quality of evidence). Trial sequential analysis demonstrated lack of data and high risk of random errors. The quantity and quality of evidence supporting untargeted antifungal treatment in adult patients with complicated intra-abdominal infection are low to very low with no firm evidence for benefit or harm.

Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study

Publisher: Springer Science and Business Media LLC

Date: 09-06-2020

DOI: 10.1007/S00134-020-06111-5

Piperacillin/tazobactam vs carbapenems for patients with bacterial infection: Protocol for a systematic review

Publisher: Wiley

Date: 24-04-2019

DOI: 10.1111/AAS.13382

Abstract: Early empirical broad-spectrum antimicrobial therapy is recommended for patients with severe infections, including sepsis. β-lactam/β-lactamase inhibitor combinations or carbapenems are often used to ensure coverage of likely pathogens. Piperacillin/tazobactam is proposed as a carbapenem-sparing agent to reduce the incidence of multidrug-resistant bacteria and superinfections. In the recently published MERINO trial, increased mortality from piperacillin/tazobactam was suggested in patients with bacteraemia with resistant Escherichia coli or Klebsiella species. Whether these findings also apply to empirical piperacillin/tazobactam in patients with other severe infections, including sepsis, is unknown. We aim to assess the benefits and harms of empirical and definitive piperacillin/tazobactam vs carbapenems for patients with severe bacterial infections. This protocol has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols statement, the Cochrane Handbook and the Grading of Recommendations, Assessment, Development, and Evaluation approach. We will include randomised clinical trials assessing piperacillin/tazobactam vs carbapenems in patients with severe bacterial infections of any origin. The primary outcome will be all-cause short-term mortality ≤ 90 days. Secondary outcomes will include all-cause long-term mortality > 90 days, adverse events, quality of life, use of life support, secondary infections, antibiotic resistance, and length of stay. We will conduct meta-analyses, including pre-planned subgroup and sensitivity analyses for all assessed outcomes. The risk of random errors in the meta-analyses will be assessed by trial sequential analysis.

Rigshospitalet

Location: Denmark

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Skånes Universitetssjukhus Malmö

Location: Sweden

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Lund University

Location: Sweden

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Lunds Universitet

Location: Sweden

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Linköpings Universitet

Location: Sweden

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