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PurposeThis Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients. MethodsLiterature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes.ResultsTDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.ConclusionAlthough TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.

Purpose To use the World Health Organisation’s International Classification of Functioning to measure disability following critical illness using patient-reported outcomes. Methods A prospective, multicentre cohort study conducted in five metropolitan intensive care units (ICU). Participants were adults who had been admitted to the ICU, received more than 24 h of mechanical ventilation and survived to hospital discharge. The primary outcome was measurement of disability using the World Health Organisation’s Disability Assessment Schedule 2.0. The secondary outcomes included the limitation of activities and changes to health-related quality of life comparing survivors with and without disability at 6 months after ICU. Results We followed 262 patients to 6 months, with a mean age of 59 ± 16 years, and of whom 175 (67%) were men. Moderate or severe disability was reported in 65 of 262 (25%). Predictors of disability included a history of anxiety/depression [odds ratio (OR) 1.65 (95% confidence interval (CI) 1.22, 2.23), P  = 0.001]; being separated or divorced [OR 2.87 (CI 1.35, 6.08), P  = 0.006]; increased duration of mechanical ventilation [OR 1.04 (CI 1.01, 1.08), P  = 0.03 per day]; and not being discharged to home from the acute hospital [OR 1.96 (CI 1.01, 3.70) P  = 0.04]. Moderate or severe disability at 6 months was associated with limitation in activities, e.g. not returning to work or studies due to health ( P  < 0.002), and reduced health-related quality of life ( P  < 0.001). Conclusion Disability measured using patient-reported outcomes was prevalent at 6 months after critical illness in survivors and was associated with reduced health-related quality of life. Predictors of moderate or severe disability included a prior history of anxiety or depression, separation or divorce and a longer duration of mechanical ventilation. Trial registration: NCT02225938.

Several mechanisms in critically ill patients make them susceptible to augmented renal clearance (ARC). The authors of this Perspectives article focus on the causes, risk factors and monitoring of ARC in these patients, and examine the clinical consequences of ARC with regard to achieving target therapeutic concentrations of renally excreted drugs. Critically ill patients can display markedly abnormal physiological parameters compared with those in ward-based or ambulatory settings. As a function of both the underlying inflammatory state and the interventions provided, these patients manifest substantial changes in their cardiovascular and renal function that are not always immediately discernable using standard diagnostic tests. Impaired renal function is well documented among such individuals; however, even patients with normal serum creatinine concentrations might display elevated glomerular filtration rates, a phenomenon we have termed augmented renal clearance (ARC). This finding has important ramifications for the accurate dosing of renally eliminated drugs, given that most pharmaceutical dosing regimens were validated outside the critical care environment. Empirical approaches to dosing are unlikely to achieve therapeutic drug concentrations in patients with ARC, placing them at risk of suboptimal drug exposure and potential treatment failure. With an increasing appreciation of this phenomenon, alternative dosing strategies will need to be investigated.

Background Metabolic acidosis is a major complication of critical illness. However, its current epidemiology and its treatment with sodium bicarbonate given to correct metabolic acidosis in the ICU are poorly understood. Method This was an international retrospective observational study in 18 ICUs in Australia, Japan, and Taiwan. Adult patients were consecutively screened, and those with early metabolic acidosis (pH < 7.3 and a Base Excess < –4 mEq/L, within 24-h of ICU admission) were included. Screening continued until 10 patients who received and 10 patients who did not receive sodium bicarbonate in the first 24 h (early bicarbonate therapy) were included at each site. The primary outcome was ICU mortality, and the association between sodium bicarbonate and the clinical outcomes were assessed using regression analysis with generalized linear mixed model. Results We screened 9437 patients. Of these, 1292 had early metabolic acidosis (14.0%). Early sodium bicarbonate was given to 18.0% (233/1292) of these patients. Dosing, physiological, and clinical outcome data were assessed in 360 patients. The median dose of sodium bicarbonate in the first 24 h was 110 mmol, which was not correlated with bodyweight or the severity of metabolic acidosis. Patients who received early sodium bicarbonate had higher APACHE III scores, lower pH, lower base excess, lower PaCO 2 , and a higher lactate and received higher doses of vasopressors. After adjusting for confounders, the early administration of sodium bicarbonate was associated with an adjusted odds ratio (aOR) of 0.85 (95% CI, 0.44 to 1.62) for ICU mortality. In patients with vasopressor dependency, early sodium bicarbonate was associated with higher mean arterial pressure at 6 h and an aOR of 0.52 (95% CI, 0.22 to 1.19) for ICU mortality. Conclusions Early metabolic acidosis is common in critically ill patients. Early sodium bicarbonate is administered by clinicians to more severely ill patients but without correction for weight or acidosis severity. Bicarbonate therapy in acidotic vasopressor-dependent patients may be beneficial and warrants further investigation.

To use machine learning (ML) to predict short-term requirements for invasive ventilation in patients with COVID-19 admitted to Australian intensive care units (ICUs). A machine learning study within a national ICU COVID-19 registry in Australia. Adult patients who were spontaneously breathing and admitted to participating ICUs with laboratory-confirmed COVID-19 from 20 February 2020 to 7 March 2021. Patients intubated on day one of their ICU admission were excluded. Six machine learning models predicted the requirement for invasive ventilation by day three of ICU admission from variables recorded on the first calendar day of ICU admission; (1) random forest classifier (RF), (2) decision tree classifier (DT), (3) logistic regression (LR), (4) K neighbours classifier (KNN), (5) support vector machine (SVM), and (6) gradient boosted machine (GBM). Cross-validation was used to assess the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of machine learning models. 300 ICU admissions collected from 53 ICUs across Australia were included. The median [IQR] age of patients was 59 [50-69] years, 109 (36%) were female and 60 (20%) required invasive ventilation on day two or three. Random forest and Gradient boosted machine were the best performing algorithms, achieving mean (SD) AUCs of 0.69 (0.06) and 0.68 (0.07), and mean sensitivities of 77 (19%) and 81 (17%), respectively. Machine learning can be used to predict subsequent ventilation in patients with COVID-19 who were spontaneously breathing and admitted to Australian ICUs.

IntroductionA literature review provides a synthesis on a selection of papers about a specific topic. This is used by health practitioners in critical care as in other specialities when making clinical practice decisions. The task of knowledge transfer through the review process of scientific papers involves a variety of methodologies with differing expectations on the quality and rigour that is applied. Exploration on the types of review methodologies selected by the authors of critical care literature may reveal the extent that choice of methodology has on how papers are selected and appraised may influence evidence-based practice recommendations. This scoping review aims to systematically map the breadth of current literature with the objective of identifying the types of review methodologies used by interdisciplinary authors synthesising the literature in adult critical care.Methods and analysisArksey and O’Malley’s approach in conducting a scoping review will be followed and use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review guidelines in the reporting of findings. Papers with diverse review methodologies will be identified by searching four electronic databases (CINAHL/EBSCO, MEDLINE/PubMed, Scopus and Embase). Grey literature will be excluded due to the clinical nature of the review question. Search results will be reviewed independently by two researchers based on title and abstract followed by full-text papers that meet inclusion criteria. Characteristics of review methodologies will be collected and analysed using a tool developed by the interdisciplinary research team.Ethics and disseminationThis scoping review will provide an overview of the types of review methodologies most often undertaken with the interdisciplinary research team synthesising the quality of critical care literature. Scrutiny will be applied to the review methodologies selected, the challenges faced and current trends in the transfer of knowledge towards evidence-based practice. The results will be disseminated by publication through a peer-reviewed journal and by presentation as a part of conference proceedings. Ethics approval is not applicable for this scoping review.

Comparisons between institutions of intensive care unit (ICU) length of stay (LOS) are significantly confounded by individual patient characteristics, and currently there is a paucity of methods available to calculate risk-adjusted metrics. We extracted de-identified data from the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database for admissions between January 1 2011 and December 31 2015. We used a mixed-effects log-normal regression model to predict LOS using patient and admission characteristics. We calculated a risk-adjusted LOS ratio (RALOSR) by dividing the geometric mean observed LOS by the exponent of the expected Ln-LOS for each site and year. The RALOSR is scaled such that values <1 indicate a LOS shorter than expected, while values >1 indicate a LOS longer than expected. Secondary mixed effects regression modelling was used to assess the stability of the estimate in units over time. During the study there were a total of 662,525 admissions to 168 units (median annual admissions = 767, IQR:426-1121). The mean observed LOS was 3.21 days (median = 1.79 IQR = 0.92-3.52) over the entire period, and declined on average 1.97 hours per year (95%CI:1.76-2.18) from 2011 to 2015. The RALOSR varied considerably between units, ranging from 0.35 to 2.34 indicating large differences after accounting for case-mix. There are large disparities in risk-adjusted LOS among Australian and New Zealand ICUs which may reflect differences in resource utilization.

ObjectivesWe aimed to assess the healthcare costs and impact on the economy at large arising from emergency medical services (EMS) treated non-traumatic shock.DesignWe conducted a population-based cohort study, where EMS-treated patients were individually linked to hospital-wide and state-wide administrative datasets. Direct healthcare costs (Australian dollars, AUD) were estimated for each element of care using a casemix funding method. The impact on productivity was assessed using a Markov state-transition model with a 3-year horizon.SettingPatients older than 18 years of age with shock not related to trauma who received care by EMS (1 January 2015–30 June 2019) in Victoria, Australia were included in the analysis.Primary and secondary outcome measuresThe primary outcome assessed was the total healthcare expenditure. Secondary outcomes included healthcare expenditure stratified by shock aetiology, years of life lived (YLL), productivity-adjusted life-years (PALYs) and productivity losses.ResultsA total of 21 334 patients (mean age 65.9 (±19.1) years, and 9641 (45.2%) females were treated by EMS with non-traumatic shock with an average healthcare-related cost of $A11 031 per episode of care and total cost of $A280 million. Annual costs remained stable throughout the study period, but average costs per episode of care increased (Ptrend=0.05). Among patients who survived to hospital, the average cost per episode of care was stratified by aetiology with cardiogenic shock costing $A24 382, $A21 254 for septic shock, $A19 915 for hypovolaemic shock and $A28 057 for obstructive shock. Modelling demonstrated that over a 3-year horizon the cohort lost 24 355 YLLs and 5059 PALYs. Lost human capital due to premature mortality led to productivity-related losses of $A374 million. When extrapolated to the entire Australian population, productivity losses approached $A1.5 billion ($A326 million annually).ConclusionThe direct healthcare costs and indirect loss of productivity among patients with non-traumatic shock are high. Targeted public health measures that seek to reduce the incidence of shock and improve systems of care are needed to reduce the financial burden of this syndrome.

IntroductionCritically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting.Methods and analysisA beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity.Ethics and disseminationThis study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial.Trial registration numberAustralian New Zealand Clinical Trials Registry, ACTRN12623000032651.

Successful antibiotic therapy in the critically ill requires sufficient drug concentrations at the site of infection that kill or suppress bacterial growth. The relationship between antibiotic exposure and achieving the above effects is referred to as pharmacokinetics/pharmacodynamics (PK/PD). The associated indices therefore provide logical targets for optimal antibiotic therapy. While dosing regimens to achieve such targets have largely been established from studies in animals and non-critically ill patients, they are often poorly validated in the ICU. Endothelial dysfunction, capillary leak, altered major organ blood flow, deranged plasma protein concentrations, extremes of body habitus, the application of extracorporeal support modalities, and a higher prevalence of intermediate susceptibility, independently, and in combination, significantly confound successful antibiotic treatment in this setting. As such, the prescription of standard doses are likely to result in sub-therapeutic concentrations, which in turn may promote treatment failure or the selection of resistant pathogens. This review article considers these issues in detail, summarizing the key changes in antibiotic PK/PD in the critically ill, and suggesting alternative dosing strategies that may improve antibiotic therapy in these challenging patients.