Health-related quality of life trajectories in critical illness: Protocol for a Monte Carlo simulation study.

BACKGROUND: Health-related quality of life (HRQoL) is a patient-centred outcome increasingly used as a secondary outcome in critical care research. It may cover several important dimensions of clinical status in intensive care unit (ICU) patients that arguably elude other more easily quantified outcomes such as mortality. Poor associations with harder outcomes, conflicting data on HRQoL in critically ill compared to the background population, and paradoxical effects on HRQoL and mortality complicate the current operationalisation in critical care trials. This protocol outlines a simulation study that will gauge if the areas under the HRQoL trajectories could be a viable alternative. METHODS: We will gauge the behaviour of the proposed HRQoL operationalisation through Monte Carlo simulations, under clinical scenarios that reflect a broad critical care population eligible for inclusion in a large pragmatic trial. We will simulate 15,360 clinical scenarios based on a full factorial design with the following seven simulation parameters: number of patients per arm, relative mortality reduction in the interventional arm, acceleration of HRQoL improvement in the interventional arm, the relative improvement in final HRQoL in the interventional arm, dampening effect of mortality on HRQoL values at discharge from the ICU, proportion of so-called mortality benefiters in the interventional arm and mortality trajectory shape. For each clinical scenario, we will simulate 100,000 two-arm trials with 1:1 randomisation. HRQoL will be sampled fortnightly after ICU discharge. Outcomes will include HRQoL in survivors and all patients at the end of follow-up; mean areas under the HRQoL trajectories in both arms; and mean difference between areas under the HRQoL trajectories and single-sampled HRQoLs at the end of follow-up. DISCUSSION: In the outlined simulation study, we aim to assess whether the area under the HRQoL trajectory curve could be a candidate for reconciling the seemingly paradoxical effects on improved mortality and reduced HRQoL while remaining sensitive to early or accelerated improvement in patient outcomes. The resultant insights will inform subsequent methodological work on prudent collection and statistical analysis of such data from real critically ill patients.

The effects of pantoprazole vs. placebo on 1-year outcomes, resource use and employment status in ICU patients at risk for gastrointestinal bleeding: a secondary analysis of the SUP-ICU trial.

PURPOSE: Patients in intensive care units (ICUs) are at risk of stress-related gastrointestinal (GI) bleeding and stress ulcer prophylaxis (SUP), including proton pump inhibitors, is widely used in the attempt to prevent this. In this secondary analysis of Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, we assessed 1-year outcomes in the pantoprazole vs. placebo groups. METHODS: In the SUP-ICU trial, 3298 acutely admitted ICU patients at risk of GI bleeding were randomly allocated, stratified for site, to pantoprazole or placebo. In this secondary analysis, we assessed clinically important GI bleedings in ICU and 1-year mortality, health care resource use (e.g. readmission with GI bleeding, use of home care and general practitioner), health care costs, and employment status for the Danish participants using registry data. RESULTS: Among the 2099 Danish participants, 2092 had data in the registries; 1045 allocated to pantoprazole and 1047 to placebo. The number of clinically important GI bleedings in ICU was 1.9 percentage points [95% CI 0.3-3.5] lower in the pantoprazole group vs. the placebo group, but none of the 1-year outcomes differed statistically significantly between groups, including total health care costs (€1954 [- 2992 to 6899]), readmission with GI bleeding (- 0.005 admissions [- 0.016 to 0.005]), 1-year mortality (- 0.013 percentage points [- 0.051 to 0.026]), and employment (- 0.178 weeks [- 0.390 to 0.034]). CONCLUSION: Among ICU patients at risk of GI bleeding, pantoprazole reduced clinically important GI bleeding in ICU, but this did not translate into a reduction in 1-year mortality, health care resource use or improvements in employment status.

Defining optimal dosing of ciprofloxacin in patients with septic shock.

BACKGROUND: Patients with septic shock may undergo extensive physiological alterations that can alter antibiotic pharmacokinetics. OBJECTIVES: To describe the population pharmacokinetics of ciprofloxacin in septic shock and to define recommendations for effective ciprofloxacin dosing in these patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Danish public research investments in clinical trials].

Clinical trials are important to ensure that patients and society benefit from healthcare interventions. Among the Danish public research investments in medical sciences the main part of funding is given to preclinical and translational research, and less than ten per cent is given to clinical trials. This imbalance may have negative consequences for patients and society, because public investment in clinical trials is likely to ensure broader availability of tested interventions independent of diseases, patient groups, caregivers and clinical settings.

[Disease burden and definition of sepsis in adults].

Sepsis is the terminal event for most infectious diseases and is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is frequent, deathly and associated with high burden for patients, relatives and societies. Sepsis is underreported in diagnostic coding, making estimation difficult of the true burden of the disease in Denmark. It is likely, however, that sepsis contributes to 15% of all deaths in Denmark.

Sepsis: frontiers in supportive care, organisation and research.

Because of its high incidence and clinical complexity, sepsis is a major challenge to clinicians and researchers and a global burden to healthcare systems and society. Despite recent progress, short- and long-term morbidity, mortality and costs remain high in both developed and developing countries. Thus, further improvements in supportive interventions and organisation of care are likely to have a substantial impact upon global health. In this narrative review, invited experts describe the challenges and progress to be made in sepsis research and care in the near future. We focus on supportive care (pulmonary, endocrine, renal, and nutritional support, mediator modulation and precision medicine), organisational themes (guidelines, outcome measures and stakeholder involvement) and clinical research as key areas to improving the care and outcomes of patients with sepsis.

Predictive Performance of the Simplified Acute Physiology Score (SAPS) II and the Initial Sequential Organ Failure Assessment (SOFA) Score in Acutely Ill Intensive Care Patients: Post-Hoc Analyses of the SUP-ICU Inception Cohort Study.

PURPOSE: Severity scores including the Simplified Acute Physiology Score (SAPS) II and the Sequential Organ Failure Assessment (SOFA) score are used in intensive care units (ICUs) to assess disease severity, predict mortality and in research. We aimed to assess the predictive performance of SAPS II and the initial SOFA score for in-hospital and 90-day mortality in a contemporary international cohort. METHODS: This was a post-hoc study of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) inception cohort study, which included acutely ill adults from ICUs across 11 countries (n = 1034). We compared the discrimination of SAPS II and initial SOFA scores, compared the discrimination of SAPS II in our cohort with the original cohort, assessed the calibration of SAPS II customised to our cohort, and compared the discrimination for 90-day mortality vs. in-hospital mortality for both scores. Discrimination was evaluated using areas under the receiver operating characteristics curves (AUROC). Calibration was evaluated using Hosmer-Lemeshow's goodness-of-fit C-statistic. RESULTS: AUROC for in-hospital mortality was 0.80 (95% confidence interval (CI) 0.77-0.83) for SAPS II and 0.73 (95% CI 0.69-0.76) for initial SOFA score (P<0.001 for the comparison). Calibration of the customised SAPS II for predicting in-hospital mortality was adequate (P = 0.60). Discrimination of SAPS II was reduced compared with the original SAPS II validation sample (AUROC 0.80 vs. 0.86; P = 0.001). AUROC for 90-day mortality was 0.79 (95% CI 0.76-0.82; P = 0.74 for comparison with in-hospital mortality) for SAPS II and 0.71 (95% CI 0.68-0.75; P = 0.66 for comparison with in-hospital mortality) for the initial SOFA score. CONCLUSIONS: The predictive performance of SAPS II was similar for in-hospital and 90-day mortality and superior to that of the initial SOFA score, but SAPS II's performance has decreased over time. Use of a contemporary severity score with improved predictive performance may be of value.

Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial.

BACKGROUND: Critically ill patients in the intensive care unit (ICU) are at risk of clinically important gastrointestinal bleeding, and acid suppressants are frequently used prophylactically. However, stress ulcer prophylaxis may increase the risk of serious adverse events and, additionally, the quantity and quality of evidence supporting the use of stress ulcer prophylaxis is low. The aim of the SUP-ICU trial is to assess the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the ICU. We hypothesise that stress ulcer prophylaxis reduces the rate of gastrointestinal bleeding, but increases rates of nosocomial infections and myocardial ischaemia. The overall effect on mortality is unpredictable. METHODS/DESIGN: The SUP-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomised, blinded, parallel-group trial of stress ulcer prophylaxis with a proton pump inhibitor versus placebo (saline) in 3350 acutely ill ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support in the 90-day period, serious adverse reactions, 1-year mortality, and health economic analyses. The sample size will enable us to detect a 20 % relative risk difference (5 % absolute risk difference) in 90-day mortality assuming a 25 % event rate with a risk of type I error of 5 % and power of 90 %. The trial will be externally monitored according to Good Clinical Practice standards. Interim analyses will be performed after 1650 and 2500 patients. CONCLUSION: The SUP-ICU trial will provide high-quality data on the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in critically ill adult patients admitted in the ICU. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02467621 .

Variable assessment of the circulation in intensive care unit patients with shock.

INTRODUCTION: Circulatory failure is frequent in intensive care unit (ICU) patients and is associated with a high mortality and morbidity. There is no current consensus on which parameters best evaluate circulatory failure, and clinical practice regarding haemodynamic assessment is unknown. This study describes current clinical practice regarding circulatory assessment in ICU patients with shock. MATERIAL AND METHODS: This was a prospective, observational cohort study conducted in a university hospital ICU over a four-month period. Doctors working in the ICU were divided into two groups: trainees and specialists. They registered their circulatory assessments of consecutive patients with shock. The parameters included type of shock, kind of parameters used (markers of hypoperfusion, hypovolaemia and flow), which parameter was considered to be most important and the clinical action taken. RESULTS: A total of 23 doctors performed 210 patient assessments, which was equivalent to a median of eight (interquartile range: 5-14) per doctor. Trainees used six (5-8) parameters compared with five (3-6) parameters per assessment among specialists (p < 0.01). Mean arterial pressure (MAP) was the most frequently assessed parameter (n = 178) and both specialist (in 23% of assessments) and trainees (30%) considered MAP to be the most important parameter. Hypoperfusion markers were assessed in 99% of the cases, and a marker of hypovolaemia was also assessed in 83% (95% confidence interval (CI) 78-88) of these cases. Fluid was the most frequent clinical action taken, and was given after 150 assessments, but a marker of hypovolaemia was not assessed in 13% (95% CI 9-20) of these situations. Trainees assessed heart rate (76% versus 54%; p < 0.01), diastolic (45% versus 28%, p < 0.01) and systolic blood pressure (70% versus 46%; p < 0.01) and central venous oxygen saturation (63% versus 35%; p < 0.01) more frequently than specialists. CONCLUSION: MAP was the most frequently used parameter and fluid the most frequently given treatment by ICU doctors assessing patients with shock. The study indicates that assessment of hypoperfusion leads to the use of a marker of hypovolaemia, but in some cases fluid was given without this assessment. The haemodynamic assessment differed between ICU specialists and trainees. FUNDING: Righospitalet's Research Council supported the study. TRIAL REGISTRATION: not relevant.

Biomechanical and nonfunctional assessment of physical capacity in male ICU survivors.

OBJECTIVES: ICU admission is associated with decreased physical function for years after discharge. The underlying mechanisms responsible for this muscle function impairment are undescribed. The aim of this study was to describe the biomechanical properties of the quadriceps muscle in ICU survivors 12 months after ICU discharge. DESIGN: Case-control study with consecutive inclusion of ICU survivors and age- and sex-matched controls. SETTING: Patients were treated at a mixed 18-bed ICU at a tertiary care university hospital and tested at a biomechanical university laboratory. PATIENTS: We included 16 male ICU patients (Acute Physiology and Chronic Health Evaluation II score 20 ± 7, mean ± SD), who had stayed in the ICU >72 hrs and survived to 12 months and 15 age- and sex-matched controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An extensive battery of biomechanical tests, including maximum, fast, and endurance contractions, was administered during isometric knee extensions while simultaneously recording surface electromyography (quadriceps and hamstrings). Compared to controls, ICU survivors had reduced maximal voluntary torque (22%, 179 ± 64 Nm vs. 230 ± 57 Nm, p = 0.03), absolute rate of force development (50%, 868 ± 372 Nm/sec vs. 1739 ± 470 Nm/sec, p < 0.001) and relative rate of force development (32%, 512 ± 260% maximum voluntary contraction/sec vs. 754 ± 189% maximum voluntary contraction/sec, p < 0.01), and endurance time (40%, 136 ± 84 sec vs. 226 ± 111 sec, p < 0.02). Rate of force development, but not maximal voluntary torque, was significantly reduced after adjusting for muscle mass. Electromyography data indicated no impairment of motor activation strategy or central motor drive. Also, no difference in reaction time was found between patients and controls. CONCLUSIONS: ICU survivors had reduced rate of force development and muscular endurance 1 yr after ICU discharge. Our data indicate that the functional deficits experienced by ICU survivors originate in muscle tissue rather than the nervous system. Also, increased attention to velocity-orientated exercise during rehabilitation of ICU patients may have the potential to better physical outcome after critical illness.

[Various methods for monitoring cardiac output in intensive care patients]. / Forskellige metoder til kredsløbsmonitorering hos intensivpatienter.

This article presents a mini medical technology evaluation of three less invasive monitoring techniques for monitoring cardiac output, CardioQ, ECOM and PiCCO, with focus on validation, usability and costs in intensive care. In conclusion, when identifying patients with low cardiac output, we suggest starting with simple screening tools (e.g. CardioQ or central venous O2 saturation), and when in doubt, upgrade to better validated, yet more time-consuming techniques (e.g. PiCCO using thermodilution). Also consults should be made to other intensive care units in terms of the practical implementation of the monitors.

[Critical care research]. / Forskning i kritisk sygdom.

Critical care research has facilitated the development of clinical guidelines to improve the outcome of critically-ill patients. The high mortality needs to be reduced further, by means of increased research to the benefit of patients, relatives and society. Clinicians, researchers, public officials and politicians at all levels must work together towards this aim.