Empirical meropenem versus piperacillin/tazobactam for adult patients with sepsis (EMPRESS) trial: Protocol.

BACKGROUND: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. METHODS: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90- and 180-day all-cause mortality and 180-day health-related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow-up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference <2.5%-points) and response-adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios. CONCLUSIONS: EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

INTRODUCTION: Early empirical broad-spectrum antimicrobial therapy is recommended for patients with severe infections, including sepsis. ß-lactam/ß-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. METHODS AND ANALYSIS: 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.

How is intensive care reimbursed? A review of eight European countries.

Reimbursement schemes in intensive care are more complex than in other areas of healthcare, due to special procedures and high care needs. Knowledge regarding the principles of functioning in other countries can lead to increased understanding and awareness of potential for improvement. This can be achieved through mutual exchange of solutions found in other countries. In this review, experts from eight European countries explain their respective intensive care unit reimbursement schemes. Important conclusions include the apparent differences in the countries' reimbursement schemes-despite all of them originating from a DRG system-, the high degree of complexity found, and the difficulties faced in several countries when collecting the data for this collaborative work. This review has been designed to assist the intensivist clinician and researcher in understanding neighbouring countries' approaches and in putting research into the context of a European perspective. In addition, steering committees and decision makers might find this a valuable source to compare different reimbursement schemes.

Intensive care of haematological patients.

INTRODUCTION: This article presents the treatment results of 320 consecutive patients with malignant haematological diagnoses admitted to a tertiary intensive care unit at a Danish University hospital over a six-year period (2005-2010). With reference to international publications, we describe the development in treatment. MATERIAL AND METHODS: This was a retrospective observational study. RESULTS: The median age was 59 years. The median intensive care unit (ICU) stay was six days. A total of 88% required mechanical ventilation, and 72% received vasopressor treatment. The median Simplified Acute Physiology Score II score was 58. The ICU and one-year mortality rates were 44% and 77%, respectively, but mortality was significantly lower for patients aged 0-20 years. For patients aged 20-80 years, the mortality risk was independent of age. For the group of patients admitted acutely to the ICU with other diagnoses, the ICU- and the one-year mortality rate was 13% and 33%, respectively. CONCLUSION: Despite progress, the mortality rate for haematological patients in ICUs is high. We lack valid tools that allow us to differentiate between those who can benefit from intensive care and those for whom transfer to an ICU is futile. One patient out of five is alive after one year. This supports a strategy offering haematological patients intensive care on an equal footing with other patients. Follow-up studies of survivors, clarification of function level and quality of life are needed. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Quality improvements based on detailed and precise terminology.

This article describes a comparative study within intensive care where possibilities for quality monitoring have been examined regarding the data input. The study compared the results of making quality statistics based on ICD10 and on SNOMED CT. The article describes the method deployed for defining the subset used in the study and how the data comparison has been established. The study shows that the use of a more granulated, precise and well defined terminology used in daily clinical work can help clinicians doing better quality monitoring and quality development and at the same time may reduce time and costs in quality management. The study shows further that the use of an international terminology can increase the possibilities of international benchmarking and research. The article ends up by drawing attention to some challenges which must be dealt with especially regarding reimbursement.

[Necrotizing fasciitis]. / Nekrotiserende fasciitis.

INTRODUCTION: Necrotizing fasciitis (NF) is an acute soft-tissue infection, associated with a high mortality and morbidity. To reduce the mortality, an early diagnosis and treatment is essential. Our study aims to identify the number of patients, the microorganisms involved, and NF treatment outcomes among patients admitted to our unit. MATERIAL AND METHODS: This retrospective cohort study enrolled 85 patients admitted to the multidisciplinary, tertiary Intensive Care Unit, Abdominal Center, Rigshospitalet, Denmark in 2005-2007. All received the same protocolled treatment of intensive care, extensive surgical débridements, broad-spectrum antibiotics, intravenous immunoglobulin and hyperbaric oxygen. RESULTS: The microbiological analyses of specimens demonstrated that 51% were positive for polymicrobial infection, 40% for a single pathogen, 74% of these caused by beta-hemolytic streptococci, and 9% of the analyses were inconclusive. Of the patients, 91% required treatment in a respirator, 67.5% presented with septic shock and 25.3% developed acute renal failure needing dialysis. Intensive care unit mortality was 6% and 30-day mortality was 9.5%. Expected mortality based on SAPS II and APACHE II scoring was 38%. Our patients had a significantly higher body mass index than other patients admitted to the unit. CONCLUSION: NF is a complex disease, often associated with multi-organ failure. A protocolled treatment plan with close cooperation between the intensive care, clinical microbiology, medical and surgical specialties seems to reduce mortality considerably in this vulnerable group of patients.

[Mortality and morbidity in surgery for abdominal aortic aneurysm]. / Mortalitet og morbiditet ved operation for rumperet abdominalt aortaaneurisme.

INTRODUCTION: Patients undergoing surgery for ruptured abdominal aortic aneurysm (rAAA) have a mortality of 40-50%. The purpose of the present investigation is to document the mortality and morbidity of such patients at Rigshospitalet (RH) in 2005. The results are compared with the best results published internationally (benchmark) and with predicted mortality. Factors in postoperative intensive therapy that can improve morbidity and mortality are identified. MATERIAL AND METHODS: This is a retrospective calculation and analysis of mortality and morbidity. Data were collected from an Intensive Care Unit's (ICU) Critical Information System, a blood bank and the database of a vascular surgery unit. RESULTS: The perioperative mortality was 8%, ICU mortality 22%, postoperative mortality 33% and 30-day mortality 39%. The ICU mortality for patients with renal failure and septic shock was significantly higher than the overall ICU mortality. The ICU mortality and morbidity increased with the amount of postoperative blood loss. Patients with an initial serum creatinine concentration of <0.100 mmol/l had a 30-day mortality that was lower than that of patients with a higher initial serum creatinine concentration. CONCLUSION: The treatment of patients with rAAA at RH is comparable to leading clinical practice results. Postoperative bleeding, septic shock and renal failure are identified as predictive factors for increased ICU mortality and morbidity, for which reason future monitoring and postoperative rAAA therapy should include improved monitoring and intervention against postoperative bleeding and early identification of signs of sepsis and renal dysfunction.

[Methods for cost-effectiveness evaluation of intensive care]. / Metoder til sundhedsøkonomisk evaluering af intensiv terapi.

Intensive care costs are a challenge to the health care system. Because of a political strategy aiming at competition as well as the documentation of treatment quality, cost-effectiveness evaluations are important in order to clarify the association between quality and the costs of treating critically-ill patients. The context of cost-effect analyses is important. Most studies apply the hospital's perspective based on surrogate markers such as organ failure and length of stay as a replacement for health status evaluation in the context of society. The treatment of critically-ill patients aims at improved health. Cost-effectiveness analyses should therefore include quality variables in that the healthcare system is an integral and inseparable part of society.

[Diagnosis Related Groups in intensive care units--cost model for critically ill patients]. / Diagnoserelaterede grupper på intensivafdelinger--afregningsmodel for kritisk syge patienter.

The actual contribution of intensive care to total hospital costs in Denmark has yet not been completely identified. In order to adapt the DRG system to better reflect the actual costs of the intensive care units (ICUs) the original primarily diagnosis-based DRG system was modified in order to be based on ICU-related procedure codes. A new DRG system for ICU patients was developed and implemented in 2004. The ICU DRG-system consists of four groups reflecting progressive deterioration in organ failure. As a result there has since been a qualitative improvement in the documentation of the activities in the ICUs. The information categorized according to the new ICU DRG-groups allows for better differentiation of patients, and might lead to an increasing understanding of the quality of healthcare provision in the ICU by the use of comparisons in a database. A meaningful cost comparison between intensive care units can only be made by combining activity with quality of delivered care.

[Clinical database for intensive care patients]. / Kliniske databaser for kritisk syge patienter.

Intensive care contributes to a substantial part of health care expenses. Admission to intensive care units is associated with a high mortality rate and a high risk of long-term disability. Data from several studies suggest that suboptimal standards of intensive care are relatively common. Lack of knowledge regarding the use of intensive care and long-term outcome as well as the effectiveness and adverse effects of intensive care impede a systematic and evidence-based development and quality improvement. An initiative to establish a Danish national clinical database for intensive care has been launched.

Inhalation of activated protein C: A possible new adjunctive intervention in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a potential lethal disease. At present time no evidence based intervention reduces mortality. The pathophysiology of ARDS include intraalveolar fibrin deposition, hyperinflammation and reduced cellular host defense in the airspace. The normal lung activates protein C (PC) to activated protein C (APC), in contrast to the ARDS lung where the PC-APC axis is disrupted. The lungs have targets for inhaled APC as illustrated by a patient case with ARDS, unresponsive to conventional therapy. After inhalation of 190 mug/kg of APC (Drotrecogin alpha activated) three times a day for seven days, a clear reduction in infiltrates on chest X-ray and a 138% increase in oxygenation capacity as reflected by the PaO(2)/FiO(2) ratio was brought about. The patient, however, died later after cardiac arrest after suspected recurrence of the T-cell lymphoma. No local or systemic adverse effects was found related to the iAPC, during, after or at the time of death. It is suggested based on existing studies and the presented case that inhaled APC is a new treatment option in patients with ARDS - a hypothesis which should be substantiated in a larger series of ARDS patients.