A Randomized Clinical Trial of Bayesian-Guided Beta-Lactam Infusion Strategy and Associated Bacterial Resistance and Clinical Outcomes in Patients With Severe Pneumonia.

BACKGROUND: Antimicrobial resistance is a growing health concern worldwide. The objective of this study was to evaluate the effect of beta-lactam infusion on the emergence of bacterial resistance in patients with severe pneumonia in the intensive care unit. METHODS: Adult intensive care patients receiving cefepime, meropenem, or piperacillin-tazobactam for severe pneumonia caused by Gram-negative bacteria were randomized to receive beta-lactams as an intermittent (30 minutes) or continuous (24 hours) infusion. Respiratory samples for culture and susceptibility testing, with minimum inhibitory concentrations (MIC), were collected once a week for up to 4 weeks. Beta-lactam plasma concentrations were measured and therapeutic drug monitoring was performed using Bayesian software as the standard of care. RESULTS: The study was terminated early owing to slow enrollment. Thirty-five patients were enrolled in this study. Cefepime (n = 22) was the most commonly prescribed drug at randomization, followed by piperacillin (n = 8) and meropenem (n = 5). Nineteen patients were randomized into the continuous infusion arm and 16 into the intermittent infusion arm. Pseudomonas aeruginosa was the most common respiratory isolate (n = 19). Eighteen patients were included in the final analyses. No differences in bacterial resistance were observed between arms ( P = 0.67). No significant differences in superinfection ( P = 1), microbiological cure ( P = 0.85), clinical cure at day 7 ( P = 0.1), clinical cure at end of therapy ( P = 0.56), mortality ( P = 1), intensive care unit length of stay ( P = 0.37), or hospital length of stay ( P = 0.83) were observed. Achieving 100% ƒT > MIC ( P = 0.04) and ƒT > 4 × MIC ( P = 0.02) increased likelihood of clinical cure at day 7 of therapy. CONCLUSIONS: No differences in the emergence of bacterial resistance or clinical outcomes were observed between intermittent and continuous infusions. Pharmacokinetic/pharmacodynamic target attainment may be associated with a clinical cure on day 7.

Ustekinumab associated chronic eosinophilic pneumonia.

INTRODUCTION: Ustekinumab-induced eosinophilic pneumonia is rare and to our knowledge, this is the fifth reported case of such an entity. CASE STUDY: A 60-year-old female was admitted with worsening shortness of breath and a nonproductive cough for 4 months. Her past medical history was significant for Crohn's disease and psoriatic arthritis that was previously managed with adalimumab and switched to ustekinumab 2 months before symptoms. Initial diagnostic workup showed 10% peripheral eosinophilia and a CT chest showed numerous 5 mm nodules scattered throughout the lungs along with some peripheral reticulations. Her BAL fluid analysis showed abnormally high eosinophil count (67%), greatly limiting her potential diagnoses to eosinophilic pneumonia, EGPA, and tropical pulmonary eosinophilia (TPE). AEP typically causes more severe disease with a rapid onset, and there was low suspicion for TPE based on history, leaving EGPA and CEP. Based on her negative autoimmune serology, a negative biopsy of the nasal mucosa (no vasculitis/granulomata or eosinophils), and negative infectious workup, the patient was diagnosed with CEP secondary to ustekinumab and the drug was stopped. She was started on high dose prednisone and after a prolonged taper over 5 months, her symptoms and nodules and reticulations on her CT scan resolved. DISCUSSION: This case exemplifies the importance of identifying drug-induced lung diseases which in many cases might not have a strong temporal association with the symptom onset. It also highlights that some drugs owing to their long elimination half-time can remain in the system for a prolonged period and continues to cause symptoms despite their cessation and require prolonged treatment and reassurance. CONCLUSION: The association of eosinophilic pneumonia with ustekinumab, a drug used in the treatment of psoriasis and other autoimmune diseases, is rare and there is a paucity of literature regarding this association.

Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease.

AIM: To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis (CF) patients with hepatic steatosis as compared to normal CF controls. METHODS: We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging (ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls. RESULTS: Data was collected on 114 patients meeting inclusion criteria. Seventeen patients (14.9%) were found to have hepatic steatosis on imaging. Being overweight (BMI > 25) (P = 0.019) and having a higher ppFEV1 (75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level (27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes. CONCLUSION: Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher ppFEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.

Mapping physicians' admission diagnoses to structured concepts towards fully automatic calculation of acute physiology and chronic health evaluation score.

Objective Acute Physiology and Chronic Health Evaluation (APACHE) is most widely used as a mortality prediction score in US intensive care units (ICUs), but its calculation is onerous. The authors aimed to develop and validate automatic mapping of physicians' admission diagnoses to structured concepts for automated APACHE IV calculation. Methods This retrospective study was conducted in medical ICUs of a tertiary healthcare and academic centre. Boolean-logic text searches were used to map admission diagnoses, and these were compared with conventional APACHE database entry by bedside nurses and a gold-standard physician chart review. The primary outcome was APACHE IV predicted hospital mortality. The tool was developed in a larger cohort of ICU patients. Results In a derivation cohort of 192 consecutive critically ill patients, the diagnosis coefficient coded by three different methods had a positive correlation, highest between manual and gold standard (r(2)=0.95; mean square error (MSE)=0.040) and least between manual and automatic tool (r(2)=0.88; MSE=0.066). The automatic tool had an area under the curve (95% CI) value of 0.82 (0.74 to 0.90) which was similar to the physician gold standard, 0.83 (0.75 to 0.91) and standard manual entry, 0.81 (0.73 to 0.89). The Hosmer-Lemeshow goodness-of-fit test demonstrated good calibration of automatically calculated APACHE IV score (χ(2)=6.46; p=0.6). The automatic tool demonstrated excellent discrimination with an area under the curve value of 0.87 (95% CI 0.83 to 0.92) and good calibration (p=0.58) in the validation cohort of 593 patients. Conclusion A Boolean-logic text search is an efficient alternative to manual database entry for mapping of ICU admission diagnosis to structured APACHE IV concepts.

Epidemiology of critical care syndromes, organ failures, and life-support interventions in a suburban US community.

BACKGROUND: ICU services represent a significant and increasing proportion of medical care. Population-based epidemiologic studies are essential to inform physicians and policymakers about current and future ICU demands. We aimed to determine the incidence of critical care syndromes, organ failures, and life-support interventions in a defined US suburban community with unrestricted access to critical care services. METHODS: This population-based observational cohort from January 1 to December 31, 2006, in Olmsted County, Minnesota, included all consecutive critically ill adult residents admitted to the ICU. Main outcomes were incidence of critical care syndromes, life-support interventions, and organ failures as defined by standard criteria. Incidences are reported per 100,000 population (95% CIs) and were age adjusted to the 2006 US population. RESULTS: A total of 1,707 ICU admissions were identified from 1,461 patients. Incidences of critical care syndromes were respiratory failure, 430 (390-470); acute kidney injury, 290 (257-323); severe sepsis, 286 (253-319); all-cause shock, 194 (167-221); acute lung injury, 86 (68-105); all-cause coma, 43 (30-55); and overt disseminated intravascular coagulation, 18 (10-26). Incidence of mechanical ventilation was invasive, 310 (276-344); noninvasive, 180 (154-206); vasopressors and inotropes, 183(155-208). Renal replacement therapy incidence was 96 (77-116). Of the cohort, 1,330 patients (91%) survived to hospital discharge. Short- and long-term survival decreased by the number of failing organs. CONCLUSIONS: In a suburban US community with high access to critical care services, cumulative incidences of critical care syndromes and life-support interventions were higher than previously reported. The results of this study have important implications for future planning of critical care delivery.

Long-term survival in patients with tracheostomy and prolonged mechanical ventilation in Olmsted County, Minnesota.

BACKGROUND: An increasing number of patients require prolonged mechanical ventilation (PMV), which is associated with high morbidity and poor long-term survival, but there are few data regarding the incidence and outcome of PMV patients from a community perspective. METHODS: We retrospectively reviewed the electronic medical records of adult Olmsted county, Minnesota, residents admitted to the intensive care units at the 2 Mayo Clinic Rochester hospitals from January 1, 2003, to December 31, 2007, who underwent tracheostomy for PMV. RESULTS: Sixty-five patients, median age 68 years (interquartile range [IQR] 49-80 y), 39 male, underwent tracheostomy for PMV, resulting in an age-adjusted incidence of 13 (95% CI 10-17) per 100,000 patient-years at risk. The median number of days on mechanical ventilation was 24 days (IQR 18-37 d). Forty-six patients (71%) survived to hospital discharge, and 36 (55%) were alive at 1-year follow-up. After adjusting for age and baseline severity of illness, the presence of COPD was independently associated with 1-year mortality (hazard ratio 3.4, 95% CI 1.4-8.2%). CONCLUSIONS: There was a considerable incidence of tracheostomy for PMV. The presence of COPD was an independent predictor of 1-year mortality.

Towards the prevention of acute lung injury: a population based cohort study protocol.

BACKGROUND: Acute lung injury (ALI) is an example of a critical care syndrome with limited treatment options once the condition is fully established. Despite improved understanding of pathophysiology of ALI, the clinical impact has been limited to improvements in supportive treatment. On the other hand, little has been done on the prevention of ALI. Olmsted County, MN, geographically isolated from other urban areas offers the opportunity to study clinical pathogenesis of ALI in a search for potential prevention targets. METHODS/DESIGN: In this population-based observational cohort study, the investigators identify patients at high risk of ALI using the prediction model applied within the first six hours of hospital admission. Using a validated system-wide electronic surveillance, Olmsted County patients at risk are followed until ALI, death or hospital discharge. Detailed in-hospital (second hit) exposures and meaningful short and long term outcomes (quality-adjusted survival) are compared between ALI cases and high risk controls matched by age, gender and probability of developing ALI. Time sensitive biospecimens are collected for collaborative research studies. Nested case control comparison of 500 patients who developed ALI with 500 matched controls will provide an adequate power to determine significant differences in common hospital exposures and outcomes between the two groups. DISCUSSION: This population-based observational cohort study will identify patients at high risk early in the course of disease, the burden of ALI in the community, and the potential targets for future prevention trials.

Diabetes mellitus does not adversely affect outcomes from a critical illness.

OBJECTIVE: Chronic diabetes mellitus (DM) is a known cause of multisystem injury. The effect of DM in acute critical illness may also be detrimental, but is not specifically known. We hypothesized that the preexisting diagnosis of DM is an independent risk factor for mortality in critically ill patients. DESIGN: Parallel retrospective and prospective cohort study. SETTING: Two large patient datasets were used: the retrospective University HealthSystem Consortium database (UHC) and the prospective Mayo Clinic Acute Physiology And Chronic Health Evaluation III critical care database (Mayo). PATIENTS: Inclusion criteria were admission to an intensive care unit and age > or =18 yrs. Patients with diabetic ketoacidosis or hyperosmolar nonketotic coma were excluded. A total of 1,509,890 patients (including 143,078 deaths) in the UHC cohort and 36,414 patients (including 3562 deaths) in the Mayo cohort were included in the study analysis. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality compared between patients with a history of DM and all other patients. Other outcomes included in-hospital mortality in prespecified subgroups. In the UHC dataset, patients with DM had a lower unadjusted odds ratio (0.90, 95% confidence interval 0.89-0.91, p < .001) and a lower adjusted effect on mortality (odds ratio 0.75, 0.74-0.76, p < .001) compared with that seen in patients without DM. In the Mayo dataset, patients with DM had a comparable unadjusted odds ratio (1.07, 0.97-1.17, p = NS) and a lower adjusted effect on mortality (odds ratio 0.88, 0.79-0.98, p = .022) compared with that seen in patients without DM. A lower mortality in diabetic patients held across multiple demographic subgroups, including patients who underwent coronary-artery bypass grafting (UHC data: unadjusted odds ratio 0.66, 0.62-0.71, p < .001). CONCLUSIONS: Critically ill adults with DM do not have an increased mortality compared with that seen in patients without DM, and may have a decreased mortality. Further investigation needs to be done to determine the mechanism for this effect.

Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.

This retrospective population-based study evaluated the effects of alcohol consumption on the development of acute respiratory distress syndrome (ARDS). Alcohol consumption was quantified based on patient and/or family provided information at the time of hospital admission. ARDS was defined according to American-European consensus conference (AECC). From 1,422 critically ill Olmsted county residents, 1,357 had information about alcohol use in their medical records, 77 (6%) of whom developed ARDS. A history of significant alcohol consumption (more than two drinks per day) was reported in 97 (7%) of patients. When adjusted for underlying ARDS risk factors (aspiration, chemotherapy, high-risk surgery, pancreatitis, sepsis, shock), smoking, cirrhosis and gender, history of significant alcohol consumption was associated with increased risk of ARDS development (odds ratio 2.9, 95% CI 1.3-6.2). This population-based study confirmed that excessive alcohol consumption is associated with higher risk of ARDS.

Evaluation of "Loss" and "End stage renal disease" after acute kidney injury defined by the Risk, Injury, Failure, Loss and ESRD classification in critically ill patients.

PURPOSE: The Risk, Injury, Failure, Loss and ESRD (RIFLE) classification has been widely accepted for the definition of acute kidney injury (AKI); however, no study has described in detail the last two stages of the classification: "Loss" and "ESRD". We aim to describe and evaluate the development of "Loss" and "ESRD" in a group of critically ill patients. METHODS: We conducted a retrospective analysis of cases prospectively collected from the Acute Physiology and Chronic Health Assessment (APACHE III) database. Subjects were consecutive critically ill patients >18 years of age admitted to three ICUs of two tertiary care academic hospitals, from January 2003 through August 2006, excluding those who denied research authorization, chronic hemodialysis therapy, kidney transplant recipients, readmissions, and admissions for less than 12 h for low risk monitoring. RESULTS: 11,644 patients were included in the study. The median age was 66 (interquartile range, 52-76), 90% were Caucasians and 54% of the patients were male. Half of the patients developed AKI, and most of the patients were in the Risk and Injury stages. From the patients that developed AKI, a total of 1,065 (19%) patients required renal replacement therapy (RRT), 415 (39%) underwent continuous renal replacement therapy (CRRT) and 650 (61%) underwent intermittent hemodialysis. A total of 281 patients on RRT did not survive hospital discharge, 97 patients progressed to "Loss", and 282 patients progressed to "ESRD". After multivariable adjustment, the progression to "ESRD" was associated with higher baseline creatinine, odds ratio (OR) 1.19 per every increase in creatinine of 0.1 mg/dl (95% CI, 1.11-1.29) P < 0.001; and less frequent use of CRRT, OR 0.18 (95% CI, 0.11-0.29) P < 0.001. CONCLUSION: In this large retrospective study we found that almost 50% developed some form of AKI as defined by the RIFLE classification. Of these, 19% required RRT, and 4.9% progressed to "ESRD". "ESRD" was more likely in patients with elevated baseline creatinine and those treated with intermittent hemodialysis.