Association of delayed adequate antimicrobial treatment and organ dysfunction in pediatric bloodstream infections.

BACKGROUND: Bloodstream infections (BSIs) are associated with significant mortality and morbidity, including multiple organ dysfunction. We explored if delayed adequate antimicrobial treatment for children with BSIs is associated with change in organ dysfunction as measured by PELOD-2 scores. METHODS: We conducted a multicenter, retrospective cohort study of critically ill children <18 years old with BSIs. The primary outcome was change in PELOD-2 score between days 1 (index blood culture) and 5. The exposure variable was delayed administration of adequate antimicrobial therapy by ≥3 h from blood culture collection. We compared PELOD-2 score changes between those who received early and delayed treatment. RESULTS: Among 202 children, the median (interquartile range) time to adequate antimicrobial therapy was 7 (0.8-20.1) hours; 124 (61%) received delayed antimicrobial therapy. Patients who received early and delayed treatment had similar baseline characteristics. There was no significant difference in PELOD-2 score changes from days 1 and 5 between groups (PELOD-2 score difference -0.07, 95% CI -0.92 to 0.79, p = 0.88). CONCLUSIONS: We did not find an association between delayed adequate antimicrobial therapy and PELOD-2 score changes between days 1 and 5 from detection of BSI. PELOD-2 score was not sensitive for clinical effects of delayed antimicrobial treatment. IMPACT: In critically ill children with bloodstream infections, there was no significant change in organ dysfunction as measured by PELOD-2 scores between patients who received adequate antimicrobial therapy within 3 h of their initial positive blood culture and those who started after 3 h. Higher PELOD-2 scores on day 1 were associated with larger differences in PELOD-2 scores between days 1 and 5 from index positive blood cultures. Further study is required to determine if PELOD-2 or alternative measures of organ dysfunction could be used as primary outcome measures in trials of antimicrobial interventions in pediatric critical care research.

Antimicrobial treatment duration for uncomplicated bloodstream infections in critically ill children: a multicentre observational study.

BACKGROUND: Bloodstream infections (BSIs) cause significant morbidity and mortality in critically ill children but treatment duration is understudied. We describe the durations of antimicrobial treatment that critically ill children receive and explore factors associated with treatment duration. METHODS: We conducted a retrospective observational cohort study in six pediatric intensive care units (PICUs) across Canada. Associations between treatment duration and patient-, infection- and pathogen-related characteristics were explored using multivariable regression analyses. RESULTS: Among 187 critically ill children with BSIs, the median duration of antimicrobial treatment was 15 (IQR 11-25) days. Median treatment durations were longer than two weeks for all subjects with known sources of infection: catheter-related 16 (IQR 11-24), respiratory 15 (IQR 11-26), intra-abdominal 20 (IQR 14-26), skin/soft tissue 17 (IQR 15-33), urinary 17 (IQR 15-35), central nervous system 33 (IQR 15-46) and other sources 29.5 (IQR 15-55) days. When sources of infection were unclear, the median duration was 13 (IQR 10-16) days. Treatment durations varied widely within and across PICUs. In multivariable linear regression, longer treatment durations were associated with severity of illness (+ 0.4 days longer [95% confidence interval (CI), 0.1 to 0.7, p = 0.007] per unit increase in PRISM-IV) and central nervous system infection (+ 17 days [95% CI, 6.7 to 27.4], p = 0.001). Age and pathogen type were not associated with treatment duration. CONCLUSIONS: Most critically ill children with BSIs received at least two weeks of antimicrobial treatment. Further study is needed to determine whether shorter duration therapy would be effective for selected critically ill children.

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) randomised clinical trial: study protocol.

INTRODUCTION: Bloodstream infections are a leading cause of mortality and morbidity; the duration of treatment for these infections is understudied. METHODS AND ANALYSIS: We will conduct an international, multicentre randomised clinical trial of shorter (7 days) versus longer (14 days) antibiotic treatment among hospitalised patients with bloodstream infections. The trial will include 3626 patients across 60 hospitals and 6 countries. We will include patients with blood cultures confirming a pathogenic bacterium after hospital admission. Exclusion criteria will include patient factors (severe immunosuppression), infection site factors (endocarditis, osteomyelitis, undrained abscesses, infected prosthetic material) and pathogen factors (Staphylococcus aureus, Staphylococcus lugdunensis, Candida and contaminant organisms). We will leave the selection of specific antibiotics, doses and route of delivery to the discretion of treating physicians; no placebo control will be used given the diversity of pathogens and sources of bacteraemia. The intervention will be assignment of treatment duration to be 7 versus 14 days. We will minimise selection bias via central randomisation with variable block sizes, with concealed allocation until day 7 of adequate antibiotic treatment. The primary outcome is 90-day survival; we will test whether 7 days is non-inferior to 14 days of treatment, with a non-inferiority margin of 4% absolute mortality. Secondary outcomes include hospital and intensive care unit (ICU) mortality, relapse rates of bacteraemia, hospital and ICU length of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile infection, antibiotic allergy and adverse events and colonisation/infection with antibiotic-resistant organisms. ETHICS AND DISSEMINATION: The study has been approved by the ethics review board at each participating site. Sunnybrook Health Sciences Centre is the central ethics committee. We will disseminate study results via the Canadian Critical Care Trials Group and other collaborating networks to set the global paradigm for antibiotic treatment duration for non-staphylococcal Gram-positive, Gram-negative and anaerobic bacteraemia, among patients admitted to hospital. TRIAL REGISTRATION NUMBER: The BALANCE (Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness) trial was registered at www.clinicaltrials.gov (registration number: NCT03005145).

A pilot randomized controlled trial of 7 versus 14 days of antibiotic treatment for bloodstream infection on non-intensive care versus intensive care wards.

BACKGROUND: The optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards. METHODS: We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients. RESULTS: A total of 134 patients were recruited over 47 site-months (mean 2.9 patients/site-month, median 1.0, range 0.1-4.4 patients/site-month). The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT (125/134, 93% vs 89/115, 77%, p = 0.0003). BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the ICU pilot RCT (17/115, 14.8%) (p = 0.65). Simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-ICU versus ICU patients. CONCLUSION: It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02917551. Registered on September 28, 2016.

7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial.

BACKGROUND: Shorter-duration antibiotic treatment is sufficient for a range of bacterial infections, but has not been adequately studied for bloodstream infections. Our systematic review, survey, and observational study indicated equipoise for a trial of 7 versus 14 days of antibiotic treatment for bloodstream infections; a pilot randomized clinical trial (RCT) was a necessary next step to assess feasibility of a larger trial. METHODS: We conducted an open, pilot RCT of antibiotic treatment duration among critically ill patients with bloodstream infection across 11 intensive care units (ICUs). Antibiotic selection, dosing and route were at the discretion of the treating team; patients were randomized 1:1 to intervention arms consisting of two fixed durations of treatment - 7 versus 14 days. We recruited adults with a positive blood culture yielding pathogenic bacteria identified while in ICU. We excluded patients with severe immunosuppression, foci of infection with an established requirement for prolonged treatment, single cultures with potential contaminants, or cultures yielding Staphylococcus aureus or fungi. The primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. Secondary outcomes included 90-day, ICU and hospital mortality, relapse of bacteremia, lengths of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile, antibiotic adverse events, and secondary infection with antimicrobial-resistant organisms. RESULTS: We successfully achieved our target sample size (n = 115) and average recruitment rate of 1 (interquartile range (IQR) 0.3-1.5) patient/ICU/month. Adherence to treatment duration was achieved in 89/115 (77%) patients. Adherence differed by underlying source of infection: 26/31 (84%) lung; 18/29 (62%) intra-abdominal; 20/26 (77%) urinary tract; 8/9 (89%) vascular-catheter; 4/4 (100%) skin/soft tissue; 2/4 (50%) other; and 11/12 (92%) unknown sources. Patients experienced a median (IQR) 14 (8-17) antibiotic-free days (of the 28 days after blood culture collection). Antimicrobial-related adverse events included hepatitis in 1 (1%) patient, Clostridium difficile infection in 4 (4%), and secondary infection with highly resistant microorganisms in 10 (9%). Ascertainment was complete for all study outcomes in ICU, in hospital and at 90 days. CONCLUSION: It is feasible to conduct a RCT to determine whether 7 versus 14 days of antibiotic treatment is associated with comparable 90-day survival. TRIAL REGISTRATION: ClinicalTrials.gov , identifier: NCT02261506 . Registered on 26 September 2014.

Time required to initiate outbreak and pandemic observational research.

PURPOSE: Observational research focused upon emerging infectious diseases such as Ebola virus, Middle East respiratory syndrome, and Zika virus has been challenging to quickly initiate. We aimed to determine the duration of start-up procedures and barriers encountered for an observational study focused upon such infectious outbreaks. MATERIALS AND METHODS: At 1 pediatric and 5 adult intensive care units, we measured durations from protocol receipt to a variety of outbreak research milestones, including research ethics board (REB) approval, data sharing agreement (DSA) execution, and patient study screening initiation. RESULTS: The median (interquartile range) time from site receipt of the protocol to REB submission was 73 (30-126) days; to REB approval, 158 (42-188) days; to DSA completion, 276 (186-312) days; and to study screening initiation, 293 (269-391) days. The median time from REB submission to REB approval was 43 (13-85) days. The median time for all start-up procedures was 335 (188-335) days. CONCLUSIONS: There is a lengthy start-up period required for outbreak-focused research. Completing DSAs was the most time-consuming step. A reactive approach to newly emerging threats such as Ebola virus, Middle East respiratory syndrome, and Zika virus will likely not allow sufficient time to initiate research before most outbreaks are advanced.

Pathogens and antimicrobial susceptibility profiles in critically ill patients with bloodstream infections: a descriptive study.

BACKGROUND: Surveillance of antimicrobial resistance is vital to guiding empirical treatment of infections. Collating and reporting routine data on clinical isolate testing may offer more timely information about resistance patterns than traditional surveillance network methods. METHODS: Using routine microbiology testing data collected from the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness retrospective cohort study, we conducted a descriptive secondary analysis among critically ill patients in whom bloodstream infections had been diagnosed in 14 intensive care units (ICUs) in Canada. The participating sites were located within tertiary care teaching hospitals and represented 6 provinces and 10 cities. More than 80% of the study population was accrued from 2011-2013. We assessed the epidemiologic features of the infections and corresponding antimicrobial susceptibility profiles. Susceptibility testing was done according to Clinical Laboratory Standards Institute guidelines at accredited laboratories. RESULTS: A total of 1416 pathogens were isolated from 1202 patients. The most common organisms were Escherichia coli (217 isolates [15.3%]), Staphylococcus aureus (175 [12.4%]), coagulase-negative staphylococci (117 [8.3%]), Klebsiella pneumoniae (86 [6.1%]) and Streptococcus pneumoniae (85 [6.0%]). The contribution of individual pathogens varied by site. For 13 ICUs, gram-negative susceptibility rates were high for carbapenems (95.4%), tobramycin (91.2%) and piperacillin-tazobactam (90.0%); however, the proportion of specimens susceptible to these agents ranged from 75.0%-100%, 66.7%-100% and 75.0%-100%, respectively, across sites. Fewer gram-negative bacteria were susceptible to fluoroquinolones (84.5% [range 64.1%-97.2%]). A total of 145 patients (12.1%) had infections caused by highly resistant microorganisms, with significant intersite variation (range 2.6%-24.0%, χ2 = 57.50, p < 0.001). INTERPRETATION: We assessed the epidemiologic features of bloodstream infections in a geographically diverse cohort of critically ill Canadian patients using routine pathogen and susceptibility data extracted from readily available microbiology testing databases. Expanding data sharing across more ICUs, with serial measurement and prompt reporting, could provide much-needed guidance for empiric treatment for patients as well as system-wide prevention methods to limit antimicrobial resistance.

The Effect of Inadequate Initial Empiric Antimicrobial Treatment on Mortality in Critically Ill Patients with Bloodstream Infections: A Multi-Centre Retrospective Cohort Study.

Hospital mortality rates are elevated in critically ill patients with bloodstream infections. Given that mortality may be even higher if appropriate treatment is delayed, we sought to determine the effect of inadequate initial empiric treatment on mortality in these patients. A retrospective cohort study was conducted across 13 intensive care units in Canada. We defined inadequate initial empiric treatment as not receiving at least one dose of an antimicrobial to which the causative pathogen(s) was susceptible within one day of initial blood culture. We evaluated the association between inadequate initial treatment and hospital mortality using a random effects multivariable logistic regression model. Among 1,190 patients (1,097 had bacteremia and 93 had candidemia), 476 (40%) died and 266 (22%) received inadequate initial treatment. Candidemic patients more often had inadequate initial empiric therapy (64.5% versus 18.8%), as well as longer delays to final culture results (4 vs 3 days) and appropriate therapy (2 vs 0 days). After adjustment, there was no detectable association between inadequate initial treatment and mortality among bacteremic patients (Odds Ratio (OR): 1.02, 95% Confidence Interval (CI) 0.70-1.48); however, candidemic patients receiving inadequate treatment had nearly three times the odds of death (OR: 2.89, 95% CI: 1.05-7.99). Inadequate initial empiric antimicrobial treatment was not associated with increased mortality in bacteremic patients, but was an important risk factor in the subgroup of candidemic patients. Further research is warranted to improve early diagnostic and risk prediction methods in candidemic patients.

Duration of Antimicrobial Treatment for Bacteremia in Canadian Critically Ill Patients.

OBJECTIVES: The optimum duration of antimicrobial treatment for patients with bacteremia is unknown. Our objectives were to determine duration of antimicrobial treatment provided to patients who have bacteremia in ICUs, to assess pathogen/patient factors related to treatment duration, and to assess the relationship between treatment duration and survival. DESIGN: Retrospective cohort study. SETTINGS: Fourteen ICUs across Canada. PATIENTS: Patients with bacteremia and were present in the ICU at the time culture reported positive. INTERVENTIONS: Duration of antimicrobial treatment for patients who had bacteremia in ICU. MEASUREMENTS AND MAIN RESULTS: Among 1,202 ICU patients with bacteremia, the median duration of treatment was 14 days, but with wide variability (interquartile range, 9-17.5). Most patient characteristics were not associated with treatment duration. Coagulase-negative staphylococci were the only pathogens associated with shorter treatment (odds ratio, 2.82; 95% CI, 1.51-5.26). The urinary tract was the only source of infection associated with a trend toward lower likelihood of shorter treatment (odds ratio, 0.67; 95% CI, 0.42-1.08); an unknown source of infection was associated with a greater likelihood of shorter treatment (odds ratio, 2.14; 95% CI, 1.17-3.91). The association of treatment duration and survival was unstable when analyzed based on timing of death. CONCLUSIONS: Critically ill patients who have bacteremia typically receive long courses of antimicrobials. Most patient/pathogen characteristics are not associated with treatment duration; survivor bias precludes a valid assessment of the association between treatment duration and survival. A definitive randomized controlled trial is needed to compare shorter versus longer antimicrobial treatment in patients who have bacteremia.

The impact of onset time on the isolated pathogens and outcomes in ventilator associated pneumonia.

Several guidelines base the empirical therapy of ventilator-associated pneumonia (VAP) on the time of onset. However, there is emerging evidence that the isolated microorganisms may be similar regardless of onset time. This study evaluated the characteristics and outcomes of VAP with different onset times. All of the mechanically ventilated patients admitted to the ICU of a 900-bed tertiary-care hospital between 01/08/2003 and 31/12/2010 were prospectively followed for VAP development according to the National Healthcare Safety Network criteria. The patients were categorized into four groups: EO if VAP occurred within 4 days of intubation and hospital admission; LO if VAP occurred after 4 days of admission; EL if VAP occurred within 4 days of intubation, but after the fourth hospitalization day; and LL if VAP occurred after the fourth day of intubation and hospitalization. Out of the 394 VAP episodes, 63 (16%) were EO episodes, 331 (84.0%) were LO episodes, 40 (10.1%) were EL episodes and 291 (73.1%) were LL episodes. The isolated microorganisms were comparable among the four groups, with a similar rate of potentially multidrug resistant organisms in the EO-VAP (31.7%), LO-VAP (40.8%), EL-VAP (37.5%) and LL-VAP (43.3%) samples. The hospital mortality was 24% for EO-VAP cases, 28% for LO-VAP cases, 40% for EL-VAP cases and 49% for LL-VAP cases. However, in the adjusted multivariate analysis, neither LO-VAP, EL-VAP nor LL-VAP was associated with an increased risk of hospital mortality compared with EO-VAP (OR, 0.86 95% CI, 0.34-2.19; 1.22; 95% CI, 0.41-3.68, and 0.95; 95% CI, 0.43-2.10, respectively). In this study, the occurrence of potential multidrug resistant pathogens and the mortality risk were similar regardless of VAP timing from hospital admission and intubation. The bacterial isolates obtained from the VAP cases did not follow an early vs. late-onset pattern, and thus, these terms may not be clinically helpful.

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE): study protocol for a pilot randomized controlled trial.

BACKGROUND: Bacteremia is a leading cause of mortality and morbidity in critically ill adults. No previous randomized controlled trials have directly compared shorter versus longer durations of antimicrobial treatment in these patients. METHODS/DESIGN: This is a multicenter pilot randomized controlled trial in critically ill patients with bacteremia. Eligible patients will be adults with a positive blood culture with pathogenic bacteria identified while in the intensive care unit. Eligible, consented patients will be randomized to either 7 days or 14 days of adequate antimicrobial treatment for the causative pathogen(s) detected on blood cultures. The diversity of pathogens and treatment regimens precludes blinding of patient and clinicians, but allocation concealment will be extended to day 7 and outcome adjudicators will be blinded. The primary outcome for the main trial will be 90-day mortality. The primary outcome for the pilot trial is feasibility defined by (i) rate of recruitment exceeding 1 patient per site per month and (ii) adherence to treatment duration protocol ≥ 90%. Secondary outcomes include intensive care unit, hospital and 90-day mortality rates, relapse rates of bacteremia, antibiotic-related side effects and adverse events, rates of Clostridium difficile infection, rates of secondary infection or colonization with antimicrobial resistant organisms, ICU and hospital lengths of stay, mechanical ventilation and vasopressor duration in intensive care unit, and procalcitonin levels on the day of randomization, and day 7, 10 and 14 after the index blood culture. DISCUSSION: The BALANCE pilot trial will inform the design and execution of the subsequent BALANCE main trial, which will evaluate shorter versus longer duration treatment for bacteremia in critically ill patients, and thereby provide an evidence basis for treatment duration decisions for these infections. TRIAL REGISTRATION: The Pilot Trial was registered on 26 September 2014. TRIAL REGISTRATION NUMBER: NCT02261506.

Serum procalcitonin in cirrhotic patients with septic shock: relationship with adrenal insufficiency and clinical outcomes.

BACKGROUND: Serum procalcitonin is commonly used to differentiate systemic inflammation due to infection from non-infectious causes. Limited data exist on the value of procalcitonin in predicting relative adrenal insufficiency (RAI). This study evaluated the value of procalcitonin in predicting RAI and mortality in cirrhotic patients with septic shock. METHODS: This was a post-hoc analysis of a randomized placebo-controlled trial that evaluated low-dose hydrocortisone in cirrhotic patients with septic shock. Extracted first study-day data included serum procalcitonin, baseline serum cortisol, cortisol level after 250 microg - adrenocorticotropic hormone stimulation test and 28 - day mortality. RAI was defined as a baseline serum cortisol < 10 microg/dL or cortisol not rising by > 9 microg/dL after stimulation. Procalcitonin > 0.5 ng/mL was considered high. RESULTS: Forty-five patients had serum procalcitonin measured (mean = 2.7 +/- 3.2 ng/mL, first and third quartiles were 0.3 and 3.3 ng/mL, respectively). Most (78%) patients had high procalcitonin levels. RAI was present in 34 (76%) patients. Patients with high procalcitonin were more likely to have RAI (odds ratio, 4.8; 95% confidence interval, 1.1 - 22.1). Receiver operator characteristic curve analysis showed that the best cut-off for detecting RAI was 1.0 ng/mL (sensitivity = 79% and specificity = 55%). High serum procalcitonin was not associated with 28 -day mortality (80% for normal procalcitonin and 77% for high procalcitonin, p = 0.61). CONCLUSIONS: High serum procalcitonin was highly associated with RAI in cirrhotic patients with septic shock. Procalcitonin was not associated with 28 - day mortality in this patient population.

Drug-resistant ventilator associated pneumonia in a tertiary care hospital in Saudi Arabia.

BACKGROUND: There is a wide geographic and temporal variability of bacterial resistance among microbial causes of ventilator-associated pneumonia (VAP). The contribution of multi-drug resistant (MDR) pathogens to the VAP etiology in Saudi Arabia was never studied. We sought to examine the extent of multiple-drug resistance among common microbial causes of VAP. MATERIALS AND METHODS: We conducted a retrospective susceptibility study in the adult intensive care unit (ICU) of King Abdulaziz Medical City, Riyadh, Saudi Arabia. Susceptibility results of isolates from patients diagnosed with VAP between October 2004 and June 2009 were examined. The US National Healthcare Safety Network definition of MDR was adopted. RESULTS: A total of 248 isolates including 9 different pathogens were included. Acinetobacter spp. was highly (60-89%) resistant to all tested antimicrobials, including carbapenems (three- and four-class MDR prevalence were 86% and 69%, respectively). Pseudomonas aeruginosa was moderately (13-31%) resistant to all tested antimicrobials, including antipseudomonal penicillins (three- and four-class MDR prevalence were 13% and 10%, respectively). With an exception of ampicillin (fully resistant), Klebsiella spp. had low (0-13%) resistance to other tested antimicrobials with no detected MDR. Staphylococcus aureus was fully susceptible to vancomycin with 42% resistance to oxacillin. There were significant increasing trends of MDR Acinetobacter spp. however not P. aeruginosa during the study. Resistant pathogens were associated with worse profile of ICU patients but not patients' outcomes. CONCLUSION: Acinetobacter in the current study was an increasingly resistant VAP-associated pathogen more than seen in many parts of the world. The current finding may impact local choice of initial empiric antibiotics.

The association between statin therapy during intensive care unit stay and the incidence of venous thromboembolism: a propensity score-adjusted analysis.

BACKGROUND: Studies have shown that statins have pleiotropic effects on inflammation and coagulation; which may affect the risk of developing venous thromboembolism (VTE). The objective of this study was to evaluate the association between statin therapy during intensive care unit (ICU) stay and the incidence of VTE in critically ill patients. METHODS: This was a post-hoc analysis of a prospective observational cohort study of patients admitted to the intensive care unit between July 2006 and January 2008 at a tertiary care medical center. The primary endpoint was the incidence of VTE during ICU stay up to 30 days. Secondary endpoint was overall 30-day hospital mortality. Propensity score was used to adjust for clinically and statistically relevant variables. RESULTS: Of the 798 patients included in the original study, 123 patients (15.4%) received statins during their ICU stay. Survival analysis for VTE risk showed that statin therapy was not associated with a reduction of VTE incidence (crude hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.28-1.54, P=0.33 and adjusted HR 0.63, 95% CI 0.25-1.57, P=0.33). Furthermore, survival analysis for hospital mortality showed that statin therapy was not associated with a reduction in hospital mortality (crude HR 1.26, 95% CI 0.95-1.68, P=0.10 and adjusted HR 0.98, 95% CI 0.72-1.36, P=0.94). CONCLUSION: Our study showed no statistically significant association between statin therapy and VTE risk in critically ill patients. This question needs to be further studied in randomized control trials.

Even mild hyperlactatemia is associated with increased mortality in critically ill patients.

INTRODUCTION: The clinical significance of elevation of lactate levels within the reference range is not well studied. The objective of this study was to determine the best cutoff threshold for serum lactate within the reference range (0.01 to 2.00 mM) that best discriminated between survivors and nonsurvivors of critical illness and to examine the association between relative hyperlactatemia (lactate above the identified threshold) and mortality. METHODS: This was a retrospective cohort study of adult patients admitted to the medical-surgical intensive care unit (ICU) of a tertiary care academic center. Youden index was calculated to identify the best lactate cutoff threshold that discriminated between survivors and nonsurvivors. Patients with lactate above the identified threshold were defined as having relative hyperlactatemia. Multivariate logistic regression, adjusting for baseline variables, was performed to determine the relationship between the above two ranges of lactate levels and mortality. In addition, a test of interaction was performed to assess the effect of selected subgroups on the association between relative hyperlactatemia and hospital mortality. RESULTS: During the study period, 2,157 patients were included in the study with mean lactate of 1.3 ± 0.4 mM, age of 55.1 ± 20.3 years, and acute physiology and chronic health evaluation (APACHE) II score of 22.1 ± 8.2. Vasopressors were required in 42.4%. Lactate of 1.35 mM was found to be the best cutoff threshold for the whole cohort. Relative hyperlactatemia was associated with increased hospital mortality (adjusted odds ratio (aOR), 1.60, 95% confidence interval (CI) 1.29 to 1.98), and ICU mortality (aOR, 1.66; 95% CI, 1.26 to 2.17) compared with a lactate level of 0.01 to 1.35 mM. This association was consistent among all examined subgroups. CONCLUSIONS: Relative hyperlactatemia (lactate of 1.36 to 2.00 mM) within the first 24 hours of ICU admission is an independent predictor of hospital and ICU mortality in critically ill patients.

Demographics and outcomes of critically ill patients transferred from other hospitals to a tertiary care academic referral center in Saudi Arabia.

BACKGROUND: The objective of this study was to examine the outcomes of critically ill patients who were transferred from other hospitals to a tertiary care center in Saudi Arabia as a quality improvement project. METHODS: This was a retrospective study of adult patients admitted to the medical-surgical intensive care unit (ICU) of a tertiary care hospital. Patients were divided according to the source of referral into three groups: transfers from other hospitals, and direct admissions from emergency department (ED) and from hospital wards. Standardized mortality ratio (SMR) was calculated. Multivariate analysis was performed to determine the independent predictors of mortality. RESULTS: Of the 7,654 patients admitted to the ICU, 611 patients (8%) were transferred from other hospitals, 2,703 (35.3%) were direct admissions from ED and 4,340 (56.7%) from hospital wards. Hospital mortality for patients transferred from other hospitals was not significantly different from those who were directly admitted from ED (35% vs. 33.1%, p = 0.37) but was lower than those who were directly admitted from hospital wards (35% vs. 51.2%, p < 0.0001). SMRs did not differ significantly across the three groups. CONCLUSIONS: Critically ill patients who were transferred from other hospitals constituted 8% of all ICU admissions. Mortality of these patients was similar to patients with direct admission from the ED and lower than that of patients with direct admission from hospital wards. However, risk-adjusted mortality was not different from the other two groups.

Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study.

INTRODUCTION: Data are sparse as to whether obesity influences the risk of death in critically ill patients with septic shock. We sought to examine the possible impact of obesity, as assessed by body mass index (BMI), on hospital mortality in septic shock patients. METHODS: We performed a nested cohort study within a retrospective database of patients with septic shock conducted in 28 medical centers in Canada, United States and Saudi Arabia between 1996 and 2008. Patients were classified according to the World Health Organization criteria for BMI. Multivariate logistic regression analysis was performed to evaluate the association between obesity and hospital mortality. RESULTS: Of the 8,670 patients with septic shock, 2,882 (33.2%) had height and weight data recorded at ICU admission and constituted the study group. Obese patients were more likely to have skin and soft tissue infections and less likely to have pneumonia with predominantly Gram-positive microorganisms. Crystalloid and colloid resuscitation fluids in the first six hours were given at significantly lower volumes per kg in the obese and very obese patients compared to underweight and normal weight patients (for crystalloids: 55.0 ± 40.1 ml/kg for underweight, 43.2 ± 33.4 for normal BMI, 37.1 ± 30.8 for obese and 27.7 ± 22.0 for very obese). Antimicrobial doses per kg were also different among BMI groups. Crude analysis showed that obese and very obese patients had lower hospital mortality compared to normal weight patients (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.66 to 0.97 for obese and OR 0.61, 95% CI 0.44 to 0.85 for very obese patients). After adjusting for baseline characteristics and sepsis interventions, the association became non-significant (OR 0.80, 95% CI 0.62 to 1.02 for obese and OR 0.69, 95% CI 0.45 to 1.04 for very obese). CONCLUSIONS: The obesity paradox (lower mortality in the obese) documented in other populations is also observed in septic shock. This may be related in part to differences in patient characteristics. However, the true paradox may lie in the variations in the sepsis interventions, such as the administration of resuscitation fluids and antimicrobial therapy. Considering the obesity epidemic and its impact on critical care, further studies are warranted to examine whether a weight-based approach to common therapeutic interventions in septic shock influences outcome.

Acinetobacter is the most common pathogen associated with late-onset and recurrent ventilator-associated pneumonia in an adult intensive care unit in Saudi Arabia.

BACKGROUND: The guidelines for initial empiric antimicrobial therapy for ventilator-associated pneumonia (VAP) are highly dependent on the type of causative pathogen and the time of diagnosis. The objective of this study was to examine the microbial causes of VAP and describe any variability by the timing of VAP onset and over time. METHODS: A prospective surveillance study was conducted in the adult general intensive care unit of a tertiary care hospital in Riyadh, Saudi Arabia. Microbial isolates obtained from blood and different respiratory specimens of patients diagnosed with VAP (using the US Centers for Disease Control and Prevention definition) between August 2003 and June 2009 were included. RESULTS: A total of 457 pathogens were identified during the study; 380 (83.2%) were associated with primary VAP and 77 (16.8%) were associated with recurrent VAP. Of primary VAP pathogens, 159 (41.8%) were associated with early-onset (<5 days) and 221 (58.2%) were associated with late-onset (≥5 days) VAP. The most common pathogen identified was Acinetobacter spp (26.5%), followed by Pseudomonas aeruginosa (21.7%), Staphylococcus aureus including methicillin-resistant S. aureus (MRSA) (15.3%), Klebsiella spp (6.8%), Haemophilus spp (6.1%), and Enterobacter spp (5.0%). Acinetobacter spp and MRSA were significantly associated with late-onset VAP while Haemophilus spp and Streptococcus pneumoniae were significantly associated with early-onset VAP. Acinetobacter spp was the only pathogen associated with recurrent VAP and its incidence showed a significant increasing trend during the study period. Acinetobacter spp was significantly associated with prolonged ventilation, sedation, and nasogastric intubation. CONCLUSIONS: Acinetobacter baumannii is the most common and increasingly important pathogen associated with VAP in our patients, especially late-onset and recurrent VAP.

Intra-abdominal pressure and abdominal perfusion pressure in cirrhotic patients with septic shock.

BACKGROUND: The importance of intra-abdominal pressure (IAP) and abdominal perfusion pressure (APP) in cirrhotic patients with septic shock is not well studied. We evaluated the relationship between IAP and APP and outcomes of cirrhotic septic patients, and assessed the ability of these measures compared to other common resuscitative endpoints to differentiate survivors from nonsurvivors. METHODS: This study was a post hoc analysis of a randomized double-blind placebo-controlled trial in which mean arterial pressure (MAP), central venous oxygen saturation (ScvO2) and IAP were measured every 6 h in 61 cirrhotic septic patients admitted to the intensive care unit. APP was calculated as MAP - IAP. Intra-abdominal hypertension (IAH) was defined as mean IAP ≥ 12 mmHg, and abdominal hypoperfusion as mean APP < 60 mmHg. Measured outcomes included ICU and hospital mortality, need for renal replacement therapy (RRT) and ventilator- and vasopressor-free days. RESULTS: IAH prevalence on the first ICU day was 82%, and incidence in the first 7 days was 97%. Compared to patients with normal IAP, IAH patients had significantly higher ICU mortality (74.0% vs. 27.3%, p = 0.005), required more RRT (78.0% vs. 45.5%, p = 0.06) and had lower ventilator- and vasopressor-free days. On a multivariate logistic regression analysis, IAH was an independent predictor of both ICU mortality (odds ratio (OR), 12.20; 95% confidence interval (CI), 1.92 to 77.31, p = 0.008) and need for RRT (OR, 6.78; 95% CI, 1.29 to 35.70, p = 0.02). Using receiver operating characteristic curves, IAP (area under the curve (AUC) = 0.74, p = 0.004), APP (AUC = 0.71, p = 0.01), Acute Physiology and Chronic Health Evaluation II score (AUC = 0.71, p = 0.02), but not MAP, differentiated survivors from nonsurvivors. CONCLUSIONS: IAH is highly prevalent in cirrhotic patients with septic shock and is associated with increased ICU morbidity and mortality.