A Frailty Index to Predict Mortality, Resource Utilization and Costs in Patients Undergoing Coronary Artery Bypass Graft Surgery in Ontario.

Background: People living with frailty are vulnerable to poor outcomes and incur higher health care costs after coronary artery bypass graft (CABG) surgery. Frailty-defining instruments for population-level research in the CABG setting have not been established. The objectives of the study were to develop a preoperative frailty index for CABG (pFI-C) surgery using Ontario administrative data; assess pFI-C suitability in predicting clinical and economic outcomes; and compare pFI-C predictive capabilities with other indices. Methods: A retrospective cohort study was conducted using health administrative data of 50,682 CABG patients. The pFI-C comprised 27 frailty-related health deficits. Associations between index scores and mortality, resource use and health care costs (2022 Canadian dollars [CAD]) were assessed using multivariable regression models. Capabilities of the pFI-C in predicting mortality were evaluated using concordance statistics; goodness of fit of the models was assessed using Akakie Information Criterion. Results: As assessed by the pFI-C, 22% of the cohort lived with frailty. The pFI-C score was strongly associated with mortality per 10% increase (odds ratio [OR], 3.04; 95% confidence interval [CI], [2.83,3.27]), and was significantly associated with resource utilization and costs. The predictive performances of the pFI-C, Charlson, and Elixhauser indices and Johns Hopkins Aggregated Diagnostic Groups were similar, and mortality models containing the pFI-C had a concordance (C)-statistic of 0.784. Cost models containing the pFI-C showed the best fit. Conclusions: The pFI-C is predictive of mortality and associated with resource utilization and costs during the year following CABG. This index could aid in identifying a subgroup of high-risk CABG patients who could benefit from targeted perioperative health care interventions.

Contexte: Les personnes dont l'état de santé est fragilisé sont susceptibles de connaître des issues défavorables et de générer des coûts plus élevés pour le système de santé après un pontage aortocoronarien. Aucun instrument n'a été établi pour définir la fragilité dans la recherche populationnelle en contexte de pontage aortocoronarien. Les objectifs de l'étude étaient les suivants : 1) concevoir un indice de fragilité préopératoire en vue d'un pontage aortocoronarien (preoperative frailty index for CABG surgery, pFI-C) en utilisant des données administratives de l'Ontario; 2) évaluer la capacité de cet indice à prédire les issues cliniques et économiques; et 3) comparer la valeur prédictive de cet indice avec celle d'autres indices. Méthodologie: Une étude de cohorte rétrospective a été menée à partir de données médico-administratives portant sur 50 682 patients ayant subi un pontage aortocoronarien. Le pFI-C comprenait 27 déficits de santé liés à la fragilité. Des liens entre les scores de l'indice et la mortalité, l'utilisation des ressources et les coûts de soins de santé (en $ CA de 2022) ont été évalués à l'aide de modèles de régression multivariable. La capacité du pFI-C à prédire la mortalité a été évaluée à l'aide de la statistique de concordance; la qualité de l'ajustement des modèles a été évaluée en fonction du critère d'information d'Akaike. Résultats: Selon l'évaluation par le pFI-C, 22 % de la cohorte vivait avec une fragilité. Le score de l'indice était fortement corrélé à la mortalité par tranche d'augmentation de 10 % (rapport de cotes de 3,04; intervalle de confiance à 95 % de 2,83 à 3,27) et était corrélé de manière significative à l'utilisation des ressources et aux coûts. La valeur prédictive du pFI-C, des indices de Charlson et Elixhauser, et de Johns Hopkins Aggregated Diagnostic Groups était similaire, et les modèles de mortalité contenant le pFI-C affichaient une valeur statistique C de 0,784. Les modèles de coûts contenant le pFI-C affichaient le meilleur ajustement. Conclusions: Le pFI-C est un facteur prédictif de mortalité et est corrélé à l'utilisation des ressources et aux coûts engagés durant l'année qui suit un pontage aortocoronarien. Cet indice pourrait faciliter la détection d'un sous-groupe de patients subissant un pontage aortocoronarien et présentant un risque élevé qui pourraient bénéficier de soins périopératoires ciblés.

Patient-important upper gastrointestinal bleeding in the ICU: A mixed-methods study of patient and family perspectives.

INTRODUCTION: The objective of this study was to create a definition of patient-important upper gastrointestinal bleeding during critical illness as an outcome for a randomized trial. DESIGN: This was a sequential mixed-methods qualitative-dominant multi-center study with an instrument-building aim. In semi-structured individual interviews or focus groups we elicited views from survivors of critical illness and family members of patients in the intensive care unit (ICU) regarding which features indicate important gastrointestinal bleeding. Quantitative demographic characteristics were collected. We analyzed qualitative data using inductive content analysis to develop a definition for patient-important upper gastrointestinal bleeding. SETTING: Canada and the United States. PARTICIPANTS: 51 ICU survivors and family members of ICU patients. RESULTS: Participants considered gastrointestinal bleeding to be important if it resulted in death, disability, or prolonged hospitalization. The following also signaled patient-important upper gastrointestinal bleeding: blood transfusion, vasopressors, endoscopy, CT-angiography, or surgery. Whether an intervention evinced concern depended on its effectiveness, side-effects, invasiveness and accessibility; contextual influences included participant familiarity and knowledge of interventions and trust in the clinical team. CONCLUSIONS: Survivors of critical illness and family members described patient-important upper gastrointestinal bleeding differently than current definitions of clinically-important upper gastrointestinal bleeding.

Development and validation of a hospital frailty risk measure using Canadian clinical administrative data.

BACKGROUND: Accessible measures specific to the Canadian context are needed to support health system planning for older adults living with frailty. We sought to develop and validate the Canadian Institute for Health Information (CIHI) Hospital Frailty Risk Measure (HFRM). METHODS: Using CIHI administrative data, we conducted a retrospective cohort study involving patients aged 65 years and older who were discharged from Canadian hospitals from Apr. 1, 2018, to Mar. 31, 2019. We used a 2-phase approach to develop and validate the CIHI HFRM. The first phase, construction of the measure, was based on the deficit accumulation approach (identification of age-related conditions using a 2-year look-back). The second phase involved refinement into 3 formats (continuous risk score, 8 risk groups and binary risk measure), with assessment of their predictive validity for several frailty-related adverse outcomes using data to 2019/20. We assessed convergent validity with the United Kingdom Hospital Frailty Risk Score. RESULTS: The cohort consisted of 788 701 patients. The CIHI HFRM included 36 deficit categories and 595 diagnosis codes that cover morbidity, function, sensory loss, cognition and mood. The median continuous risk score was 0.111 (interquartile range 0.056-0.194, equivalent to 2-7 deficits); 35.1% (n = 277 000) of the cohort were found at risk of frailty (≥ 6 deficits). The CIHI HFRM showed satisfactory predictive validity and reasonable goodness-of-fit. For the continuous risk score format (unit = 0.1), the hazard ratio (HR) for 1-year risk of death was 1.39 (95% confidence interval [CI] 1.38-1.41), with a C-statistic of 0.717 (95% CI 0.715-0.720); the odds ratio for high users of hospital beds was 1.85 (95% CI 1.82-1.88), with a C-statistic of 0.709 (95% CI 0.704-0.714), and the HR of 90-day admission to long-term care was 1.91 (95% CI 1.88-1.93), with a C-statistic of 0.810 (95% CI 0.808-0.813). Compared with the continuous risk score, using a format of 8 risk groups had similar discriminatory ability and the binary risk measure had slightly weaker performance. INTERPRETATION: The CIHI HFRM is a valid tool showing good discriminatory power for several adverse outcomes. The tool can be used by decision-makers and researchers by providing information on hospital-level prevalence of frailty to support system-level capacity planning for Canada's aging population.

FLUID trial: a hospital-wide open-label cluster cross-over pragmatic comparative effectiveness randomised pilot trial comparing normal saline to Ringer's lactate.

OBJECTIVES: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids used for fluid therapy. Despite evidence of possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function and death), few large multi-centre randomised trials have evaluated the effect of these fluids on clinically important outcomes. We conducted a pilot trial to explore the feasibility of a large trial powered for clinically important outcomes. DESIGN: FLUID was a pragmatic pilot cluster randomised cross-over trial. SETTING: Four hospitals in the province of Ontario, Canada PARTICIPANTS: All hospitalised adult and paediatric patients with an incident admission to the hospital over the course of each study period. INTERVENTIONS: A hospital wide policy/strategy which stocked either NS or RL throughout the hospital for 12 weeks before crossing over to the alternate fluid for the subsequent 12 weeks. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary feasibility outcome was study fluid protocol adherence. Secondary feasibility outcomes included time to Research Ethics Board (REB) approval and trial initiation. Primary (composite of death or re-admission to hospital in first 90 days of index hospitalisation) and secondary clinical outcomes were analysed descriptively. RESULTS: Among 24 905 included patients, mean age 59.1 (SD 20.5); 13 977 (56.1%) were female and 21 150 (85.0%) had medical or surgical admitting diagnoses. Overall, 96 821 L were administered in the NS arm, and 78 348 L in the RL arm. Study fluid adherence to NS and RL was 93.7% (site range: 91.6%-98.0%) and 79.8% (site range: 72.5%-83.9%), respectively. Time to REB approval ranged from 2 to 48 days and readiness for trial initiation from 51 to 331 days. 5544 (22.3%) patients died or required hospital re-admission in the first 90 days. CONCLUSIONS: The future large trial is feasible. Anticipating and addressing logistical challenges during the planning stages will be imperative. TRIAL REGISTRATION NUMBER: NCT02721485.

PREPARE trial: a protocol for a multicentre randomised trial of frailty-focused preoperative exercise to decrease postoperative complication rates and disability scores.

INTRODUCTION: Frailty is a strong predictor of adverse postoperative outcomes. Prehabilitation may improve outcomes after surgery for older people with frailty by addressing physical and physiologic deficits. The objective of this trial is to evaluate the efficacy of home-based multimodal prehabilitation in decreasing patient-reported disability and postoperative complications in older people with frailty having major surgery. METHODS AND ANALYSIS: We will conduct a multicentre, randomised controlled trial of home-based prehabilitation versus standard care among consenting patients >60 years with frailty (Clinical Frailty Scale>4) having elective inpatient major non-cardiac, non-neurologic or non-orthopaedic surgery. Patients will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of >3 weeks of prehabilitation (exercise (strength, aerobic and stretching) and nutrition (advice and protein supplementation)). The study has two primary outcomes: in-hospital complications and patient-reported disability 30 days after surgery. Secondary outcomes include survival, lower limb function, quality of life and resource utilisation. A sample size of 750 participants (375 per arm) provides >90% power to detect a minimally important absolute difference of 8 on the 100-point patient-reported disability scale and a 25% relative risk reduction in complications, using a two-sided alpha value of 0.025 to account for the two primary outcomes. Analyses will follow intention to treat principles for all randomised participants. All participants will be followed to either death or up to 1 year. ETHICS AND DISSEMINATION: Ethical approval has been granted by Clinical Trials Ontario (Project ID: 1785) and our ethics review board (Protocol Approval #20190409-01T). Results will be disseminated through presentation at scientific conferences, through peer-reviewed publication, stakeholder organisations and engagement of social and traditional media. TRIAL REGISTRATION NUMBER: NCT04221295.

The relationship between immune status as measured by stimulated ex-vivo tumour necrosis factor alpha levels and the acquisition of nosocomial infections in critically ill mechanically ventilated patients.

INTRODUCTION: Immunological dysfunction is common in critically ill patients but its clinical significance and the optimal method to measure it are unknown. The level of tumor necrosis factor alpha (TNF-α) after ex-vivo whole blood stimulation with lipopolysaccharide (LPS) has been proposed as a possible method to quantify immunological function. We hypothesized that in a cohort of critically ill patients, those with a lower post-stimulation TNF-α level would have increased rates of nosocomial infections (NIs) and worse clinical outcomes. METHODS: A secondary analysis of a phase 2 randomized, multi-centre, double-blinded placebo-controlled trial. As there was no difference between treatment and control arms in outcomes and NI rate, all the patients were analyzed as one cohort. On enrolment, day 4, 7, and weekly until day 28, whole blood was incubated with LPS ex-vivo and subsequent TNF-α level was measured. Patients were grouped in tertiles according to delta and peak TNF-α level. The primary outcome was the association between NIs and tertiles of TNF-α level post LPS stimulation; secondary outcomes included ICU and 90-day mortality, and ICU and hospital length of stay. RESULTS: Data was available for 201 patients. Neither the post LPS stimulation delta TNF-α group nor the peak TNF-α post-stimulation group were associated with the development of NIs or clinical outcomes. Patients in the highest tertile for post LPS stimulation delta TNF-α compared to the lowest tertile were younger [61.1 years ± 15.7 vs. 68.6 years ± 12.8 standard deviations (SD) in the lowest tertile], had lower acuity of illness (APACHE II 25.0 ± 9.7 vs. 26.7 ± 6.1) and had lower baseline TNF-α (9.9 pg/mL ± 19.0 vs. 31.0 pg/mL ± 68.5). When grouped according to peak post-stimulation TNF-α levels, patients in the highest tertile had higher serum TNF-α at baseline (21.3 pg/mL ± 66.7 compared to 6.5 pg/mL ± 9.0 in the lowest tertile). CONCLUSION: In this prospective multicenter study, ex-vivo stimulated TNF-α level was not associated with the occurrence of NIs or clinical outcomes. Further study is required to better ascertain whether TNF levels and ex-vivo stimulation can be used to characterize immune function in critical illness and if other assays might be better suited to this task.

The physiological determinants of near-infrared spectroscopy-derived regional cerebral oxygenation in critically ill adults.

BACKGROUND: To maintain adequate oxygen delivery to tissue, resuscitation of critically ill patients is guided by assessing surrogate markers of perfusion. As there is no direct indicator of cerebral perfusion used in routine critical care, identifying an accurate strategy to monitor brain perfusion is paramount. Near-infrared spectroscopy (NIRS) is a non-invasive technique to quantify regional cerebral oxygenation (rSO2) that has been used for decades during cardiac surgery which has led to targeted algorithms to optimize rSO2 being developed. However, these targeted algorithms do not exist during critical care, as the physiological determinants of rSO2 during critical illness remain poorly understood. MATERIALS AND METHODS: This prospective observational study was an exploratory analysis of a nested cohort of patients within the CONFOCAL study ( NCT02344043 ) who received high-fidelity vital sign monitoring. Adult patients (≥ 18 years) admitted < 24 h to a medical/surgical intensive care unit were eligible if they had shock and/or required mechanical ventilation. Patients underwent rSO2 monitoring with the FORESIGHT oximeter for 24 h, vital signs were concurrently recorded, and clinically ordered arterial blood gas samples and hemoglobin concentration were also documented. Simultaneous multiple linear regression was performed using all available predictors, followed by model selection using the corrected Akaike information criterion (AICc). RESULTS: Our simultaneous multivariate model included age, heart rate, arterial oxygen saturation, mean arterial pressure, pH, partial pressure of oxygen, partial pressure of carbon dioxide (PaCO2), and hemoglobin concentration. This model accounted for a significant proportion of variance in rSO2 (R2 = 0.58, p < 0.01) and was significantly associated with PaCO2 (p < 0.05) and hemoglobin concentration (p < 0.01). Our selected regression model using AICc accounted for a significant proportion of variance in rSO2 (R2 = 0.54, p < 0.01) and was significantly related to age (p < 0.05), PaCO2 (p < 0.01), hemoglobin (p < 0.01), and heart rate (p < 0.05). CONCLUSIONS: Known and established physiological determinants of oxygen delivery accounted for a significant proportion of the rSO2 signal, which provides evidence that NIRS is a viable modality to assess cerebral oxygenation in critically ill adults. Further elucidation of the determinants of rSO2 has the potential to develop a NIRS-guided resuscitation algorithm during critical illness. TRIAL REGISTRATION: This trial is registered on clinicaltrials.gov (Identifier: NCT02344043 ), retrospectively registered January 8, 2015.

Relationship Between Near-Infrared Spectroscopy-Derived Cerebral Oxygenation and Delirium in Critically Ill Patients: A Systematic Review.

BACKGROUND: A common neurological complication of critical illness is delirium, defined as an acute change in level of consciousness, with impaired attention and disorganized thinking. Patients with delirium have increased risk of long-term cognitive dysfunction and mortality. The cause is unknown, which limits our ability to design therapeutic interventions. In patients undergoing surgery, low regional cerebral oxygenation (rSO2), as measured by near-infrared spectroscopy (NIRS), is associated with postoperative neurological dysfunction (eg delirium and long-term cognitive impairment). However, the relationship between NIRS-derived rSO2 and neurological outcomes in critically ill patients is unclear. The objective of this study was to assess the utilization of NIRS-derived rSO2 in critically ill patients outside the operating theater. We aimed to examine the relationship between rSO2 and neurological outcomes as well as to report rSO2 values in this population. METHODS: The following databases were searched from inception to August 14, 2017: Ovid MedLine, Embase, Cochrane Library, and Web of Science. RESULTS: Of 1410 articles identified by the search strategy, 8 were ultimately selected for final review. Most (7 of 8) were published since 2014. These studies included a total of 213 patients primarily with shock or respiratory failure. A variety of devices were used to measure rSO2, including INVOS and FORESIGHT. The duration of recording varied from 5 minutes to 72 hours. Four of the 8 studies reported on neurological outcomes. In all 4 studies, rSO2 was lower in critically ill patients who were delirious compared to controls, but this was only statistically significant in 2 of the studies. The heterogeneity in devices and duration of recording precluded meta-analysis. CONCLUSIONS: There is limited literature describing rSO2 in critically ill patients outside the operating room. Although there may be a slight signal of an association between low rSO2 and delirium, more study is needed to explore this relationship.

Proceedings of the Canadian Frailty Network Summit: Medication Optimization for Frail Older Canadians, Toronto, Monday April 24, 2017.

Appropriate and optimal use of medication and polypharmacy are especially relevant to the care of older Canadians living with frailty, often impacting their health outcomes and quality of life. A majority (two thirds) of older adults (65 or older) are prescribed five or more drug classes and over one-quarter are prescribed 10 or more drugs. The risk of adverse drug-induced events is even greater for those aged 85 or older where 40% are estimated to take drugs from 10 or more drug classes. The Canadian Frailty Network (CFN), a pan-Canadian non-for-profit organization funded by the Government of Canada through the Networks of Centres of Excellence Program (NCE), is dedicated to improving the care of older Canadian living with frailty and, as part of its mandate, convened a meeting of stakeholders from across Canada to seek their perspectives on appropriate medication prescription. The CFN Medication Optimization Summit identified priorities to help inform the design of future research and knowledge mobilization efforts to facilitate optimal medication prescribing in older adults living with frailty. The priorities were developed and selected through a modified Delphi process commencing before and concluding during the summit. Herein we describe the overall approach/process to the summit, a summary of all the presentations and discussions, and the top ten priorities selected by the participants.

Screening for Frailty in Canada's Health Care System: A Time for Action.

As Canada's population ages, frailty - with its increased risk of functional decline, deterioration in health status, and death - will become increasingly common. The physiology of frailty reflects its multisystem, multi-organ origins. About a quarter of Canadians over age 65 are frail, increasing to over half in those older than 85. Our health care system is organized around single-organ systems, impairing our ability to effectively treat people having multiple disorders and functional limitations. To address frailty, we must recognize when it occurs, increase awareness of its significance, develop holistic models of care, and generate better evidence for its treatment. Recognizing how frailty impacts lifespan will allow for integration of care goals into treatment options. Different settings in the Canadian health care system will require different strategies and tools to assess frailty. Given the magnitude of challenges frailty poses for the health care system as currently organized, policy changes will be essential.

Whole-blood neutrophil gelatinase-associated lipocalin to predict adverse events in acute kidney injury: A prospective observational cohort study.

PURPOSE: Acute kidney injury is common in intensive care units and is associated with increased morbidity and mortality. We evaluated the ability of whole-blood neutrophil gelatinase-associated lipocalin (wbNGAL) to predict mortality and need for renal replacement therapy (RRT) in critically ill patients with kidney dysfunction. METHODS: We prospectively enrolled adult patients in 5 Canadian intensive care units. We measured wbNGAL at the time of enrollment to determine whether NGAL concentration could predict the primary composite outcome of death or need for RRT by day 30 in addition to other secondary outcomes. RESULTS: We recruited 234 patients; 227 were included in the analysis. In a multivariable model, wbNGAL did not predict 30-day mortality or need for RRT (odds ratio, 1.05; 95% confidence interval, 0.99-1.12). Neutrophil gelatinase-associated lipocalin was similar in patients who died (654 [303-1180] ng/mL) vs those who survived (541.5 [255.5-1080] ng/mL, P=.26) by 90 days. Whole-blood NGAL poorly predicted the primary outcome (area under receiver operator curve, 0.65; 95% confidence interval, 0.58-0.73). CONCLUSIONS: In a cohort of critically ill patients with abnormal kidney function, wbNGAL was not effective in the prediction of death or RRT within 30 days. These data do not support the use of this biomarker for the detection of clinical outcomes in this population.

Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.

BACKGROUND: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. MATERIALS AND METHODS: This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). RESULTS: The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. CONCLUSIONS: After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.

Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*.

OBJECTIVES: To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU. DESIGN: Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial. SETTING: Sixty-seven medical-surgical ICUs in six countries. PATIENTS: Three thousand seven hundred forty-six medical-surgical critically ill patients. INTERVENTIONS: All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses. MEASUREMENTS AND MAIN RESULTS: Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004). CONCLUSIONS: Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.

Thromboprophylaxis patterns and determinants in critically ill patients: a multicenter audit.

INTRODUCTION: Heparin is safe and prevents venous thromboembolism in critical illness. We aimed to determine the guideline concordance for thromboprophylaxis in critically ill patients and its predictors, and to analyze factors associated with the use of low molecular weight heparin (LMWH), as it may be associated with a lower risk of pulmonary embolism and heparin-induced thrombocytopenia without increasing the bleeding risk. METHODS: We performed a retrospective audit in 28 North American intensive care units (ICUs), including all consecutive medical-surgical patients admitted in November 2011. We documented ICU thromboprophylaxis and reasons for omission. Guideline concordance was determined by adding days in which patients without contraindications received thromboprophylaxis to days in which patients with contraindications did not receive it, divided by the total number of patient-days. We used multilevel logistic regression including time-varying, center and patient-level covariates to determine the predictors of guideline concordance and use of LMWH. RESULTS: We enrolled 1,935 patients (62.3 ± 16.7 years, Acute Physiology and Chronic Health Evaluation [APACHE] II score 19.1 ± 8.3). Patients received thromboprophylaxis with unfractionated heparin (UFH) (54.0%) or LMWH (27.6%). Guideline concordance occurred for 95.5% patient-days and was more likely in patients who were sicker (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.17, 1.75 per 10-point increase in APACHE II), heavier (OR 1.32, 95% CI 1.05, 1.65 per 10-m/kg2 increase in body mass index), had cancer (OR 3.22, 95% CI 1.81, 5.72), previous venous thromboembolism (OR 3.94, 95% CI 1.46,10.66), and received mechanical ventilation (OR 1.83, 95% CI 1.32,2.52). Reasons for not receiving thromboprophylaxis were high risk of bleeding (44.5%), current bleeding (16.3%), no reason (12.9%), recent or upcoming invasive procedure (10.2%), nighttime admission or discharge (9.7%), and life-support limitation (6.9%). LMWH was less often administered to sicker patients (OR 0.65, 95% CI 0.48, 0.89 per 10-point increase in APACHE II), surgical patients (OR 0.41, 95% CI 0.24, 0.72), those receiving vasoactive drugs (OR 0.47, 95% CI 0.35, 0.64) or renal replacement therapy (OR 0.10, 95% CI 0.05, 0.23). CONCLUSIONS: Guideline concordance for thromboprophylaxis was high, but LMWH was less commonly used, especially in patients who were sicker, had surgery, or received vasopressors or renal replacement therapy, representing a potential quality improvement target.

Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study.

IMPORTANCE: Critically ill patients are at risk of venous thrombosis, and therefore guidelines recommend daily thromboprophylaxis. Deep vein thrombosis (DVT) commonly occurs in the lower extremities but can occur in other sites including the head and neck, trunk, and upper extremities. The risk of nonleg deep venous thromboses (NLDVTs), predisposing factors, and the association between NLDVTs and pulmonary embolism (PE) or death are unclear. OBJECTIVE: To describe the frequency, anatomical location, risk factors, management, and consequences of NLDVTs in a large cohort of medical-surgical critically ill adults. DESIGN, SETTING, AND PARTICIPANTS: A nested prospective cohort study in the setting of secondary and tertiary care intensive care units (ICUs). The study population comprised 3746 patients, who were expected to remain in the ICU for at least 3 days and were enrolled in a randomized clinical trial of dalteparin vs standard heparin for thromboprophylaxis. MAIN OUTCOMES AND MEASURES: The proportion of patients who had NLDVTs, the mean number per patient, and the anatomical location. We characterized NLDVTs as prevalent or incident (identified within 72 hours of ICU admission or thereafter) and whether they were catheter related or not. We used multivariable regression models to evaluate risk factors for NLDVT and to examine subsequent anticoagulant therapy, associated PE, and death. RESULTS Of 3746 trial patients, 84 (2.2%) developed 1 or more non-leg vein thromboses (superficial or deep, proximal or distal). Thromboses were more commonly incident (n = 75 [2.0%]) than prevalent (n = 9 [0.2%]) (P < .001) and more often deep (n = 67 [1.8%]) than superficial (n = 31 [0.8%]) (P < .001). Cancer was the only independent predictor of incident NLDVT (hazard ratio [HR], 2.22; 95% CI, 1.06-4.65). After adjusting for Acute Physiology and Chronic Health Evaluation (APACHE) II scores, personal or family history of venous thromboembolism, body mass index, vasopressor use, type of thromboprophylaxis, and presence of leg DVT, NLDVTs were associated with an increased risk of PE (HR, 11.83; 95% CI, 4.80-29.18). Nonleg DVTs were not associated with ICU mortality (HR, 1.09; 95% CI, 0.62-1.92) in a model adjusting for age, APACHE II, vasopressor use, mechanical ventilation, renal replacement therapy, and platelet count below 50 × 10(9)/L. CONCLUSIONS AND RELEVANCE Despite universal heparin thromboprophylaxis, nonleg thromboses are found in 2.2% of medical-surgical critically ill patients, primarily in deep veins and proximal veins. Patients who have a malignant condition may have a significantly higher risk of developing NLDVT, and patients with NLDVT, compared with those without, appeared to be at higher risk of PE but not higher risk of death. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00182143.

Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes.

BACKGROUND: Thrombocytopenia is the most common hemostatic disorder in critically ill patients. The objective of this study was to describe the incidence, risk factors, and outcomes of thrombocytopenia in patients admitted to medical-surgical ICUs. METHODS: Three thousand seven hundred forty-six patients in 67 centers were enrolled in a randomized trial in which unfractionated heparin was compared with low-molecular-weight heparin (LMWH) for thromboprophylaxis. Patients who had baseline platelet counts < 75 × 10(9)/L or severe coagulopathy at screening were excluded. We analyzed the risk of developing mild (100-149 × 10(9)/L), moderate (50-99 × 10(9)/L), and severe (< 50 × 109/L) thrombocytopenia during an ICU stay. We also assessed independent and time-varying predictors of thrombocytopenia and the effect of thrombocytopenia on major bleeding, transfusions, and death. RESULTS: The incidences of mild, moderate, and severe thrombocytopenia were 15.3%, 5.1%, and 1.6%, respectively. The predictors of each category of thrombocytopenia were APACHE (Acute Physiology and Chronic Health Evaluation) II score, use of inotropes or vasopressors, and renal replacement therapy. The risk of moderate thrombocytopenia was lower in patients who received LMWH thromboprophylaxis but higher in surgical patients and in patients who had liver disease. Each category of thrombocytopenia was associated with subsequent bleeding and transfusions. Moderate and severe thrombocytopenia were associated with increased ICU and hospital mortality. CONCLUSION: A high severity of illness, prior surgery, use of inotropes or vasopressors, renal replacement therapy, and liver dysfunction are associated with a higher risk of thrombocytopenia developing in the ICU, whereas LMWH thromboprophylaxis is associated with a lower risk. Patients who develop thrombocytopenia in the ICU are more likely to bleed, receive transfusions, and die.

Longitudinal changes in procalcitonin in a heterogeneous group of critically ill patients.

OBJECTIVE: The utility of procalcitonin for the diagnosis of infection in the critical care setting has been extensively investigated with conflicting results. Herein, we report procalcitonin values relative to baseline patient characteristics, presence of shock, intensive care unit time course, infectious status, and Gram stain of infecting organism. DESIGN: Prospective, multicenter, observational study of critically ill patients admitted to intensive care unit for >24 hrs. SETTING: Three tertiary care intensive care units. PATIENTS: All consenting patients admitted to three mixed medical-surgical intensive care units. Patients who had elective surgery, overdoses, and who were expected to stay <24 hrs were excluded. INTERVENTIONS: Patients were followed prospectively to ascertain the presence of prevalent (present at admission) or incident (developed during admission) infections and clinical outcomes. Procalcitonin levels were measured daily for 10 days and were analyzed as a function of the underlying patient characteristics, presence of shock, time of infection, and pathogen isolated. MAIN RESULTS: Five hundred ninety-eight patients were enrolled. Medical and surgical infected cohorts had similar baseline procalcitonin values (3.0 [0.7-15.3] vs. 3.7 [0.6-9.8], p=.68) and peak procalcitonin (4.5 [1.0-22.9] vs. 5.0 [0.9-16.0], p=.91). Infected patients were sicker than their noninfected counterparts (Acute Physiology and Chronic Health Evaluation II 22.9 vs. 19.3, p<.001); those with infection at admission had a trend toward higher peak procalcitonin values than did those whose infection developed in the intensive care unit (4.9 vs. 1.4, p=.06). The presence of shock was significantly associated with elevations in procalcitonin in cohorts who were and were not infected (both groups p<.003 on days 1-5). CONCLUSIONS: Procalcitonin dynamics were similar between surgical and medical cohorts. Shock had an association with higher procalcitonin values independent of the presence of infection. Trends in differences in procalcitonin values were seen in patients who had incident vs. prevalent infections.

The relationship between Candida species cultured from the respiratory tract and systemic inflammation in critically ill patients with ventilator-associated pneumonia.

PURPOSE: In patients with ventilator-associated pneumonia (VAP), the isolation of Candida species (spp.) in respiratory secretions has been associated with worse outcomes. It is unclear whether Candida colonization is causally related or is a marker of disease severity. The objective of this study was to compare systemic inflammatory markers in patients with a clinical suspicion of VAP with Candida in respiratory tract (RT) cultures vs patients who have bacteria and those with no pathogens. METHODS: This was a prospective observational study in adults with a clinical suspicion of VAP who were enrolled within 24 hr of intensive care unit (ICU) admission. Patients were divided into four groups according to RT cultures, i.e., bacterial pathogens only, Candida spp. only, culture negative, and a control group with no clinical suspicion of VAP. Clinical outcomes were collected and compared as were systemic inflammatory and coagulation markers, including procalcitonin (PCT), C-reactive protein (CRP) and interleukin (IL)-6. RESULTS: The PCT, CRP, and IL-6 levels were similar in the Candida, bacterial pathogen, and culture negative groups but were significantly increased between the Candida group and the control group (P < 0.05). In the first 28 days, the number of ICU free days was significantly lower in the Candida group compared with the other groups, and mortality at 28 days was greater (Candida 42.9%, bacterial pathogen 25.0%, culture negative 19.8%, control 0.0%; P < 0.05). CONCLUSIONS: In patients with a clinical suspicion of VAP, the presence of Candida spp. only in the RT is associated with similar levels of inflammation and worse clinical outcomes compared with patients without Candida in RT secretions.

The safety of targeted antibiotic therapy for ventilator-associated pneumonia: a multicenter observational study.

PURPOSE: The aim of this study was to determine the safety of targeted antibiotic therapy (TT) in ventilator-associated pneumonia (VAP). MATERIALS AND METHODS: This was a secondary analysis from a multicenter trial of 740 patients with suspected VAP randomized to bronchoscopy or endotracheal aspirate cultures; all received empirical broad-spectrum antibiotics. Patients were grouped by whether they received TT, defined as tailoring or discontinuing antibiotics in response to enrolment culture results. RESULTS: For patients with a positive culture (n = 412), baseline demographics, clinical progression of infection and multiple organ dysfunction scores (MODS), and mortality were similar for those on TT (n = 320) or those who did not receive TT (NoTT) (n = 92). The TT group had more days alive and off broad-spectrum antibiotics (14.5 vs 13.2, P = .04). In patients with a negative culture (n = 327), those on TT (n = 230) had similar baseline demographics, less frequent final adjudicated diagnosis of VAP (63.0% vs 76.3%, P = .02), and less severe clinical progression of infection and MODS compared with NoTT (n = 97). The TT group had more days alive and off broad-spectrum antibiotics (15.9 vs 13.1, P < .001), lower delta MODS (2.0 vs 3.0, P = .01), fewer mechanical ventilation days (9.8 vs 14.7, P = .03), and similar mortality compared to NoTT. CONCLUSIONS: Targeted therapy is associated with less antibiotic use and no evidence of harm in the management of patients with VAP.

Venous thromboembolism in critical illness in a community intensive care unit.

BACKGROUND: Venous thromboembolism (VTE) can be a life-threatening complication of critical illness. Venous thromboembolism rates observed depend on the population studied, the screening modality used, and thromboprophylaxis prescribed. Few studies report on the rates of clinically diagnosed VTE in critically ill patients. The purpose of this study was to characterize the incidence of clinically diagnosed VTE, prophylactic strategies used, and diagnostic studies ordered in a critically ill population at a tertiary community intensive care unit (ICU), both during and after their ICU stay. METHODS: We did a retrospective chart review of 600 consecutive critically ill patients admitted to a tertiary community ICU. RESULTS: Fifty (8.3%) patients developed VTE over the course of their ICU and hospital stay (18 [3.0%] patients during their ICU stay and 32 [5.7% of 561 ICU survivors] patients after ICU discharge). By ICU admission diagnosis, most events occurred in neurosurgical patients, although this group comprised only 24.8% of the population. Across all subgroups, most VTE events occurred after ICU discharge. Intensive care unit patients received thromboprophylaxis 87.6% (95% confidence interval, 81.5-93.7) of the time spent in ICU. However, thromboprophylaxis was administered significantly less often after transfer to the ward compared with within the ICU (from 87.6% to 59.8%, P < .001). CONCLUSION: The rates of clinically diagnosed VTE rates in critically ill patients are substantial. Venous thromboembolism occurs before, during, and after ICU discharge. Continued vigilance and thromboprophylaxis are warranted across the continuum of critical illness.