Jorge I. F. Salluh

Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis

IntroductionThe current shortage of accurate and readily available, validated biomarkers of disease severity in sepsis is an important limitation when attempting to stratify patients into homogeneous groups, in order to study pathogenesis or develop therapeutic interventions. The aim of the present study was to determine the cytokine profile in plasma of patients with severe sepsis by using a multiplex system for simultaneous detection of 17 cytokines.MethodsThis was a prospective cohort study conducted in four tertiary hospitals. A total of 60 patients with a recent diagnosis of severe sepsis were included. Plasma samples were collected for measurement of cytokine concentrations. A multiplex analysis was performed to evaluate levels of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-γ, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein-1 and tumour necrosis factor-α). Cytokine concentrations were related to the presence of severe sepsis or septic shock, the severity and evolution of organ failure, and early and late mortality.ResultsConcentrations of IL-1β, IL-6, IL-7, IL-8, IL-10, IL-13, interferon-γ, MCP-1 and tumour necrosis factor-α were significantly higher in septic shock patients than in those with severe sepsis. Cytokine concentrations were associated with severity and evolution of organ dysfunction. With regard to the severity of organ dysfunction on day 1, IL-8 and MCP-1 exhibited the best correlation with Sequential Organ Failure Assessment score. In addition, IL-6, IL-8 and G-CSF concentrations during the first 24 hours were predictive of worsening organ dysfunction or failure of organ dysfunction to improve on day three. In terms of predicting mortality, the cytokines IL-1β, IL-4, IL-6, IL-8, MCP-1 and G-CSF had good accuracy for predicting early mortality (< 48 hours), and IL-8 and MCP-1 had the best accuracy for predicting mortality at 28 days. In multivariate analysis, only MCP-1 was independently associated with prognosis.ConclusionIn this exploratory analysis we demonstrated that use of a multiple cytokine assay platform allowed identification of distinct cytokine profiles associated with sepsis severity, evolution of organ failure and death.

Characteristics and outcomes of patients with cancer requiring admission to intensive care units: A prospective multicenter study*

Objective:To evaluate the characteristics and outcomes of patients with cancer admitted to several intensive care units. Knowledge on patients with cancer requiring intensive care is mostly restricted to single-center studies. Design:Prospective, multicenter, cohort study. Setting:Intensive care units from 28 hospitals in Brazil. Patients:A total of 717 consecutive patients included over a 2-mo period. Interventions:None. Measurements and Main Results:There were 667 (93%) patients with solid tumors and 50 (7%) patients had hematologic malignancies. The main reasons for intensive care unit admission were postoperative care (57%), sepsis (15%), and respiratory failure (10%). Overall hospital mortality rate was 30% and was higher in patients admitted because of medical complications (58%) than in emergency (37%) and scheduled (11%) surgical patients (p < .001). Adjusting for covariates other than the type of admission, the number of hospital days before intensive care unit admission (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.01–1.37), higher Sequential Organ Failure Assessment scores (OR, 1.25; 95% CI, 1.17–1.34), poor performance status (OR, 3.40; 95% CI, 2.19 –5.26), the need for mechanical ventilation (OR, 2.42; 95% CI, 1.51–3.87), and active underlying malignancy in recurrence or progression (OR, 2.42; 95% CI, 1.51–3.87) were associated with increased hospital mortality in multivariate analysis. Conclusions:This large multicenter study reports encouraging survival rates for patients with cancer requiring intensive care. In these patients, mortality was mostly dependent on the severity of organ failures, performance status, and need for mechanical ventilation rather than cancer-related characteristics, such as the type of malignancy or the presence of neutropenia.

Outcome of delirium in critically ill patients: systematic review and meta-analysis

Objectives To determine the relation between delirium in critically ill patients and their outcomes in the short term (in the intensive care unit and in hospital) and after discharge from hospital. Design Systematic review and meta-analysis of published studies. Data sources PubMed, Embase, CINAHL, Cochrane Library, and PsychINFO, with no language restrictions, up to 1 January 2015. Eligibility criteria for selection studies Reports were eligible for inclusion if they were prospective observational cohorts or clinical trials of adults in intensive care units who were assessed with a validated delirium screening or rating system, and if the association was measured between delirium and at least one of four clinical endpoints (death during admission, length of stay, duration of mechanical ventilation, and any outcome after hospital discharge). Studies were excluded if they primarily enrolled patients with a neurological disorder or patients admitted to intensive care after cardiac surgery or organ/tissue transplantation, or centered on sedation management or alcohol or substance withdrawal. Data were extracted on characteristics of studies, populations sampled, identification of delirium, and outcomes. Random effects models and meta-regression analyses were used to pool data from individual studies. Results Delirium was identified in 5280 of 16 595 (31.8%) critically ill patients reported in 42 studies. When compared with control patients without delirium, patients with delirium had significantly higher mortality during admission (risk ratio 2.19, 94% confidence interval 1.78 to 2.70; P<0.001) as well as longer durations of mechanical ventilation and lengths of stay in the intensive care unit and in hospital (standard mean differences 1.79 (95% confidence interval 0.31 to 3.27; P<0.001), 1.38 (0.99 to 1.77; P<0.001), and 0.97 (0.61 to 1.33; P<0.001), respectively). Available studies indicated an association between delirium and cognitive impairment after discharge. Conclusions Nearly a third of patients admitted to an intensive care unit develop delirium, and these patients are at increased risk of dying during admission, longer stays in hospital, and cognitive impairment after discharge.

Delirium epidemiology in critical care (DECCA): an international study

IntroductionDelirium is a frequent source of morbidity in intensive care units (ICUs). Most data on its epidemiology is from single-center studies. Our aim was to conduct a multicenter study to evaluate the epidemiology of delirium in the ICU.MethodsA 1-day point-prevalence study was undertaken in 104 ICUs from 11 countries in South and North America and Spain.ResultsIn total, 975 patients were screened, and 497 fulfilled inclusion criteria and were enrolled (median age, 62 years; 52.5% men; 16.7% and 19.9% for ICU and hospital mortality); 64% were admitted to the ICU because of medical causes, and sepsis was the main diagnosis (n = 76; 15.3%). In total, 265 patients were sedated with the Richmond agitation and sedation scale (RASS) deeper than -3, and only 232 (46.6%) patients could be evaluated with the confusion-assessment method for the ICU. The prevalence of delirium was 32.3%. Compared with patients without delirium, those with the diagnosis of delirium had a greater severity of illness at admission, demonstrated by higher sequential organ-failure assessment (SOFA (P = 0.004)) and simplified acute physiology score 3 (SAPS3) scores (P < 0.0001). Delirium was associated with increased ICU (20% versus 5.7%; P = 0.002) and hospital mortality (24 versus 8.3%; P = 0.0017), and longer ICU (P < 0.0001) and hospital length of stay (LOS) (22 (11 to 40) versus 7 (4 to 18) days; P < 0.0001). Previous use of midazolam (P = 0.009) was more frequent in patients with delirium. On multivariate analysis, delirium was independently associated with increased ICU mortality (OR = 3.14 (1.26 to 7.86); CI, 95%) and hospital mortality (OR = 2.5 (1.1 to 5.7); CI, 95%).ConclusionsIn this 1-day international study, delirium was frequent and associated with increased mortality and ICU LOS. The main modifiable risk factors associated with the diagnosis of delirium were the use of invasive devices and sedatives (midazolam).

Prognosis of Critically Ill Patients With Cancer and Acute Renal Dysfunction

PURPOSE To evaluate the outcomes of critically ill patients with cancer and acute renal dysfunction. PATIENTS AND METHODS Prospective cohort study conducted at a 10-bed oncologic medical-surgical intensive care unit (ICU) over a 56-month period. RESULTS Of 975 patients, 309 (32%) had renal dysfunction and were studied. Their mean age was 60.9 +/- 15.9 years; 233 patients (75%) had solid tumors and 76 (25%) had hematologic malignancies. During the ICU stay, 98 patients (32%) received dialysis. Renal dysfunction was multifactorial in 56% of the patients, and the main associated factors were shock/ischemia (72%) and sepsis (63%). Overall hospital and 6-month mortality rates were 64% and 73%, respectively. Among patients who required dialysis, mortality rates were lower in patients who received dialysis on the first day of ICU in comparison with those who required it thereafter. In a multivariable Cox model, age more than 60 years, uncontrolled cancer, impaired performance status, and more than two associated organ failures were associated with increased 6-month mortality. Renal function was completely re-established in 82% and partially re-established in 12%, and only 6% of survivors required chronic dialysis. CONCLUSION Acute renal dysfunction is frequent in critically ill patients with cancer. Although mortality rates are high, selected patients can benefit from ICU care and advanced organ support. When evaluating prognosis and the appropriateness of dialysis in these patients, older age, functional capacity, cancer status and the severity of associated organ failures are important variables to take into consideration.

Characteristics and outcomes of cancer patients requiring mechanical ventilatory support for >24 hrs*

Objectives:To describe the characteristics of a large cohort of cancer patients receiving mechanical ventilation for >24 hrs and to identify clinical features predictive of in-hospital death. Design:Prospective cohort study. Setting:Ten-bed oncologic medical-surgical intensive care unit. Patients:A total of 463 consecutive patients were included over a 45-month period. Interventions:None. Measurements and Main Results:Data were collected on the day of admission to the intensive care unit. The intensive care unit and hospital mortality rates were 50% and 64%, respectively. There were 359 (78%) patients with solid tumors and 104 (22%) with hematologic malignancies; 35 (8%) patients had leukopenia. Sepsis (63%), coma (15%), invasion or compression by tumor (11%), pulmonary embolism (7%), and cardiopulmonary arrest (6%) were the main reasons for mechanical ventilation. The independent unfavorable risk factors for mortality were older age (odds ratio, 3.09; 95% confidence interval, 1.61–5.93, for patients 40–70 yrs old, and odds ratio, 9.26; 95% confidence interval, 4.16–20.58, for patients >70 yrs old); performance status 3–4 (odds ratio, 2.51; 95% confidence interval, 1.40–4.51); cancer recurrence/progression (odds ratio, 3.43; 95% confidence interval, 1.81–6.53); Pao2/Fio2 ratio <150 (odds ratio, 2.64; 95% confidence interval, 1.40–4.99); Sequential Organ Failure Assessment score (excluding respiratory domain, each 4 points; odds ratio, 2.34; 95% confidence interval, 1.70–3.24); and airway/pulmonary invasion or compression by tumor as a reason for mechanical ventilation (odds ratio, 5.73; 95% confidence interval, 1.92–17.08). Conclusions:Severity of acute organ failures, poor performance status, cancer status, and older age were the main determinants of mortality. The appropriate use of such easily available clinical characteristics may avoid forgoing intensive care for patients with a chance of survival.

Prognosis of Lung Cancer Patients With Life-Threatening Complications

BACKGROUND The management of patients with lung cancer has improved recently, and many of them will require admission to the ICU. The aims of this study were to determine hospital mortality and to identify risk factors for death in a large cohort of critically ill patients. METHODS Cohort study in two ICUs specialized in the management of patients with cancer, in France and Brazil. RESULTS Of the 143 patients (mean age, 61.6 +/- 9.9 years [+/- SD]), 25 patients (17%) had small cell lung cancer and 118 patients (83%) had non-small cell lung cancer. The main reasons for ICU admission were sepsis (44%) and acute respiratory failure (31%). Mechanical ventilation (MV) was used in 100 patients (70%), including 38 patients in whom lung cancer was considered a reason for MV. Hospital mortality was 59% overall and 69% in patients receiving MV. By multivariate logistic regression, airway infiltration or obstruction by cancer, number of organ failures, cancer recurrence or progression, and severity of comorbidities were associated with increased mortality. CONCLUSIONS The improved survival previously reported in patients with cancer admitted to the ICU seems to extend to patients with lung cancer, including those who need MV. Mortality increased with the number of organ failures, severity of comorbidities, and presence of respiratory failure due to cancer progression. The type of the cancer per se was not associated with mortality and, therefore, should not be factored into ICU triage decisions.

Positive end-expiratory pressure at minimal respiratory elastance represents the best compromise between mechanical stress and lung aeration in oleic acid induced lung injury.

IntroductionProtective ventilatory strategies have been applied to prevent ventilator-induced lung injury in patients with acute lung injury (ALI). However, adjustment of positive end-expiratory pressure (PEEP) to avoid alveolar de-recruitment and hyperinflation remains difficult. An alternative is to set the PEEP based on minimizing respiratory system elastance (Ers) by titrating PEEP. In the present study we evaluate the distribution of lung aeration (assessed using computed tomography scanning) and the behaviour of Ers in a porcine model of ALI, during a descending PEEP titration manoeuvre with a protective low tidal volume.MethodsPEEP titration (from 26 to 0 cmH2O, with a tidal volume of 6 to 7 ml/kg) was performed, following a recruitment manoeuvre. At each PEEP, helical computed tomography scans of juxta-diaphragmatic parts of the lower lobes were obtained during end-expiratory and end-inspiratory pauses in six piglets with ALI induced by oleic acid. The distribution of the lung compartments (hyperinflated, normally aerated, poorly aerated and non-aerated areas) was determined and the Ers was estimated on a breath-by-breath basis from the equation of motion of the respiratory system using the least-squares method.ResultsProgressive reduction in PEEP from 26 cmH2O to the PEEP at which the minimum Ers was observed improved poorly aerated areas, with a proportional reduction in hyperinflated areas. Also, the distribution of normally aerated areas remained steady over this interval, with no changes in non-aerated areas. The PEEP at which minimal Ers occurred corresponded to the greatest amount of normally aerated areas, with lesser hyperinflated, and poorly and non-aerated areas. Levels of PEEP below that at which minimal Ers was observed increased poorly and non-aerated areas, with concomitant reductions in normally inflated and hyperinflated areas.ConclusionThe PEEP at which minimal Ers occurred, obtained by descending PEEP titration with a protective low tidal volume, corresponded to the greatest amount of normally aerated areas, with lesser collapsed and hyperinflated areas. The institution of high levels of PEEP reduced poorly aerated areas but enlarged hyperinflated ones. Reduction in PEEP consistently enhanced poorly or non-aerated areas as well as tidal re-aeration. Hence, monitoring respiratory mechanics during a PEEP titration procedure may be a useful adjunct to optimize lung aeration.

Outcomes for Patients With Cancer Admitted to the ICU Requiring Ventilatory Support: Results From a Prospective Multicenter Study

BACKGROUND This study was undertaken to evaluate the clinical characteristics and outcomes of patients with cancer requiring nonpalliative ventilatory support. METHODS This was a secondary analysis of a prospective cohort study conducted in 28 Brazilian ICUs evaluating adult patients with cancer requiring invasive mechanical ventilation (MV) or noninvasive ventilation (NIV) during the first 48 h of their ICU stay. We used logistic regression to identify the variables associated with hospital mortality. RESULTS Of 717 patients, 263 (37%) (solid tumors = 227; hematologic malignancies = 36) received ventilatory support. NIV was initially used in 85 patients (32%), and 178 (68%) received MV. Additionally, NIV followed by MV occurred in 45 patients (53%). Hospital mortality rates were 67% in all patients, 40% in patients receiving NIV only, 69% when NIV was followed by MV, and 73% in patients receiving MV only (P < .001). Adjusting for the type of admission, newly diagnosed malignancy (OR, 3.59; 95% CI, 1.28-10.10), recurrent or progressive malignancy (OR, 3.67; 95% CI, 1.25-10.81), tumoral airway involvement (OR, 4.04; 95% CI, 1.30-12.56), performance status (PS) 2 to 4 (OR, 2.39; 95% CI, 1.24-4.59), NIV followed by MV (OR, 3.00; 95% CI, 1.09-8.18), MV as initial ventilatory strategy (OR, 3.53; 95% CI, 1.45-8.60), and Sequential Organ Failure Assessment score (each point except the respiratory domain) (OR, 1.15; 95% CI, 1.03-1.29) were associated with hospital mortality. Hospital survival in patients with good PS and nonprogressive malignancy and without tumoral airway involvement was 53%. Conversely, patients with poor functional capacity and cancer progression had unfavorable outcomes. CONCLUSIONS Patients with cancer with good PS and nonprogressive disease requiring ventilatory support should receive full intensive care, because one-half of these patients survive. On the other hand, provision of palliative care should be considered the main goal for patients with poor PS and progressive underlying malignancy.

The role of corticosteroids in severe community-acquired pneumonia: a systematic review

IntroductionThe purpose of this review was to evaluate the impact of corticosteroids on the outcomes of patients with severe community-acquired pneumonia (CAP).MethodsWe performed a systematic MEDLINE, Cochrane database, and CINAHL search (1966 to November 2007) to identify full-text publications that evaluated the use of corticosteroids in CAP.ResultsAn initial literature search yielded 109 articles, and 105 studies were excluded after the first analysis. We found four studies eligible for analysis. On the basis of their results, the use of corticosteroids as adjunctive therapy in severe CAP should be categorized as a weak recommendation (two studies) and a strong recommendation (two studies) with either low- or moderate-quality evidence. However, no evidence of adverse outcomes or harm is present in the evaluated studies.ConclusionAccording to the GRADE system, available studies do not support the recommendation of corticosteroids as a standard of care for patients with severe CAP. Further randomized controlled trials with this aim should enroll a larger number of severely ill patients. However, in patients needing corticosteroids, it may be reasonable to conclude that corticosteroid administration is safe in patients with severe infections receiving antimicrobial therapy.