Lina Pérez-Méndez

A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: A randomized, controlled trial*

Objective:It has been shown in a two-center study that high positive end-expiratory pressure (PEEP) and low tidal volume (LTV) improved outcome in ARDS. However, that study involved patients with underlying diseases unique to the study area, was conducted at only two centers, and enrolled a small number of patients. We similarly hypothesized that a ventilatory strategy based on PEEP above the lower inflection point of the pressure volume curve of the respiratory system (Pflex) set on day 1 with a low tidal volume would result in improved outcome in patients with severe and persistent acute respiratory distress syndrome (ARDS). Design:Randomized, controlled clinical trial. Setting:Network of eight Spanish multidisciplinary intensive care units (ICUs) under the acronym of ARIES (Acute Respiratory Insufficiency: España Study). Patients:All consecutive patients admitted into participating Spanish ICUs from March 1999 to March 2001 with a diagnosis of ARDS were considered for the study. If 24 hrs after meeting ARDS criteria, the Pao2/Fio2 remained ≤200 mm Hg on standard ventilator settings, patients were randomized into two groups: control and Pflex/LTV. Interventions:In the control group, tidal volume was 9–11 mL/kg of predicted body weight (PBW) and PEEP ≥5 cm H2O. In the Pflex/LTV group, tidal volume was 5–8 mL/kg PBW and PEEP was set on day 1 at Pflex + 2 cm H2O. In both groups, Fio2 was set to maintain arterial oxygen saturation >90% and Pao2 70–100 mm Hg, and respiratory rate was adjusted to maintain Paco2 between 35 and 50 mm Hg. Measurements and Main Results:The study was stopped early based on an efficacy stopping rule as described in the methods. Of 103 patients who were enrolled (50 control and 53 Pflex), eight patients (five in control, three in Pflex) were excluded from the final evaluation because the random group assignment was not performed in one center according to protocol. Main outcome measures were ICU and hospital mortality, ventilator-free days, and nonpulmonary organ dysfunction. ICU mortality (24 of 45 [53.3%] vs. 16 of 50 [32%], p = .040), hospital mortality (25 of 45 [55.5%] vs. 17 of 50 [34%], p = .041), and ventilator-free days at day 28 (6.02 ± 7.95 in control and 10.90 ± 9.45 in Pflex/LTV, p = .008) all favored Pflex/LTV. The mean difference in the number of additional organ failures postrandomization was higher in the control group (p < .001). Conclusions:A mechanical ventilation strategy with a PEEP level set on day 1 above Pflex and a low tidal volume compared with a strategy with a higher tidal volume and relatively low PEEP has a beneficial impact on outcome in patients with severe and persistent ARDS.

Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome

Background: Despite intensive research, there are no universally accepted clinical definitions for acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). A recent joint American-European Consensus Conference on ARDS formally defined the difference between ALI and ARDS based on the degree of oxygenation impairment. However, this definition may not reflect the true prevalence, severity and prognosis of these syndromes. Methods: During a 22-month period, 56 consecutive mechanically ventilated patients who met the American-European Consensus definition for ARDS [arterial oxygen tension/fractional inspired oxygen (PaO2/FIO2≤ 200 mmHg regardless of the level of positive end-expiratory pressure (PEEP), bilateral pulmonary infiltrates, and no evidence of left heart failure] were admitted into the intensive care units (ICU) of the Hospital del Pino, Las Palmas, Spain, and prospectively studied. The diagnosis of ALI and ARDS was made by a PEEP-FIO2 trial, 24 h after patients met the Consensus inclusion criteria. Patients were classified as having ALI–24 h if the PaO2/FIO2 was > 150 mmHg with PEEP = 5 cmH2O, and ARDS–24 h if the PaO2 /FIO2 was ≤ 150 mmHg with PEEP ≥ 5 cmH2O. Results: Overall mortality was 43 % (24 of 56). However, 24 h after inclusion, PaO2 response to PEEP 5 cmH2O allowed the separation of our patients into two different groups: 31 patients met our ALI–24 h criteria (PaO2/FIO2 > 150 mmHg) and their mortality was 22.6 %; 25 patients met our ARDS–24 h criteria (PaO2/FIO2≤ 150 mmHg) and their mortality was 68 % (p = 0.0016). The differences in the respiratory severity index during the first 24 h of inclusion, PaO2/FIO2 ratio at baseline and at 24 h, maximum plateau airway pressure, maximum level of PEEP, and number of organ system failures during the ICU stay were statistically significant. Conclusions: Since the use of PEEP in the American-European Consensus criteria for ARDS is not mandatory, that definition does not reflect the true severity of lung damage and outcome. Our data support the need for guidelines based on a specific method of evaluating oxygenation status before the American-European Consensus definition is adopted.

Bench-to-bedside review: understanding genetic predisposition to sepsis.

Sepsis is a complex syndrome that develops when the initial, appropriate host response to an infection becomes amplified, and is then dysregulated. Among other factors, the innate immune system is of central importance to the early containment of infection. Death from infection is strongly heritable in human populations. Hence, genetic variations that disrupt innate immune sensing of infectious organisms could explain the ability of the immune system to respond to infection, the diversity of the clinical presentation of sepsis, the response to current medical treatment, and the genetic predisposition to infection in each individual patient. Such genetic variations may identify patients at high risk for the development of sepsis and organ dysfunction during severe infections. Single base variations, known as single nucleotide polymorphisms (SNPs), are the most commonly used variants. There has been great interest in exploring SNP in those genes involved in the inflammatory cascade resulting from the systemic inflammatory response to micro organisms. The rationale for studying gene SNPs in critical illnesses seeks to identify potential markers of susceptibility, severity, and clinical outcome; seeks to identify potential markers for responders and non-responders in clinical trials, and seeks to identify targets for therapeutic intervention. In this review, we focus on the current state of association studies of those genes governing the powerful bacterial infection-induced inflammation and provide guidelines for future studies describing disease associations with genetic variations based on current recommendations. We envision a time in the near future when genotyping will be include in the standard evaluation of critically ill patients and will help to prioritize a therapeutic option.

A Tale of Aborigines, Conquerors and Slaves: Alu Insertion Polymorphisms and the Peopling of Canary Islands

Classical, mitochondrial DNA (mtDNA) and Y chromosome markers have been used to examine the genetic admixture in present day inhabitants of the Canary Islands. In this study, we report the analysis of ten autosomal Alu insertion polymorphisms in 364 samples from the seven main islands of the Archipelago, and their comparison to continental samples. The detection of population‐specific alleles from the Iberian Peninsula and Northwest Africa, as well as their affinities on the basis of genetic distances and principal component analysis, support a clear link between these populations. Coincident with previous results, the Canarian gene pool can be distinguished as being halfway between those of its putative parents, although with a major Iberian contribution (62‐78%). Both the substantial Northwest African contribution (23‐38%), and the minor sub‐Saharan African input (3%), suggest that the genetic legacy from the aborigines and slaves still persists in the Canary Islanders.

Evaluating an educational intervention to improve the accuracy of death certification among trainees from various specialties

BackgroundThe inaccuracy of death certification can lead to the misallocation of resources in health care programs and research. We evaluated the rate of errors in the completion of death certificates among medical residents from various specialties, before and after an educational intervention which was designed to improve the accuracy in the certification of the cause of death.MethodsA 90-min seminar was delivered to seven mixed groups of medical trainees (n = 166) from several health care institutions in Spain. Physicians were asked to read and anonymously complete a same case-scenario of death certification before and after the seminar. We compared the rates of errors and the impact of the educational intervention before and after the seminar.ResultsA total of 332 death certificates (166 completed before and 166 completed after the intervention) were audited. Death certificates were completed with errors by 71.1% of the physicians before the educational intervention. Following the seminar, the proportion of death certificates with errors decreased to 9% (p < 0.0001). The most common error in the completion of death certificates was the listing of the mechanism of death instead of the cause of death. Before the seminar, 56.8% listed respiratory or cardiac arrest as the immediate cause of death. None of the participants listed any mechanism of death after the educational intervention (p < 0.0001).ConclusionMajor errors in the completion of the correct cause of death on death certificates are common among medical residents. A simple educational intervention can dramatically improve the accuracy in the completion of death certificates by physicians.

African Ancestry Is Associated with Asthma Risk in African Americans

Background Asthma is a common complex condition with clear racial and ethnic differences in both prevalence and severity. Asthma consultation rates, mortality, and severe symptoms are greatly increased in African descent populations of developed countries. African ancestry has been associated with asthma, total serum IgE and lower pulmonary function in African-admixed populations. To replicate previous findings, here we aimed to examine whether African ancestry was associated with asthma susceptibility in African Americans. In addition, we examined for the first time whether African ancestry was associated with asthma exacerbations. Methodology/Principal Findings After filtering for self-reported ancestry and genotype data quality, samples from 1,117 self-reported African-American individuals from New York and Baltimore (394 cases, 481 controls), and Chicago (321 cases followed for asthma exacerbations) were analyzed. Genetic ancestry was estimated based on ancestry informative markers (AIMs) selected for being highly divergent among European and West African populations (95 AIMs for New York and Baltimore, and 66 independent AIMs for Chicago). Among case-control samples, the mean African ancestry was significantly higher in asthmatics than in non-asthmatics (82.0±14.0% vs. 77.8±18.1%, mean difference 4.2% [95% confidence interval (CI):2.0–6.4], p<0.0001). This association remained significant after adjusting for potential confounders (odds ratio: 4.55, 95% CI: 1.69–12.29, p = 0.003). African ancestry failed to show an association with asthma exacerbations (p = 0.965) using a model based on longitudinal data of the number of exacerbations followed over 1.5 years. Conclusions/Significance These data replicate previous findings indicating that African ancestry constitutes a risk factor for asthma and suggest that elevated asthma rates in African Americans can be partially attributed to African genetic ancestry.

Serum Lipopolysaccharide Binding Protein Levels Predict Severity of Lung Injury and Mortality in Patients with Severe Sepsis

Background There is a need for biomarkers insuring identification of septic patients at high-risk for death. We performed a prospective, multicenter, observational study to investigate the time-course of lipopolysaccharide binding protein (LBP) serum levels in patients with severe sepsis and examined whether serial serum levels of LBP could be used as a marker of outcome. Methodology/Principal Findings LBP serum levels at study entry, at 48 hours and at day-7 were measured in 180 patients with severe sepsis. Data regarding the nature of infections, disease severity, development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and intensive care unit (ICU) outcome were recorded. LBP serum levels were similar in survivors and non-survivors at study entry (117.4±75.7 µg/mL vs. 129.8±71.3 µg/mL, P = 0.249) but there were significant differences at 48 hours (77.2±57.0 vs. 121.2±73.4 µg/mL, P<0.0001) and at day-7 (64.7±45.8 vs. 89.7±61.1 µg/ml, p = 0.017). At 48 hours, LBP levels were significantly higher in ARDS patients than in ALI patients (112.5±71.8 µg/ml vs. 76.6±55.9 µg/ml, P = 0.0001). An increase of LBP levels at 48 hours was associated with higher mortality (odds ratio 3.97; 95%CI: 1.84–8.56; P<0.001). Conclusions/Significance Serial LBP serum measurements may offer a clinically useful biomarker for identification of patients with severe sepsis having the worst outcomes and the highest probability of developing sepsis-induced ARDS.

Experimental ventilator-induced lung injury: exacerbation by positive end-expiratory pressure.

Background:Previous experimental studies of ventilator-induced lung injury have shown that positive end-expiratory pressure (PEEP) is protective. The authors hypothesized that the application of PEEP during volume-controlled ventilation with a moderately high tidal volume (VT) in previously healthy in vivo rats does not attenuate ventilator-induced lung injury if the peak airway pressure markedly increases during the application of PEEP. Methods:Sixty healthy, male Sprague-Dawley rats were anesthetized and randomized to be mechanically ventilated for 4 h at (1) VT of 6 ml/kg, (2) VT of 20 ml/kg, or (3) VT of 20 ml/kg plus 10 cm H2O of PEEP. Peak airway pressures, gas exchange, histologic evaluation, mortality, total lung tissue cytokine gene expression, and serum cytokine concentrations were analyzed. Results:Peak airway pressures exceeded 30 cm H2O with high VT plus PEEP. All lungs ventilated with high VT had perivascular edema and inflammatory infiltrates. In addition, those ventilated with PEEP had small hemorrhages foci. Five animals from the high VT plus PEEP group died (P = 0.020). Animals ventilated with high VT (with or without PEEP) had a substantial increase in serum interleukin-6 (P = 0.0002), and those ventilated with high VT plus PEEP had a 5.5-fold increase in systemic levels of tumor necrosis factor-alpha (P = 0.007). Conclusions:In contrast to previous reports, PEEP exacerbated lung damage and contributed to fatal outcome in an in vivo, mild overdistension model of ventilator-induced lung injury in previously healthy rats. That is, the addition of high PEEP to a constant large VT causes injury in previously healthy animals.

Association of IL-6 gene polymorphisms and COPD in a Spanish Population

Interleukin-6 (IL-6) is a potential mediator of systemic effects of Chronic Obstructive Pulmonary Disease (COPD). In the present case-control study we investigated the association of promoter polymorphisms of this gene and COPD in a cohort of 191 patients, smokers without COPD (n=75) and a healthy control population (n=296). Besides spirometry, exercise capacity (6MWD, 6 min walking distance) and body mass index (BMI) were measured in COPD patients. Genotyping of the IL-6 polymorphisms at positions -174, -572 and -597 was performed. The -597G/A and -174G/C polymorphisms were not associated with the disease. However, the -572G/C polymorphism was significantly associated with COPD susceptibility under a dominant model of inheritance. The frequency of the genotypes containing the C allele was significantly lower in the COPD cases (9.9%) compared with the healthy control group (16.9%) and smokers (23.1%), (OR=0.46, p=0.032 and OR=0.28, p=0.012, respectively). The GCG (-597/-572/-174) haplotype was significantly associated with the disease (OR=0.37, p=0.022, COPD cases vs. healthy subjects and OR=0.17, p=0.011, COPD cases vs. smokers). Moreover, a borderline association was also found for the -572G allele and hypoxemia (PaO(2)<60 mmHg) (p=0.05). Our data suggest that the IL-6 -572C allele may confer a diminished risk of developing COPD.

A risk tertiles model for predicting mortality in patients with acute respiratory distress syndrome: age, plateau pressure, and P(aO(2))/F(IO(2)) at ARDS onset can predict mortality.

BACKGROUND: Predicting mortality has become a necessary step for selecting patients for clinical trials and defining outcomes. We examined whether stratification by tertiles of respiratory and ventilatory variables at the onset of acute respiratory distress syndrome (ARDS) identifies patients with different risks of death in the intensive care unit. METHODS: We performed a secondary analysis of data from 220 patients included in 2 multicenter prospective independent trials of ARDS patients mechanically ventilated with a lung-protective strategy. Using demographic, pulmonary, and ventilation data collected at ARDS onset, we derived and validated a simple prediction model based on a population-based stratification of variable values into low, middle, and high tertiles. The derivation cohort included 170 patients (all from one trial) and the validation cohort included 50 patients (all from a second trial). RESULTS: Tertile distribution for age, plateau airway pressure (Pplat), and PaO2/FIO2 at ARDS onset identified subgroups with different mortalities, particularly for the highest-risk tertiles: age (> 62 years), Pplat (> 29 cm H2O), and PaO2/FIO2 (< 112 mm Hg). Risk was defined by the number of coexisting high-risk tertiles: patients with no high-risk tertiles had a mortality of 12%, whereas patients with 3 high-risk tertiles had 90% mortality (P < .001). CONCLUSIONS: A prediction model based on tertiles of patient age, Pplat, and PaO2/FIO2 at the time the patient meets ARDS criteria identifies patients with the lowest and highest risk of intensive care unit death.