Pilar Fernández-Segoviano

Acute respiratory distress syndrome: Underrecognition by clinicians and diagnostic accuracy of three clinical definitions*

Objective:To determine and compare the diagnostic accuracy of three clinical definitions of acute respiratory distress syndrome (ARDS): (1) the American-European consensus conference definition; (2) the lung injury score; and (3) a recently developed Delphi definition. A second objective was to determine the accuracy of clinical diagnoses of ARDS made in daily practice. Design:Independent comparison of autopsy findings with the daily status of clinical definitions, constructed with data abstracted retrospectively from medical records. Setting:Tertiary intensive care unit. Patients:One hundred thirty-eight patients from the period 1995 through 2001 who were autopsied after being mechanically ventilated. Interventions:Clinical ARDS diagnoses were determined daily without knowledge of autopsy results. Charts were reviewed for any mention of ARDS in the clinical notes. Autopsies were reviewed independently by two pathologists for the presence of diffuse alveolar damage. The sensitivity and specificity of the definitions were determined with use of diffuse alveolar damage at autopsy as the reference standard. Measurements and Main Results:Diffuse alveolar damage at autopsy was documented in 42 of 138 cases (30.4%). Only 20 of these 42 patients (47.6%) had any mention of ARDS in their chart. Sensitivities and specificities (95% confidence intervals) were as follows: American-European definition, 0.83 (0.72–0.95), 0.51 (0.41–0.61); lung injury score, 0.74 (0.61–0.87), 0.77 (0.69–0.86); and Delphi definition, 0.69 (0.55–0.83), 0.82 (0.75–0.90). Specificity was significantly higher for both the lung injury score and Delphi definition than for the American-European definition (p < .001 for both), whereas comparisons of sensitivity, which was higher for the American-European definition, were not significantly different (p = .34 and p = .07, respectively). Conclusions:Acute respiratory distress syndrome appears underrecognized by clinicians in patients who die with this syndrome. In this population, the specificities of existing clinical definitions vary considerably, which may be problematic for clinical trials.

Comparison of the Berlin Definition for Acute Respiratory Distress Syndrome with Autopsy

RATIONALE A revised definition of clinical criteria for acute respiratory distress syndrome (ARDS), the Berlin definition, was recently established to classify patients according to their severity. OBJECTIVE To evaluate the accuracy of these clinical criteria using diffuse alveolar damage (DAD) at autopsy as the reference standard. METHODS All patients who died and had a clinical autopsy in our intensive care unit over a 20-year period (1991-2010) were included. Patients with clinical criteria for ARDS were identified from the medical charts and were classified as mild, moderate, or severe according to the Berlin definition using PaO2/FiO2 oxygenation criteria. Microscopic analysis from each pulmonary lobe was performed by two pathologists. MEASUREMENTS AND MAIN RESULTS Among 712 autopsies analyzed, 356 patients had clinical criteria for ARDS at time of death, classified as mild (n = 49, 14%), moderate (n = 141, 40%), and severe (n = 166, 46%). Sensitivity was 89% and specificity 63% to identify ARDS using the Berlin definition. DAD was found in 159 of 356 (45%) patients with clinical criteria for ARDS (in 12, 40, and 58% of patients with mild, moderate, and severe ARDS, respectively). DAD was more frequent in patients who met clinical criteria for ARDS during more than 72 hours and was found in 69% of those with severe ARDS for 72 hours or longer. CONCLUSIONS Histopathological findings were correlated to severity and duration of ARDS. Using clinical criteria the revised Berlin definition for ARDS allowed the identification of severe ARDS of more than 72 hours as a homogeneous group of patients characterized by a high proportion of DAD.

Accuracy of clinical definitions of ventilator-associated pneumonia: comparison with autopsy findings.

METHODS We studied patients requiring mechanical ventilation for more than 48 hours who died in the intensive care unit and whose bodies were autopsied. We evaluated 3 clinical definitions of ventilator-associated pneumonia: loose definition, defined as chest radiograph infiltrates and 2 of 3 clinical criteria (leukocytosis, fever, purulent respiratory secretions); rigorous definition, defined as chest radiograph infiltrates and all of the clinical criteria; and a clinical pulmonary infection score higher than 6 points. Sensitivity, specificity, and likelihood ratios were calculated by using pathology pattern as criterion standard. RESULTS One hundred forty-two (56%) of the 253 patients included had histological criteria of pneumonia. Patients who met the clinical criteria of ventilator-associated pneumonia were 163 (64%) for the loose definition, 32 (13%) for the rigorous definition, and 109 (43%) for the clinical pulmonary infection score. The operative indexes (sensitivity and specificity) of each definition were as follows: loose definition, 64.8% and 36%; rigorous definition, 91% and 15.5%; and clinical pulmonary infection score higher than 6, 45.8% and 60.4%. The addition of microbiological data to the clinical definitions increased the specificity and decreased the sensitivity but not significantly. CONCLUSIONS Accuracy of 3 commonly used clinical definitions of ventilator-associated pneumonia was poor taking the autopsy findings as reference standard.

Massive brain injury enhances lung damage in an isolated lung model of ventilator-induced lung injury

Objective:To assess the influence of massive brain injury on pulmonary susceptibility to injury attending subsequent mechanical or ischemia/reperfusion stress. Design:Prospective experimental study. Setting:Animal research laboratory. Subjects:Twenty-four anesthetized New Zealand White rabbits randomized to control (n = 12) or induced brain injury (n = 12) group. Interventions:After randomization, brain injury was induced by inflation of an intracranial balloon-tipped catheter, and animals were ventilated with a tidal volume of 10 mL/kg and zero end-expiratory pressure for 120 mins. Following heart-lung block extraction, isolated and perfused lungs were subjected to injurious ventilation with peak airway pressure 30 cm H2O and positive end-expiratory pressure 5 cm H2O for 30 mins. Measurements and Main Results:No difference was observed between groups in gas exchange, lung mechanics, or hemodynamics during the 2-hr in vivo period following induction of brain injury. However, after 30 mins of ex vivo injurious mechanical ventilation, lungs from the brain injury group showed greater change in ultrafiltration coefficient, weight gain, and alveolar hemorrhage (all p < .05). Conclusions:Massive brain injury might increase lung vulnerability to subsequent injurious mechanical or ischemia-reperfusion insults, thereby increasing the risk of clinical posttransplant graft failure.

Ventilation-induced lung injury in rats is associated with organ injury and systemic inflammation that is attenuated by dexamethasone.

Objective:To determine whether mechanical ventilation using high tidal volume is associated with nonpulmonary organ dysfunction that can be attenuated by dexamethasone. Design:Prospective randomized animal intervention study. Setting:Animal care facility in a university hospital. Subjects:Sedated and tracheostomized male Sprague-Dawley rats. Interventions:Three groups of rats were ventilated with different strategies: tidal volume = 9 mL/kg, positive end-expiratory pressure = 8 cm H2O, control group (C); tidal volume = 35 mL/kg, positive end-expiratory pressure = 0 cm H2O, overventilated group (OV); and tidal volume = 35 mL/kg, positive end-expiratory pressure = 0 cm H2O, plus administration of 6 mg/kg dexamethasone intraperitoneally (OV + dexamethasone). All rats were ventilated for 75 mins with respiratory rate = 70 breaths/min, Fio2 = 0.35, and plateau time = 0. Measurements and Main Results:Mean arterial pressure and peak airway pressure were monitored. We measured arterial blood gases, aspartate aminotransferase, alanine aminotransferase, lactate, nitrates and nitrites, tumor necrosis factor-α, and interleukin-6 serum concentration. Lung slices were prepared for blind histologic examination. Heart tissue was analyzed for cyclooxygenase-1 and -2 expression (reverse transcription-polymerase chain reaction). Compared with the C group, the OV group showed hypotension; worsened gas exchange; increased aspartate aminotransferase, lactate, nitrates and nitrites, and interleukin-6 serum concentrations; and hyaline membrane formation in the lungs, as well as increased cyclooxygenase-1 and cyclooxygenase-2 expression in the heart. Dexamethasone prevented the pulmonary and cardiovascular injury and attenuated the increase in aspartate aminotransferase, nitrates and nitrites, interleukin-6, and cyclooxygenase-1 and cyclooxygenase-2 expression. Conclusions:High tidal volume ventilation induces cardiovascular, pulmonary, and liver injury as well as a systemic proinflammatory response. These changes are attenuated by dexamethasone, suggesting that inflammatory rather than purely hemodynamic mechanisms are involved in the changes induced by high tidal volume ventilation.

Contributions of vascular flow and pulmonary capillary pressure to ventilator-induced lung injury.

Objective:To evaluate the influence of vascular flow on ventilator-induced lung injury independent of vascular pressures. Design:Laboratory study. Setting:Hospital laboratory. Subjects:Thirty-two New Zealand White rabbits. Interventions:Thirty-two isolated perfused rabbit lungs were allocated into four groups: low flow/low pulmonary capillary pressure; high flow/high pulmonary capillary pressure; low flow/high pulmonary capillary pressure, and high flow/low pulmonary capillary pressure. All lungs were ventilated with peak airway pressure 30 cm H2O and positive end-expiratory pressure 5 cm H2O for 30 mins. Measurements and Main Results:Outcome measures included frequency of gross structural failure (pulmonary rupture), pulmonary hemorrhage, edema formation, changes in lung compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. Lungs exposed to high pulmonary vascular flow ruptured more frequently, displayed more hemorrhage, developed more edema, suffered larger decreases in compliance, and had larger increases in vascular resistance than lungs exposed to low vascular flows (p < .05 for each pairwise comparison between groups). Conclusions:These findings suggest that high pulmonary vascular flows might exacerbate ventilator-induced lung injury independent of their effects on pulmonary vascular pressures.

Clinical diagnoses and autopsy findings: Discrepancies in critically ill patients

Objectives:To determine the proportion of clinical errors by comparing clinical and pathological diagnoses, and to evaluate changes of errors over time. Design:We conducted a prospective study of all consecutive autopsies performed on patients who died in the intensive care unit of the Hospital Universitario de Getafe, Madrid, Spain, between January 1982 and December 2007. The diagnostic errors were classified in two categories: class I errors that were major misdiagnoses with direct impact on therapy, and class II diagnostic errors which comprised major unexpected findings that probably would not have changed therapy. Main Results:Of 2,857 deaths during the study period, autopsies were performed in 866 patients (30.3%). Autopsy reports were available in 834 patients, of whom 63 (7.5%) had class I errors and 95 (11.4%) had type II errors. The most frequently missed diagnoses were pulmonary embolism, pneumonia, secondary peritonitis, invasive aspergillosis, endocarditis and myocardial infarction. The autopsy did not determine the cause of death in 22 patients (2.6%). Our rate of diagnostic discrepancy remained relatively constant over time, and the conditions leading to discrepancies have slightly changed, with pneumonia showing a decline in diagnostic accuracy in the last years. Conclusions:This study found significant discrepancies in 18.5% of patients who underwent autopsy, 7.5% of them were diagnoses with impact on therapy and outcome. This reinforces the importance of the postmortem examination in confirming diagnostic accuracy and improving the quality of care of critically ill patients.

Modulation of systemic hemodynamics by exogenous L-arginine in normal and bacteremic sheep.

OBJECTIVE To investigate whether exogenous L-arginine, the substrate for nitric oxide synthase, modulates systemic hemodynamics in sepsis. DESIGN Prospective, controlled study in a sheep model of sepsis. SETTING Animal research facility in a university hospital. SUBJECTS Adult sheep weighing between 35 and 55 kg. INTERVENTIONS Adult sheep sedated and mechanically ventilated, were monitored with a pulmonary arterial catheter and an ileal tonometer. Four groups of sheep were studied: nonseptic, septic, nonseptic treated with L-arginine, and septic treated with L-arginine. Sepsis was induced by the intravenous administration of Escherichia coli (1.5x10(8) colony-forming units/kg for 30 mins). L-arginine was administered as an intravenous bolus (200 mg/kg for 10 mins) before the septic challenge followed by 200 mg/kg/hr for 300 mins. MEASUREMENTS AND MAIN RESULTS Sepsis induced a state of acidosis, hyperlactatemia, hypoxemia, and gastric intramucosal acidosis. During the first 30 mins after the septic challenge, there was a decrease in cardiac index and blood pressure, and an increase in systemic vascular resistance. Thereafter, blood pressure returned to baseline values, and systemic vascular resistance fell. Treatment with L-arginine in nonseptic sheep did not induce any biochemical or hemodynamic effect. In septic sheep, treatment with L-arginine was associated with a greater increase in systemic vascular resistance during the first 30 mins, and a more marked decrease in blood pressure and systemic vascular resistance after 180 mins. CONCLUSIONS Exogenous administration of L-arginine does not induce hemodynamic effects in normal animals, exacerbates the acute vasoconstriction associated with the intravenous infusion of E. coli and potentiates the sepsis-induced vasodilation. Our results suggest that a) nitric oxide production is not constitutively modulated by exogenous L-arginine, b) L-arginine probably enhances the sepsis-induced sympathetic discharge, and c) L-arginine becomes rate-limiting for the formation of nitric oxide at approximately 3 hrs after the initiation of the septic challenge.

High-tidal Volume Ventilation Aggravates Sepsis-induced Multiorgan Dysfunction In A Dexamethasone-inhibitable Manner

High-tidal volume (Vt) ventilation induces lung injury and systemic inflammation, and small doses of endotoxin have been shown to increase the susceptibility to ventilation-induced lung injury. We studied whether high-Vt ventilation increases organ injury in a model of bacterial sepsis and whether an anti-inflammatory treatment averts those changes. Anesthetized rats, monitored with an arterial catheter and a blood flow probe in the aorta, were assigned to one of four different groups: nonseptic low-Vt group (Vt = 9 mL/kg, positive end-expiratory pressure = 8 cm H2O, control group), septic low-Vt group, septic overventilated group (Vt = 35 mL/kg, positive end-expiratory pressure = 0), and septic overventiled group pretreated with dexamethasone (6 mg/kg i.p., 30 min before mechanical ventilation). Rats were ventilated for 75 min. Septic rats had undergone cecal ligation and puncture 48 h before mechanical ventilation. We measured hemodynamics, lung mechanics, blood chemistry and gas exchange, liver and heart expression of cyclooxygenase 2 (COX-2) and iNOS (reverse transcriptase-polymerase chain reaction), and lung histopathology. Septic rats showed metabolic acidosis, hiperlactatemia, lung and liver injury, increased liver and heart COX-2, and liver iNOS expression. High-Vt ventilation of septic rats was associated with more marked liver injury and heart COX-2 upregulation, as well as lung inflammation and dysfunction (impaired oxygenation, increased bronchoalveolar lavage fluid protein and IL-6 concentration, decreased thoracic system compliance) and systemic hypotension. All inflammatory changes, as well as pulmonary and vascular dysfunctions, were abrogated by dexamethasone. High-Vt ventilation in bacterial sepsis upregulates the inflammatory response and aggravates the sepsis-induced cardiovascular, pulmonary, and liver dysfunction. Dexamethasone averts mechanical ventilation-induced changes under conditions of bacterial sepsis.

Classification of renal proteinuria: a simple algorithm.

Abstract Total protein, albumin, α1-microglobulin, and immunoglobulin G (IgG) were analyzed in 1622 urine samples without Bence-Jones proteinuria or gross hematuria. There was correlation with the histological picture obtained on renal biopsy in 61 patients. We established 24-h reference intervals for α1-microglobulin and IgG on 659 urine samples with total protein and albumin excretion rates below 100 mg/24 h and 30 mg/24 h, respectively, and creatinine clearance above 80 ml/min. The central 95% reference interval was found to be between 4 and 17 mg/24 h for α1-microglobulin and between 3 and 8.5 mg/24 h for IgG. In 80 urine samples with albumin excretion rate above 30 mg/24 h and α1-microglobulin and IgG within their reference intervals, we analyzed the 95% central interval of the distribution of the IgG/albumin ratios, and it was found to be within 0.01 and 0.20 (0.90 confidence interval: 0.17–0.24). Proteinuria was considered to be of the selective glomerular type if the albumin excretion rate was abnormal and the IgG/albumin ratio was under 0.20, even when the IgG excretion was within a pathological range. For the classification of proteinuria as predominantly tubular, we estimated the α1-microglobulin/albumin ratio in 173 urine samples with normal excretion rates of albumin and IgG and pathological excretion of α1-microglobulin. The discriminating value of 0.91 (0.90 confidence interval: 0.78–1.08) was accepted in order to define proteinuria of a tubular origin in the presence of a pathological albumin excretion rate. The association between albumin and IgG excretion rates and tubular reabsorption of the α1-microglobulin normally filtered by the glomerulus was studied in 33 urine samples from patients with no histologically significant tubulo-interstitial or vascular disease and a serum creatinine concentration below 141 μmol/l. The optimal curve-fitting function between albumin plus IgG and α1-microglobulin excretion rates was of the quadratic type (r=0.927). Mixed proteinuria was considered when both, albumin and α1-microglobulin excretion rates were pathological and could not be included in the previously described groups.