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Arthur S Slutsky

Publications and source records attributed to Arthur S Slutsky.

At least 55 records · Page 3Linked to original sources
PubMed2004

Inflammation and the acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of non-cardiogenic pulmonary oedema associated with bilateral pulmonary infiltrates, stiff lungs and refractory hypoxaemia. ARDS is characterized by an explosive acute inflammatory response in the lung parenchyma, leading to alveolar oedema, decreased lung compliance and, ultimately, hypoxaemia. Although our understanding of the causes and pathophysiology of ARDS has increased, the mortality rate remains in the range of 30-50%. No major advances in pharmacological therapy have been achieved. Mechanical ventilation is the main therapeutic intervention in the management of ARDS. The only approach that has been shown to reduce the inflammatory response and mortality is the use of lung-protective ventilatory strategy with a low tidal volume and high positive-end expiratory pressure. This chapter will review the current state of the literature on the pathogenesis of ARDS and ventilatory and pharmacotherapy approaches to its management.

Acute Disease↗
PubMed2004

Effect of mechanical ventilation on cytokine response to intratracheal lipopolysaccharide.

BACKGROUND: Mechanical ventilation may cause lung injury through the excitation of an inflammatory response and the release of mediators, such as cytokines. The authors tested the hypothesis that intratracheal lipopolysaccharide amplifies the cytokine response to mechanical ventilation. METHODS: Rat lungs were intratracheally instilled with lipopolysaccharide followed by ex vivo mechanical ventilation for 2 h with low tidal volume of 7 ml/kg with 3 cm H2O positive end-expiratory pressure (PEEP), high tidal volume of 40 ml/kg with zero PEEP, medium tidal volume of 15 ml/kg with 3 cm H2O PEEP, or medium tidal volume and zero PEEP. RESULTS: In the absence of lipopolysaccharide, lung lavage concentrations of tumor necrosis factor and interleukin 1 beta but not macrophage inflammatory protein 2 were significantly higher in lungs ventilated at high tidal volume/zero PEEP than at low tidal volume. There was a marked increase in lavage tumor necrosis factor and macrophage inflammatory protein 2 concentrations in lungs ventilated at low tidal volume after exposure to intratracheal lipopolysaccharide at doses of 100 ng/ml or greater. However, in lungs ventilated at high tidal volume, this response to lipopolysaccharide was markedly reduced. In addition, the number of alveolar macrophages recovered in the lavage was significantly lower in lungs ventilated at high tidal volume. CONCLUSION: Ventilation strategy can modify lung cytokine responses to lipopolysaccharide, likely through an effect on the alveolar macrophage population.

Administration, Inhalation↗
PubMed2004

Effects of cyclic opening and closing at low- and high-volume ventilation on bronchoalveolar lavage cytokines.

OBJECTIVE: To examine the mechanisms of ventilator-induced lung injury at low and high lung volumes. DESIGN: Prospective, randomized, laboratory study. SETTING: University research laboratory. SUBJECTS: Eighty-eight adult male Sprague-Dawley rats. INTERVENTIONS: Mechanical ventilation using low and high lung volumes. MEASUREMENTS AND MAIN RESULTS: An ex vivo rat lung model was used. In study I (ventilation at low lung volumes), rat lungs (n = 40) were randomly assigned to various modes of ventilation: a) opening and closing with positive end-expiratory pressure (PEEP; control): tidal volume 7 mL/kg and PEEP 5 cm H2O; b) opening and closing from zero end-expiratory pressure (ZEEP): tidal volume 7 mL/kg and PEEP 0; or c) atelectasis. Peak inspiratory pressure was monitored at the beginning and end of 3 hrs of ventilation. At the end of 3 hrs of ventilation, the lungs were lavaged, and the concentrations of tumor necrosis factor-alpha, macrophage inflammatory protein-2, and interleukin-6 cytokines were measured in the lavage. In study II (ventilation at high volumes), rat lungs (n = 45) were randomly assigned to a) cyclic lung stretch: pressure-controlled ventilation, peak inspiratory pressure 50 cm H2O, and PEEP 8 cm H2O; b) continuous positive airway pressure at 50 cm H2O (CPAP50); or c) CPAP at the mean airway pressure of the cyclic stretch group (CPAP 31 cm H2O). Bronchoalveolar lavage cytokine concentrations (tumor necrosis factor-alpha, macrophage inflammatory protein-2, and interleukin-6) were measured at the end of 3 hrs of ventilation. In the low volume study, there was no difference in bronchoalveolar lavage cytokine concentrations between the PEEP group and the atelectatic group. All cytokines were significantly higher in the ZEEP group compared with the atelectasis group. Macrophage inflammatory protein-2 was significantly higher in the ZEEP group compared with the PEEP group. Lung compliance, as reflected by change in peak inspiratory pressure, was also significantly worse in the ZEEP compared with the PEEP group. In the high-volume study, tumor necrosis factor-alpha and interleukin-6 were significantly higher in the cyclic stretch group compared with the CPAP 31 group. There was no significant difference between the cytokine concentrations in the cyclic stretch group compared with the CPAP 50 group. CONCLUSION: We conclude that at low lung volumes, cyclic opening and closing from ZEEP leads to greater increases in bronchoalveolar lavage cytokines than atelectasis. With high-volume ventilation, over time, the degree of overdistension is more associated with increases in bronchoalveolar lavage cytokines than cyclic opening and closing alone.

Animals↗
PubMed2004

Airway pressure-time curve profile (stress index) detects tidal recruitment/hyperinflation in experimental acute lung injury.

OBJECTIVE: To evaluate whether the shape of the airway pressure-time (Paw-t) curve during constant flow inflation corresponds to radiologic evidence of tidal recruitment or tidal hyperinflation in an experimental model of acute lung injury. DESIGN: Prospective randomized laboratory animal investigation. SETTING: Department of Clinical Physiology, University of Uppsala, Sweden. SUBJECTS: Anesthetized, paralyzed, and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced by lung lavage. During constant inspiratory flow, the Paw-t curve was fitted to a power equation: airway pressure =a x time + c, where coefficient b (stress index) describes the shape of the curve:b = 1, straight curve; b < 1, progressive increase in slope; and b > 1, progressive decrease in slope. Tidal volume (Vt) was 6 mL/kg, and positive end-expiratory pressure was set to obtain a b value between 0.9 and 1.1 before (b = 1) and after (b = 1 after recruiting maneuver) application of a recruiting maneuver. Positive end-expiratory pressure was decreased and Vt increased to obtain 0.9 >b > 0.8 and 0.8 >b > 0.6, whereas positive end-expiratory pressure and Vt were both increased to obtain 1.3 >b > 1.1 and 1.5 >b > 1.3. Experimental conditions sequence was random. MEASUREMENTS AND MAIN RESULTS: Pulmonary computed tomography was obtained during end-expiratory and end-inspiratory occlusions. Tidal recruitment was quantified as nonaerated (between -100 and +100 Hounsfield units) lung area at end-expiration minus end-inspiration. Tidal hyperinflation was quantified as hyperinflated (between -900 and -1000 Hounsfield units) lung area at end-inspiration minus end-expiration. Computed tomography images showed that tidal recruitment and tidal hyperinflation corresponded to b < 1 and b > 1, respectively. Stress index values and tidal recruitment and tidal hyperinflation values were significantly correlated (R =.917 and R =.911, p <.0001, respectively). CONCLUSIONS: Shape of the Paw-t curve detects tidal recruitment and tidal hyperinflation.

Animals↗
PubMed2003

Modulation of bacterial growth by tumor necrosis factor-alpha in vitro and in vivo.

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in innate immunity. Recent in vitro studies have shown that TNF-alpha may also serve as a growth factor for some bacteria. We examined the physiologic relevance of this phenomenon both in vitro and in vivo. Recombinant mouse TNF-alpha increased in vitro proliferation of Escherichia coli but not Pseudomonas aeruginosa in a concentration-dependent manner, and this effect was attenuated by anti-TNF-alpha antibodies. However, in vivo, TNF-alpha gene-deficient (TNF-alpha-/-) mice showed higher mortality than wild-type (TNF-alpha+/+) mice after inoculation of intranasal bacteria. An impaired bacterial clearance in TNF-alpha-/- mice was associated with decreased systemic concentrations of chemokine macrophage inflammatory protein-2, reduced pulmonary neutrophil recruitment, and depressed expression of neutrophil CD11b and CD16/CD32, suggesting that the effect of TNF-alpha on E. coli growth was outweighed by the recruited neutrophils. We also demonstrated that neutropenic TNF-alpha+/+ mice had approximately 100-fold higher E. coli counts in their lungs than TNF-alpha-/- mice, although survival rates in both groups were similar. We conclude that TNF-alpha augments E. coli growth in vitro and in vivo. However, in vivo, this effect becomes only apparent in neutropenic animals. The relevance of these findings for immune compromised patients remains to be investigated.

Animals↗
PubMed2003

Critically ill patients with severe acute respiratory syndrome.

CONTEXT: Severe acute respiratory syndrome (SARS) is a newly recognized infectious disease capable of causing severe respiratory failure. OBJECTIVE: To determine the epidemiological features, course, and outcomes of patients with SARS-related critical illness. DESIGN, SETTING, AND PATIENTS: Retrospective case series of 38 adult patients with SARS-related critical illness admitted to 13 intensive care units (ICUs) in the Toronto area between the onset of the outbreak and April 15, 2003. Data were collected daily during the first 7 days in the ICUs, and patients were followed up for 28 days. MAIN OUTCOME MEASURES: The primary outcome was mortality at 28 days after ICU admission. Secondary outcomes included rate of SARS-related critical illness, number of tertiary care ICUs and staff placed under quarantine, and number of health care workers (HCWs) contracting SARS secondary to ICU-acquired transmission. RESULTS: Of 196 patients with SARS, 38 (19%) became critically ill, 7 (18%) of whom were HCWs. The median (interquartile range [IQR]) age of the 38 patients was 57.4 (39.0-69.6) years. The median (IQR) duration between initial symptoms and admission to the ICU was 8 (5-10) days. Twenty-nine (76%) required mechanical ventilation and 10 of these (34%) experienced barotrauma. Mortality at 28 days was 13 (34%) of 38 patients and for those requiring mechanical ventilation, mortality was 13 (45%) of 29. Six patients (16%) remained mechanically ventilated at 28 days. Two of these patients had died by 8 weeks' follow-up. Patients who died were more often older, had preexisting diabetes mellitus, and on admission to hospital were more likely to have bilateral radiographic infiltrates. Transmission of SARS in 6 study ICUs led to closure of 73 medical-surgical ICU beds. In 2 university ICUs, 164 HCWs were quarantined and 16 (10%) developed SARS. CONCLUSIONS: Critical illness was common among patients with SARS. Affected patients had primarily single-organ respiratory failure, and half of mechanically ventilated patients died. The SARS outbreak greatly strained regional critical care resources.

APACHE↗
PubMed2003

Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group.

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure that result from acute pulmonary edema and inflammation. The development of ALI/ARDS is associated with several clinical disorders including direct pulmonary injury from pneumonia and aspiration as well as indirect pulmonary injury from trauma, sepsis, and other disorders such as acute pancreatitis and drug overdose. Although mortality from ALI/ARDS has decreased in the last decade, it remains high. Despite two major advances in treatment, low VT ventilation for ALI/ARDS and activated protein C for severe sepsis (the leading cause of ALI/ARDS), additional research is needed to develop specific treatments and improve understanding of the pathogenesis of these syndromes. The NHLBI convened a working group to develop specific recommendations for future ALI/ARDS research. Improved understanding of disease heterogeneity through use of evolving biologic, genomic, and genetic approaches should provide major new insights into pathogenesis of ALI. Cellular and molecular methods combined with animal and clinical studies should lead to further progress in the detection and treatment of this complex disease.

Academies and Institutes↗
PubMed2003

Identification of severe acute respiratory syndrome in Canada.

BACKGROUND: Severe acute respiratory syndrome (SARS) is a condition of unknown cause that has recently been recognized in patients in Asia, North America, and Europe. This report summarizes the initial epidemiologic findings, clinical description, and diagnostic findings that followed the identification of SARS in Canada. METHODS: SARS was first identified in Canada in early March 2003. We collected epidemiologic, clinical, and diagnostic data from each of the first 10 cases prospectively as they were identified. Specimens from all cases were sent to local, provincial, national, and international laboratories for studies to identify an etiologic agent. RESULTS: The patients ranged from 24 to 78 years old; 60 percent were men. Transmission occurred only after close contact. The most common presenting symptoms were fever (in 100 percent of cases) and malaise (in 70 percent), followed by nonproductive cough (in 100 percent) and dyspnea (in 80 percent) associated with infiltrates on chest radiography (in 100 percent). Lymphopenia (in 89 percent of those for whom data were available), elevated lactate dehydrogenase levels (in 80 percent), elevated aspartate aminotransferase levels (in 78 percent), and elevated creatinine kinase levels (in 56 percent) were common. Empirical therapy most commonly included antibiotics, oseltamivir, and intravenous ribavirin. Mechanical ventilation was required in five patients. Three patients died, and five have had clinical improvement. The results of laboratory investigations were negative or not clinically significant except for the amplification of human metapneumovirus from respiratory specimens from five of nine patients and the isolation and amplification of a novel coronavirus from five of nine patients. In four cases both pathogens were isolated. CONCLUSIONS: SARS is a condition associated with substantial morbidity and mortality. It appears to be of viral origin, with patterns suggesting droplet or contact transmission. The role of human metapneumovirus, a novel coronavirus, or both requires further investigation.

Adult↗
PubMed2003

One-year outcomes in survivors of the acute respiratory distress syndrome.

BACKGROUND: As more patients survive the acute respiratory distress syndrome, an understanding of the long-term outcomes of this condition is needed. METHODS: We evaluated 109 survivors of the acute respiratory distress syndrome 3, 6, and 12 months after discharge from the intensive care unit. At each visit, patients were interviewed and underwent a physical examination, pulmonary-function testing, a six-minute-walk test, and a quality-of-life evaluation. RESULTS: Patients who survived the acute respiratory distress syndrome were young (median age, 45 years) and severely ill (median Acute Physiology, Age, and Chronic Health Evaluation score, 23) and had a long stay in the intensive care unit (median, 25 days). Patients had lost 18 percent of their base-line body weight by the time they were discharged from the intensive care unit and stated that muscle weakness and fatigue were the reasons for their functional limitation. Lung volume and spirometric measurements were normal by 6 months, but carbon monoxide diffusion capacity remained low throughout the 12-month follow-up. No patients required supplemental oxygen at 12 months, but 6 percent of patients had arterial oxygen saturation values below 88 percent during exercise. The median score for the physical role domain of the Medical Outcomes Study 36-item Short-Form General Health Survey (a health-related quality-of-life measure) increased from 0 at 3 months to 25 at 12 months (score in the normal population, 84). The distance walked in six minutes increased from a median of 281 m at 3 months to 422 m at 12 months; all values were lower than predicted. The absence of systemic corticosteroid treatment, the absence of illness acquired during the intensive care unit stay, and rapid resolution of lung injury and multiorgan dysfunction were associated with better functional status during the one-year follow-up. CONCLUSIONS: Survivors of the acute respiratory distress syndrome have persistent functional disability one year after discharge from the intensive care unit. Most patients have extrapulmonary conditions, with muscle wasting and weakness being most prominent.

APACHE↗
PubMed2003

Predicting length of stay out of hospital following lung resection using preoperative health status measures.

Studies evaluating predictors of operative outcome for lung resection have focused on physiological measures of cardiorespiratory impairment, but these have proved inadequate. This study evaluated the predictive abilities of six preoperative variables: the global quality of life (QL), social function (SF), and emotional function (EF) scales of the European Organization for the Research and Treatment of Cancer's (EORTC) QLQ-C30 questionnaire, 6-min walk distance (6MWD), forced expiratory volume (FEV1), and diffusion capacity (DLCO). Operative outcome was represented by the surrogate measure length of stay, out of hospital within the first 30 days (LOSOH). A single-centre prospective cohort study evaluating 70 subjects was conducted using multiple regression. LOSOH was bimodally distributed, therefore analysis was undertaken for the entire sample and for two separate groups (A and B). Group B (n = 4) experienced severe complications (LOSOH = 0-5 days) and was too small for statistical analysis. Group A (n = 66) suffered fewer and less severe complications (LOSOH = 14-26 days). For the entire sample, age was the sole predictor of LOSOH (R2 = 0.123, p = 0.003). In Group A, the strongest predictors of LOSOH were global QL score and 6MWD (R2 = 0.224, p < 0.001). LOSOH was inversely correlated with complications. While it remains difficult to predict severe complications in this population, within Group A, health status measures demonstrated a limited ability to predict LOSOH.

Aged↗
PubMed2003

Mechanical ventilation may increase susceptibility to the development of bacteremia.

OBJECTIVE: We examined the hypothesis that mechanical ventilation with a potentially injurious strategy would predispose animals to the detrimental effects of subsequent instillation of bacteria. DESIGN: Interventional animal study. SETTING: A university hospital research laboratory. SUBJECTS: Fifty Sprague-Dawley male rats. INTERVENTIONS: Rats were anesthetized and randomized to receive a protective (tidal volume 7 mL/kg, positive end-expiratory pressure 5 cm H(2)O, n = 25) or an injurious ventilatory strategy (tidal volume 21 mL/kg, zero positive end-expiratory pressure, n = 25). Hemodynamics were similar during the 1-hr ventilation period in the two groups. Animals were then disconnected from the ventilator and Pseudomonas aeruginosa was instilled intratracheally before extubation. Thereafter, animals breathed spontaneously; mortality rate was assessed up to 48 hrs, at which time the animals were killed. MEASUREMENTS AND MAIN RESULTS: The 48-hr mortality rate was 28% in the protective group and 40% in the injurious group (p = not significant). A positive bacterial culture from the lung was obtained in 56% of the surviving rats in the low tidal volume group and 67% in the high tidal volume group (p =.059). A positive blood bacterial culture was found in 11% of the low tidal volume group and 33% in the high tidal volume group (p <.05). The absolute bacterial count in the blood was lower in the low tidal volume group compared with the high tidal volume group (p <.05). Concentrations of blood tumor necrosis factor-alpha and macrophage inflammatory protein-2, and lung macrophage inflammatory protein-2 at 48 hrs were significantly higher in the low tidal volume group than in the high tidal volume group. CONCLUSIONS: An injurious ventilatory strategy predisposes animals to subsequent bacteremia associated with an impaired host defense reflected by cytokine response.

Airway Resistance↗
PubMed2003

Effects of albumin and Ringer's lactate on production of lung cytokines and hydrogen peroxide after resuscitated hemorrhage and endotoxemia in rats.

RATIONALE AND HYPOTHESIS: Acute lung injury is a frequent complication of severe sepsis or blood loss and is often associated with an excessive inflammatory response requiring mechanical ventilation. We tested the hypothesis that the types of fluids used during early resuscitation have an important effect on the evolution of lung injury. METHODS: Rats were subjected to either hemorrhage or endotoxemia for 1 hr, followed by resuscitation to a controlled mean blood pressure with Ringer's lactate, 5% albumin, or 25% albumin for 1 hr. After resuscitation, blood cytokine levels were measured. The lung was then excised and ventilated with a tidal volume of 30 mL/kg for 2 hrs. RESULTS: The volume of fluids required was significantly smaller in the albumin-treated groups than in the Ringer's lactate groups. In the hemorrhagic shock model, plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and macrophage inflammatory protein-2 were significantly lower and interleukin-10 was significantly higher in the albumin-treated groups compared with the Ringer's lactate-treated group. The levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were lower and interleukin-10 was higher in the albumin-treated groups than in the Ringer's lactate group. The decreased cytokine production was associated with a reduction of hydrogen peroxide formation with albumin resuscitation. The lung wet/dry ratio was lower in the 5% albumin (0.54 +/- 0.01) and 25% albumin (0.55 +/- 0.02) groups than in the Ringer's lactate group (0.62 +/- 0.02; both p <.05). These effects of albumin seen in the hemorrhagic shock model were not observed in the endotoxic shock model. CONCLUSIONS: We conclude that resuscitation with albumin may have utility in reducing ventilator-induced lung injury after hemorrhagic shock, but not after endotoxic shock. These findings suggest that the mechanisms leading to ventilator-induced lung injury after hemorrhage differ from those after endotoxemia.

Albumins↗
PubMed2002

ARDSNet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory pressure in patients with acute respiratory distress syndrome.

The ARDSNet trial revealed that the use of a smaller tidal volume (VT) reduced mortality by 22%. However, three earlier studies that lowered VT did not find a decrease in mortality. We tested the hypothesis that the increased respiratory rate used in the ARDSNet lower VT strategy might have led to intrinsic positive end-expiratory pressure (PEEP(i)), raising total PEEP (PEEP(total)). Ten patients with acute respiratory distress syndrome (ARDS) were ventilated using the ARDSNet lower VT protocol. Respiratory rate was then reduced (10-15 breaths/minute) to obtain a VT of 12 ml/kg (ARDSNet traditional VT). PEEP on the ventilator (PEEP(nominal): 10.1 +/- 0.7 cm H2O), FIO2 (0.7 +/- 0.1), and minute ventilation (VE: 12.4 +/- 1.7 L/minute) were set using the ARDSNet protocol and maintained constant during the two ventilatory strategies. Values of airway pressure at end-expiration of a regular breath (PEEP(external)) and 3-5 seconds after the onset of an end-expiratory occlusion (PEEP(total)) were measured. PEEP(i) was calculated by subtracting PEEP(external) from PEEP(total). PEEP(total) and PEEP(i) were, respectively, 16.3 +/- 2.9 and 5.8 +/- 3.0 cm H2O during the lower VT strategy and 11.7 +/- 0.9 and 1.4 +/- 1.0 cm H2O during the traditional VT strategy (p < 0.01). The reduced mortality observed with the ARDSNet strategy may have been due to the protective effect of a higher PEEP(total).

Adult↗
PubMed2002

Mechanical ventilation alters the immune response in children without lung pathology.

OBJECTIVE: This study was undertaken to examine the hypothesis that mechanical ventilation in association with anesthesia would alter the cytokine profile in infants without preexisting lung pathology. DESIGN AND SETTING: Prospective observational study in pediatric intensive care unit in a university hospital. PATIENTS: Twelve infants who were subjected to an uncomplicated diagnostic cardiac catheterization procedure were studied. All subjects were ventilated with a volume control mode, 0.3 FIO(2), 4 cmH(2)O PEEP, and 10 ml/kg tidal volume. Volatile (servoflurane) anesthetics were given. MEASUREMENTS AND RESULTS: Tracheal aspirates and blood samples were obtained before and after 2 h of mechanical ventilation. In tracheal aspirates and in supernatants of stimulated whole-blood cultures cytokine concentrations were measured. In the tracheal aspirates the immune balance was characterized by a proinflammatory response pattern, with a significant increase in TNF-alpha and IL-6 concentrations; concentrations of anti-inflammatory mediators remained very low. The functional capacity of peripheral blood leukocytes to produce INF-gamma, TNF-alpha, and IL-6 in vitro was significantly decreased. This was accompanied by a significant decrease in the killing activity of natural killer cells. CONCLUSIONS: Two hours of servoflurane and mechanical ventilation using a tidal volume of 10 ml/kg is associated with remarkable changes in the immune response in infants without preexisting lung pathology undergoing cardiac catheterization. In the lungs the immune balance favors a proinflammatory response pattern without detectable concentrations of anti-inflammatory mediators. The Th1 immune response by peripheral blood leukocytes was decreased. The observed change in Th1/Th2 balance in favor of Th2 cytokine activity may be a systemic adaptation to the proinflammatory milieu in the lung.

Anesthetics↗