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Biomedical subjects

Arthur S Slutsky

Publications and source records attributed to Arthur S Slutsky.

At least 19 recordsLinked to original sources
PubMed2007

Role of human neutrophil peptides in the initial interaction between lung epithelial cells and CD4+ lymphocytes.

Human neutrophil peptides (HNP) exert immune-modulating effects. We hypothesized that HNP link innate and adaptive immunity through activation of costimulatory molecules. Human lung epithelial cells and CD4+ lymphocytes were treated with HNP separately or in coculture. Stimulation with HNP induced an increase in cell surface expression of CD54 (ICAM-1), CD80, and CD86 on lung epithelial cells and the corresponding major ligands, CD11a (LFA-1), CD152 (CTLA-4), and CD28 on CD4+ lymphocytes. There was an increased nuclear expression of the transcription factor p53 in human alveolar A549 cells and an elevated NF-kappaB (p50) and a degradation of I-kappaB protein in CD4+ lymphocytes following HNP stimulation. HNP enhanced the interaction between A549 cells and CD4+ lymphocytes by increasing cell adhesion and release of IFN-gamma, IL-2, and IL-8. This was attenuated by using an alpha1-proteinase inhibitor to neutralize HNP. We conclude that HNP play an important role in linking innate to acquired immunity by activation of costimulatory molecules in lung epithelial cells and CD4+ lymphocytes.

Anti-Infective Agents↗
PubMed2006

Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome.

RATIONALE: Tidal volume and plateau pressure limitation decreases mortality in acute respiratory distress syndrome. Computed tomography demonstrated a small, normally aerated compartment on the top of poorly aerated and nonaerated compartments that may be hyperinflated by tidal inflation. OBJECTIVES: We hypothesized that despite tidal volume and plateau pressure limitation, patients with a larger nonaerated compartment are exposed to tidal hyperinflation of the normally aerated compartment. MEASUREMENTS AND MAIN RESULTS: Pulmonary computed tomography at end-expiration and end-inspiration was obtained in 30 patients ventilated with a low tidal volume (6 ml/kg predicted body weight). Cluster analysis identified 20 patients in whom tidal inflation occurred largely in the normally aerated compartment (69.9 +/- 6.9%; "more protected"), and 10 patients in whom tidal inflation occurred largely within the hyperinflated compartments (63.0 +/- 12.7%; "less protected"). The nonaerated compartment was smaller and the normally aerated compartment was larger in the more protected patients than in the less protected patients (p = 0.01). Pulmonary cytokines were lower in the more protected patients than in the less protected patients (p < 0.05). Ventilator-free days were 7 +/- 8 and 1 +/- 2 d in the more protected and less protected patients, respectively (p = 0.01). Plateau pressure ranged between 25 and 26 cm H(2)O in the more protected patients and between 28 and 30 cm H(2)O in the less protected patients (p = 0.006). CONCLUSIONS: Limiting tidal volume to 6 ml/kg predicted body weight and plateau pressure to 30 cm H(2)O may not be sufficient in patients characterized by a larger nonaerated compartment.

Aged↗
PubMed2006

Year in review 2005: Critical Care--respirology: mechanical ventilation, infection, monitoring, and education.

We summarize all original research in the field of respiratory intensive care medicine published in 2005 in Critical Care. Twenty-seven articles were grouped into the following categories and subcategories to facilitate rapid overview: mechanical ventilation (physiology, spontaneous breathing during mechanical ventilation, high frequency oscillatory ventilation, side effects of mechanical ventilation, sedation, and prone positioning); infection (pneumonia and sepsis); monitoring (ventilatory monitoring, pulmonary artery catheter and pulse oxymeter); and education (training and health outcome).

Critical Care↗
PubMed2006

Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome.

RATIONALE: Little is known about the long-term outcomes and costs of survivors of acute respiratory distress syndrome (ARDS). OBJECTIVES: To describe functional and quality of life outcomes, health care use, and costs of survivors of ARDS 2 yr after intensive care unit (ICU) discharge. METHODS: We recruited a cohort of ARDS survivors from four academic tertiary care ICUs in Toronto, Canada, and prospectively monitored them from ICU admission to 2 yr after ICU discharge. MEASUREMENTS: Clinical and functional outcomes, health care use, and direct medical costs. RESULTS: Eighty-five percent of patients with ARDS discharged from the ICU survived to 2 yr; overall 2-yr mortality was 49%. At 2 yr, survivors continued to have exercise limitation although 65% had returned to work. There was no statistically significant improvement in health-related quality of life as measured by Short-Form General Health Survey between 1 and 2 yr, although there was a trend toward better physical role at 2 yr (p = 0.0586). Apart from emotional role and mental health, all other domains remained below that of the normal population. From ICU admission to 2 yr after ICU discharge, the largest portion of health care costs for a survivor of ARDS was the initial hospital stay, with ICU costs accounting for 76% of these costs. After the initial hospital stay, health care costs were related to hospital readmissions and inpatient rehabilitation. CONCLUSIONS: Survivors of ARDS continued to have functional impairment and compromised health-related quality of life 2 yr after discharge from the ICU. Health care use and costs after the initial hospitalization were driven by hospital readmissions and inpatient rehabilitation.

Adult↗
PubMed2006

Ischemia and reperfusion increases susceptibility to ventilator-induced lung injury in rats.

OBJECTIVES: Hemorrhagic shock followed by resuscitation (HSR) commonly triggers an inflammatory response that leads to acute respiratory distress syndrome. HYPOTHESIS: HSR exacerbates mechanical stress-induced lung injury by rendering the lung more susceptible to ventilator-induced lung injury. METHODS: Rats were subjected to HSR, and were randomized into an HSR + high tidal volume and zero positive end-expiratory pressure (PEEP) or a HSR + low tidal volume with 5 cm H(2)O PEEP. A sham-operated rat + high tidal volume and zero PEEP served as a control. RESULTS: HSR increased susceptibility to ventilator-induced lung injury as evidenced by an increase in lung elastance and the wet/dry ratio and a reduction in Pa(O(2)) as compared with the other groups. The lung injury observed in the HSR + high tidal volume group was associated with a higher level of interleukin 6 in the lung and blood, increased epithelial cell apoptosis in the kidney and small intestine villi, and a tendency toward high levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatinine in plasma. CONCLUSIONS: HSR priming renders the lung and kidney more susceptible to mechanical ventilation-induced organ injury.

Alanine Transaminase↗
PubMed2006

Role of oxidative stress in experimental sepsis and multisystem organ dysfunction.

Massive increase in radical species can lead to oxidative stress, promoting cell injury and death. This review focuses on experimental evidence of oxidative stress in critical illnesses, sepsis and multisystem organ dysfunction. Oxidative stress could negatively affect organ injury and thus overall survival of experimental models. Based on this experimental evidence, we could improve the rationale of supplementation of antioxidants alone or in combination with standard therapies aimed to reduce oxidative stress as novel adjunct treatment in critical care.

Animals↗
PubMed2006

Influence of neurally adjusted ventilatory assist and positive end-expiratory pressure on breathing pattern in rabbits with acute lung injury.

OBJECTIVE: To evaluate the influence of neurally adjusted ventilatory assist (NAVA) and positive end-expiratory pressure (PEEP) on the control of breathing in rabbits with acute lung injury. DESIGN: Prospective animal study. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Male White New Zealand rabbits (n = 18). INTERVENTION: Spontaneously breathing rabbits with hydrochloric acid-induced lung injury were ventilated with NAVA and underwent changes in NAVA gain and PEEP (six nonvagotomized and five vagotomized). Seven other nonvagotomized rabbits underwent 4 hrs of ventilation with hourly titration of PEEP, Fio2, and NAVA gain. MEASUREMENTS AND MAIN RESULTS: We studied diaphragm electrical activity, respiratory pressures, and breathing pattern. After lung injury, 0 cm H2O of PEEP resulted in high tonic and no discernible phasic diaphragm electrical activity in the nonvagotomized rabbits; stepwise increases in PEEP (up to 11.7 +/- 2.6 cm H2O) reduced tonic but increased phasic diaphragm electrical activity. Increasing the NAVA gain reduced phasic diaphragm electrical activity to almost half and abolished esophageal pressure swings. Tidal volume remained at 4-5 mL/kg, and respiratory rate did not change. In the vagotomized group, lung injury did not induce tonic activity, and phasic activity and tidal volume were several times higher than in the nonvagotomized rabbits. Four hours of breathing with NAVA restored breathing pattern and neural and mechanical breathing efforts to pre-lung injury levels. CONCLUSIONS: Acute lung injury can cause a vagally mediated atypical diaphragm activation pattern in spontaneously breathing rabbits. Modulation of PEEP facilitates development of phasic diaphragm electrical activity, whereupon implementation of NAVA can efficiently maintain unloading of the respiratory muscles without delivering excessive tidal volume in rabbits with intact vagal function.

Animals↗
PubMed2006

Five percent albumin for adult burn shock resuscitation: lack of effect on daily multiple organ dysfunction score.

BACKGROUND: The effect of 5 percent human albumin on multiple organ dysfunction was investigated during the first 14 days of treatment to determine whether albumin resuscitation might benefit adult burn patients. STUDY DESIGN AND METHODS: Multicenter unblinded controlled trial with stratified block (two patients per block) randomization by center and mortality prediction at enrollment (high-risk stratum [predicted mortality, 50%-90%] and low-risk stratum [predicted mortality, <50%]). The primary outcome was the worst multiple organ dysfunction score (MODS), excluding the cardiovascular component, to Day 14. Eligible adults (>15 years) suffering from thermal injury not more than 12 hours before enrollment received fluid resuscitation with Ringer's lactate (n=23) or 5 percent human albumin plus Ringer's lactate (n=19) by protocol to achieve recommended (American Burn Association) resuscitation endpoints. RESULTS: Forty-two patients were randomly assigned. There were no significant differences (median [95% confidence intervals]) in age (36 [24-45] vs. 31 [25-39] years), burn size (39 [32-53] vs. 32 [26-34] total body surface area percentage), inhalation injury (n=12/19 vs. n=11/23), or baseline MODS (3 [1-5] vs. 1.5 [0-2]) between the treatment and control groups. In an intention-to-treat analysis, there was no significant difference between the treatment and control group in the lowest MODS from Day 0 to Day 14 (analysis of covariance, p=0.73). CONCLUSION: Treatment with 5 percent albumin from Day 0 to Day 14 does not decrease the burden of MODS in adult burn patients.

Adult↗
PubMed2006

The contribution of biophysical lung injury to the development of biotrauma.

Patients with severe acute respiratory distress syndrome who die usually succumb to multiorgan failure as opposed to hypoxia. Despite appropriate resuscitation, some patients' symptoms persist on a downward spiral, apparently propagated by an uncontained systemic inflammatory response. This phenomenon is not well understood. However, a novel hypothesis to explain this observation proposes that it is related to the life-saving ventilatory support used to treat the respiratory failure. According to this hypothesis, mechanical ventilation per se, by altering both the magnitude and the pattern of lung stretch, can cause changes in gene expression and/or cellular metabolism that ultimately can lead to the development of an overwhelming inflammatory response-even in the absence of overt structural damage. This mechanism of injury has been termed biotrauma. In this review we explore the biotrauma hypothesis, the causal relationship between biophysical injury and organ failure, and its implications for the future therapy and management of critically ill patients.

Animals↗
PubMed2006

Assisted spontaneous breathing during early acute lung injury.

In the early phase of their disease process, patients with acute lung injury are often ventilated with strategies that control the tidal volume or airway pressure, while modes employing spontaneous breathing are applied later to wean the patient from the ventilator. Spontaneous breathing modes may integrate intrinsic feedback mechanisms that should help prevent ventilator-induced lung injury, and should improve synchrony between the ventilator and the patient's demand. Airway pressure release ventilation with spontaneous breathing was shown to decrease cyclic collapse/recruitment of dependent, juxtadiaphragmatic lung areas compared with airway pressure release ventilation without spontaneous breathing. Combined with previous data demonstrating improved cardiorespiratory variables, airway pressure release ventilation with spontaneous breathing may turn out to be a less injurious ventilatory strategy.

Animals↗
PubMed2006

Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia--a review.

OBJECTIVES: To review the involvement of coagulation and fibrinolysis in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pulmonary infection, and ventilator-induced lung injury (VILI). DATA SOURCE: Published articles on experimental and clinical studies of coagulation and fibrinolysis in ALI/ARDS, pneumonia, and mechanical ventilation. CONCLUSIONS: Alveolar fibrin deposition is an important feature of ALI/ARDS and pulmonary infection. The mechanisms that contribute to disturbed alveolar fibrin turnover are localized tissue factor-mediated thrombin generation and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. These effects on pulmonary coagulation and fibrinolysis are regulated by various proinflammatory cytokines and are similar to those found in the intravascular spaces during severe systemic inflammation. Some studies also suggest that pulmonary coagulopathy is a feature of VILI. Recent studies have demonstrated the beneficial effect of anticoagulant therapy in sepsis. Theoretical considerations suggest that this anticoagulant therapy will benefit patients with primary lung pathology including VILI, but clinical studies are needed to examine this hypothesis before such therapy is to be advocated as a standard of care in critically ill patients.

Blood Coagulation Disorders↗
PubMed2005

Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway.

Antimicrobial human neutrophil peptides (HNPs) play a pivotal role in innate host defense against a broad spectrum of prokaryotic pathogens. In addition, HNPs modulate cellular immune responses by producing the chemokine interleukin-8 (IL-8) in myeloid and epithelial cells and by exerting chemotaxis to T cells, immature dendritic cells, and monocytes. However, the mechanisms by which HNPs modulate the immune responses in the eukaryotic cells remain unclear. We demonstrated that, as with adenosine triphosphate (ATP) and uridine diphosphate (UDP), HNP stimulation of human lung epithelial cells selectively induced IL-8 production in 10 pro- and anti-inflammatory cytokines examined. HNP-induced IL-8 release was inhibited by treatment with the nucleotide receptor antagonists suramin and reactive blue. Transfection of lung epithelial cells with antisense oligonucleotides targeting specific purinergic P2Y receptors revealed that the P2Y6 (ligand of UDP) signaling pathway plays a predominant role in mediating HNP-induced IL-8 production.

Base Sequence↗
PubMed2005

The role of oxidative stress in adult critical care.

Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in adult critical illnesses characterized by tissue ischemia-reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome. Oxidative stress could exacerbate organ injury and thus overall clinical outcome. We searched MEDLINE databases (January 1966 to June 2005). For interventional studies, we accepted only randomized trials. Several small clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. These studies have reported controversial results. Newer large multicenter trials with antioxidant supplementation should be performed, considering administration at an early stage of illness and a wider population of critically ill patients.

Adult↗
PubMed2005

Partial liquid ventilation in adult patients with acute respiratory distress syndrome.

RATIONALE: Despite recent clinical trials demonstrating improved outcome in acute respiratory distress syndrome (ARDS), mortality remains high. Partial liquid ventilation (PLV) using perfluorocarbons has been shown to improve oxygenation and decrease lung injury in various animal models. OBJECTIVE: To determine if PLV would have an impact on outcome in patients with ARDS. METHODS: Patients with ARDS were randomized to (1) conventional mechanical ventilation (CMV; n=107), (2) "low-dose" perfluorocarbon (10 ml/kg; n=99), and (3) "high-dose" perfluorocarbon (20 ml/kg; n=105). Patients in all three groups were ventilated using volume ventilation, Vt or= 0.5, and positive end-expiratory pressure >or= 13 cm H(2)O. RESULTS: The 28-d mortality in the CMV group was 15%, versus 26.3% in the low-dose (p=0.06) and 19.1% in the high-dose (p=0.39) PLV groups. There were more ventilator-free days in the CMV group (13.0+/-9.3) compared with both the low-dose (7.4+/-8.5; p<0.001) and high-dose (9.9+/-9.1; p=0.043) groups. There were more pneumothoraces, hypoxic episodes, and hypotensive episodes in the PLV patients. CONCLUSIONS: PLV at both high and low doses did not improve outcome in ARDS compared with CMV and cannot be recommended for patients with ARDS.

Dose-Response Relationship, Drug↗