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Biomedical subjects

A S Slutsky

Publications and source records attributed to A S Slutsky.

At least 109 records · Page 6Linked to original sources
PubMed1995

Intermittent warm blood cardioplegia. Warm Heart Investigators.

BACKGROUND: Warm heart surgery implies continuous perfusion with normothermic blood cardioplegia. Interruption of cardioplegia, however, facilitates construction of distal coronary anastomoses and is the method practiced by many surgeons. To determine whether intermittency is harmful, we present results from 720 coronary bypass patients, protected with intermittent antegrade warm blood cardioplegia, that were derived from a previous study of normothermic versus hypothermic cardioplegia. METHODS AND RESULTS: Mean +/- SD age was 60.8 +/- 9.0 years; 27% of cases were urgent; 16% of patients had > 50% left main stenosis, and 19% had grade III or IV ventricles. A mean of 3.2 +/- 0.9 grafts was constructed. The average aortic cross-clamp time was 61.8 +/- 22.2 minutes. The longest single time off cardioplegia (LTOC) averaged 11.4 +/- 4.0 minutes per patient. The cumulative time off cardioplegia as a percentage of the cross-clamp time (PTOC) was 48.2 +/- 18.6% per patient. LTOC and PTOC were divided into quartiles (LTOC, < 10, 10 to 11, 12 to 13, and > 13 minutes; PTOC, < 36%, 36% to 49%, 50% to 62%, and > 62%) and related to the prespecified composite outcome of mortality, myocardial infarction according to serial CK-MB sampling, and low-output syndrome (LOS). Longer LTOC was harmful (event rates per quartile, 13.5%, 10.3%, 10.9%, and 19.0%; P = .046), whereas longer PTOC was protective (16.1%, 17.2%, 9.4%, and 10.6%; P = .07). Stepwise logistic regression was performed, controlling for demographic and angiographic predictors. In the multivariate models, LTOC remained detrimental (P = .07) and PTOC remained beneficial (P = .053). Additional modeling after entering surgeon identity (P < .001) into the risk equation eliminated the PTOC effect, whereas LTOC remained predictive of adverse outcomes (P = .053; odds ratio, 1.06; 95% CI, 1.00, 1.13). CONCLUSIONS: The data indicate that a reasonable margin of safety exists with intermittent, antegrade warm blood cardioplegia. Repeated interruptions of warm blood cardioplegia are unlikely to lead to adverse clinical results if single interruptions are < or = 13 minutes.

Aged↗
PubMed1995

Effect of the combination of human thioredoxin and L-cysteine on ischemia-reperfusion injury in isolated rat lungs.

We studied the role of human thioredoxin and L-cysteine in ischemia-reperfusion lung injury. Thirty adult Wistar rats were allocated to five groups, according to the drug added to the pulmonary artery flush solution before ischemia (groups 1 and 2: none; group 3: human thioredoxin; group 4: L-cysteine, and group 5: human thioredoxin and L-cysteine) and according to the ex vivo ischemic interval at 37 degrees C (group 1: no ischemia; groups 2-5: 90 min). After ischemia, the lungs were reperfused for 60 min with Krebs-Henseleit solution containing 4% bovine serum albumin. In nonischemic lungs, the pulmonary arterial pressure, airway pressure, wet to dry lung weight ratio and the albumin concentration in bronchoalveolar fluid were within normal ranges. In contrast, all parameters of ischemic untreated lungs were generally poor. Compared to the ischemic untreated lungs, treatment with the combination of human thioredoxin and L-cysteine significantly reduced the wet to dry lung weight ratio (group 2: 9.18 +/- 0.25, group 5: 7.88 +/- 0.27), and the albumin concentration in the bronchoalveolar lavage fluid (group 2: 78.3 +/- 17.1 micrograms/ml, group 5: 24.0 +/- 3.8 micrograms/ml). No significant improvement was found in pulmonary arterial pressure and airway pressure. These results suggested that treatment with human thioredoxin (adult T cell leukemia-derived factor) and L-cysteine attenuates ischemia-reperfusion injury in isolated rat lungs.

Animals↗
PubMed1995

Increased nitric oxide in exhaled gas as an early marker of lung inflammation in a model of sepsis.

Nitric Oxide (NO) has been implicated in the pathologic vasodilation of sepsis. Because NO can be measured in the exhaled gas of animals and humans, we hypothesized that increases in exhaled NO would occur in a septic model. Using a blinded design, 10 male Sprague-Dawley rats (300 to 400 g) were anesthetized, paralyzed, tracheotomized, and randomized (5/group) to receive an intravenous injection of either lipopolysaccharide (LPS) (Salmonella typhosa, 20 mg/kg) or placebo (equal volume of saline). Thereafter, exhaled gas was collected and measurements of NO concentration were made using chemiluminescence every 20 min for 300 min during ventilation (RR 40 breaths/min, VT 3 ml; PEEP 0, FIO2 0.21). Another group of 10 animals (5 LPS; 5 control) were treated in the same fashion and then killed at 240 min and an arterial blood sample obtained for blood gas and TNF alpha determinations. Pressure volume (PV) curves were constructed and lungs removed, preserved, and submitted for histologic evaluation. LPS-treated rats had lower mean arterial pressures than the control group, p < 0.0001. No significant differences in static lung compliance and PV curves were found in the two groups. TNF alpha levels were greater in the LPS group (1.40 +/- 0.24 ng/ml) versus control group (0.09 +/- 0.04 ng/ml), p < 0.001. By contrast to the control group, exhaled NO concentration rose in all LPS-treated rats at approximately 100 min and at about 160 min reached a plateau that was 6 times greater than control levels (p < 0.0001). There was greater interstitial, airspace, and total lung injury in the LPS group (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1995

Induction of the stress response to prevent organ injury.

Septic shock, multiorgan dysfunction, and the acute respiratory distress syndrome are major contributors to morbidity and mortality in the ICU setting. Animal studies have shown that these forms of injury can be attenuated or prevented if a phenomenon, called the stress response, is activated. The stress response, characterized by a transient downregulation of most cellular products and by the upregulation of the heat-shock proteins (HSPs), has been shown to provide protection to cells and experimental animals if triggered prior to an otherwise lethal injury. The mechanisms by which the stress response is protective are not known with certainty, but HSPs appear to play an important role. HSPs are constitutively present in all cells studied to date and can also be induced by artificial fever and by nonthermal means. They act as molecular chaperones, interacting transiently with newly synthesized proteins and proteins experiencing difficulty in proper folding. HSPs also escort and help proteins to cross membranes. This chaperone function is essential for cellular protection since it provides a mechanism by which defective polypeptides may be directed to lisosomes for degradation. This article summarizes the current literature on the effects of the stress response in protecting cells and animals from lethal forms of systemic and organ damage.

Animals↗
PubMed1994

A critical role for thiol, but not ATP, depletion in 95% O2-mediated injury of preterm pneumocytes in vitro.

Prolonged exposure to elevated partial pressures of oxygen results in lung cell toxicity, both in vivo and in vitro, due to the excess production and target molecule reactions of reactive oxygen species. Events primarily responsible for cell death vary with the type of oxidant injury and with cell type. Because of the susceptibility of the premature lung to oxygen toxicity, and the critical barrier function of the epithelium, we have investigated the role of two potentially lethal consequences of O2 exposure in premature distal lung epithelial cells in vitro. A 48-h exposure of distal fetal rat lung epithelial cells to 95% O2 caused cytotoxicity, which was associated with DNA injury and depletion of both cellular protein and nonprotein reduced sulfhydryls. The observed DNA injury preceded other markers of cell injury and was not sufficient to either activate the chromosomal enzyme poly(ADP-ribose) polymerase or cause secondary ATP depletion. Buthionine sulfoxamine-induced depletion of nonprotein reduced sulfhydryls increased the sensitivity of cells to subsequent O2-mediated cytotoxicity. Addition of the glutathione precursor N-acetylcysteine to the culture medium maintained cellular protein and nonprotein reduced sulfhydryl concentrations and prevented O2-mediated cytotoxicity. We conclude that loss of protein and nonprotein reduced sulfhydryls, but not DNA injury, is causally related to the toxic effects of elevated O2 on premature distal lung epithelial cells.

Adenosine Triphosphate↗
PubMed1994

Effect of methylprednisolone on angiogenesis in syngeneic rat tracheal grafts.

Airway anastomotic complications remain a cause of morbidity after clinical lung transplantation. The use of corticosteroid therapy to control pulmonary rejection has raised concern over delayed airway healing. We therefore investigated the hypothesis that the effects of methylprednisolone (MP) impair the revascularization and epithelial regeneration of heterotopic syngeneic tracheal isografts. Lewis rat tracheal segments were wrapped in omentum and implanted in the abdomen of recipient rats. All recipients received cyclosporin A (CsA) (5 mg.kg-1.day-1) and were randomly allocated into three groups of 12 rats each according to the daily MP dose: group II, no MP; group III, 1 mg.kg-1.day-1; and group IV, 2 mg.kg-1.day-1. In each group, 6 animals were sacrificed after 7 and 14 days. Normal, untreated rats served as controls (group I). Epithelial regeneration was assessed histologically by a blinded subjective scoring system and by measurement of epithelial thickness. Tracheal revascularization was quantitated in terms of the number of blood vessels per square millimeter of tracheal wall and the vessel area was quantitated in terms of the percentage of the tracheal wall area. In animals treated with MP and CsA, the trachea exhibited significantly better regeneration after 14 days than it did in animals treated only with CsA. Epithelial regeneration was improved between 7 and 14 days in the groups treated with MP (group III, p = 0.01; group IV, p = 0.04). The epithelial thickness for all three study groups was significantly greater than that in the control group and returned toward normal after 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Hemodilution reduces early reperfusion injury in an ex vivo rabbit lung preservation model.

We sought to reduce early ischemia-reperfusion injury after lung preservation by an initial brief period of hemodilute reperfusion. Left lungs of New Zealand White rabbits were ventilated with room air and reperfused in an ex vivo ventilation-perfusion apparatus after 18 hours of storage at 10 degrees C. Lungs were randomly assigned to one of three groups (n = 6) according to the composition of initial reperfusate. In group 1 (control), preserved lungs were reperfused with whole blood for 20 minutes (hematocrit, 38%). In the experimental groups, blood was diluted to a hematocrit of 10% with Ringer's lactate (group 2) or low-potassium-dextran solution (group 3) for the first 10 minutes of reperfusion, followed immediately by whole blood for 10 minutes. Oxygen tension of left ventricular effluent at the end of the 20-minute assessment period was significantly higher in both hemodiluted groups (mean +/- standard error of the mean: group 2, 81.3 +/- 6.6 mmHg; group 3, 77.0 +/- 9.5 mmHg, versus Group 1, 46.3 +/- 7.4 mmHg; p < 0.006). Similarly, mean tracheal airway pressure was reduced in the hemodiluted groups, suggesting improved compliance (group 2; 3.1 +/- 0.3 mmHg; group 3, 2.8 +/- 0.6 mmHg; versus group 1, 6.5 +/- 1.4 mm Hg; p < 0.05). An initial 10-minute period of hemodilute reperfusion appears to reduce early pulmonary ischemia-reperfusion injury in this 18-hour ex vivo rabbit lung preservation model.

Airway Resistance↗
PubMed1994

A short course of FK506 can induce limited donor-specific graft acceptance.

To examine the hypothesis that a short course of FK506 would induce permanent graft acceptance after lung transplantation, left lung allotransplantation was performed in 14 mongrel dogs. In group 1 (control; n = 3), no immunosuppressive agent was given. In group 2 (n = 7), FK506 (1.2 mg/kg intramuscularly) was given on posttransplantation days 0, 1, and 2. In group 3 (n = 4), FK506 was given at the same dose on posttransplantation days 0, 1, and 2 as well as on days 29 and 30. Allograft function was evaluated by temporarily occluding the right pulmonary artery. A mixed lymphocyte reaction study was performed preoperatively and monthly thereafter. Control lungs were all rejected within 8 days. Group 2 dogs showed improved survival, with a median survival of 49.5 days. One dog in group 2 lived more than 400 days after transplantation. The mixed lymphocyte reaction data suggests that some donor-specific unresponsiveness occurs, which lasts for only a limited time. Supplemental doses of FK506 did not significantly improve survival (median, 74 days). The whole blood level of FK506 was 17.7 +/- 3.98 ng/mL on day 15; however, on day 29 the FK506 level was almost undetectable. We conclude that a 3-day course of 1.2 mg/kg of FK506 can induce donor-specific graft acceptance, but this acceptance is not permanent.

Animals↗
PubMed1994

Sodium arsenite induces heat shock protein-72 kilodalton expression in the lungs and protects rats against sepsis.

OBJECTIVE: To examine the hypothesis that induction of heat shock proteins by a nonthermal mechanism would confer protection against experimental sepsis. DESIGN: Prospective, blind, randomized, laboratory study. SETTING: University research laboratory. SUBJECTS: Sixty-two adult male Sprague-Dawley rats (weight range 250 to 350 g). INTERVENTIONS: Administration of sodium arsenite or saline in an animal model of sepsis by cecal ligation and perforation. MEASUREMENTS AND MAIN RESULTS: Sixty-two rats were randomly divided into two groups: group 1 received sodium arsenite (6 mg/kg iv) and group 2 received saline injection, in a blinded fashion. Eighteen hours after receiving sodium arsenite or saline, cecal ligation and perforation were performed and the animals were monitored for mortality for 96 hrs. Sodium arsenite injection, in the absence of an increase in body temperature, induced heat shock protein of 72-kilodalton molecular weight expression in the lung, which was detected 2 hrs after injection, peaked between 9 and 24 hrs, and returned to baseline by 48 hrs. Prior administration of sodium arsenite conferred significant protection against cecal ligation and perforation-induced mortality at 18 hrs (p = .002) and 24 hrs (p v .026) after cecal ligation and perforation, and correlated with expression of heat shock proteins in the lungs. However, at 48 and 96 hrs, when heat shock protein expression returned to basal values, the mortality rates of both groups were indistinguishable. CONCLUSIONS: We conclude that in vivo injection of sodium arsenite induces expression of HSP-72 in the lungs, and confers transient protection against experimental sepsis during the period that heat shock proteins are also expressed.

Animals↗
PubMed1994

Endotoxin-stimulated alveolar macrophages impair lung epithelial Na+ transport by an L-Arg-dependent mechanism.

The Na+ transport function of alveolar epithelium represents an important mechanism for air space fluid clearance after acute lung injury. We studied the effect of endotoxin-stimulated rat alveolar macrophages on lung epithelial ion transport and permeability in vitro. Cultured rat distal lung (alveolar) epithelial monolayers incubated with both endotoxin and macrophages demonstrated a 75% decline in transepithelial resistance and a selective 60% reduction in amiloride-sensitive short-circuit current (Isc). Single-channel patch-clamp analysis demonstrated a 60% decrease in the density of 25-pS nonselective cation (NSC) channels on the apical membrane of epithelium exposed to both endotoxin and macrophages. A concurrent reduction in epithelial F-actin content suggested a role for actin depolymerization in mediating this effect. Incubation of cocultures with the methylated L-arginine (Arg) derivative NG-monomethyl-L-arginine prevented the reduction in epithelial Isc, as did substitution of L-Arg with D-Arg or incubation in L-Arg-free medium. Furthermore, the stable and products of Arg metabolism were found to have no effect on epithelial ion transport. These studies show that endotoxin-stimulated alveolar macrophages impair distal lung epithelial ion transport by an L-Arg-dependent mechanism by inactivating amiloride-sensitive 25-pS NSC channels. This may represent a novel mechanism whereby local inflammatory cells regulate lung epithelial ion transport. This could affect the ability of the lung to clear fluid from the air space.

Adenine↗
PubMed1994

Functional and biochemical assessment of postpreservation lung viability in a rat model.

We examined the relationship between DNA synthesis and postpreservation lung hemodynamics and gas exchange. Adult male Wistar rats (n = 168) were randomly allocated into seven groups (n = 24) according to the pulmonary vascular flush used [EuroCollins (EC), saline, or no flush] and to the temperature of flush and storage (4, 21, or 37 degrees C). In each group, lungs were stored for four different time periods (0-24 h). After storage, incorporation of [3H]-thymidine into DNA was measured in the right lung, and in 72 rats the left lung was reperfused for 1 h with venous blood in an ex vivo paracorporeal rat lung system. Autoradiography of EC lungs revealed that alveolar macrophages and epithelial cells were the two major cell types synthesizing DNA during ischemia. Gas exchange after preservation with EC was universally poor. In unflushed and saline-flushed lungs, a critical threshold for viability was detected beyond which DNA synthesis and lung effluent PO2 decreased more rapidly at higher storage temperatures. A positive correlation was found between the final lung effluent PO2 and [3H]thymidine uptake (R2 = 0.62; P < 0.0001). In this model, deoxyribonucleic acid synthesis was a good index of postpreservation hemodynamics and gas exchange function.

Animals↗
PubMed1994

Canine model of obstructive sleep apnea: model description and preliminary application.

This report describes a canine model of obstructive sleep apnea (OSA) developed in our laboratory and the results of its preliminary short-term application. Healthy adult dogs were prepared with a tracheostomy and with implanted electroencephalographic and nuchal electromyographic recording electrodes. A silent occlusion valve was attached to the outer end of the endotracheal tube. The electroencephalogram and electromyogram were monitored continuously by a computer that determined sleep-wake state using software developed in our laboratory. At a predetermined time (e.g., 12 s) after each sleep onset, a signal was transmitted from the computer to the valve controller, resulting in airway occlusion. When the dog aroused from sleep, the occlusion was released. These events therefore mimic those that occur in human OSA. Successful operation of the model was confirmed during 5-day continuous trials in two dogs. During the trials, the dogs became increasingly somnolent both by behavioral observation and objective measurement. The frequency of occlusions increased, and measures of apnea severity, including apnea duration and end-apneic arterial oxygen saturation, worsened. We conclude that this experimental model of repeated airway occlusion during sleep provides a potentially powerful tool for investigating the sequelae of OSA.

Airway Obstruction↗
PubMed1994

Tidal ventilation at low airway pressures can augment lung injury.

Intermittent positive pressure ventilation with large tidal volumes and high peak airway pressures can result in pulmonary barotrauma. In the present study, we examined the hypothesis that ventilation at very low lung volumes can also worsen lung injury by repeated opening and closing of airway and alveolar duct units as ventilation occurs from below to above the infection point (Pinf) as determined from the inspiratory pressure-volume curve. We ventilated isolated, nonperfused, lavaged rat lungs with physiologic tidal volumes (5 to 6 ml/kg) at different end-expiratory pressures (above and below Pinf) and studied the effect on compliance and lung injury. In the groups ventilated with positive end-expiratory pressure (PEEP) below Pinf compliance fell dramatically after ventilation. It did not change in either the control group or the group ventilated with PEEP above Pinf. Lung injury assessed morphologically was significantly greater in the groups ventilated with a PEEP below Pinf, and in these groups the site of injury was dependent on the level of PEEP. The group ventilated without PEEP had significantly greater respiratory and membranous injury to bronchioles, while the group ventilated with PEEP of 4 cm H2O had significantly greater alveolar duct injury. In conclusion, ventilation at lung volumes below those found at Pinf caused a significant decrease in lung compliance and progression of lung injury. Therefore, in addition to high airway pressures, end-expiratory lung volume is an important determinant of the degree and site of lung injury during positive-pressure ventilation.

Animals↗