Biomedical subjects
H E Fessler
Publications and source records attributed to H E Fessler.
Management of acute coronary syndromes.
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Mechanical ventilation in acute lung injury and acute respiratory distress syndrome.
Mechanical ventilation provides life-sustaining support for most patients with acute lung injury and acute respiratory distress syndrome; however, traditional approaches to mechanical ventilation may cause ventilator-associated lung injury, which could exacerbate or perpetuate respiratory failure caused initially by conditions such as pneumonia, sepsis, and trauma. This article reviews the theory, laboratory data, and results of recent clinical trials that suggest that modified ventilator strategies can reduce ventilator-associated lung injury and improve clinical outcomes.
Accuracy of hemodynamic measurements during partial liquid ventilation with perflubron.
Patients undergoing partial liquid ventilation (PLV) are often monitored with pulmonary artery catheters and receive positive end-expiratory pressure (PEEP). PEEP can dissociate wedge pressure (Pcw) from transmural left atrial pressure (Platm) by elevating pleural pressure and can dissociate Pcw from Pla by elevating alveolar pressure, PLV, like PEEP, also elevates pleural and alveolar pressures. However, the artifacts PLV may cause in measured vascular pressures are unknown. In 6 anesthetized, paralyzed healthy adult sheep, we compared effects of gas ventilation (GV) and PLV with 10 and 30 ml/kg perflubron on pericardial pressure (Pperi), Pcw, Pla, thermodilution cardiac output, and pulmonary artery flow measured with a doppler probe. PEEP was applied from 0-15 mm Hg during GV and PLV. PLV changed pericardial pressure or cardiac output minimally (at PEEP(0), GV: Pperi = -1.7 +/- 0.6 mm Hg, CO = 3. 2 +/- 0.1 L/m; 10 ml/kg perflubron: Pperi = -1.3 +/- 0.6 mm Hg, CO = 3.4 +/- 0.2 L/m; 30 ml/kg perflubron: Pperi = -1.6 +/- 0.7 mm Hg, CO = 3.4 +/- 0.2 L/m; all mean +/- SEM). On PEEP, Pcw agreed with Pla and Platm as well or better during PLV as during gas ventilation. Cardiac output by thermodilution and probe agreed equally well under all conditions. We conclude that hemodynamic values are as accurate during PLV as during gas ventilation.
Biologic variability in mechanical ventilation rate and tidal volume does not improve oxygenation or lung mechanics in canine oleic acid lung injury.
Mechanical ventilation in patients with acute respiratory distress syndrome and acute lung injury (ALI) remains a difficult challenge because of the conflict between maintaining adequate gas exchange and furthering lung injury via overdistention. In a recent study, Lefevre and colleagues (Am. J. Respir. Crit. Care Med. 1996;154: 1567-1572) suggested that mechanical ventilation with natural biologic variability (BV) in breath-to-breath respiratory frequency (f) and VT could reduce lung injury and improve gas exchange without increases in mean airway pressure (Paw) or peak inspiratory pressure (PIP). However, significant differences in cardiac output (CO), Pa(CO(2)), pH, and delivered VT between the treatment groups in their study could have influenced these results. Because of the potential implications of these findings for patient care, we attempted to confirm these findings by Lefevre and colleagues in a canine model of oleic acid-induced lung injury. Eighteen mongrel dogs were anesthetized in the supine position, paralyzed, and mechanically ventilated with 50% O(2) at f = 15 breaths/min, and VT was adjusted to achieve an end-tidal CO(2) of 30 to 35 mm Hg. Lung injury was produced by infusion of 0.06 ml/kg oleic acid solution into the right atrium over a 30-min period. Animals were then randomized to either conventional ventilation at the baseline settings (n = 9) or to BV at the same mean VT and f (n = 9). Both groups received comparable degrees of injury, and hemodynamic and ventilatory parameters were closely matched, with no differences in mean VT, PIP, mean Paw, Pa(CO(2)), pH, CO, pulmonary artery occlusion pressure, or arterial pressure (Pa). However, no differences between the two groups were found in Pa(O(2)), shunt, or static compliance over a 4-h period. When hemodynamic and ventilatory parameters were well matched in a canine model of ALI, BV showed no advantage over conventional ventilation at constant VT and f.
Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.
OBJECTIVE: To assess the safety and potential efficacy of a mechanical ventilation strategy designed to reduce stretch-induced lung injury in acute respiratory distress syndrome. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: Eight intensive care units in four teaching hospitals. PATIENTS: Fifty-two patients with acute respiratory distress syndrome. INTERVENTIONS: Traditional tidal volume patients: tidal volume 10-12 mL/kg ideal body weight, reduced if inspiratory plateau pressure was > 55 cm H2O (7.3 kPa). Small tidal volume patients: tidal volume 5-8 mL/kg ideal body weight, to keep plateau pressure < 30 cm H2O (4.0 kPa). MEASUREMENTS AND MAIN RESULTS: Mean tidal volumes during the first 5 days in traditional and small tidal volume patients were 10.2 and 7.3 mL/kg, respectively (p < .001), with mean plateau pressure = 30.6 and 24.9 cm H2O (3.3 kPa), respectively (p < .001). There were no significant differences in requirements for positive end-expiratory pressure or FIO2, fluid intakes/outputs, requirements for vasopressors, sedatives, or neuromuscular blocking agents, percentage of patients that achieved unassisted breathing, ventilator days, or mortality. CONCLUSIONS: The reduced tidal volume strategy used in this study was safe. Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a) the sample size was too small to discern small treatment effects; b) the differences in tidal volumes and plateau pressures were modest; or c) reduced tidal volume ventilation is not beneficial.
Lung volume reduction surgery: is less really more?
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Lung volume reduction surgery and airflow limitation.
Interest has recently been renewed in lung volume reduction surgery (LVRS) for end-stage emphysema. However, numerous questions about its role in the treatment of emphysema remain, including the clinical characteristics of optimal candidates and its mechanism of improvement in pulmonary function. In this report, we develop a mathematical analysis and graphic depiction of the mechanism of improvement in expiratory airflow and vital capacity. This analysis is based on consideration of the interaction between lung function and respiratory muscle function. We also reexamine previously published pulmonary mechanics in patients with alpha1-antitrypsin deficiency, chronic obstructive pulmonary disease, and asthma. We find a major determinant of airflow limitation common to these diseases is the ratio of residual volume to total lung capacity (RV/TLC). Moreover, RV/TLC is found to be the single most important determinant of the improvement in pulmonary function after LVRS. Regardless of the specific underlying lung disease, the impairment of airflow is due primarily to mismatch between the sizes of the lung and the chest wall, and the effects of LVRS are almost exclusively due to improvement of that match. This analysis can be used to develop testable hypotheses to guide patient selection for this procedure.
Mechanism of hemoglobin-induced protection against endotoxemia in rats: a ferritin-independent pathway.
Hemoglobin (Hb) induces heme oxygenase-1 (HO-1), which catalyzes the breakdown of heme to bilirubin, and ferritin. Rats pretreated with Hb have been shown to survive lethal doses of lipopolysaccharide (LPS; see L. Otterbein, S. L. Sylvester, and A. M. Choi. Am. J. Respir. Cell Mol. Biol. 13: 595-601, 1995). The physiological basis of this increased survival and the mechanism(s) involved in the protection against LPS by Hb are unknown. Here we investigated 1) the effects of Hb on the hemodynamic and biochemical parameters of LPS-induced tissue injury and 2) the mechanism(s) by which Hb conferred protection against shock and tissue injury. Hb-treated rats maintained normal mean arterial blood pressure, whereas control rats experienced cardiovascular collapse after a lethal dose of LPS. Hepatic and renal functions, peripheral white blood cells, serum lactate dehydrogenase, and phosphate also remained normal after LPS in Hb-treated rats. Hb also attenuated LPS-induced neutrophil alveolitis and tumor necrosis factor-alpha levels. Pretreatment with both desferoxamine, which, like ferritin, can bind iron, and with exogenous apoferritin failed to protect against LPS. In contrast, treatment with Hb plus desferoxamine, which induced HO-1 but not ferritin, did protect against LPS. Treatment with iron-dextran, which induced ferritin but not HO-1, did not protect against LPS. We conclude that Hb pretreatment reduces the inflammatory and physiological consequences of LPS and that the Hb-induced protection against LPS is dependent on HO-1 and not ferritin induction.
Heart-lung interactions: applications in the critically ill.
Since the circulatory and pulmonary systems are both driven by pressure and share space in the thorax, it is inevitable that they interact. These mechanical interactions, whilst relatively few in number, are protean in their manifestations. The circulatory system of the critically ill is often particularly susceptible to interference from respiration. Compensatory reserve is limited, ventilatory effort increased, and many critical care respiratory interventions place strain on the circulation, not seen in health. This review will examine the basic physiological mechanisms through which the pulmonary and circulatory systems interact. These mechanisms will then be applied to a variety of weaning, positive end-expiratory pressure (PEEP), and cardiopulmonary resuscitation techniques. It is hoped that this will provide the tools to understand clinical observations which would otherwise appear inexplicable.
Endotoxic shock alters distribution of blood flow within the intestinal wall.
OBJECTIVE: To investigate whether a redistribution of blood flow from the mucosa to the muscular layer of the intestinal wall contributes to the observed increased arterial-mucosal Pco2 gradient and the decreased mucosal tonometric pH during endotoxic shock. DESIGN: A prospective, controlled, animal study. SETTING: Animal laboratory in a university medical center. SUBJECTS: Ten domestic pigs. INTERVENTIONS: Pigs were anesthetized with ketamine and pentobarbital, mechanically ventilated, hemodynamically monitored, and then challenged with Escherichia coli endotoxin (10 micrograms/ kg i.v.). MEASUREMENTS AND MAIN RESULTS: Cardiac output, mesenteric artery blood flow, and systemic, pulmonary, and portal pressures were measured. Intestinal mucosa tonometric Pco2 and pH were determined with saline-filled balloon tonometers. The tissue blood flow to the mucosa and the muscular layer were independently measured with colored microspheres, using the arterial reference sample method. Thus, total intestinal blood flow was evaluated with respect to its transmural (mucosa vs. muscularis) and geographical (proximal jejunum, mid-small intestine, and terminal ileum) distribution. Endotoxin administration with fluid resuscitation induced a distributive shock with a decrease in intestinal mucosa tonometric pH. Under endotoxemic conditions, the mucosal flow increased in each geographical area, with the increase being larger proximally in the jejunum than distally in the ileum. The mucosal tonometric pH was found to correlate inversely with mucosal blood flow. The increase in blood flow to the mucosa was balanced by a decrease in blood flow to the muscularis, with total mesenteric flow remaining unchanged. CONCLUSIONS: Mucosal hypoperfusion does not account for the acidotic mucosal tonometric pH in endotoxic shock. The results suggest either a primary cytotoxic effect or an enhanced counter-current-mediated hypoxic insult in the apical villus. The decrease in blood flow to the muscularis may contribute to loss of intestinal wall peristaltic activity and structural wall integrity.
Alpha-2 adrenoceptor blockade protects rats against lipopolysaccharide.
Alpha-2 adrenoceptors are widely distributed in vascular and nonvascular tissue where they mediate diverse physiologic effects. We noted the laboratory anesthetic urethane, which possesses alpha-2 adrenergic blocking activity, protected rats against lethal endotoxemia (1). Therefore, we undertook the present study to examine whether specific alpha-2 adrenoceptor antagonism would protect against lethality and organ injury induced by lipopolysaccharide (LPS). Sprague-Dawley rats were pretreated with doses of the alpha-2 antagonist rauwolscine up to 1 mg/kg, followed by 20 mg/kg LPS. The highest rauwolscine dose decreased mortality from 100% to zero. In contrast, the alpha-2 agonists xylazine or UK 14,304 increased the lethality of a lower, 10-mg/kg dose of LPS from 20% to 80 to 100%. Rauwolscine administered after LPS had no protective effect against mortality. Rauwolscine pretreatment significantly reduced bowel hemorrhage and liver dysfunction induced by 20 mg/kg LPS, but it had no effect on hematologic changes, the rise in plasma creatinine, or lung myeloperoxidase content. Peak tumor necrosis factor-alpha levels were decreased from 1,305 +/- 333 to 493 +/- 155 pg/ml (p < 0.05) in animals pretreated with rauwolscine. Arterial pressure and heart rate was higher after LPS in animals pretreated with rauwolscine. We conclude that alpha-2 adrenergic blockade protects against LPS, either by decreasing tumor necrosis factor-alpha production or through direct effects on the target tissues of endotoxemia.
Low efficiency of oxygen utilization during exercise in hyperthyroidism.
STUDY OBJECTIVE: The mechanism of exercise intolerance in hyperthyroidism has not been fully elucidated. This study was undertaken to determine if hyperthyroidism reduced the efficiency of sub-maximal exercise. STUDY DESIGN: We measured cardiorespiratory variables up to the anaerobic threshold (AT) during ramp-loading cycle ergometry in 12 patients (New York Heart Association functional class II or III). Studies were performed in the hyperthyroid state and repeated in the euthyroid state after 10 months of medical treatment. In 10-W steps from rest to the AT, we measured oxygen uptake (VO2) as a measure of total body work rate, and pressure rate product (PRP) as a measure of cardiac work rate. Loading watts at AT divided by the increment of Vo2 from rest to the AT (delta Watt/delta VO2) was calculated as an index of work efficiency (where delta means the increment of each value from rest to the AT). RESULTS: VO2 and PRP at the AT were not significantly different between hyperthyroid and euthyroid states (VO2, 16.6 +/- 3.0 vs 17.5 +/- 2.3 mL/min/kg; PRP, 229 +/- 41 vs 218 +/- 28 x 10(2) mm Hg/min). However, loading watts at the AT were significantly lower in the hyperthyroid than the euthyroid state (28 +/- 22 vs 60 +/- 14 W: p < 0.01). VO2 and PRP while hyperthyroid were significantly higher than when euthyroid at every 10-W step during ramp-loading exercise. Furthermore, delta Watt/delta VO2 was significantly lower in hyperthyroid than euthyroid states (p < 0.001). There was a significant inverse correlation-ship between triiodothyronine and delta Watt/delta Vo2 (r = -0.654, p < 0.001). CONCLUSION: Hyperthyroidism causes low work efficiency, which may limit exercise tolerance.
Urethan anesthesia protects rats against lethal endotoxemia and reduces TNF-alpha release.
Urethan is a commonly used animal anesthetic for nonrecovery laboratory surgery. However, urethan has diverse biological effects that may complicate the interpretation of experimental findings. This study examined the effect of urethan on the response to an intravenous bolus of lipopolysaccharide (LPS; 30 mg/kg) in rats. In instrumented rats, urethan (1.2 gm/kg i.p.) completely prevented the fall in arterial pressure immediately after LPS administration but did not prevent late cardiovascular collapse. In uninstrumented rats, urethan also attenuated indexes of organ injury measured 4 h after LPS administration, including mural bowel hemorrhage, hemoconcentration, hypoglycemia, metabolic acidosis, and lung myeloperoxidase activity, a measure of neutrophil sequestration. The peak increase in tumor necrosis factor-alpha (TNF-alpha) 90 min after LPS administration was reduced 88% by urethan (2,060 +/- 316 vs. 16,934 +/- 847 pg/ml; P < 0.001). In uninstrumented animals, urethan at 1.2 gm/kg reduced the 90% mortality rate of a lethal dose of LPS to 0-10% when given up to 24 h before LPS administration but did not reduce mortality when given 2 h after LPS. Urethan neither directly bound LPS by Limulus assay nor inhibited LPS-stimulated TNF-alpha mRNA expression in cultured mouse peritoneal macrophages, but TNF-alpha mRNA expression was suppressed by serum from a urethan-treated rat. Moreover, rauwolscine, which shares alpha 2-adrenoceptor-blocking activity with urethan, also prevented death from a subsequent 90% lethal dose LPS bolus. We conclude that urethan or its metabolites protect against LPS, in part, by reducing TNF-alpha release and speculate that this may be mediated by alpha 2-adrenoceptors. These actions of urethan make it an undesirable anesthetic agent for in vivo studies of sepsis or LPS.
Polystyrene microspheres decrease bronchial artery resistance in anesthetized sheep.
The use of microspheres to measure tissue blood flow requires that the microspheres themselves do not alter regional arterial tone. To determine whether microspheres affected bronchial artery resistance, we cannulated and perfused the bronchial artery in anesthetized sheep. In seven sheep, the change in bronchial artery pressure at constant flow was recorded during infusion of 5 doses (1 x 10(5), 2 x 10(5), 5 x 10(5), 1 x 10(6), and 1.5 x 10(6)) of 15-microns microspheres. Microspheres produced a dose-dependent, self-limited decrease in bronchial artery pressure (1.5 x 10(6) microspheres decreased bronchial artery pressure by 36% for 31 min). This was a decrease in bronchial artery resistance, as evidenced by a shift in the slope, but not the intercept, of a pressure-flow curve (n = 4 sheep). Left atrial injection of 1 x 10(7) microspheres decreased bronchial artery resistance by 17% in six sheep with intact bronchial arteries in which flow was measured by ultrasound probe. The adenosine-receptor antagonist 8-phenyltheophylline attenuated the fall in resistance by 79% (n = 4 sheep). Cyclooxygenase inhibition by indomethacin attenuated the response by 37% (n = 4 sheep). These results suggest that microspheres caused the release of adenosine and a vasodilator prostaglandin. Repetitive measurements of bronchial blood flow by microspheres could overestimate true bronchial blood flow if the interval between measurements is < 30 min.
CPAP reduces inspiratory work more than dyspnea during hyperinflation with intrinsic PEEP.
Hyperinflation with intrinsic positive end-expiratory pressure (PEEPi) loads the respiratory muscles and causes dyspnea in obstructive lung disease. Continuous positive airway pressure (CPAP) has shown some efficacy in reducing inspiratory work and dyspnea. However, in obstructive lung disease, inspiratory work and dyspnea may be increased by additional factors that may not be affected by CPAP. Therefore, to study the effects of hyperinflation with intrinsic PEEP and CPAP in isolation, we used a mechanical analog of airway closure to increase end-expiratory lung volume in normal subjects. In five subjects in whom inspiratory work was measured, increasing end-expiratory lung volume by 1 and 2 L increased inspiratory work per breath from 0.42 +/- 0.04 J to 1.17 +/- 0.15 J (p < 0.05 compared with baseline) and 1.58 +/- 0.22 J (p < 0.05 compared with baseline and to the lesser level of hyperinflation). Although CPAP reduced work per breath and per minute to levels not significantly different from baseline, it had little effect on dyspnea. In ten subjects hyperinflated to 2.4 +/- 0.12 L above FRC, breathing could be sustained 19.5 +/- 4.5 min before quitting the load. This was increased to 26.7 +/- 5.2 min by 10 cm H2O CPAP (p = 0.052). Inspiratory dyspnea was modestly reduced by CPAP during these endurance trials. We conclude that CPAP can substantially ameliorate the respiratory work load induced by hyperinflation with intrinsic PEEP. However, the effects of CPAP on dyspnea and endurance are more limited. This suggests that the limits to breathing at high lung volumes are related to factors in addition to respiratory muscle work, and that CPAP may be of more value in reducing the work than in relieving the distress of obstructive lung disease.
Should intensive care be limited for patients with self-induced disease?
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