We used radioligand binding techniques and measurement of beta-agonist-mediated positive inotropic responses in isolated cardiac tissue to examine beta-adrenergic-receptor subpopulations in nonfailing and failing human left and right ventricular myocardium. In tissue derived from 48 human hearts the receptor subtypes identified in nonfailing ventricle by radioligand binding were beta 1 (77%) and beta 2 (23%), with no evidence of an "atypical" beta-adrenergic receptor. In failing left ventricle the beta 1:beta 2 ratio was markedly different, i.e., 60:38. This decrease in the beta 1 proportion and increase in the beta 2 proportion in the failing ventricles were due to a 62%, "selective" down-regulation of the beta 1 subpopulation, with little or no change in beta 2 receptors. In muscle bath experiments in isolated trabeculae derived from nonfailing and failing right ventricles, both beta 1- and beta 2-adrenergic receptors were coupled to a positive inotropic response. In nonfailing myocardium, beta 1 responses predominated, as the selective beta 1 agonist denopamine produced a response that was 66% of the total contractile response of isoproterenol. In heart failure the beta 1 component was markedly decreased, while the beta 2 component was not significantly diminished. Moreover, in heart failure the beta 2 component increased in prominence, as the contractile response to the selective beta 2 agonist zinterol increased from a minority (39%) to a majority (60%) of the total response generated by isoproterenol. We conclude that failing human ventricular myocardium contains a relatively high proportion of beta 2 receptors, due to selective down-regulation of beta 1 receptors. As a result, in the failing human heart the beta 2-receptor subpopulation is a relatively important mediator of inotropic support in response to nonselective beta-agonist stimulation and is available for inotropic stimulation by selective beta 2 agonists.

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We conclude that in surgical practice there is considerable variation in the timing of prophylactic administration of antibiotics and that administration in the two hours before surgery reduces the risk of wound infection.

The impact of a new therapy that includes pressure-controlled inverse ratio ventilation followed by extracorporeal CO2 removal on the survival of patients with severe ARDS was evaluated in a randomized controlled clinical trial. Computerized protocols generated around-the-clock instructions for management of arterial oxygenation to assure equivalent intensity of care for patients randomized to the new therapy limb and those randomized to the control, mechanical ventilation limb. We randomized 40 patients with severe ARDS who met the ECMO entry criteria. The main outcome measure was survival at 30 days after randomization. Survival was not significantly different in the 19 mechanical ventilation (42%) and 21 new therapy (extracorporeal) (33%) patients (p = 0.8). All deaths occurred within 30 days of randomization. Overall patient survival was 38% (15 of 40) and was about four times that expected from historical data (p = 0.0002). Extracorporeal treatment group survival was not significantly different from other published survival rates after extracorporeal CO2 removal. Mechanical ventilation patient group survival was significantly higher than the 12% derived from published data (p = 0.0001). Protocols controlled care 86% of the time. Average PaO2 was 59 mm Hg in both treatment groups. Intensity of care required to maintain arterial oxygenation was similar in both groups (2.6 and 2.6 PEEP changes/day; 4.3 and 5.0 FIO2 changes/day). We conclude that there was no significant difference in survival between the mechanical ventilation and the extracorporeal CO2 removal groups. We do not recommend extracorporeal support as a therapy for ARDS. Extracorporeal support for ARDS should be restricted to controlled clinical trials.

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An interferon-'y, tumor necrosis factor, and interleukin-1-inducible, high-output pathway synthesizing nitric oxide (NO) from L-arginine was recently identified in rodents. High-dose interleukin-2 (IL-2) therapy is known to induce the same cytokines in patients with advanced cancer. Therefore, we examined renal cell carcinoma (RCC; n = 5) and malignant melanoma (MM; n = 7) patients for evidence of cytokine-inducible NO synthesis. Activity of this pathway was evaluated by measuring serum and urine nitrate (the stable degradation product of NO) during IL-2 therapy. IL-2 administration caused a striking increase in NO generation as reflected by serum nitrate levels (10-and 8-fold increase IP < 0.001, P < 0.0031 for RCC and MM patients, respectively) and 24-h urinary nitrate excretion (6.5-and 9-fold increase [both P < 0.0011 for RCC and MM patients, respectively). IL-2-induced renal dysfunction made only a minor contribution to increased serum nitrate levels. Metabolic tracer studies using L-[guanidino-5N2Jarginine demonstrated that the increased nitrate production was derived from a terminal guanidino nitrogen atom of L-arginine. Our results showing increased endogenous nitrate synthesis in patients receiving IL-2 demonstrate for the first time that a cytokine-inducible, highoutput L-arginine/NO pathway exists in humans. (J. Clin. Invest. 1992. 89:867-877.) Key words: acute renal failure * malignant melanoma * nitrate * nitrite * renal cell carcinoma

BACKGROUND Coronary patency has been used as a measure of thrombolysis success after acute myocardial infarction. The Thrombolysis in Myocardial Infarction (TIMI) Study Group perfusion grades have gained wide acceptance, with grades 0 (no distal flow) and 1 perfusion (minimal flow) being designated as thrombolysis failures and grades 2 (partial perfusion) and 3 (complete perfusion) as thrombolysis successes. However, the significance of the individual TIMI grades on clinical outcome has not been adequately assessed. METHODS AND RESULTS To evaluate the functional significance of TIMI perfusion grades, we compared 1-day coronary patency status with ventriculographic, enzymatic, and ECG indexes of acute myocardial infarction in 298 patients treated with anistreplase or alteplase within 4 hours of myocardial infarction symptom onset. Radionuclide ejection fraction was determined at 1 week and at 1 month. Perfusion grades for the entire study population were distributed as 12% (n = 37) grades 0/1, 13% (n = 40) grade 2, and 74% (n = 221) grade 3. Patency profile did not differ between the two thrombolytic regimens. Further coronary interventions were performed after the 1-day patency determination in 43% of patients (43%, 48%, 42%, respectively, in grades 0/1, 2, and 3 patients). The outcome of grade 2 patients did not differ from grades 0/1 patients in ejection fraction, enzyme peaks, ECG markers, or morbidity index. In contrast, grade 3 patients, compared with grades 0-2 patients, showed 1) a greater global ejection fraction at 1 week (54% versus 49%, p = 0.006) and at 1 month (54% versus 49%, p = 0.01), 2) a greater infarct zone ejection fraction at 1 week (41% versus 33%, p = 0.003) and at 1 month (42% versus 32%, p = 0.003), 3) smaller enzyme peaks, significant for lactate dehydrogenase, and shorter times to enzyme peaks, significant for all four enzymes, 4) a smaller QRS score at discharge and at 1 month, and 5) a trend toward a lower morbidity index. CONCLUSIONS Grade 3 flow predicts significantly better outcomes than lesser grades of flow and represents an important measure of reperfusion success.

We conclude that beta-blockade may produce quantitatively different degrees of response in different kinds of heart muscle disease.