Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Hypoxia initiates pulmonary vasoconstriction (HPV) by inhibiting one or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth muscle cells (PASMCs) of resistance arteries. The resulting membrane depolarization increases opening of voltage-gated calcium channels, raising cytosolic Ca2+ and initiating HPV. There are presently nine families of Kv channels known and pharmacological inhibitors lack the specificity to distinguish those involved in control of resting membrane potential (Em) or HPV. However, the Kv channels involved in Em and HPV have characteristic electrophysiological and pharmacological properties which suggest their molecular identity. They are slowly inactivating, delayed rectifier currents, inhibited by 4-aminopyridine (4-AP) but insensitive to charybdotoxin. Candidate Kv channels with these traits (Kv1.5 and Kv2.1) were studied. Antibodies were used to immunolocalize and functionally characterize the contribution of Kv1. 5 and Kv2.1 to PASMC electrophysiology and vascular tone. Immunoblotting confirmed the presence of Kv1.1, 1.2, 1.3, 1.5, 1.6, and 2.1, but not Kv1.4, in PASMCs. Intracellular administration of anti-Kv2.1 inhibited whole cell K+ current (IK) and depolarized Em. Anti-Kv2.1 also elevated resting tension and diminished 4-AP-induced vasoconstriction in membrane-permeabilized pulmonary artery rings. Anti-Kv1.5 inhibited IK and selectively reduced the rise in [Ca2+]i and constriction caused by hypoxia and 4-AP. However, anti-Kv1.5 neither caused depolarization nor elevated basal pulmonary artery tone. This study demonstrates that antibodies can be used to dissect the whole cell K+ currents in mammalian cells. We conclude that Kv2. 1 is an important determinant of resting Em in PASMCs from resistance arteries. Both Kv2.1 and Kv1.5 contribute to the initiation of HPV.

Fulminant Pneumocystis carinii pneumonia in 4 patients with dermatomyositis.

Between 1989 and 1996, 4 cases of Pneumocystis carinii pneumonia (PCP) were observed in patients seronegative for the human immunodeficiency virus who were receiving corticosteroid therapy for dermatomyositis in our institution. These cases were considered unusual in light of the short delay of their onset after initiation of immunosuppressive therapy and their fulminant course: 3 of these patients died of PCP occurring during the first month of treatment with prednisone. In all 4 patients lymphopenia was observed before the initiation of corticosteroid treatment and low CD4 and CD8 cell counts were evident at the time of PCP. These observations support the view of an increase in both the severity and incidence of PCP in patients without human immunodeficiency virus infection and question the need for a primary prophylaxis in patients with connective tissue diseases receiving high-dose corticosteroid therapy.

Value of elementary, combined, and modeled hemodynamic variables.

PURPOSE: It has been well recognized that the usefulness of the clinical examination and simple hemodynamic variables in the critically ill is limited. Modelization for hemodynamic analysis may improve the diagnostic performance by a systematic and multivariate analysis. This requires a rigorous formalization that may otherwise expand the usefulness of hemodynamic data, both as predictors and as therapeutic targets. Our study was designed to test the value of a model for assessing the pathophysiology of circulatory disorders and for establishing the diagnosis. METHODS: We tested all available variables using survival as the end point. A population of 223 patients (652 measurements) with compromised circulatory status was studied. We evaluated traditional variables: (1) morphological and physical data, (2) elementary right heart catheterization data, and (3) usually calculated variables, versus (4) new modeled variables. These new modeled variables were derived from a previously validated computer program for hemodynamic evaluation. They expressed differences between observed hemodynamic performance and estimated needs. RESULTS: Among traditional variables, major prognostic factors were: (1) in all patients, lactate level elevation, physical signs of hypoperfusion, and a decreased systemic arterial pressure; (2) in septic patients, a high PaO2/SaO2 ratio; (3) in nonseptic patients, low left ventricle work indices. In all cases, modeled hemodynamic variables assessing performance-needs adequacy enhanced the prognostic value of hemodynamic monitoring. CONCLUSIONS: Compared with traditional variables, modeled variables were found of greater interest to quantify pathophysiology of shock. These results enabled us to validate the initial step of the hemodynamic reasonning formalization and to develop "new" diagnostic criteria that more closely fit the interrelationship between pathophysiology, diagnosis, and prognosis.

Negative catheter-tip culture and diagnosis of catheter-related bacteremia.

The accuracy of paired quantitative blood cultures (PQtBCs) collected in pediatric Isolator 1.5-ml tubes compared to central venous catheter (CVC) segment cultures (hub and tip) to diagnose catheter-related bacteremia (CRB) was evaluated in 58 bacteremic adult patients. The second aim of this study was to state precisely whether the tip or the hub (or both) of the infected device was the source of the bacteremia in case of significant results of PQtBC. Fifty-eight bacteremic patients with suspected CRB entered the study. In 52 patients, the diagnosis was obtained before CVC removal by PQtBC and was confirmed by CVC segment cultures: CRB in 30 patients, non-catheter-related bacteremia in 22 patients. Six patients had CRB not found by PQtBC. 1) PQtBC is 83% sensitive, 100% specific (negative predictive values 78%, positive predictive values 100%). 2) Sixteen bacteremic patients had authentic hub-related bacteremia (positive hub culture associated with negative tip cultures). When CRB is suspected in bacteremic patients, a negative tip culture cannot exclude the diagnosis of CRB. In all cases, CVC tip culture must be associated either with PQtBC or with hub cultures.

Adult overwhelming meningococcal purpura. A study of 35 cases, 1977-1989.

The study objective was to describe the clinical, biologic, and hemodynamic features of adult overwhelming meningococcal purpura and to examine the prognostic factors by multivariate analysis at the time of admission to the intensive care unit. Thirty-five patients (greater than or equal to 13 years of age) with meningococcal infection, circulatory shock, and generalized purpuric lesions of abrupt onset were recorded in eight intensive care units from 1977 to 1989. The patients were young (mean age, 26.6 years; range, 13 to 68 years) and had been previously healthy. The female-to-male ratio was 3:1. Mortality was 54.3%, with most deaths occurring within the first 48 hours, usually secondary to irreversible shock with multiple organ failure. Ischemic complications (eight cases), prolonged heart failure (seven cases), and secondary septicemia (five cases) were the chief complications among survivors. Initial hemodynamic study after volume loading showed low stroke volume index (mean +/- SD, 29.4 +/- 13 mL/m2) and tachycardia (mean +/- SD, 138 +/- 16 beats per minute), a profile suggesting a greater myocardial depression than usually observed in gram-negative bacillary septic shock. Univariate prognostic analysis showed that four variables at the time of admission were associated with fatal outcome: a plasma fibrinogen level of 1.5 g/L or less, a factor V concentration of 0.20 or less, a platelet count lower than 80 x 10(9)/L, and a cerebrospinal fluid leukocyte count of 20 x 10(6)/L or less. Stepwise regression analysis showed that low fibrinogen level (less than or equal to 1.5 g/L) was the sole adverse prognostic variable (odds ratio = 2, 95% confidence interval, 1.5 to 2.7). Adult overwhelming meningococcal purpura is still associated with high mortality and morbidity. Low fibrinogen level at time of admission may permit early recognition of the most severely ill patients.

Role of tricuspid regurgitation and left ventricular damage in the treatment of right ventricular infarction-induced low cardiac output syndrome.

To evaluate, in right ventricular (RV) myocardial infarction, the role of tricuspid regurgitation (TR) and left ventricular (LV) damage and the response to treatment of low cardiac output, 20 patients were prospectively studied. Volume infusion increased cardiac output only slightly (11%, p less than 0.001), despite a dramatic increase in ventricular filling pressures. Dobutamine (4 micrograms.kg-1.min-1) markedly increased cardiac output (24%, p less than 0.001) with a decrease in ventricular filling pressures. In the 5 patients with TR, dobutamine only modestly increased cardiac output (9 vs 26%, p less than 0.001), while stroke index and LV end-diastolic dimensions decreased in comparison (-5 vs 33% and -6 vs 9%, respectively, p less than 0.001). In the absence of TR (n = 15), there was no significant difference in response to volume expansion between patients with normal (n = 7) and depressed LV ejection fraction (n = 8). In contrast, dobutamine, in patients with depressed LV function, induced a greater increase in cardiac output (38 vs 17%, p less than 0.01) and RV ejection fraction (36 vs 12%, p less than 0.05). All patients with RV infarction-induced low cardiac output responded only modestly to volume loading. Dobutamine is particularly efficacious in patients without TR who have depressed LV function by improving RV function and, consequently, LV preload. In the 5 patients with TR, increasing RV contractility failed to improve the forward stroke volume by increasing the regurgitant fraction.

Decreased paradoxic pulse from increased venous return in severe asthma.

During severe asthma, paradoxic pulse may result from increased impedance to left ventricular ejection, mechanical impairment of left ventricular filling by ventricular interdependence or decreased pulmonary venous return augmented by hypovolemia. We studied the effect of reversible blood volume expansion by MAST inflation during severe attacks of asthma. Ten patients with clinically detectable paradoxic pulse of more than 20 mm Hg were studied. All had a history of reversible bronchial asthma with evidence of respiratory and circulatory failure. Standard therapy for asthma was started. We observed no difference in respiratory and heart rates during MAST inflation. Paradoxic pulse was consistently decreased during MAST inflation; paradoxic pulse returned to baseline values after MAST deflation. The decrease in paradoxic pulse was produced by an increased inspiratory systolic arterial pressure. We conclude that a reduction in pulmonary venous return is more important than ventricular interdependence in producing paradoxic pulse during severe asthma.

Failure of teicoplanin therapy in two neutropenic patients with staphylococcal septicemia who recovered after administration of vancomycin.

A report is given on two neutropenic patients with staphylococcal septicemia caused by Staphylococcus haemolyticus and Staphylococcus aureus (both strains methicillin-resistant) who failed to respond to therapy with teicoplanin. Both strains were resistant to teicoplanin (MIC 16 and 8 mg/l respectively), but remained sensitive to vancomycin (MIC 2 and 4 mg/l respectively). Replacement of teicoplanin with vancomycin led to full recovery of both patients and their discharge from hospital. These two cases emphasize the importance of clinical and microbiological monitoring of patients with staphylococcal septicemia, even when glycopeptides are used for treatment.

Regulation of myocardial oxygen delivery.

In most organs, oxygen consumption is maintained at relatively constant levels as oxygen delivery decreases, until a critical level is reached. This biphasic action is not observed in the heart. Myocardial oxygen consumption is supply dependent at all levels of myocardial oxygen delivery, because changes in myocardial oxygen delivery modify ventricular loading conditions and hence myocardial oxygen consumption. Since the oxygen content of coronary sinus blood is very low, only limited increases in oxygen extraction are possible. Therefore, coronary dilation is the primary mechanism for increasing myocardial oxygen delivery. Four- to sixfold increases in coronary blood flow can occur in several animal species and in human beings. Apart from metabolic control mechanisms, the regulation of myocardial oxygen delivery is multifaceted; major factors include extravascular compressive forces, autoregulation, neural controls, and humoral factors. In situations of decreased myocardial oxygen delivery, coronary vessels dilate to increase flow, and as coronary flow reserve falls to zero, flow becomes exquisitely dependent on perfusion pressure. With onset of supply dependency, contractility falls in an effort to maintain cardiac output at a given myocardial oxygen consumption.

Heart failure in septic shock: effects of inotropic support.

Many animal studies have attempted to simulate the circulatory responses to Gram-negative septicemia (iv infusion of live bacteria, fecal inoculation into body cavities, and administration of purified endotoxins by various routes), but the contribution of the heart to the adverse hemodynamic derangements and thus to the pathogenesis of shock is difficult to determine because of peripheral vascular events that influence cardiac performance. When blood pools in the periphery, venous return decreases and cardiac output can decrease without a primary myocardial defect being present. However, early heart dysfunction has been recognized in sepsis. Hemodynamic monitoring has not reduced overall mortality, but it has been helpful in guiding fluid administration and evaluating response to vasopressor therapy.