OBJECTIVE: This study aimed to evaluate the impact of fluid loading on hemodynamics and vascular hypocontractility to norepinephrine (NE) in an endotoxic shock model. DESIGN: Mean arterial pressure (MAP), aortic blood flow velocity (AoV, 20 MHz Doppler) and aortic conductance (AoC = AoV/MAP) were studied during 180 min (T0-T180) in 41 anesthetized and ventilated rabbits. INTERVENTIONS: Shock was induced by a 600 micrograms/kg bolus injection of endotoxin. Fluid loading (20 ml/kg colloids) was infused from T90 to T120. Dose-response curves to NE were performed at T0, T60 and T120 in endotoxic and non-endotoxic animals with or without fluid loading. MEASUREMENTS AND RESULTS: Endotoxin decreased pressure (-23%, p < 0.05) and flow (-42%, p < 0.05) corresponding to a decrease in conductance (-19%, p < 0.05). Fluid loading did not improve hypotension but markedly increased systemic flow (+51%, p < 0.01), corresponding to a hyperkinetic syndrome. Vascular reactivity to NE was impaired after endotoxin at T60 since the pressure response to NE was depressed (p < 0.01) and flow did not decrease. In non-fluid-loaded groups, the pressure response to NE recovered at T120, with no reduction in flow. In fluid-loaded endotoxic animals, however, the pressure response to NE was still impaired at T120 (p < 0.05), but with a decrease in flow. CONCLUSIONS: Fluid loading transformed the hypodynamic profile of endotoxic shock into a hyperdynamic state without improving blood pressure. Depressed vascular reactivity to NE was observed in both hyperdynamic and hypodynamic states, suggesting that a reduced vascular reactivity does not necessarily imply systemic vasodilation.

Animals↗

PubMed1998

Inhaled nitric oxide, almitrine infusion, or their coadministration as a treatment of severe hypoxemic focal lung lesions.

BACKGROUND: The partition of pulmonary blood flow between normal and shunting zones is an important determinant of oxygen tension in arterial blood (PaO2). The authors hypothesized that the combination of inhaled nitric oxide (iNO) and almitrine infusion might have additional effects related to their pharmacologic properties to improve PaO2. Such a combination was tested in patients with hypoxia caused by focal lung lesions, distinct from the acute respiratory distress syndrome. METHODS: Fifteen patients with hypoxic focal lung lesions despite optimal therapy were included and successively treated with (1) 5 ppm iNO, (2) low-dose almitrine infusion (5.5 +/- 1.7 microg x kg(-1) min(-1)) during iNO, and (3) almitrine infusion alone (with NO turned off). Then iNO was reintroduced and we studied the effect of the coadministration in reducing the fractional concentration of oxygen in inspired gas (FI(O2)) and positive end-expiratory pressure (PEEP) levels. Changes in blood gases and pulmonary and systemic hemodynamics were measured. RESULTS: Systemic hemodynamic variables remained stable in all protocol conditions. Use of iNO improved arterial oxygenation and decreased intrapulmonary shunt. Almitrine similarly improved PaO2 but increased pulmonary artery pressure and right atrial pressure. Coadministration of iNO and almitrine improved PaO2 compared with each drug alone and with control. All patients responded (that is, they had at least a +30% increase in PaO2) to this coadministration. When the drug combination was continued, FI(O2) and PEEP could be reduced over 8 h. The hospital mortality rate was 33% and unrelated to hypoxia. CONCLUSIONS: In hypoxemic focal lung lesions, iNO or low-dose almitrine markedly improved PaO2 to a similar extent. Furthermore, the coadministration amplified the PaO2 increase at a level that allowed reductions in FI(O2) and PEEP levels.

Administration, Inhalation↗

PubMed1998

Impact of inhaled nitric oxide on platelet aggregation and fibrinolysis in rats with endotoxic lung injury. Role of cyclic guanosine 5'-monophosphate.

As inhaled nitric oxide (iNO) may differently increase bleeding time (BT) and inhibit platelet aggregation in normal and lung-injured patients or experimental models, we studied the effects of iNO on hemostasis in presence and absence of an endotoxic lung injury in the rat. Eight hours after intratracheal administration of endotoxin (lipopolysaccharide [LPS]) or its solvent (phosphate-buffered solution [PBS]), four groups of rats were randomized according to the presence or absence of 15 ppm iNO added for an additional 10 h. We measured BT, ex vivo platelet aggregation, plasma fibrinogen, euglobulin clot lysis time (ECLT), and platelet and aortic cyclic guanosine 5'-monophosphate (cGMP) contents. Acute lung inflammation did not influence BT, but increased platelet aggregability, fibrinogen levels, and platelet and aortic cGMP. In control and endotoxic rats, iNO increased BT, reduced platelet aggregability, and increased platelet cGMP. iNO increased aortic cGMP only in healthy rats. ECLT was increased by LPS and unchanged with iNO. These results suggest that the extrapulmonary "systemic" effects induced by iNO on hemostasis were not strictly similar in healthy and LPS rats, inflammation inducing proper changes in coagulation parameters. However, iNO attenuated the procoagulant activity induced by acute lung inflammation, suggesting a potentially beneficial effect of this therapy.

Administration, Inhalation↗

PubMed1998

Alveolar neutrophil oxidative burst and beta2 integrin expression in experimental acute pulmonary inflammation are not modified by inhaled nitric oxide.

It was recently proposed that nitric oxide (NO) inhalation interferes with polymorphonuclear neutrophil (PMN) activation status during acute pulmonary inflammation, although variable results have been observed considering timing of NO administration, species, and model differences. After intratracheal administration of lipopolysaccharide (LPS) in rats, we characterized pulmonary inflammatory reaction (lung wet, dry, and wet to dry weights) and, using flow cytometry, the activation status (H2O2 production and beta2 integrin CD11b/CD18 expression) of PMN obtained from blood and from bronchoalveolar lavage (BAL). Eight hours after LPS injection, rats received for an additional 10 h, at a same Fio2 (85%), either 15 parts per million NO or the same gas flow of nitrogen. We found that 18 h after LPS, lung wet, dry, and wet-to-dry weights, H2O2 production, and CD11b/CD18 expression were increased. PMN obtained from BAL were highly activated as evidenced by an already maximal expression of the beta2 integrin CD11b/CD18, whereas the high H2O2 production at basal state could be further enhanced after ex vivo stimulation. Blood PMN were not different from control cells at basal state; however, their increased capacity to be stimulated ex vivo suggested an in vivo priming effect of intratracheal LPS. In conclusion, inhaled NO, given with a high FiO2, in the presence of this established endotoxinic lung injury did not reverse the markers of PMN activation studied nor lung edema formation in this rat model.

Administration, Inhalation↗

PubMed1997

Intubation and mechanical ventilation avoided by using almitrine bismesylate in an acute hypoxemic pneumonia.

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Aged↗

PubMed1997

Coupled vs. uncoupled pericardial constraint: effects on cardiac chamber interactions.

The effects of pericardial constraint on cardiac chamber interactions were evaluated by mathematical model analyses based on a novel concept of coupled vs. uncoupled pericardial constraint. We hypothesized that the nature of pericardial constraint can be classified as a "coupled" constraint exerted by uniform liquid pressure or an "uncoupled" constraint exerted by regional surface pressure. The numerical solution of the model of atrioventricular interaction produced the characteristic waveforms in venous flows and right atrial/ventricular pressures in classical pericardial diseases. Coupled constraint accounted for the patterns in cardiac tamponade; uncoupled constraint accounted for those in constrictive pericarditis. Analytic solution of the model of ventricular interdependence demonstrated that coupled constraint (tamponade) produced greater gains in ventricular interdependence, increasing the occurrence of pulsus paradoxus, whereas uncoupled constraint (constriction) produced a greater effective right ventricular elastance, increasing the likelihood of Kussmaul's sign. Thus the concept of coupled vs. uncoupled constraint may offer a coherent framework to understand the characteristic steady-state and respiratory-induced hemodynamic events in multiple forms of pericardial diseases.

Atrial Function↗

PubMed1997

Interest of a therapeutic optimization strategy in severe ARDS.

STUDY OBJECTIVE: Evaluate the interest of the response to a therapeutic optimization as a predictor of prognosis in ARDS. DESIGN: Prospective study. SETTING: ICU of a University Hospital. PATIENTS: Thirty-six consecutive patients with severe ARDS addressed for extracorporeal carbon dioxide removal (ECCO2R). INTERVENTIONS: We studied the response during the first 2 days after arrival to the therapeutic optimization strategy consisting in a combination of the following: (1) decrease in extravascular lung water (diuretics or hemofiltration); (2) selection of the best ventilatory mode; (3) permissive hypercarbia; and (4) correction of hypoxemia by alveolar recruitment, additional continuous oxygen insufflation, body position changes (prone position), inhaled nitric oxide, enhancement of hypoxic pulmonary vasoconstriction with almitrine, and drainage of pleural or mediastinal effusions. In patients remaining severely hypoxemic despite these modalities, ECCO2R was then proposed. MEASUREMENTS AND RESULTS: Thirty-six patients were addressed after 8.3+/-5.5 days of mechanical ventilation. On arrival, mean simplified acute physiologic score was 46.8+/-14.2, multiple system organ failure score was 1.8+/-1.6, Murray score was 3.4+/-0.4, PaO2 was 75.3+/-31.3 (fraction of inspired oxygen [FIO2]=1) for a positive end-expiratory pressure level of 12.3+/-3.4 cm H2O. Nineteen of 36 patients improved their gas exchange within 2 days and their mortality was 21%. The seventeen remaining patients did not improve PaO2/FIO2; PaCO2 and airway pressures remained high and their mortality was 88%. This different response to therapeutic optimization appeared using stepwise logistic regression as the most predictive factor for mortality (p<0.05). CONCLUSIONS: In patients with severe ARDS, the response to an early performed therapeutic optimization used to improve hypoxemia appeared to be a highly discriminant factor distinguishing deceased from surviving patients.

Adolescent↗

PubMed1996

Nitric oxide in sepsis.

The synthesis of nitric oxide (NO) and its targets are reviewed physiologically during sepsis and wound healing, a self-limiting process in which mechanisms are still identified incompletely. NO also plays an active and direct role during infection, aimed at protecting the host and destroying the microbe. During septic shock, an overproduction of NO has been described experimentally and clinically that might be responsible for the systemic vasodilatation with hyporesponsiveness to exogenous vasoconstrictive agents. The different manipulations of NO pathway during sepsis are described (transcription and post-transcription of iNOS, enzymatic function, substrate availability, NO concentration, and NO effector molecules), although their clinical benefit remains controversial.

Animals↗

PubMed1995

Distinct behavior of portal venous and arterial vascular waterfalls in porcine liver.

PURPOSE: Hepatic dysfunction is associated with morbidity and mortality in critically ill patients. Understanding liver hemodynamics in pathological states requires characterization of the normal portal venous and hepatic arterial circulations. Using pressure flow analysis, we tested the hypothesis that vascular waterfalls determine blood flows in the normal liver. METHODS: In 14 vascularly isolated porcine livers, steady-state pressure-flow relationships, which defined a slope (incremental resistance) and a zero flow pressure intercept (Po), were generated for each vessel over a range of hepatic venous pressures (Phv). RESULTS: Critical closing pressures occurred in the portal venous circulation (Po = 3.8 +/- 0.4 mm Hg) with classical waterfall physiology observed as Phv was raised. The hepatic arterial critical closing pressure (Po = 8.3 +/- 1 mm Hg) showed a constant positive pressure difference of mm Hg versus Phv as the latter was increased from 0 to 28 mm Hg (P < .05). Portal venous resistance decreased when Phv was greater than Po (P < .05), but no effect on hepatic arterial resistance was seen as Phv was increased. CONCLUSION: Both critical closing pressures and incremental resistances showed markedly different responses to increased outflow pressures in the portal venous and hepatic arterial circulations. The results provide the physiological basis to analyze hemodynamic changes in the liver under normal and pathological conditions.

Animals↗

PubMed1995

Interactions between hemodynamic and hormonal modifications during PEEP-induced antidiuresis and antinatriuresis.

The interactions between hemodynamic and hormonal modifications during antidiuresis and antinatriuresis induced by positive end-expiratory pressure (PEEP) were studied in six patients under 15 cm H2O PEEP before PEEP and after the addition of lower body positive pressure (LBPP) to PEEP (PEEP+LBPP). We measured or calculated the following: cardiac index, systemic arterial, right atrial, pulmonary arterial, and pulmonary artery occlusive pressures; indexed renal blood flow (iodohippurate 131 sodium clearance); total blood volume (chromium 51 radiolabeled RBCs); glomerular filtration rate; urinary output; fractional excretion of sodium (FE Na+); plasma concentrations of antidiuretic hormone (ADH), plasma renin activity (PRA), norepinephrine and epinephrine; urinary concentration of PGE2 (PGE2u). Although LBPP application corrected PEEP deleterious effects on systemic and renal hemodynamics, sustained fall in Vu and in FE Na+ were observed. Antidiuresis was not due to ADH release. Sympathetic activation and high PRA appeared the main determinants of renal function alterations in PEEP ventilation.

Adult↗

PubMed1993

Effect of anesthesia and surgery on plasma cytokine levels.

Cytokines released in response to stress may have a profound impact on circulatory stability. There is no information on the effect of general anesthesia alone on plasma cytokine levels and little information on cytokine release following surgery. Plasma cytokine levels and hemodynamic parameters were measured during anesthesia and abdominal surgery under sterile and nonpyrogenic conditions in seven pigs anesthetized with ketamine and pentobarbital. Tumor necrosis factor (TNF) was measured by bioassay. Bioassays of low and high sensitivity were used to measure interleukin 6 (IL-6). Measurements were made sequentially during: (1) 4 hours observation with anesthesia alone; (2) 2 hours following laparotomy and traumatic intestinal manipulation (IM) sufficient to produce shock; and (3) after an intravenous bolus of 1 microgram/kg endotoxin as a positive control. Arterial blood pressure decreased following IM from 91.5 +/- 5.8 to 48.6 +/- 3.2 mm Hg, (mean +/- SE, P < .05), with no further change following endotoxin. Heart rate was unchanged during the experiment, and central venous pressure decreased after endotoxin (P < .05). There were no increases in TNF or IL-6 (using a low sensitivity assay) with anesthesia alone or following IM with shock, but both increased after endotoxin administration (P < .05); using a high sensitivity assay, IL-6 did not change during anesthesia alone but did increase fivefold following IM with shock (P < .05) and 50-fold following endotoxin administration (P < .05). We conclude that in a porcine model under sterile and nonpyrogenic conditions, prolonged anesthesia does not increase plasma cytokine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗

PubMed1992

Superior and inferior vena caval flows during respiration: pathogenesis of Kussmaul's sign.

Respiratory induced changes in superior (QSVC) and inferior (QIVC) vena caval flows and abdominal pressures were evaluated in anesthetized closed-chest dogs. QSVC and QIVC were measured with ultrasound transit time flow probes (n = 5), and general (Pab) and regional subdiaphragmatic (Pd) abdominal pressures were measured by air-filled balloons (n = 5), during two respiratory maneuvers produced by phrenic nerve stimulation, i.e., simulated spontaneous inspiration (SSI), and Mueller maneuver (MM), with the airway occluded to minimize diaphragmatic descent. With hypervolemia: during SSI, QSVC decreased, QIVC increased, and right atrial pressure increased (P less than 0.05) despite a decrease in esophageal pressure (Pes), i.e., Kussmaul's sign; during MM, both QSVC and QIVC increased (P less than 0.05) without Kussmaul's sign. The ratios delta Pab/delta Pes and delta Pd/Pes were larger during SSI than MM (P less than 0.01). With hypovolemia: during SSI and MM, QSVC increased and QIVC decreased with a venous pressure gradient across the diaphragm (P less than 0.05), consistent with development of a vascular waterfall. These results suggest that 1) changes in abdominal pressure may affect the patterns of QSVC and QIVC during respiration, depending on blood volume status; 2) a prolonged inspiration with hypovolemia may decrease QIVC because of the development of a vascular waterfall; 3) QSVC and QIVC may be interdependent during respiration; and 4) the essential mechanism of Kussmaul's sign is a substantially larger inspiratory increase in abdominal pressures produced by diaphragmatic descent compared with the decrease in intrathoracic pressure under hypervolemic conditions, rather than the presence of pericardial pathology or right heart dysfunction.

Animals↗

PubMed1992

Influence of pericardial constraint on atrioventricular interactions.

The effects of the pericardial constraint in control, tamponade, and absent pericardium conditions was studied in 18 anesthetized open-chest dogs. Atrial pressures and systolic and diastolic inflow volumes per beat in the superior (SVC), inferior vena cavae (IVC), and pulmonary vein (PV) were measured. With increasing tamponade, 1) the systolic-diastolic distribution of venous flow became almost exclusively systolic in the SVC (P less than 0.001) and IVC (P less than 0.05), as the gamma-descent disappeared; 2) similar but lesser left-sided changes occurred in PV flows (P less than 0.001) and pressure; and 3) the systolic-diastolic distribution of venous flow was modulated by heart rate. The results imply that during tamponade 1) increased pericardial liquid pressure associated with an increased pericardial constraint couples reciprocal atrial and ventricular volume changes; 2) the atria fill during ventricular ejection (atrioventricular interaction); 3) total heart volume must have been relatively constant throughout a cardiac cycle; and 4) differences in right and left heart compliances may explain persistent diastolic PV flow. Pericardiotomy produced a small increase in the ratio of diastolic to systolic venous inflow volumes (P less than 0.025), suggesting that normally the pericardium has a minor influence on atrioventricular interaction, the volume changes in the atria and ventricles being relatively uncoupled. With severe tamponade, a homogeneous pericardial fluid column tightly couples atrial and ventricular volume changes and accounts for the characteristic changes in atrial pressure waveforms and patterns of venous flow.

Animals↗