Decline In Cardiac Output Research Articles

A synthetic lipid A analog, B464, provides significant protection against the cardiopulmonary derangements in porcine Gram-negative sepsis

Many of the cardiopulmonary derangements associated with Gram-negative sepsis result from the activation of monocytes and macrophages by endotoxin with the resultant release of humoral mediators such as TNFα. Lipid A has been shown to retain the majority of endotoxin toxicity, however lipid A from nontoxic organisms has been shown, in vitro, to antagonize the action of other toxic endotoxin species. We examined the effects of a synthetic analog of lipid A (B464), on the evolution of hemodynamic derangements and acute lung injury following experimental Gram-negative sepsis. Anesthetized, ventilated swine were made septic with a 1 h intravenous infusion of live Pseudomonas aeruginosa and studied for 5 h. A treatment group received a bolus of B464 (100 μg/kg) prior to sepsis and a 1 h infusion (100 μg/kg/h) during the P. aeruginosa induction. A control group received simply 0.9% saline. All animals were studied for 5 h. B464 treatment failed to alter septic pulmonary hypertension or the decline in cardiac output. Late recovery from systemic hypotension was associated with reversal of arterial acidosis. Septic neutropenia was unaltered and was associated with increased lung neutrophil (PMN) sequestration measured by lung myeloperoxidase activity. However, decreased bronchoalveolar lavage protein content and improved arterial oxygen tension indicated attenuated acute lung injury in B464 treated animals. These preliminary data indicate that B464 may prove to be an effective tool in the treatment of human sepsis.

Effect of Nitric Oxide Synthase Inhibition during Group B Streptococcal Sepsis in Neonatal Piglets

Nitric oxide (NO), an important vasodilatory modulator of systemic and pulmonary vascular tone, is synthesized from L-arginine by the enzyme NO synthase in vascular endothelial and smooth muscle cells. L-Arginine analogs, such as N omega-nitro-L-arginine methyl ester (L-NAME), are competitive antagonists of NO synthase and inhibit NO synthesis. Group B streptococcus (GBS) causes pulmonary hypertension, hypoxemia, lung vascular injury, and reduced cardiac output in both human newborns and neonatal piglets. Lung vascular injury associated with prolonged GBS infusion in piglets may attenuate NO production and thus promote severe pulmonary hypertension. We studied the effect of the NOS inhibitor, L-NAME and the precursor of NO, L-arginine, on pulmonary and systemic hemodynamics during late-phase GBS sepsis in the piglet model. Neonatal piglets were anesthetized, ventilated with room air, and randomized to receive a continuous infusion of saline (n = 5) or GBS (n = 5) for 4 h. After 3 h of infusion, both groups received a bolus of L-NAME (3 mg/kg). Hemodynamic and gas exchange indices were measured at baseline, 30 min, and 3 h of infusion, and 30 min and 1 h after L-NAME treatment. L-NAME treatment caused 1) significant increases in mean pulmonary arterial pressure, pulmonary vascular resistance, mean systemic arterial pressure, and systemic vascular resistance for both groups; 2) a similar percentage of increase in pulmonary vascular resistance for the two groups; 3) greater reduction in cardiac output and SV in the GBS compared with the control group; and 4) no significant alterations in arterial partial pressure of oxygen or the difference between alveolar and arterial partial pressure of oxygen for either group.(ABSTRACT TRUNCATED AT 250 WORDS)

NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs

Objective: To evaluate the hemodynamic effects of the nitric oxide inhibitor, NG-methyl-L-arginine, and dobutamine during experimental endotoxemia. Design: Prospective, randomized, controlled animal study. Setting: University research laboratory. Subjects: Adult, male mongrel dogs. Interventions: After catheterization with a flow-directed, thermal-dilution pulmonary artery flotation catheter and arterial catheter, awake dogs received either NG-methyl-L-arginine or dobutamine alone or in combination (controls; n = 5). Other animals were administered endotoxin (50 μg/kg), then received either NG-methyl-L-arginine alone or in combination with dobutamine after the onset of hypotension (endotoxin-treated; n = 5). Measurements and Main Results: Both dobutamine and NG-methyl-L-arginine alone had a small, but significant vasopressor effect on control animals. In contrast, administration of the combination of NG-methyl-L-arginine and dobutamine resulted in a 48.6% increase in mean arterial pressure, an effect which was dose-dependent with respect to NG-methyl-L-arginine. In dogs treated with 50 μg/kg of endotoxin, hypotension could be only partially reversed by NG-methyl-L-arginine, mainly due to a decline in cardiac output. Co-infusion of dobutamine reversed this depression of cardiac output and resulted in a complete restoration of blood pressure. Conclusions: Later stages of septic shock are characterized by hypotension and decreased myocardial performance. A major mediator of hypotension is nitric oxide, a vasodilatory agent derived from L-arginine. Administration of the arginine derivative, NG-methyl-L-arginine, improved systemic vascular resistance but not myocardial performance. The addition of an inotropic agent to NG-methyl-L-arginine, a nitric oxide synthase inhibitor, resulted in an enhancement of the antihypotensive action of NG-methyl-L-arginine through the restoration of cardiac output. The synergistic action between dobutamine and NG-methyl-L-arginine may be of therapeutic value in the treatment of septic shock. (Crit Care Med 1994; 22:1835–1840)

NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs

To evaluate the hemodynamic effects of the nitric oxide inhibitor, NG-methyl-L-arginine, and dobutamine during experimental endotoxemia. Prospective, randomized, controlled animal study. University research laboratory. Adult, male mongrel dogs. After catheterization with a flow-directed, thermal-dilution pulmonary artery flotation catheter and arterial catheter, awake dogs received either NG-methyl-L-arginine or dobutamine alone or in combination (controls; n = 5). Other animals were administered endotoxin (50 micrograms/kg), then received either NG-methyl-L-arginine alone or in combination with dobutamine after the onset of hypotension (endotoxin-treated; n = 5). Both dobutamine and NG-methyl-L-arginine alone had a small, but significant vasopressor effect on control animals. In contrast, administration of the combination of NG-methyl-L-arginine and dobutamine resulted in a 48.6% increase in mean arterial pressure, an effect which was dose-dependent with respect to NG-methyl-L-arginine. In dogs treated with 50 micrograms/kg of endotoxin, hypotension could be only partially reversed by NG-methyl-L-arginine, mainly due to a decline in cardiac output. Co-infusion of dobutamine reversed this depression of cardiac output and resulted in a complete restoration of blood pressure. Later stages of septic shock are characterized by hypotension and decreased myocardial performance. A major mediator of hypotension is nitric oxide, a vasodilatory agent derived from L-arginine. Administration of the arginine derivative, NG-methyl-L-arginine, improved systemic vascular resistance but not myocardial performance. The addition of an inotropic agent to NG-methyl-L-arginine, a nitric oxide synthase inhibitor, resulted in an enhancement of the antihypotensive action of NG-methyl-L-arginine through the restoration of cardiac output. The synergistic action between dobutamine and NG-methyl-L-arginine may be of therapeutic value in the treatment of septic shock.

Tumor necrosis factor-alpha increases myocardial microvascular transport in vivo.

Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100 ng/kg for 60 min) on myocardial microvascular transport of a small hydrophilic indicator was examined by the single-injection, residue-detection method. Intracoronary infusion of rTNF-alpha increased myocardial microvascular transport after 120 min. This increase was preceded by a sustained decline in cardiac output and was associated with the appearance of areas with myocardial necrosis in the regional left ventricular wall. The myocardial plasma flow rate and maximum plasma flow rate in response to a 30-s coronary occlusion were not influenced by rTNF-alpha, although a decrease in the myocardial plasma flow rate was observed after 180 min. Circulating neutrophil counts were increased by rTNF-alpha, but the increase in myocardial capillary permeability could not be ascribed to regional neutrophil infiltration. We conclude that picomolar levels of rTNF-alpha can influence the movement of small hydrophilic molecules across the myocardial microvascular barrier in vivo and induce a prolonged decrease in cardiac performance. These effects may be important elements in myocardial pathophysiology.

Delayed Tumor Necrosis Factor α Blockade Attenuates Pulmonary Dysfunction and Metabolic Acidosis Associated With Experimental Gram-negative Sepsis

To ascertain the effect of delayed tumor necrosis factor alpha (TNF-alpha) on the evolution of systemic and pulmonary injury after the onset of sepsis. Prospective controlled trial. Anesthetized swine were made septic with a 1-hour infusion of live Pseudomonas aeruginosa, following which a treatment group received an infusion of anti-TNF-alpha monoclonal antibody (5 mg/kg). Control animals received 0.9% saline. Delayed anti-TNF-alpha treatment had no effect on septic pulmonary hypertension or decline in cardiac output. Late recovery in systemic arterial hypotension was associated with a reversal of arterial acidosis (P < .05 by t test and analysis of variance with Tukey's Studentized Range Test) compared with unprotected septic animals. Septic animals had a significant increase in mean (+/- SEM) plasma lactate levels at 5 hours compared with baseline values (3.8 +/- 0.7 vs 2 +/- 0.4, P < .05), but remained unchanged from baseline following anti-TNF-alpha treatment (1.5 +/- 0.1 vs 1.6 +/- 0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti-TNF-alpha treatment and was associated with downregulation (P < .05 by t test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P < .05 by t test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (+/- SEM) decrease in bronchoalveolar lavage protein indicated an attenuated permeability injury in anti-TNF-alpha animals (septic animals at 5 hours compared with baseline value, 1044 +/- 270 vs 149 +/- 28 micrograms/mL; control animals at 5 hours compared with baseline value, 217 +/- 83 vs 129 +/- 19 micrograms/mL; P < .05 by t test and analysis of variance). These data show that delayed anti-TNF-alpha treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti-TNF-alpha treatment reversed septic neutropenia, reduced PMN sequestration, and was associated with attenuated lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for potential therapeutic benefit of anti-TNF-alpha treatment in clinical practice.

Positive end-expiratory pressure increases capillary pressure relative to wedge pressure in the closed and open chest

The pulmonary arterial wedge pressure is used as a measure of left atrial pressure and frequently as an estimate of pulmonary capillary pressure. The arterial occlusion concept has recently been used to derive a pressure that is thought to be more representative of capillary pressure (Pcap) than wedge pressure (Pw). The object of this study was to measure the arterial occlusion Pcap at different positive end-expiratory pressure (PEEP) levels and to compare it with Pw. Anesthetized, paralyzed, supine, and mechanically ventilated dogs were instrumented with a Swan-Ganz balloon tip catheter (7F) for monitoring pulmonary arterial pressure (Pa), for measuring cardiac output (CO; thermodilution technique), and for performing the arterial occlusions. The postocclusion tracings were analyzed for Pcap in a conventional manner: exponential fitting of the data during the 2 seconds immediately postocclusion and back extrapolating to the instant of occlusion. Instant of occlusion was defined as the time when the Pa tracing began to deviate from the normal tracing. Pw was averaged from the data between 8 to 10 seconds after the occlusion. Increasing PEEP between 0 to 15 mm Hg caused a gradual decline in cardiac output in the closed and open chest conditions. Despite this decline, all three pressures (Pa, Pcap, and Pw) rose gradually in the closed chest. However, in the open chest, increasing PEEP from 0 to 4.7 mm Hg had no effect on the pressures, but between 4.7 and 13.4 mm Hg of PEEP, Pa and Pcap increased markedly with minimal change in Pw. In both the open and the closed chest, total vascular resistance (Pa-Pw/CO) increased, whereas the resistance of the arteries (Pa-Pcap/CO) remained unchanged. This suggested that the resistance of other vessels (most likely the alveolar vessels) had increased. The results show that occlusion Pcap can be derived at all PEEP levels, Pcap is always greater than Pw, PEEP increases resistance of downstream vessels (most likely alveolar vessels), and consequently, the occlusion Pcap deviates increasingly from Pw as PEEP increases. This study indicates that the problems that are usually associated with measurement of Pw in different zone conditions do not affect measurement of Pcap with the occlusion technique.

High-volume hemofiltration improves hemodynamics of endotoxin-induced shock in the pig

This study was designed to assess the influence of high-volume continuous hemofiltration on the hemodynamics of endotoxin-induced shock in pigs. Eighteen anesthetized and ventilated pigs were studied for 240 minutes following the start of a 30-minute infusion of 0.5 mg/kg endotoxin. They were randomly divided into three groups: group 1 served as a control group, receiving endotoxin only; group 2 received zero balance, high-volume, venovenous hemofiltration with the removal of 6,000 mL ultrafiltrate/hr; and group 3 was used to evaluate the hemodynamic effect of the extracorporeal circuit itself. The decline in mean arterial pressure for group 2 was less than for group 1 (24 ± 7.8 mm Hg [mean ± SEM] versus 60 ± 3.4 mm Hg; P < .001) as was the drop in cardiac output (0.35 ± 0.24 L/min versus 1.53 ± 0.59 L/min; P < .01). The decline in cardiac output was more pronounced in group 3 than in group 1 (3.98 ± 0.21 L/min versus 1.53 ± 0.59 L/min; P < .01). Left ventricular stroke work decreased by 61 ± 6.8 g in group 1 versus 14 ± 2.0 g in group 2 ( P < .01), while left ventricular stroke work in group 3 was lower than that in group 1 ( P < .02). Right ventricular stroke work increased further in group 2 than in group 1 (16 ± 2.1 g v 3 ± 0.8 g; P < .01). The pulmonary vascular resistance, systemic vascular resistance, right atrial pressure, and pulmonary artery wedge pressure in groups 2 and 3 did not differ from those in group 1. We conclude that in this model, high-volume venovenous hemofiltration significantly improves cardiac function but does not affect pulmonary vascular resistance or systemic vascular resistance, while the use of the extracorporeal circuit adversely affects cardiac function. The effect of hemofiltration was more pronounced in this study than in others, probably because of the higher ultrafiltrate volume.

Overnight increases in haematocrit: additional evidence for a nocturnal fall in plasma volume.

Our previously published studies with monkeys describe a characteristic nocturnal haemodynamic pattern consisting of a monotonic decline in cardiac output and central venous pressure, and a concomitant rise in total peripheral resistance. These findings led us to hypothesize that there is a reduction in total plasma volume during the night. Since a fall in plasma volume should cause an increase in haemoglobin and plasma protein concentration, we designed this experiment to test the hypothesis that haematocrit levels would be significantly greater in the morning than in the evening. In a study of five monkeys, the levels of haematocrit were measured at 1700 h and at 0900 h the next morning for 14 days. The average morning haematocrit levels were 6.5% higher than the average evening values. Lower plasma volume and possibly greater blood viscosity could contribute to the pathophysiology of the morning increase in the incidence of 'silent' ischaemia and catastrophic vascular events such as sudden cardiac death, myocardial infarctions and strokes in man.

Left ventricular diastolic function during positive end-expiratory pressure. Impact of right ventricular ischemia and ventricular interaction.

The individual and additive effects of positive end-expiratory pressure (PEEP) and right coronary artery (RCA) occlusion on left ventricular end-diastolic pressure-volume relations (LVEDPVR) were examined in six anesthetized dogs. Right ventricular (RV) and left ventricular (LV) ejection fractions (EF), end-diastolic volume (EDV) and end-systolic volumes (ESV) were measured by thermodilution as PEEP was added before and after RCA occlusion. PEEP alone caused a decline in cardiac output, transmural left atrial pressure (LAP) (6.0 +/- 0.6 to 3.2 +/- 1.4 mm Hg, p less than 0.05), and LVEDV (49 +/- 3 to 36 +/- 4 ml, p less than 0.05). RVEDV, the mean slope (+/- SD) of the LVEDPVR (0.37 +/- 0.16 to 0.30 +/- 0.19) and LAP at a common LV volume (35 ml, V35) did not change with PEEP. RCA occlusion caused cardiac output and RVEF (38 +/- 5 to 27 +/- 5%, p less than 0.05) to decline and RVESV (25 +/- 4 to 33 +/- 6 ml, p less than 0.05) to increase. RVEDV, the slope of the LVEDPVR, and LAP at V35 were unchanged from baseline. The addition of PEEP after RCA occlusion caused cardiac output to decline further. However, unlike before occlusion, there was no change in LAP (6.5 +/- 1.3 to 5.0 +/- 1.4 mm Hg) despite a decline in LVEDV (47 +/- 3 to 29 +/- 6 ml, p less than 0.05). RVESV and RVEDV increased with PEEP after RCA occlusion as did LAP at V35. The slope of the mean LVEDPVR tended to increase (0.98 +/- 1.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleotide precursors modify the effects of isoproterenol. Studies on heart function and cardiac adenine nucleotide content in intact rats.

In closed-chest rats, isoproterenol (ISO, 25 mg/kg), 5 hours after subcutaneous administration, increased heart rate by 53%, left ventricular (LV) dP/dtmax by 80%, and cardiac output by 37%. LV systolic pressure (LVSP, -10%), mean arterial pressure (MAP, -12%), and total peripheral resistance (TPR, -36%) were diminished. In separate experiments, continuous intravenous infusion of adenine (50 mg/kg/hr) for 5 hours reduced heart rate (-11%), LVSP (-16%), MAP (-20%), TPR (-33%), and LV dP/dtmax (-20%). Cardiac output was increased (+20%). Inosine has been shown to have similar effects, except for a decline in cardiac output. Adenine (50 mg/kg/hr) attenuated the ISO-induced increase in heart rate and LV dP/dtmax and aggravated the decline in LVSP, MAP, and TPR. The increase in cardiac output was not changed. Inosine (200 mg/kg/hr) modified the ISO effects to a similar extent. Ribose (200 mg/kg/hr) added to the adenine infusion did not have functional effects. However, it aggravated the modifying influence of inosine on LVSP, LV dP/dtmax, and MAP. ISO reduced the cardiac ATP content (mumol/g) from a control value of 5.02 +/- 0.06 (n = 12) to 3.51 +/- 0.13 (n = 10). Adenine (3.56 +/- 0.21, n = 7) and ribose (3.64 +/- 0.11, n = 9) alone did not affect it, but inosine attenuated it (4.33 +/- 0.08, n = 8). Adenine and inosine in combination with ribose abolished the ISO-induced ATP decline (5.18 +/- 0.23, n = 7, and 4.76 +/- 0.10, n = 8, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of cardiac output at rest and during exercise to age in essential hypertension

It has been suggested that the decline of cardiac output with age is due to increased prevalence of disease, particularly occult coronary artery disease. Therefore, the relation of cardiac output (direct oxygen Fick method) to age was analyzed in 110 sixteen- to 64-year-old men with World Health Organization stage I or II essential hypertension at the time of the hemodynamic study, who were alive and free of cardiovascular complications 7 years later. At supine and seated rest, during upright bicycle exercise at 50 W and at peak work load, cardiac output was inversely (p < 0.01) related to age. These relations were independent of weight and mean intraarterial pressure. Stroke volume decreased with advancing age at supine rest, but not at rest and during exercise in the seated position. Heart rate was not affected by age in the supine position, but was slower in older patients during upright rest and at peak exercise. In conclusion, in patients with essential hypertension who remained free of cardiovascular complications for 7 years, cardiac output was independently and inversely related to age at various levels of activity. These findings suggest that occult cardiovascular disease does not explain the decline in cardiac output with age in patients with essential hypertension.

Pathophysiologische und therapeutische Aspekte beim akuten Lungenversagen (ARDS)

Since the first characterization of the adult respiratory distress syndrome (ARDS), knowledge of its aetiology and pathogenesis has grown considerably. In spite of this, mortality remains up to 50 to 90%, particularly if multiple organ failure is present. Because no causative clinical therapy is available up to now, significant attention is given to preventive measures like early operative stabilisation of long bone fractures, or prophylaxis of nosocomial infections. After clinical manifestation of ARDS, treatment focuses on functional disturbances of the cardiopulmonary system and on the underlying disease. The aim of this symptomatic therapy is to ensure oxygen supply according to the organisms demand. It is still unknown, however, whether the mortality of patients with ARDS can be reduced by optimising the oxygen supply. In general, oxygen supply can be enhanced by improving pulmonary gas exchange, cardiac output and blood oxygen transport capacity. For practical use the therapy often ends up with a therapeutical dilemma: On one hand, the improvement of the pulmonary gas exchange by application of PEEP can be associated with a critical decline in cardiac output, particularly if the afterload of the right ventricle is elevated. On the other hand, to increase cardiac output, both volume replacement and vasodilators can severely affect pulmonary gas exchange if the alveolo-capillary permeability is increased and pulmonary hypoxic vasoconstriction is disturbed. Thus, oxygen supply can be optimised only via invasive monitoring of the cardiorespiratory system. Although still experimental, the most promising approaches seem to be pharmacological interventions directed at suppressing the formation and effects of various humoral and cellular mediators. An improved understanding of the inflammatory processes might provide new insights in the pathophysiology of ARDS and the related therapeutic interventions.

Interleukin-6 administration has no acute hemodynamic or hematologic effect in the dog

To investigate the possible hemodynamic effects of interleukin-6 (IL-6), a single dose of 15 mcg/kg of recombinant IL-6 isolated from Escherichia coli was injected intravenously in six pentobarbital-anesthetized dogs. After 30 min, saline infusion was performed to maintain the pulmonary artery balloon-occluded pressure at baseline level. The animals were observed for up to 5 hours. No other hemodynamic alteration was observed than a gradual decline in cardiac output attributed to anesthesia. Hematologic variables, blood glucose, and total serum proteins were also constant. IL-6 levels were markedly elevated in the blood, but no tumor necrosis factor activity was detected. Thus a primary role for IL-6 in the early cardiovascular alterations associated with septic shock seems unlikely.

Hemodynamic Effects of Inosine in Combination with Positive and Negative Inotropic Drugs

Inosine applied as a continuous i.v. infusion of 400 mg/kg/h for 20 min had a negative chronotropic and inotropic effect in closed-chest, anesthetized rats. In the presence of adenosine deaminase (ADA, 133 U/kg/h), the reduction in heart rate was abolished indicating that adenosine is responsible for that effect. However, the negative inotropic effect persisted. It was characterized by a 38 and 56% decrease in left ventricular systolic pressure (LVSP) and diastolic aortic pressure, respectively, a 24% decline in LV dp/dtmax and a 16% fall in cardiac output. Total peripheral resistance was diminished by 38%. Inosine in combination with ADA antagonized the noradrenaline-induced positive inotropic effect and the increase in cardiac output. On the other hand, i.v. bolus injection of noradrenaline in rats pretreated with inosine and ADA did not increase blood pressure and total peripheral resistance. Inosine administered in animals pretreated with the beta-receptor blocker metoprolol or with the calcium antagonist verapamil aggravated the negative inotropic effect. Inosine in combination with ADA caused a decline in cardiac output in metoprolol-pretreated rats that was more pronounced than that induced by inosine alone. However, in rats pretreated with verapamil, inosine did not cause a reduction in cardiac output.

Training in dogs with normal coronary arteries: lack of effect on collateral development

STUDY OBJECTIVE - The aim of the study was to investigate the effect of exercise training on coronary collateral development in a normal heart animal model. DESIGN - Dogs with normal hearts were fitted with balloon occluders around the left circumflex coronary artery. Haemodynamic variables and myocardial blood flow (using radioactive microspheres) were measured during 1 min circumflex occlusions at rest and during exercise, before and after a 12 week exercise programme. Resting measurements were also made after 4 weeks. SUBJECTS - Trained subjects were 10 one year old beagles; eight beagles served as sedentary controls. Although measurements were made in all dogs at 4 weeks, four trained and three control animals died during the experiment because of complications, so the data reported at 12 weeks are derived from six trained and five sedentary animals. Except during the few occasions when the left circumflex artery was transiently occluded to allow measurement of collateral flow, all coronary arteries were patent and without impediment to normal flow. MEASUREMENTS and RESULTS - Measurements of haemodynamic variables and coronary blood flow were made at the start and repeated at 4 weeks (resting measurements only) and 12 weeks of exercise training. Initial resting circumflex collateral flow was 0.26(SEM 0.05) cm3.g-1.min-1 in the training group and 0.23(0.03) in the control group (NS). The ratio of ischaemic to normal blood flow was 0.16(0.02) in both groups. At 4 weeks there were no changes in either group. At 12 weeks the ischaemic to normal blood flow ratio had increased in both trained and sedentary dogs to 0.24(0.05) and 0.26(0.06) respectively, but the trend over the 12 week period was not significant. The decline in cardiac output and dramatic increase in left atrial pressure during combined coronary occlusion and exercise were comparable in both groups at weeks 1 and 12. CONCLUSIONS - Exercise does not accelerate the development of coronary collaterals in dogs with normal coronary arteries.

Hemodynamic management in pulmonary embolism and acute hypoxemic respiratory failure

Management of patients with the adult respiratory distress syndrome should be directed toward maintaining adequate cardiac output and tissue oxygenation without exacerbating pulmonary edema. The aim of therapy should be to maintain low left ventricular filling pressure, which will tend to decrease the rate of edema formation. If cardiac output is low or decreases as a function of therapy, flow may be increased with inotropic agents. When a marked decline in cardiac output complicates pulmonary embolism, norepinephrine may be an excellent drug for at least short-term maintenance of hemodynamic stability. When a moderate decrease in cardiac output complicates an increase in right ventricular afterload, isoproterenol or dobutamine may be used to increase flow. Rapid administration of recombinant tissue plasminogen activator may be the treatment of choice of pulmonary thromboembolism associated with a low output state.

A functional assessment of the relative cardiotoxicity of adriamycin and epirubicin in the rat

The cardiotoxicity of the two anthracyclines, adriamycin and epirubicin, were studied in 14-week-old Sprague-Dawley rats after the intravenous administration of single doses of 1–4 mg/kg of adriamycin and 2–6 mg/kg of epirubicin. These doses of the two drugs were well tolerated with little acute toxicity. Acute toxicity was characterised by a transient reduction in body weight with recovery within 14 days. The cardiac output of the rats was measured at 4-weekly intervals, for up to 20 weeks, using an external counting technique with the radioactive tracer, 99mTc. The time-related changes in cardiac function in the rat after adriamycin and epirubicin were similar. The time course of the changes in cardiac output were biphasic. There was an initial phase of rapid decline in cardiac output in the first 12 weeks (phase I) and a second phase of persistent depression in cardiac function (phase II) after 12 weeks. The late progression of anthracycline-induced cardiotoxicity could be predicted from the measurements of cardiac output at 12 weeks. The relative cardiotoxicity of adriamycin and epirubicin was evaluated from the reductions in cardiac output and from the incidence of deaths related to cardiotoxicity. Both methods of evaluation showed that adriamycin was approximately twice as cardiotoxic as epirubicin. This relationship was independent both of the dose level of drugs used and of the damage level used for the evaluation. Dose-response curves were steeper for adriamycin than for epirubicin. The present findings agree with the somewhat limited clinical data suggesting that the present rat model is highly predictive and clinically relevant.

Mixed venous blood gases are superior to arterial blood gases in assessing acid-base status and oxygenation during acute cardiac tamponade in dogs.

Recent reports using anesthetized ventilator-dependent animal models, have suggested that in certain shock states, a disparity exists between arterial and mixed venous blood gases with regard to acid-base status and oxygenation. In a chronically instrumented unanesthetized canine model of acute cardiac tamponade breathing room air, we studied the effect of a graded decline in cardiac output on arterial and mixed venous pH, PCO2, and PO2. Cardiac tamponade resulted in a profound arterial respiratory alkalosis, whereas mixed venous pH, PCO2, and calculated serum bicarbonate levels remained relatively unchanged. As intrapericardial pressure increased and cardiac output declined, the difference between arterial and mixed venous PCO2 progressively increased. Further, whereas arterial oxygenation improved as cardiac output declined, mixed venous oxygenation steadily worsened. This disparity began early in cardiac tamponade (reductions in cardiac output of 20-40%) long before arterial blood pressure began to fall and progressively worsened as hemodynamic deterioration and lactic acidosis developed. Our findings are consistent with the hypothesis that a reduction in blood flow, resulting in decreased CO2 delivery to the lungs, is the primary mechanism responsible for the difference in pH and PCO2 observed between arterial and mixed venous blood. In this conscious, spontaneously breathing animal model, mixed venous blood gases thus are superior to arterial blood gases in assessing acid-base status and oxygenation, even early in acute cardiac tamponade when the decline in cardiac output is in the range of 20 to 40% and arterial blood pressure has not changed significantly.

Comparison of effects of dextran-70 and Ringerʼs acetate on pulmonary function, hemodynamics, and survival in experimental septic shock

The effects of dextran-70 with NaCl vs. Ringer's acetate on hemodynamics, gas exchange, oxygen transport, and survival were evaluated in a porcine model of pulmonary and circulatory insufficiency induced by a continuous iv endotoxin infusion over 6 h. Dextran and Ringer's acetate were infused continuously to maintain baseline mean left atrial pressure (LAP) throughout the endotoxin period. Twelve pigs receiving endotoxin + Ringer's acetate displayed a progressive 45% decline in cardiac output (Qt) and a two-peaked increase in pulmonary vascular resistance (PVR) with a late increase of 250%. Venous admixture (Qva/Qt) increased progressively more than six-fold and extravascular lung water (EVLW) increased by 55%. Mean arterial BP (MAP) fell by 25%, oxygen delivery by 40%, base excess (BE) ranged between -4.5 and -9 mmol/L at the end of the endotoxin period and four of 12 animals died. Polymorphonuclear cell count (PMN) fell rapidly by 90% and was decreased severely throughout the endotoxin period. By contrast, the 12 pigs that received endotoxin + dextran maintained Qt near baseline and PVR was significantly lower in this group. Qva/Qt increased progressively more than four-fold, but it was significantly lower than in the Ringer's acetate group as was the increase in EVLW (23%). MAP only decreased by 10%, oxygen delivery only decreased by 20%. BE ranged between -1.0 and -3.0 mmol/L at the end of the endotoxin period and all animals survived. PMN fell by 90% at 0.5 h but subsequently tended to return toward baseline, and PMN were significantly increased compared with the Ringer's acetate group.(ABSTRACT TRUNCATED AT 250 WORDS)