Effects of phentolamine or yohimbine on naloxone's actions during endotoxin shock in rats.

Endogenous opioids are known to mediate some of the cardiovascular sequelae of sepsis. Inhibition of adrenergic action has been implicated as a physiological path by which endogenous opioids cause deleterious changes in cardiovascular function during endotoxin shock, but where and to what extent this accounts for changes in regional vascular resistance remains unclear. In this study, we addressed this question by examining the role of alpha-adrenergic actions in cardiovascular performance and the regional perfusion changes caused by naloxone during endotoxin shock. Rats had catheters inserted into the tail artery, left cardiac ventricle, and jugular vein. Twenty-four hours later, rats received saline or endotoxin (2 mg/kg) challenge intravenously over 30 min, followed at 40 min by intravenous naloxone (or saline) treatment (4 mg/kg + 2 mg/kg x h) in the presence or absence of phentolamine (100 micrograms/kg + 600 micrograms/kg x h) or yohimbine (40 micrograms/kg + 4 micrograms/kg x h). Radiolabeled microspheres were used to determine cardiac outputs and blood flows at 0, 30, 60, and 120 min after beginning endotoxin infusion. Naloxone attenuated the endotoxin-induced decline in mean arterial pressure (MAP) and cardiac output (CO), but had no effect on increased systemic vascular resistance (SVR). Phentolamine blocked naloxone's ability to increase MAP and CO, but permitted an increase in SVR by naloxone. In the presence of yohimbine, naloxone still increased MAP, but not CO nor SVR. Regional vascular responses varied, with naloxone demonstrating a vasoconstrictive effect despite alpha-adrenergic receptor blockade in some beds, and no effect in others. The response of individual organs in the hepatosplanchnic circulation was heterogenous as well. These data suggest that some effects of endogenous opioids during endotoxin shock are mediated via inhibition of alpha-adrenergic effects, but that some cardiovascular effects of endogenous opioids are independent of adrenergic control during endotoxin shock.

Starling resistor effects on pulmonary artery occlusion pressure in endotoxin shock provide inaccuracies in left ventricular compliance assessments.

OBJECTIVES: Assessment of left ventricular preload and left ventricular compliance changes in septic shock using pulmonary artery occlusion pressure (PAOP) presumes that this pressure accurately reflects left heart filling pressure. We tested the hypothesis that Starling resistor forces render PAOP inaccurate as an index of left heart filling pressure, resulting in misleading assessments of left ventricular compliance changes. DESIGN: Prospective, randomized, controlled study. SETTING: Large-animal research laboratory at a university. SUBJECTS: Fourteen anesthetized domestic pigs weighing 20 to 25 kg. INTERVENTIONS: Pulmonary artery flotation catheters and systemic arterial catheters were placed via right cervical vessels. The left atrium was directly catheterized for left atrial pressure measurements. Left ventricular end-diastolic diameter was measured using sonomicrometry. Other measured or calculated variables were mean arterial pressure, mean pulmonary arterial pressure, PAOP, pulmonary capillary pressure, and pulmonary arterial and venous resistances. Pigs received endotoxin (0.5 mg/kg i.v. over 30 mins), or an equivalent volume of saline. At t = 60 mins, pigs were resuscitated with lactated Ringer's solution (40 mL/kg over 30 mins). Measurements were taken before and after endotoxin administration, and immediately and 30 mins after lactated Ringer's solution administration. Data were analyzed by two-way analysis of variance (p < or = .05). MEASUREMENTS AND MAIN RESULTS: PAOP, mean pulmonary arterial pressure, and pulmonary capillary pressure increased after endotoxin infusion, while left atrial pressure and left ventricular end-diastolic diameter decreased. Left atrial pressure and left ventricular end-diastolic diameter returned to baseline immediately after lactated Ringer's solution administration, while PAOP remained increased. Pulmonary arterial resistance and pulmonary venous resistance increased after endotoxin administration, with pulmonary venous resistance showing the greater percent increase. Pulmonary venous resistance decreased transiently immediately after lactated Ringer's solution administration. These changes were not observed in the control group. Accordingly, comparisons of PAOP vs. left ventricular end-diastolic diameter, and left atrial pressure vs. left ventricular end-diastolic diameter yielded divergent results. CONCLUSIONS: The dissociation between PAOP and left atrial pressure, while left ventricular and -diastolic diameter (preload volume) decreased, and changes in pulmonary venous resistance, are strong evidence for Starling resistor forces (venocompression) rather than active venoconstriction. These data indicate that PAOP overestimates left atrial pressure during endotoxin shock, making it an inaccurate index of left ventricular preload. This overestimation can cause misleading assessments of left ventricular compliance.

Iced temperature injectate for thermodilution cardiac output determination causes minimal effects on cardiodynamics.

OBJECTIVES: Controversy exists regarding the ideal injectate temperature for measuring cardiac output. Iced temperature injectate gives a higher signal/noise ratio and less variability in the measured cardiac output. Thus, less volume and fewer measurements are required. Advocates of room temperature injectate have suggested that iced temperature injectate may perturb cardiodynamics. This concern has remained largely untested. To help resolve this controversy, we examined the effects of 5 mL iced injectate (0 degrees to 4 degrees) infusions on cardiodynamics. DESIGN: Prospective, randomized, controlled study. SETTING: A critical care research laboratory. SUBJECTS: Five domestic pigs, weighing between 20 to 25 kg. INTERVENTIONS: Under barbiturate anesthesia, pigs underwent placement of a) a thermodilution catheter in the right internal jugular vein; b) a right carotid artery catheter for mean arterial pressure; and c) sonomicrometry crystals for dynamic measurements of left ventricular dimensions. Calculations were made of end-systolic and end-diastolic left ventricular volume and ejection fraction. Six cardiac output measurements were performed in each pig. Data were obtained at baseline (just before iced temperature injectate infusion) and every 3 sec for 9 secs. MEASUREMENTS AND MAIN RESULTS: The only significant effect seen with iced temperature injectate infusion was a small, transient decrease in heart rate (-5.9 +/- 1.1 beats/min from a baseline heart rate of 144.8 +/- 20.6 beats/min). Indices of preload, contractile function, and dynamic cardiac geometry were unaffected. CONCLUSIONS: Iced temperature injectate used in clinically relevant volumes causes transient negative chronotropic effects, but reservations regarding other perturbations of cardiodynamics are unfounded. Thus, the use of iced temperature injectate for cardiac output determination is still a viable alternative to room temperature injectate use, especially when a larger signal/noise ratio is required.

Pulmonary capillary wedge pressure estimates of left ventricular preload are inaccurate in endotoxin shock: contribution of Starling resistor forces to septic pulmonary hypertension.

We tested the hypothesis that Starling resistor forces play a significant role in the increase in pulmonary vascular resistance during endotoxin shock. Anesthetized pigs (n = 9) were given Escherichia coli endotoxin (ETX; .5 mg/kg intravenously over 30 min). Mean pulmonary arterial pressure (MPAP) and pulmonary capillary wedge pressure (PCWP) were recorded through a Swan-Ganz catheter. Pulmonary capillary pressure (Pc) was obtained from the analysis of the transient pulmonary artery pressure decay curve upon balloon inflation. Both proximal (Ra) and distal (Rv) pulmonary vascular resistance were calculated from cardiac output (CO), MPAP, Pc, and PCWP. Left atrial pressure (LAP) was measured directly via a left atrial catheter. Left ventricular end-diastolic wall thickness (LV-EDWT) was monitored by sonomicrometry, and used as an index of left ventricular preload. The results at baseline (t = 0) and t = 60 (30 min after the cessation of endotoxin infusion) were compared with saline control animals (n = 6). Data were analyzed with a two-way ANOVA followed by contrast of residuals (p < or = .05). After endotoxin, arterial blood pressure and CO fell significantly, an effect not seen in control pigs. In the control group neither LAP nor PCWP changed significantly over time, and remained equivalent to each other. In the septic shock group there was no difference between LAP and PCWP at t = 0. However, by t = 60 LAP dropped and PCWP rose significantly. This fall in LAP and increase in PCWP were significantly different from the time-matched control values, and from each other.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity of reperfusion after reversible regional myocardial ischemia in a canine model.

Variability of regional myocardial blood flow (RMBF) during reflow after 20 minutes of left anterior descending (LAD) coronary occlusion was measured by the radioactive microsphere technique in nine open-chest dogs. Preocclusion RMBF in the LAD territory was 0.89 +/- 0.27 ml/min/gm. Twenty minutes of LAD occlusion resulted in uniform and severe ischemia (RMBF < or = 0.25 ml/min/gm). After 1 minute of reperfusion, RMBF in the LAD territory rose to 3.48 +/- 1.88 ml/min/gm, and declined to 1.06 +/- 0.29 ml/min/gm after 20 minutes of reperfusion. RMBF variance increased significantly from 0.046 preocclusion to 0.2857 after 1 minute of reperfusion (p < 0.01) and declining to 0.086 after 20 minutes of reperfusion. By contrast, RMBF variance analysis of myocardial segments from the nonischemic left circumflex territory exhibited no significant change throughout the experiment. In any given dog this heterogeneous reperfusion of previously ischemic tissue resulted in a disorganized topography of blood flow rates. Myocardium with relatively high regional flow was intermingled with islands of tissue with relatively low blood flow. In conclusion, despite a relatively uniform and severe myocardial ischemic insult, the subsequent initial hyperemic response during reperfusion exhibits marked spatial heterogeneity. The juxtaposition of myocardial regions exposed to vastly differing rates of oxygen delivery and washout of toxic metabolites may set the stage for nonuniform recovery of myocardial function.

Regional blood flow redistribution due to acetate.

There is little information about the effects of acetate on regional blood flow in unanesthetized animals. Isosmolal sodium acetate or saline was infused at a rate of 250 mumol/kg.min into conscious rats such that, in the acetate group, plasma acetate levels averaged 2.06 +/- 0.23 mM. Sequential injections of tracer-tagged microspheres were used to determine the effect of acetate infusion on cardiac output, total peripheral vascular resistance, and various organ blood flow rates. At this infusion level, acetate had no discernible effect on either central hemodynamics or arterial blood gases. However, there was marked alteration of regional organ perfusion. After 5 min of infusion, acetate (relative to control) increased blood flow markedly to the splanchnic bed (+40 +/- 6.1%), including all individual splanchnic organs except for the stomach. Acetate also increased blood flow to the heart (+33 +/- 5.2%) and kidneys (+29 +/- 5.4%); all P < 0.05. Acetate had no specific effect on total cerebral blood flow or on regional brain circulations. Acetate had no effect on flow to skeletal muscle (-30 +/- 11%; P = not significant) or fat (-5 +/- 6.3%; P = 0.097), although flow to muscle tended to decrease. These data suggest that low plasma levels of acetate, which do not alter total peripheral resistance, cause a marked redistribution of blood flow to the splanchnic organs and to the kidneys. Brain blood flow is unaffected.

Regional changes in blood flow, extracellular potassium and conduction during myocardial ischemia and reperfusion.

OBJECTIVES: We postulated that ventricular arrhythmias may arise from the heterogeneous washout of ischemic metabolites. Our objective was to investigate the distribution of extracellular potassium concentration ([K+]o) during myocardial ischemia and reperfusion and to correlate this distribution with regional differences in myocardial blood flow. BACKGROUND: Our previous study showed that reperfusion after a brief period of ischemia resulted in heterogeneous reflow of the ischemic myocardium. METHODS: The changes in regional myocardial blood flow, midmyocardial [K+]o and electrogram duration were quantitated in 14 dogs undergoing 20 min of left anterior descending coronary artery occlusion and 1 min of reperfusion. Regional myocardial blood flow was measured by using 15-microns radioactive microspheres in 1- to 1.5-g full thickness myocardial samples. The [K+]o was measured with intramyocardial K(+)-sensitive electrodes. RESULTS: During coronary occlusion, the ischemic zone exhibited a reduction in regional blood flow to 0.13 +/- 0.06 ml/g per min and increases in [K+]o to 9.3 +/- 2.6 mmol/liter and electrogram duration to 131.8 +/- 38.6% of control. Heterogeneous reduction in regional blood flow at various sites in the ischemic zone had fair correlations with variable increases in [K+]o (r = -0.70) and electrogram duration (r = -0.75). During min 1 of reperfusion, regional blood flow ranged from two to more than seven times baseline, resulting in a disorganized spatial distribution of perfusion with islands of high and low blood flows. Associated with the heterogeneous early reperfusion regional myocardial blood flow, [K+]o and electrogram duration changed at different rates toward normal. Whereas correlation between regional blood flow and [K+]o or standardized electrogram duration was fair during ischemia, this correlation was poor during early reperfusion. CONCLUSIONS: Spatial heterogeneity in regional myocardial blood flow during myocardial ischemia and early reperfusion is associated with heterogeneity in [K+]o and electrophysiologic characteristics, which in turn may play an important role in the genesis of arrhythmias arising from the ischemic and reperfused myocardium.

Coronary flow by left atrial and left ventricular microsphere injection in the rat.

Previous studies have reported significantly higher variability in coronary blood flow (CBF) measurements obtained by microsphere injection into the left ventricle (LV) as compared with microsphere injection into the left atrium (LA) of the rat. Questions have arisen concerning whether or not some of the variability may have been due to successive rather than simultaneous injections at the two sites, thereby giving measurements at different cardiovascular states. To address this question, we measured cardiac output (CO) and CBF as well as other systemic organ blood flows by employing simultaneous injection of two different sets of radiolabeled microspheres into the left atrium and left ventricle of semiconscious rats. Using this technique, CBF values (ml.min-1.g-1) of 5.45 +/- 0.43 and 5.24 +/- 0.46 for LA and LV injection sites, respectively, were measured (all values reported as means +/- SE). CO values (ml/min) of 67.5 +/- 3.5 for LA and 67.6 +/- 3.4 for LV were obtained. Paired left atrial and left ventricular measurements of CBF, CO, and other systemic organ blood flows using tracer microsphere methodology were not significantly different. All variabilities in these measurements by LA and LV injection were not significantly different. Our procedure did not significantly alter physiological parameters such as heart rate, mean arterial pressure, hematocrit, or blood gases. These findings indicate that, in our rat model, measurements made by LV microsphere injection are not only adequate for determining systemic blood flow at distal beds but provide coronary blood flow data with variability not significantly different from that of left atrial injection.