Hepatic insufficiency and increased proteolysis, cardiac output, and oxygen consumption following hemorrhage.

Thirty dogs underwent hemorrhage over a 60-min period to a predetermined O2 debt of 60-120 mL O2/kg, monitored with a Beckman metabolic cart, and then were resuscitated with 120% of the shed volume. Twenty survived and were followed over the next 7 days. On day 4, hepatic insufficiency was suggested by an elevation in [total amino acids] and [lactate] and a decrease in [urea] and [branched-chain amino acids]/[aromatic amino acids]. Net whole body catabolism on day 4 is suggested by a decrease in [glutamine] and an increase in plasma [3-methylhistidine], [phenylalanine], and [tyrosine]. These changes were significantly related to cardiac index, mean blood pressure, [lactate], O2 debt, and shed volume during the hemorrhage 4 days earlier. On day 7 there was a significant increase in the cardiac index and the VO2. These data suggest that hemorrhage induces sequelae similar to major injury or sepsis: hepatic insufficiency, net catabolism, hypermetabolism, and a hyperdynamic circulation. The hyperdynamic circulation may be necessary to meet increased tissue delivery requirements for O2 and amino acids.     

Canine peripheral vascular response to endotoxin shock at a constant cardiac output

The peripheral vascular response to Escherichia coli endotoxin (1 mg/kg/i.v.) was measured for 2 hr in the pentobarbital anesthetized dog. Total venous return was collected and returned by a pump to the right atrium to maintain a constant cardiac output. Occlusion of the venous lines permitted estimation of venous compliance in the systems drained by the superior (SVC) and inferior vena cavae (IVC). After endotoxin administration, arterial pressure and total peripheral resistance rapidly dropped and remained low for 2 hr. IVC compliance was decreased at 10-30 min and SVC compliance at 10 min after endotoxin. The decrease in compliance is interpreted as venous dilation and probably venous pooling. The latter may account for a substantial portion of the total venous pooling reported in early endotoxin shock. After 30 min, compliance increased and by 60 min was equal to control. Left ventricular relaxation ability decreased as indicated by maximal negative dp/dt. Ibuprofen, 10 mg/kg, was administered at 120 min or earlier, depending on the state of the animal; rapid recovery of arterial pressure and ventricular function occurred without a significant change in venous compliance.     

Verapamil improves cardiac function and increases survival in canine E. coli endotoxin shock

The effects of verapamil, a calcium antagonist, on survival and on hemodynamic and metabolic parameters were studied in canines administered E. coli endotoxin. Shams, endotoxin controls, and endotoxin-shocked dogs treated with a 4-hour infusion of verapamil were studied. The animals were anesthetized, catheters and endotracheal tube were inserted, and an IV infusion was started after administration of endotoxin. All dogs were kept on a respirator for 4 hours while measurements were taken; they were then extubated and returned to their cages. Survival was considered permanent by 7 days. Eight of 13 treated dogs survived, in contrast with only one of 14 controls. Treated dogs had significantly higher cardiac index (4.64 vs 3.62 L/min/m2), pulmonary artery pressure (16 vs 13 mmHg), and left ventricular stroke work (44.3 vs 29.7 gm/m2 beat), and significantly lower heart rate and systemic vascular resistance at 4 hours. Serum glucose, acid phosphatase, pH, and Hct were also significantly improved by verapamil treatment.     

Left ventricular performance in canine endotoxin shock

Left ventricular performance was studied in 6 control and 7 experimental open-chest, heart-paced dogs before and after a single 1 mg/kg dose of E. coli endotoxin under pentobarbital anesthesia. Positive maximal dp/dt, time to peak ventricular pressure (PVP time), cardiac output, stroke work, tension-time index (TTI), coronary flow, and cardiac oxygen consumption were derived from left ventricular pressure, aortic flow, left atrial pressure, coronary sinus flow and A-V oxygen difference. During a control period and for 2 h post-endotoxin, while mean arterial pressure (afterload) and heart rate were held constant, +dp/dt max, PVP time, cardiac output, and cardiac work were related to left ventricular end diastolic pressure to obtain ventricular function curves. Positive maximal dp/dt was found depressed early (60 min) during the 2 h period of endotoxicosis studied (P less than .05). PVP time values increased after endotoxin administration but not significantly. Coronary sinus flow was found to be significantly elevated at 2 h post-endotoxin. The findings indicate the presence of early (60 min) and sustained depression of ventricular performance at elevated coronary blood flows during endotoxicosis.     

Hypoxanthine in lethal canine endotoxin shock.

Endotoxin shock was induced in Labrador retriever dogs by intravenous infusion of a lethal dose of Escherichia coli endotoxin (2 mg/kg body weight) over a three-hour period in order to study plasma hypoxanthine concentrations. The animals succumbed within 14 hours after start of the infusion. Terminally when aortic blood pressure dropped below 30 mm Hg and bradycardia had developed, the animals were resuscitated by external cardiac massage, artificial ventilation, and volume therapy. During shock no significant alteration of plasma hypoxanthine concentrations occurred. During the 12-minute period of resuscitation, however, hypoxanthine concentrations of both arterial and venous plasma increased rapidly compared to the initial values. The changes of the hypoxanthine concentration revealed an exponential pattern. The likely explanation for this phenomenon is is that during shock bypoxanthine was accumlated in the tissues due to tissue hypoxia and that the metabolite was washed out into the circulation during resuscitation.     

Elevation of cardiac output and oxygen delivery improves outcome in septic shock.

Septic shock is characterized by hypoperfusion and tissue energy defects. We prospectively evaluated the therapeutic benefit of augmenting cardiac output and therefore oxygen delivery (DO2) on mortality in patients with septic shock. Twenty-five patients were randomized to a normal treatment (NT) group and 26 patients were randomized to an optimal treatment (OT) group. All patients had a clinically evident site of infection, sepsis as defined by a systemic response to the infection, and shock indicated by systemic hypoperfusion. Patients were treated during the initial 72 h by an algorithm differing only in the end point of resuscitation. The cardiac index (CI) was increased to 3.0 L/min/m2 in the NT group and to 6 L/min/m2 in the OT group. There were no significant differences in cardiorespiratory parameters in the NT and OT groups on entrance into the study. During treatment, CI averaged 3.6 +/- 0.2 L/min/m2 and DO2 averaged 8.6 +/- 0.8 ml/min/kg in the NT group and CI averaged 5.1 +/- 0.2 L/min/m2 and DO2 averaged 12.2 +/- 0.7 ml/min/kg in the OT group (p less than 0.01). A significant correlation between DO2 and survival was observed. Seventy-two percent of the OT patients died vs 50 percent of the NT patients (p = 0.14). Surviving NT patients stayed 13.7 +/- 3 days in the ICU vs 7.4 +/- 0.6 days (p less than 0.05) for the OT patients. Since some of the NT patients were spontaneously hyperdynamic and some of the OT patients did not achieve their desired end point, patients were arbitrarily subsetted using a midpoint CI of 4.5 L/min/m2. The NT less than 4.5 group had a CI of 3.1 +/- 0.2 L/min/m2 and DO2 of 10.9 +/- 1.0 ml/min/kg while the OT group greater than 4.5 L/min/m2 had a CI of 5.7 +/- 0.2 L/min/m2 and a DO2 of 13.8 +/- 0.7 ml/min/kg (p less than 0.01). Mortality in the NT less than 4.5 group was 74 percent as compared with 40 percent in the OT greater than 4.5 group (p less than 0.05).     

Limitations of the metabolic rate meter for measuring oxygen consumption and cardiac output

Over the past few years, a metabolic rate meter has been introduced for easy measurement of oxygen consumption. However, its accuracy is unproved. In 40 patients (26 men, 14 women, ages 34 to 73 years), cardiac output was measured simultaneously by thermodilution and the Fick method using the metabolic rate meter to quantitate oxygen consumption. In comparison with thermodilution, the results using the Fick method were low (5.26 +/- 1.18 vs 4.14 +/- 0.99 liters/min, respectively, p less than 0.01). In 18 patients cardiac output also was measured by the Fick method using a Douglas bag to quantitate oxygen consumption. In these patients, oxygen consumption measured with the metabolic rate meter was lower than that obtained using the Douglas bag (168 +/- 25 vs 216 +/- 42 ml/min, respectively, p less than 0.01). With the Douglas bag, the Fick and thermodilution cardiac output measurements were similar (4.68 +/- 1.08 vs 4.87 +/- 0.86 liters/min, respectively, difference not significant), and they differed by less than or equal to 10% in 15 patients. In contrast, with the metabolic rate meter, the results of thermodilution were higher than those with the Fick method (4.84 +/- 0.95 vs 3.60 +/- 0.71 liters/min, respectively, p less than 0.01), and differed by less than or equal to 10% in only 1 patient (p less than 0.01). Thus, the values for oxygen consumption and cardiac output obtained with the metabolic rate meter are lower than actual values. This device is less accurate than the Douglas bag.     

Portal venous compliance in canine endotoxin shock.

The response of the small intestinal vascular bed to endotoxin and ibuprofen was determined in mongrel dogs under pentobarbital anesthesia. Blood flow was measured in the superior mesenteric artery and pressures in the artery and portal vein. Venous compliance was calculated from the rate of pressure rise in the occluded portal vein at a constant arterial inflow. The response to endotoxin was followed for 1 hr, ibuprofen was given, and the response was followed for a second hour. Arterial pressure and mesenteric flow decreased after endotoxin, accompanied by an increase in venous compliance and in the compliance/resistance ratio. Treatment with ibuprofen increased arterial pressure but did not improve blood flow; however, it effectively reversed the changes in compliance. The results indicate a loss of arterial vasomotor tone in response to endotoxin which is not shared by the portal venous system. This may result in fluid loss into the intestinal bed. Ibuprofen restored arterial tone and released the venous constriction, but did not significantly alter the metabolic responses to endotoxin.     

Biochemical characterization of circulating Met-enkephalins in canine endotoxin shock

The alterations in arterial, venous and adrenal vein levels of immunoreactive Met-enkephalins following endotoxin administration have been investigated in dogs by direct measurement and gel filtration chromatography. Animals were anaesthetized with alpha-chloralose and allowed to breath spontaneously. The left lumbar adrenal vein, limb vein and femoral artery were cannulated for blood sampling. Severe shock was produced by the administration of a large bolus of E. coli endotoxin followed by a continuous infusion. The production of endotoxin shock was associated with significant increases in adrenal vein and systemic venous plasma immunoreactive Met-enkephalin levels. Forty-five minutes after induction of endotoxin shock arterial immunoreactive Met-enkephalin levels were generally higher than baseline values. In resting anaesthetized animals a large 31,000 molecular weight form of Met-enkephalin, presumably proenkephalin, was found in plasma obtained from the adrenal vein, systemic and pulmonary circulations. Following endotoxin this enkephalin-containing peptide still predominated in arterial and venous plasma, whereas in the adrenal vein the proportion of Met-enkephalin immunoreactivity attributable to this large peptide fell. This was associated with the appearance of increasing amounts of smaller molecular forms (18,000, 8000, 3-5000 molecular weight and the pentapeptide itself). In this model enkephalin-containing peptides were not biochemically modified by their passage through the lungs.     

The effect of pericardiectomy on maximal oxygen consumption and maximal cardiac output in untrained dogs

To test the hypothesis that the pericardium limits maximal oxygen consumption by limiting stroke volume and cardiac output, we studied 10 untrained dogs during submaximal and maximal exercise before and after pericardiectomy. Seven additional dogs were studied before and after a sham operation. All dogs were instrumented chronically with aortic and pulmonary artery catheters. Dogs were tested by running on a motor-driven treadmill, 4-6 times before and after pericardiectomy or sham operation. We measured cardiac output (dye dilution), heart rate, and arteriovenous oxygen difference. Oxygen consumption and stroke volume were calculated from these variables. After pericardiectomy, there were significant (P less than 0.01) increases in maximal oxygen consumption, maximal cardiac output, and maximal stroke volume. Maximal oxygen consumption decreased significantly in the sham group. There was no change in maximal heart rate following pericardiectomy, or in maximal cardiac output, heart rate, or stroke volume following sham operation. Both groups of dogs experienced similar significant decreases in hematocrit, arterial and venous oxygen contents, and arteriovenous oxygen difference. Neither pericardiectomy nor sham operation had any effect on oxygen consumption during submaximal exercise. However, the sham group had significant increases in cardiac output and heart rate during submaximal exercise, and the pericardiectomy group demonstrated a trend toward an increased cardiac output during submaximal exercise. These results support the hypothesis that the pericardium limits maximal oxygen consumption by limiting stroke volume and cardiac output during maximal exercise in untrained dogs. Further, these findings suggest that maximal oxygen consumption is limited by the oxygen transport capacity of the cardiovascular system, and not by the oxidative capacity of skeletal muscle in the untrained dog.     

Changes in canine leukocyte glucocorticoid receptors during endotoxin shock

We studied changes in canine leukocyte glucocorticoid receptors during endotoxin shock. Blood samples for analysis were collected and leukocytes were isolated just prior to and 2 and 6 hours after endotoxin administration. Employing 3H-dexamethasone (3H-Dex) as a ligand, we studied 3H-Dex-specific binding of the leukocytes in dogs and their changes during endotoxin shock. Results from two groups (anesthetized and conscious) showed that the specific binding of the leukocytes decreased significantly 2 hours after endotoxin administration in both groups and 6 hours after endotoxin in anesthetized dogs. In conscious dogs, the specific binding returned to normal by 6 hours. No correlation was found between the changes of serum cortisol and 3H-Dex-specific binding. It may be suggested that perturbations in glucocorticoid hormone action at the receptor level might be involved in the pathogenesis of endotoxin shock.     

Norephedrine (phenylpropanolamine) stimulates oxygen consumption and lactate production in the perfused rat hindlimb

d,l-Norephedrine (phenylpropanolamine) which is both a demethylated analogue and a metabolite of d,l-ephedrine, is a reputed anorectic agent. In the present study the proposed most active isomer of this mixture, l-norephedrine has been assessed as a peripherally acting thermogenic agent in the isolated perfused rat hindlimb. l-Norephedrine produced a dose-dependent increase in oxygen uptake and perfusion pressure and increased lactate production. Whereas propranolol potentiated the increase in oxygen uptake and perfusion pressure produced by l-norephedrine, prazosin significantly and nitroprusside totally inhibited both of these changes. Nitroprusside also completely inhibited the increase in lactate production. We conclude that norephedrine has a hitherto unrecognized peripheral thermogenic activity in the perfused rat hindlimb resulting from its interaction with alpha 1 adrenergic receptors that control vasoconstriction in this tissue.     

Direct Fick cardiac output: Are assumed values of oxygen consumption acceptable?

The use of assumed values of oxygen consumption has become anaccepted practice in the calculation of direct Fick cardiacoutput. A survey showed that the assumed values in common usewere derived from basal metabolic rate studies on normal subjects,a use which may not be valid. We have compared previous assumedvalues based on basal metabolic rate or cardiac catheterizationstudies with those obtained by direct measurement in 80 patients(age range 38–78 years) with various cardiac disorders.Comparison of the assumed and directly measured values of indexedoxygen consumption and the cardiac index showed large discrepancies,with over half the values differing by more than ± 10%and many by more than ±25% from the measured value. Assumedvalues of oxygen consumption should be used with caution whencalculating cardiac output during cardiac catheterization procedures,because large errors can result. The equations of LaFarge andMiettinen gave the closest approximation to the measured dataand their use is recommended in preference to values predictedfrom basal metabolic rate studies.     

Skeletal muscle perfusion and metabolism during canine endotoxin shock

Conflicting data exist in literature about the effects of endotoxin on skeletal muscle perfusion and metabolism during canine endotoxin shock. In 12 dogs we therefore studied (six control and six endotoxin treated, 1.5 mg X kg-1) under etomidate (4 mg X kg-1 X h-1) anaesthesia muscle blood flow (radioactive microspheres) in fore limb, thorax, diaphragm and hind limb (five different muscles) and skin blood flow before (t = 0) and 90 and 120 min after endotoxin. We also measured blood flow in the femoral artery and vein (electromagnetic flow transducers) and the arteriovenous differences of oxygen, lactate, glucose and FFA over the femoral vascular bed (at t = 0, 30, 90 and 120 min). Endotoxin administration caused a fall of flow in the femoral artery and vein (by 65 and 63%, respectively at t = 15). After t = 60 flow in the femoral artery and vein increased slowly but the flows were still below the preshock values at t = 20 (by 33 and 50%, respectively). Skeletal muscle and skin flow did not decrease or even increased after endotoxin but decreased in the control group. Percentage of cardiac output distributed to brachial, intercostal and hind limb muscle and skin increased after endotoxin (by 163, 167, 111 and 120%, respectively at t = 20). The five muscles of the hind limb did not respond differently to endotoxin. In spite of diminished arterial inflow, skeletal muscle perfusion was thus maintained in the hind limb, probably due to closing of shunts and redistribution of blood away from bone. Oxygen extraction but also lactate release by the femoral bed had increased during endotoxin shock. After endotoxin femoral glucose extraction was only elevated at t = 30 when arterial glucose concentration had also increased. The femoral bed produced free fatty acids (FFA) but during endotoxin shock the arteriovenous concentration difference of FFA decreased. Our data suggest that skeletal muscle flow nor oxygen consumption and glucose metabolism is affected during 2 h of canine endotoxin shock. Lactate production, however, tended to increase.     

Treatment of experimental canine endotoxin shock with ibuprofen, a cyclooxygenase inhibitor

The arachidonic acid derivative thromboxane A2, a very potent platelet aggregator, is increased in endotoxin shock. Ibuprofen blocks the formation of thromboxane A2 and has antiplatelet and antileukocyte aggregability properties. The effects of ibuprofen on pulmonary platelet trapping, platelet and leukocyte counts, platelet aggregability, hematocrit, and blood pressure were evaluated in endotoxin-shocked dogs. The initial decrease in blood pressure and in leukocyte and platelet counts seen in endotoxin shock was not altered by ibuprofen treatment. At 2 h the ibuprofen-treated dogs had less hypotension compared to endotoxin control. Platelet counts were also higher in the ibuprofen-treated dogs at 2 h. Significant recovery of leukocytes was seen only when pretreatment was used. Pulmonary platelet trapping was significantly lower in the ibuprofen-treated dogs compared to endotoxin controls and not significantly different from the sham dogs when ibuprofen was given before endotoxin injection. This study demonstrates the efficacy of ibuprofen not only in reducing pulmonary platelet trapping but also in obviating the late hypotension in experimental endotoxin shock.     

Effects of canine endotoxin shock on lymphocytic beta-adrenergic receptors

To determine whether beta-adrenergic receptors on circulating lymphocytes are impaired during endotoxemia and the precise role of catecholamines in this process, we allocated 16 dogs to three groups: I) control-saline vehicle (n = 5), II) endotoxin--Escherichia coli endotoxin 1.0 mg/kg iv bolus (n = 6), and III) endotoxin + propranolol--E. coli endotoxin 1.0 mg/kg after pretreatment with propranolol, 1.5 mg/kg iv bolus followed by a continuous infusion, 30 micrograms/kg per min, (n = 5). Five hours after endotoxin injection, lymphocytic beta-adrenergic receptor number and sodium fluoride (NaF)-stimulated cyclic AMP accumulation were reduced by 41 +/- 6% and 25 +/- 7% of baseline values, respectively, which were significantly different from those observed in the control group (both P less than .01). Propranolol pretreatment prevented the endotoxin-induced reduction in lymphocytic beta-adrenergic receptor number (P less than .02 compared with the endotoxin group), but not the decrease in NaF-stimulated cyclic AMP accumulation (P less than .01 compared with the control group). Myocardial beta-adrenergic receptor number was reduced in the endotoxin group compared with that observed in the control group (P less than .06). These changes were associated with a decreased chronotropic response to isoproterenol in the endotoxin group compared with the control group (P less than .05). We conclude that decreased lymphocytic beta-adrenergic receptor number in endotoxin shock is caused by circulating catecholamines, whereas alterations distal to the receptors may be due to other mechanisms.     

Pulmonary macrophage antimicrobial activity in canine endotoxin shock and lung injury

Bacterial sepsis and pneumonia are common complications of lung injury and predispose the host to a poor resolution. We studied the functional integrity of pulmonary macrophages derived from minced lung preparations in a canine model of endotoxin-induced shock with acute lung injury. Dogs given 2 mg/kg of Escherichia coli endotoxin 055:B5 developed classic shock symptoms with concomitant acute lung injury; control animals given saline showed no physiological or pathological abnormalities. Compared to previous work with this canine model, the lung injury in this extended time period (6 h) had progressed to include alveolar edema. Six hours after endotoxin infusion, the left lung was lavaged, perfused, and the resulting lung minced for isolation of pulmonary macrophages. The endotoxic-model pulmonary macrophages showed several significant functional differences from controls. Although they elicited greater production of H2O2 (p less than 0.05), both phagocytosis of radiolabeled Staphylococcus aureus and E. coli (p less than 0.05) and bactericidal activity (p less than 0.05) were diminished compared to controls. Compared to alterations previously described in alveolar macrophages, these cells produced less H2O2 and demonstrated abnormal bacterial killing at all time points. These observations suggest that the functional alterations of pulmonary macrophages that follow acute lung injury contribute to the ineffective cell-mediated antimicrobial response. These derangements may promote an increased risk of nosocomial pneumonia, the high mortality often observed subsequent to pneumonia, or the propagation of acute lung injury that facilitates respiratory failure.     

Relative importance of cardiac output and arterial pressure in determining myocardial oxygen consumption and coronary blood flow

Oxygen consumption and coronary blood flow were measured in anesthetized dogs while cardiac work was altered by changing arterial pressure or by opening an aorta to left atrial shunt. When oxygen consumption during pressure work was compared with that during flow work, at a constant heart rate, it was found that flow work increased oxygen consumption as much, or more, than did increasing pressure work. Coronary blood flow, but not A-V oxygen difference, was correlated with oxygen consumption. The highest correlation with oxygen consumption, however, was obtained for left ventricular end-diastolic pressure, which was even more highly correlated than was cardiac work. The conclusion is that it may be the initial stretch of the myocardial fiber, rather than the arterial pressure or the cardiac output, that is the primary determinant of myocardial oxygen consumption at a constant heart rate.