Biomedical subjects
Publications and source records attributed to E C Rackow.
Septic shock continues to be associated with high mortality. The systemic effects of severe infections are related to the release and activation of a myriad of mediator systems, central to which are bacterial toxins and cytokines. Therapy includes three facets--resuscitation, treatment of the underlying infection, and interventions directed at ameliorating mediator activity.
In patients with circulatory shock, monitoring of tissue perfusion requires assessment of systemic oxygen metabolism. The presence of lactic acidosis helps identify critical hypoperfusion as marked by anaerobic metabolism. Mixed venous oxygen tension and saturation help determine the use of compensatory mechanisms to maintain oxidative metabolism. Measurements of systemic oxygen consumption and oxygen delivery help define underlying pathophysiology and the direction for therapeutic intervention. Tonometrically measured gastric intramucosal pH appears to be a useful method for monitoring splanchnic hypoperfusion and may have implications for assessing global perfusion failure.
Monophosphoryl lipid A (MPL) is a nontoxic lipid A derivative that maintains many of the beneficial immunomodulatory activities of the parent lipopolysaccharide molecule, including the induction of tolerance to endotoxin. The hemodynamic effects of Salmonella minnesota MPL (300 mg/kg) and S. minnesota lipopolysaccharide (300 micrograms/kg) were compared in 20 minipigs. Decreases in cardiac output and arterial pressure and increases in pulmonary artery pressure and lactic acidosis were significantly greater in animals treated with lipopolysaccharide. These changes were associated with peak tumor necrosis factor (TNF) levels of 1373 +/- 79 U/ml in animals treated with LPS and 157 +/- 31 U/ml in animals treated with MPL. Ten minipigs were subsequently randomized to receive S. minnesota MPL (30 micrograms/kg) or diluent intravenously 48 hours before receiving S. minnesota lipopolysaccharide (300 micrograms/kg IV). MPL significantly attenuated lipopolysaccharide-induced decreases in mean arterial pressure, cardiac index, stroke volume index, and mixed venous oxygen saturation. At baseline, no significant difference could be seen in TNF levels between diluent and MPL pigs. TNF levels peaked 2 hours after LPS infusion at 1190 +/- 156 U/ml in diluent pigs and at 539 +/- 126 U/ml in MPL pigs (p less than 0.05). Each of the pigs pretreated with MPL survived endotoxic shock, whereas only one of the five diluent pigs survived. These observations are consistent with the induction of endotoxin tolerance by pretreatment with MPL.
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BACKGROUND AND METHODS: Striking increases in PCO2 of the myocardium have recently been documented during cardiac arrest. The purpose of the present study was to investigate selective effects of hypercarbia as distinct from acidosis on left ventricular contractile function and oxygen utilization. An isolated, spontaneously beating rat heart preparation was utilized. The perfusate was equilibrated with gases containing 5%, 10%, 20%, and 30% CO2. In a subset of experiments, the [H+] was adjusted independently of PCO2 by decreasing the concentration of HCO3-. RESULTS: When the PCO2 of the perfusate was progressively increased from 36 to 146 torr (4.8 to 29.5 kPa), the left ventricular systolic pressure (LVSP) generated by the isolated heart and the maximum rate of pressure change in the left ventricle (dP/dt) were decreased to 20% of their control values. However, comparable acidosis in the absence of hypercarbia produced only minimal decreases in the LVSP or dP/dt such that contractility remained at greater than or equal to 88%. Increases in the perfusate PCO2 but not in the perfusate H+ were highly correlated with decreases in both myocardial contractility and oxygen consumption (r2 = .88). CONCLUSION: Hypercarbia rather than acidosis accounts for decreased contractility and oxygen utilization in the isolated perfused rat heart.
OBJECTIVE: To quantitate the contribution of lactate, phosphate, urate, total serum proteins, and unidentified anions to the anion gap in patients with severe sepsis. DESIGN: Thirty critically ill patients with evidence of severe sepsis and systemic hypoperfusion were prospectively studied. MEASUREMENTS: The anion gap was calculated as [Na+] + [K+] - [Cl-] - [HCO3]. A corrected anion gap was calculated as the anion gap minus the anionic contribution of lactate, phosphate, urate, and total serum proteins. The corrected anion gap is a marker of unmeasured anion less unmeasured cation concentration. RESULTS: The mean anion gap was 21.8 +/- 1.4 mmol/L and the corrected anion gap was 3.7 +/- 0.8 mmol/L. The mean arterial blood lactate concentration was 5.9 +/- 0.8 mmol/L. The magnitude of the lactate concentration correlated linearly with the anion gap (r2 = .61, lactate = 0.4 anion gap - 3.9, n = 30, p less than .01). The corrected anion gap was greater than 0 in 24 (80%) of 30 patients. The magnitude of the corrected anion gap correlated linearly with the anion gap (r2 = .66, corrected anion gap = 0.5 anion gap - 6.3, n = 30, p less than .01). Since the slope of the regression line for estimating corrected anion gap from anion gap was 0.5, the contribution of unmeasured anions was as important as lactate in determining the anion gap. CONCLUSION: These data indicate that lactic acidosis does not entirely account for the metabolic acidosis during severe sepsis. Furthermore, the increased corrected anion gap suggests the presence of an unidentified anion (or anions) that is (or are) responsible, in large part, for the development of metabolic acidosis in patients with sepsis.
In a porcine model of cardiac arrest, we investigated end-tidal carbon dioxide tension as a monitor of native blood flow during resuscitation by extracorporeal circulation. After 15 minutes of cardiac arrest and after precordial compression and transthoracic countershocks had failed, extracorporeal circulation consistently restored spontaneous circulation. Native end-tidal carbon dioxide tension, which averaged 29.8 +/- 1.0 mm Hg before arrest, was only 5.2 +/- 0.8 mm Hg during precordial compression. After the start of extracorporeal circulation, native end-tidal carbon dioxide tension was measured during 15-second interruptions of pump flow. End-tidal carbon dioxide tension progressively increased with a corresponding increase in native cardiac index. The correlation coefficients between end-tidal carbon dioxide tension and native cardiac index averaged 0.92 +/- 0.03 (mean +/- standard error of the mean). When end-tidal carbon dioxide tension exceeded 15 mm Hg, mean aortic pressure in each instance was 60 mm Hg or greater, and the animal was successfully weaned from extracorporeal support. We conclude that end-tidal carbon dioxide tension serves as a reliable monitor of blood flow through the lung and therefore of native cardiac output during weaning from extracorporeal circulation. It therefore indicates when native cardiac output is likely to be adequate to sustain spontaneous circulation.
Monophosphoryl lipid A (MPL) is a nontoxic derivative of lipid A. In this study, the induction of tolerance by MPL to the hemodynamic effects of lethal endotoxemia was tested. Ten Sprague-Dawley rats were received either Salmonella minnesota MPL 0.5 mg/100 g intravenously (i.v.) or equivalent volume of diluent (control) i.v. on day zero. On day 3 S. minnesota endotoxin (LPS) 5.0 mg/100 g was administered i.v. Cardiac output (CO), arterial lactate (L), and central venous oxygen saturation (SvO2) were measured before and 3 and 6 hr after LPS administration. Survival was determined at 72 hr. At 6 hr, CO was 217 +/- 11 ml/kg/min in controls, and 435 +/- 28 ml/kg/min in the MPL animals (P less than 0.01). Arterial lactate was 2.6 +/- 0.3 mmol/liter in controls and 1.3 +/- 0.2 mmol/liter in MPL animals at 6 hr (P less than 0.05). The controls died 7.5 +/- 1.3 hr after LPS administration, whereas all the MPL-pretreated animals survived. These data indicate that MPL induces tolerance to the acute hemodynamic effects of LPS and enhances survival from lethal endotoxemia.
After cardiac arrest, return of cardiac function and effective circulation are contingent on prompt restoration of myocardial blood flow. Because conventional closed-chest CPR has limited hemodynamic efficiency, we investigated venoarterial ECC utilizing peripheral vascular access as an alternative for cardiac resuscitation. Ventricular fibrillation was induced in domestic pigs by alternating current delivered to the endocardium of the right ventricle. Conventional closed-chest CPR was begun after 10 minutes. In each instance, precordial compression and external defibrillation failed to restore a viable rhythm. ECC was begun at 15 minutes at an average flow rate of 183 ml/kg/min. In each of eight animals, sinus rhythm was restored. In six of these eight animals, spontaneous circulation was reestablished after an average interval of 152 minutes. When epinephrine was administered concomitantly with ECC in an additional eight animals so as to maintain mean aortic pressure between 60 and 100 mm Hg, sinus rhythm and spontaneous circulation were reestablished in each pig after an average of only 23 minutes. The effects of ECC in conjunction with epinephrine were then compared with those of conventional precordial compression in conjunction with epinephrine (sham ECC). In contrast to ECC, which successfully resuscitated each of five animals, none of five sham ECC-treated animals was resuscitated by continued precordial compression and maximal doses of epinephrine (p less than 0.01). We conclude that ECC in conjunction with epinephrine emerges as a highly effective experimental intervention for resuscitation when conventional techniques of precordial compression and external defibrillation fail to reverse cardiac arrest.
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We elected to test the hypothesis that the metabolic encephalopathy associated with systemic sepsis may have a pathogenesis that is similar to hepatic encepathology, ie, as the consequence of hepatic dysfunction that induces alterations in synthesis of catecholic and noncatecholic neurotransmitters. Eleven patients with septic encephalopathy were compared with nine patients with septic encephalopathy and nine normal controls with respect to blood and cerebrospinal fluid (CSF) amino acid profile, phenylethylamine and its metabolite phenylacetic acid, and blood ammonia. Blood and CSF levels of phenylacetic acid increased markedly in septic and hepatic encephalopathy while CSF phenylethylamine levels were not increased in either condition, presumably due to rapid turnover. The CSF concentrations of all the aromatic amino acids were increased in hepatic encephalopathy, whereas in the patients with sepsis, only phenylalanine levels were increased. Evidence of stimulated neutral amino acid transport into brain was demonstrated in hepatic not septic encephalopathy and appeared to correlate with the CSF glutamine concentration. Blood ammonia levels were increased in hepatic but not in septic encephalopathy. Our data support the hypothesis that metabolites of phenylethylamine contribute to encephalopathy in systemic sepsis and hepatic failure; however, the entities differ in other respects.
After failure of external defibrillation, return of cardiac activity with spontaneous circulation is contingent on rapid and effective reversal of myocardial ischemia. Closed-chest cardiopulmonary resuscitation (CPR) evolved about 30 years ago and was almost universally implemented by both professional providers and lay bystanders because of its technical simplicity and noninvasiveness. However, there is growing concern since the limited hemodynamic efficacy of precordial compression accounts for a disappointingly low success rate; especially so if there is a delay of more than 3 minutes before resuscitation is started. There is also increasing concern with the lack of objective hemodynamic measurements currently available for the assessment and quantitation of the effectiveness of resuscitation efforts. Accordingly, the resuscitation procedure proceeds without confirmation that it increases systemic and myocardial blood flows to levels that would be likely to restore spontaneous circulation. Continuous monitoring of end-tidal carbon dioxide (PETCO2) now appears to be a practical measurement which provides a noninvasive quantitative indication of both systemic blood flow and coronary perfusion pressure. Consequently, PETCO2 predicts the likelihood of successful resuscitation and guides the operator who may modify the technique of precordial compression to improve systemic and myocardial perfusion. Among the large polypharmacy for cardiac resuscitation, only alpha-adrenergic agents (which increase coronary perfusion pressure) and especially epinephrine are of proven benefit. Neither buffer agents nor calcium salts appear to improve outcome except under unique conditions. To the contrary, there is increasing awareness of adverse effects of pharmacologic interventions such that they may hinder the return of viable myocardial and cerebral function. This has constrained the routine use of all drugs except for the use of alpha-adrenergic agonists. More invasive interventions by which blood flow is restored such as open-chest cardiac massage or extra-corporeal pump oxygenation (ECPO) are consistently more effective than conventional CPR. Experimentally, both methods promptly restore systemic and myocardial perfusion to viable levels and thereby increase the likelihood that spontaneous circulation is restored even after prolonged cardiac arrest or failure of conventional CPR.
Recent studies have demonstrated an increase in carbon dioxide (CO2) tension (PCO2) in both mixed venous and coronary vein blood early in the course of cardiac arrest and cardiopulmonary resuscitation. Because increased PCO2 in the myocardium correlates with both ischemic injury and depression of contractile function, the effects of hypertonic solutions of either the CO2-"generating" sodium bicarbonate (NaHCO3) buffer, a mixture of sodium carbonate (Na2CO3) and sodium bicarbonate (carbicarb) acting as a CO2-"consuming" buffer, or saline placebo (NaCl) were compared during cardiopulmonary resuscitation in 25 healthy minipigs. Both buffer agents significantly increased the pH and HCO3- of arterial, mixed venous and coronary vein blood. Bicarbonate increased whereas carbicarb reduced blood PCO2 in the systemic circuit as anticipated. However, neither the PCO2 nor the lactate content of coronary vein blood was favorably altered by buffer therapy. Four of eight animals treated with bicarbonate, five of eight treated with carbicarb and six of nine placebo-treated animals were successfully resuscitated and had a comparable 24 h survival rate. Coronary perfusion pressure during precordial compression, a critical determinant of resuscitability, was transiently decreased by each of the hypertonic solutions. Accordingly, neither CO2-generating nor CO2-consuming buffers mitigated increases in coronary vein PCO2 or improved the outcome of cardiopulmonary resuscitation under these experimental conditions.
1. Calcium-entry blockers increase the intramyocardial pH and decrease the intramyocardial Pco2 of ischaemic canine myocardium. However, the evidence documenting improvements in myocardial acidosis and in myocardial resuscitability after administration of calcium-entry blockers during cardiac arrest is incomplete. We therefore compared the effects of verapamil (0.05 mg/kg) and diltiazem (0.075 mg/kg) with those of saline placebo in an established porcine model of cardiac arrest and cardiopulmonary resuscitation. 2. After verapamil, six of 11 animals were successfully resuscitated; after diltiazem, five of 10; and after saline placebo, six of 10. Coronary perfusion and mean aortic pressures together with end-tidal CO2 concentration during precordial compression were predictive of resuscitation, independently of the drug or placebo. 3. Coronary vein pH decreased to 6.91 +/- 0.06 units (mean +/- SEM) with concurrent increases in PCO2 to levels exceeding 100 mmHg. Coronary vein lactate increased to a maximum of 7.5 +/- 0.6 mmol/l. Coronary vein acidaemia was accompanied by decreases in intramyocardial pH to 6.64 +/- 0.06 units. However, each of these differences between success and failure of resuscitation was unrelated to treatment with calcium-entry blockers. 4. Accordingly, neither verapamil nor diltiazem selectively altered coronary perfusion pressure, attenuated intramyocardial acidosis or improved resuscitability after porcine cardiac arrest and cardiopulmonary resuscitation.
We studied the effect of mechanical ventilation on systemic oxygen extraction and lactic acidosis in peritonitis and shock in rats. Sepsis was induced by cecal ligation and perforation. After tracheostomy, rats were randomized to spontaneous breathing (S) or mechanical ventilation with paralysis (V). Five animals were studied in each group. The V animals were paralyzed with pancuronium bromide to eliminate respiratory effort. Mechanical ventilation consisted of controlled ventilation using a rodent respirator with periodic adjustment of minute ventilation to maintain PaCO2 and pH within normal range. Arterial and central venous blood gases and thermodilution cardiac output were measured at baseline before abdominal surgery, and sequentially at 0.5, 3.5, and 6 h after surgery. At 6 h, cardiac output was 193 +/- 30 ml/kg.min in S animals and 199 +/- 32 ml/kg.min in V animals (NS). The central venous oxygen saturation was 27.4 +/- 4.7% in S animals and 30.0 +/- 6.4% in V animals (NS). Systemic oxygen extraction was 70 +/- 5% in S animals and 67 +/- 6% in V animals (NS). Arterial lactate was 2.4 +/- 0.4 mmol/L in S animals and 2.2 +/- 0.5 mmol/L in V animals (NS). The S animals developed lethal hypotension at 6.6 +/- 0.4 h compared to 6.8 +/- 0.4 h in V animals (NS). These data suggest that mechanical ventilation does not decrease systemic oxygen extraction or ameliorate the development of lactic acidosis during septic shock.
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We studied 37 patients with severe sepsis and systemic hypoperfusion to assess changes in PvCO2. Before fluid administration, the cardiac index (CI) was 2.64 +/- 0.14 L/min.m2. The PvCO2 was 38 +/- 1 torr and mixed venous pH was 7.32 +/- 0.02. The venous-arterial CO2 tension gradient (P[v-a]CO2) was 6 +/- 1 torr. After fluid administration, the CI increased to 3.45 +/- 0.14 L/min.m2 (p less than .001) and the P(v-a)CO2 decreased to 5 +/- 1 torr. The correlation between the change in CI and the change in P(v-a)CO2 was r = .42, p less than .01. P(v-a)CO2 was elevated in 19 (51%) patients before fluid administration (P[v-a]CO2 greater than 6 torr) (hypercarbic group). The P(v-a)CO2 gradient in this group was 9 +/- 1 compared with 4 +/- 1 torr in 18 patients with a normal P(v-a)CO2 gradient (p less than .001) (normocarbic group). PvCO2 was 41 +/- 2 torr in the hypercarbic group compared with 35 +/- 2 torr in the normocarbic group (p less than .05). No difference was noted in PaCO2. Venous arterial pH and HCO3- gradients were of greater magnitude in the hypercarbic group, -0.05 +/- 0.003 and 2.4 +/- 0.3 mEq/L compared to -0.02 +/- 0.004 (p less than .001) and 1.1 +/- 0.2 mEq/L (p less than .001), respectively. CI in the hypercarbic group was 2.3 +/- 0.2 compared to 3.0 +/- 0.2 L/min.m2 in the normocarbic group (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)