Biomedical subjects

W R Law

Publications and source records attributed to W R Law.

At least 19 recordsLinked to original sources

PubMed1997

Splanchnic vascular control during sepsis and endotoxemia.

Endotoxemia and sepsis often result in circulatory derangements which manifest as perfusion maldistributions. It has been widely accepted that the splanchnic circulation decreases in perfusion during advanced septic or endotoxemic states. Impaired perfusion of splanchnic organs may result not only in organ dysfunction but also exacerbations of polymicrobial bacteremia due to intestinal mucosal leakage. Consequently, evaluation of the splanchnic mechanisms of vasoregulation and how perfusion is maintained is vital to any topic concerning the management of the septic patient.

Animals↗

PubMed1997

Sepsis alters myocardial and plasma concentrations of endothelin and nitric oxide in rats.

Cardiovascular derangements during sepsis may arise from a mismatch between endothelin (ET) and nitric oxide (NO). We hypothesized that progression of chronic peritoneal sepsis would affect cardiac performance and would modulate the concentrations of NO and ET in the heart and plasma. Male Sprague-Dawley rats (340-390 g) were catheterized and made septic with a cecal slurry (200 mg/kg: i.p.). Heart rate, mean arterial pressure, and plasma ET and nitrite/nitrate (NOX) were determined at 0, 4, 8, 12, 24, and 48 h after induction of sepsis. Septic rats were found to have tachycardia at 48 h following induction of sepsis. Mean arterial pressure and pulse pressure were not altered in septic and non-septic rats. In a separate series of experiments, the function of isolated hearts from septic and non-septic rats was assessed at preload pressures of 2, 5, and 10 mmHg. Sepsis produced a significant decrease in rates of pressure development and relaxation (+/-dP/dt) at 24 and 48 h as compared to the hearts of non-septic rats. In septic rats, plasma concentrations of ET were significantly increased at t = 4, 8, 12 h as compared to basal values, and at 12 h as compared to non-septic rats, and returned to basal levels at 24 and 48 h. In contrast, circulating NO levels did not become elevated until t = 8 h and remained elevated throughout the remaining times. In the left ventricle, the concentration of ET was found to be significantly increased both in septic and non-septic rats at 4 and 8 h as compared to t = 0 h. In the left ventricles of non-septic rats, ET levels returned to baseline values at 12 h, while in septic rats, the concentration of ET remained significantly elevated until 12 h. In septic rats, left ventricular NO levels were found to be significantly increased at t = 12 h. It appeared that induction of sepsis contributed to an imbalance in the plasma concentration of ET and NO 12 h after the induction of sepsis. However, a similar imbalance was not observed in the left ventricle. It is concluded from these observations that peritoneal sepsis in a chronic rat model produced a divergence of plasma NO and ET levels. This suggests a homeostatic imbalance between vasoactive mediators, i.e. ET and NO, could contribute to the cardiovascular derangements that occur during sepsis.

Animals↗

PubMed1997

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.

Adrenergic alpha-Antagonists↗

PubMed1997

Evidence that adenosine contributes to maintenance of hepatosplanchnic blood flow during peritoneal sepsis in rats.

Sepsis induced derangements in hepatosplanchnic perfusion can contribute to organ damage and death. Adenosine, a common and potent metabolic vasodilator, has not been evaluated as a mechanism for maintenance of blood flow during sepsis. We tested the hypothesis that adenosine receptor blockade would cause a decrease in hepatosplanchnic blood flow during intraperitoneal (i.p.) sepsis in the rat. Rats (250-350 g) were catheterized for hemodynamic and blood flow measurements with tracer microspheres. Sepsis was induced with an i.p. injection of cecal material (150 mg/kg in D5W; 5 mL/kg), and baseline measurements were taken 24 h later. Animals then received either the adenosine receptor antagonist 8-PTH (10 mM, 1.5 mL/kg), its vehicle (1.5 mL/kg) or normal saline (1.5 mL/kg), intravenously, and measurements were repeated 1 and 10 min later. There was a significant increase in hepatosplanchnic portal resistance in septic animals given 8-PTH, with no change in mean arterial blood pressure (MAP) or heart rate. Regionally, there was a significant decrease in gastric, small intestinal, cecal, and pancreatic blood flow when compared with vehicle. Adenosine receptor blockade caused a significant reduction in hepatosplanchnic blood flow during sepsis, suggesting that maintenance of splanchnic blood flow during sepsis involves receptor mediated adenosine actions.

Adenosine↗

PubMed1997

Cardiac contractile function during coronary stenosis in dogs: association of adenosine in glycolytic dependence.

We tested the hypothesis that during critical coronary stenosis, endogenous adenosine alters myocardial glucose utilization to support myocardial contractile function (MCF). Anesthetized mongrel dogs were instrumented to measure hemodynamic variables, regional MCF (sonomicrometry), and substrate uptakes. Critical coronary artery stenosis was established with a screw clamp on the left circumflex coronary artery (LCX). Either 8-phenyltheophylline (3 x 10(-7) mol/min; adenosine-receptor blockade), iodoacetate (1 x 10(-5) mol/min; glycolysis blockade), or vehicle was infused into the LCX and the left anterior descending coronary artery (LAD). Critical coronary stenosis caused small decreases in arterial blood pressure and LCX blood flow, but no significant changes in MCF or other hemodynamics. There was a significant decrease in the O2 supply-to-consumption ratio in the stenotic region and an increased glucose uptake. Infusion of either 8-phenyltheophylline or iodoacetate caused a decrease in MCF in the stenotic LCX region concomitant with a decreased glucose uptake and without further changes in blood flow. This was not seen in the nonstenotic (LAD) region. These data support the hypothesis, indicating that glycolysis is vital for maintaining regional MCF during a decrease in the myocardial O2 supply-to-consumption ratio and that adenosine is important in this regard, independent of its vasoactive properties.

Adenosine↗

PubMed1996

Adrenergic, insulin, and work interactions with adenosine's effects on in situ myocardial glucose uptake.

We have demonstrated that adenosine enhances insulin-stimulated myocardial glucose uptake in situ. In the present study we determined the role of adrenergic influences and myocardial work on insulin-stimulated myocardial glucose uptake while varying intracoronary adenosine concentrations. Under pentobarbital anesthesia we instrumented mongrel dogs to obtain blood pressure, heart rate, and arterial and coronary sinus blood samples for measuring oxygen and glucose concentrations. An electromagnetic blood flow probe around the circumflex coronary artery allowed determinations of blood flow, and calculation of myocardial oxygen (MVO2) and glucose (MGU) uptakes. Somatostatin was infused i.v. (0.8 microgram/kg.min-1) along with 10 mU/kg.min-1 regular insulin, and variable quantities of glucose to maintain euglycemia. Adenosine was infused at logarithmic incremental rates (0, 0.01, 0.1, 1.0, and 10 mumoles.min-1) for 30 min each into the main left coronary arteries. Adrenergic blockade was achieved with i.v. propranolol (70 micrograms/kg bolus followed by 5 micrograms/kg.min-1 infusion), and phentolamine (95 micrograms/kg bolus followed by 9.5 micrograms/kg.min-1 infusion). Insulin infusion significantly increased MGU. Adenosine increased the maximal value for insulin-stimulated glucose uptake. Adrenergic blockade alone did not alter insulin-stimulated MGU, but reduced heart rate and MVO2. When evaluated relative to MVO2 1.0 mumoles/ml adenosine infusion increased MGU independent of work-related changes in the presence or absence of adrenergic blockade. With an adenosine infusion rate of 10 mumoles/ml myocardial glucose uptake returned to baseline. These data also support our earlier speculation that the MGU response to adenosine may be biphasic. These results suggest that antagonism of adrenergic effects by adenosine cannot account for adenosine's ability to enhance insulin's effects on glucose uptake in the heart, but that work-related influences should be accounted for in interpreting results of this kind.

Adenosine↗

PubMed1996

Do performance indicators make a difference?

BACKGROUND: The Maryland Hospital Association, Inc (MHA) Quality Indicator (QI) Project, a program of indicator development and application, includes more than 1,100 participating hospitals. Access to data is limited to participants to promote improvement through comparison across hospitals. Participating hospitals have identified and acted on opportunities for improvement in information systems, communication across departments and functions, processes of care, identification of appropriateness of practice, and improvement ¿beyond the hospital door¿. CASE STUDY 1: Two teams were formed to address waiting time in the emergency department and failure of patients to find treatment. Improvements, including rapid notification of available inpatient beds, additional staffing during high-census periods, and streamlined processes for lab work and imaging turnaround times, were followed by better indicator performance. CASE STUDY 2: A hospital discovered three causes for a high rate of unscheduled admissions following ambulatory surgery. Interventions included extending the hours of the Same Day Surgery Unit (to solve a urination problem) and changing the anesthesia used (to reduce nausea and vomiting). CASE STUDY 4: To successfully bring its cesarean section (C-section) rate down closer to the statewide rate, one hospital had physicians encourage patients with previous C-sections to undergo a trial of labor, promoted the use of epidural anesthesia, and took advantage of new packaging to facilitate the use of prostaglandin gel to induce cervical dilation. CONCLUSIONS: The QI Project continues to deal with issues concerning quality of data versus quality of care, the correlation between indicator rates and care processes, and the usefulness of severity adjustment.

Adult↗

PubMed1996

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.

Analysis of Variance↗

PubMed1996

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.

Animals↗

PubMed1996

The effects of diaspirin cross-linked hemoglobin in sepsis.

We tested the hypothesis that diaspirin cross-linked hemoglobin (DCLHb; Baxter Healthcare Corp.) would improve blood pressure, organ perfusion, and mortality during sepsis. Rats were catheterized to assess general hemodynamics (protocol 1) or regional blood flow (protocol 2). Sepsis was induced by intraperitoneal introduction of a cecal slurry (100 mg/kg). In protocol 1, rats received either 100 or 250 mg/kg DCLHb, or albumin at 1, 2, or 4 h after sepsis induction. Hemodynamics were recorded at these times and daily for 72 h. DCLHb increased blood pressure, prevented 72 h leukocytosis, and reduced mortality, but the timing of DCLHb administration was crucial. In protocol 2 only moribund septic animals received 100 mg/kg DCLHb or iso-oncotic albumin i.v. Hemodynamics and regional organ blood flows were measured at baseline, immediately before and after treatment, and at 24 h. DCLHb immediately increased blood pressure with no changes in cardiac output, heart rate, or regional perfusion. DCLHb increased regional perfusion to vital areas at 24 h (compared to albumin group). Distribution of cardiac output in albumin-treated rats was significantly skewed toward skeletal muscle at a time when cardiac output was significantly lower as compared with DCLHb treated animals. In conclusion, DCLHb safely elicited a pressor response, and improved regional perfusion to selected tissues. However, DCLHb benefits were best obtained when given within a specific time frame.

Albumins↗

PubMed1994

The use of local and systemic antibiotics in rat fecal peritonitis.

Treatment of fecal peritonitis includes administration of antibiotics, physical removal of contaminants, and restoration of gastrointestinal integrity. The temporal relationship of parenteral antibiotics and peritoneal irrigation with varied antibiotic solutions was studied in a peritonitis model. Antibiotics in high concentrations may actually inhibit host immune cells; therefore, dilute solutions used were MIC (minimum inhibitory concentration) (micrograms per millimeter) equivalent to usually achieved standard therapeutic blood levels. Sprague-Dawley rats were given a quantitative intraperitoneal challenge of 2 x 10(10) CFU/kg Escherichia coli and 10 mg autoclaved rat feces. Rats were randomized to receive 30 mg/kg intramuscular ceftriaxone (CTRX) either at the time of challenge (T = 0) or 2 hr later (T = 2). Two hours after peritonitis, rats received peritoneal irrigation with 30 cc of (1) normal saline, (2) dilute (10 mg/liter) CTRX solution, or (3) concentrated (1000 mg/liter) CTRX solution or (4) no irrigation. Survival and intraperitoneal pathology were then assessed. Parenteral CTRX given concurrently with peritoneal contamination improved survival (67%) compared with parenteral administration given 2 hr later (33%) (P < 0.05). Intraperitoneal CTRX irrigation improved survival (100%) in animals that received parenteral CTRX concurrently with contamination; this beneficial effect was present with both dilute and concentrated solutions and was significantly better than saline irrigation alone. Parenteral antibiotics given early after contamination of the peritoneum associated later with peritoneal lavage with antibiotic solutions improved survival.

Abscess↗

PubMed1994

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)

Animals↗

PubMed1994

Porcine peritoneal sepsis: modeling for clinical relevance.

The characteristics of two types of intraperitoneal (i.p.) soilage sepsis models, autologous fecal inoculum (FEC) and a pure culture of Escherichia coli (EC), were studied in 26 male Yucatan minipigs (20-30 kg). Early (1-4 h) and late (24-72 h) changes were different between the two groups. The EC group was characterized early by hypotension, low cardiac output, and increased systemic and pulmonary vascular resistances, along with leukopenia, hypoglycemia, lactacidemia, and elevated blood urea nitrogen. Of the pigs in the EC group that survived the early effects, there were few significant differences in physiological parameters, compared to control pigs, that would indicate ongoing pathological processes. In contrast, the FEC group pigs demonstrated early hypotension, but with increased cardiac output and reduced systemic vascular resistance. Other parameter changes were similar to those seen in the EC pigs, but to a lesser degree, with the exception of elevations in serum lactate dehydrogenase. Also in contrast to the EC group, most of the changes in the FEC group persisted in later days, and FEC pigs demonstrated leukocytosis. There were also greater elevations in circulating lipopolysaccharide (LPS) concentrations in the EC group that returned later to baseline levels. In the FEC group, there were persistently elevated LPS concentrations over 72 h. These observations suggest that pigs challenged with intraperitoneal E. coli demonstrated an initial acute peritonitis and damaging physiologic effects of high levels of circulating LPS. Survivors in this group improved and were physiologically stable after 24 h. Pigs that received i.p. autologous feces developed an early acute peritonitis phase with lower levels of circulating LPS, and later developed pronounced peritoneal reaction as demonstrated by multiple abdominal abscesses, pyogenic granuloma formation, and adhesions with physiological evidence of developing sepsis over 72 h. These observations indicate that i.p. EC models evoke a systemic response not unlike intravenous administration of LPS or EC, however, the FEC model produced a systemic response akin to a slower developing septic process.

Animals↗

PubMed1993

Beta-adrenergic-dependent and -independent actions of naloxone on perfusion during endotoxin shock.

Naloxone, an opioid antagonist, has been shown to improve cardiovascular status during endotoxin shock, including splanchnic perfusion. Enhancement of adrenergic action has been implicated as a physiological path by which naloxone effects changes in cardiac function during endotoxin shock, but the mechanism for changes in various splanchnic vascular beds has not been examined. In this study, we examined the role of beta-adrenergic actions in cardiovascular performance and the splanchnic perfusion changes caused by naloxone during endotoxin shock. Rats were instrumented with catheters in 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 i.v. naloxone (or saline) treatment (4 mg/kg + 2 mg/kg.hr) in the presence or absence of propranolol (1 mg/kg + 1 mg/kg.hr). Radiolabelled microspheres were used to determine cardiac outputs and blood flows at 0, 30, 60, and 120 min after beginning endotoxin infusion. Blood pressure was not affected by endotoxin challenge, but cardiac output and most organ blood flows fell over time. beta-Adrenergic blockade did not alter this response. Naloxone improved cardiac output and blood flow to the stomach, small intestine, colon, and spleen but not to other splanchnic organs. Naloxone also increased renal and coronary blood flows. The improvements in cardiac output with naloxone were ablated in the presence of propranolol, as were the increases in gastric, colonic, splenic, coronary, and renal blood flows. However, the beneficial effect of naloxone on small bowel blood flow was not diminished by blockage of beta receptors. These results suggest that the effects of opioid antagonism are mediated, in part, by enhancing endogenous beta-adrenergic actions in vivo. Improvements in the splanchnic circulation are selectively altered by naloxone during endotoxin shock, some independent of beta-adrenergic actions. Understanding this phenomenon can lead to the appropriate use of opioid antagonism, should it prove clinically useful in the treatment of septic shock.

Animals↗

PubMed1992

Hepatic insulin resistance during chronic hyperdynamic sepsis.

Disturbances in normal glucose metabolism and homeostasis which manifest as hyperglycemia and glucose intolerance are often observed during clinical sepsis. Skeletal and myocardial muscle as well as whole body insulin resistance have been demonstrated in this laboratory and others during experimental and clinical sepsis. The existence of hepatic insulin resistance in sepsis has yet to be fully elucidated. This study was undertaken to assess hepatic insulin resistance during chronic hyperdynamic sepsis. Animals were randomly assigned to a septic (n = 7), sham (n = 7), or control (n = 7) group. Sepsis was induced in anesthetized dogs via a midline laparotomy whereby a fecal-soaked gauze sponge was placed amid the intestines. Sham animals underwent a laparotomy with mechanical manipulation of the intestines but no fecal implant. Control animals had no previous surgery. Sham and control dogs were pair-fed with the septic dogs. On postoperative day 7, after an overnight fast, animals were anesthetized, intubated, and ventilated. Via a left subcostal laparotomy, electromagnetic flow probes were placed to measure hepatic arterial and portal venous blood flows. Cannulae were placed in femoral, portal, and hepatic veins and femoral artery and used to calculate hepatic outputs of glucose, lactate, and oxygen during a basal period and hyperinsulinemic-euglycemic clamps which used intravenous insulin infusions which ranged from 0.4 to 4,000 mU/min. Mean arterial blood pressure decreased with increasing insulin concentrations in septic animals while no change was seen in control or sham animals. In control and sham animals, net hepatic glucose output (NHGO) decreased in response to increasing insulin levels. Septic animals showed no such inverse relationship and, moreover, showed no change in glucose output response to any insulin infusion, i.e., hepatic insulin unresponsiveness during sepsis. Net hepatic lactate output during basal pre-insulin period during sepsis was negative. This was in contrast to the positive outputs in control and sham animals. Glucose infusion rates (GIR) increased during insulin infusion but were not different between groups at any insulin infusion rate. These data demonstrated a hepatic insulin resistance (unresponsiveness) during chronic hyperdynamic, hypermetabolic sepsis.

Animals↗

PubMed1992

Pentoxifylline treatment of sepsis in conscious Yucatan minipigs.

Recent evidence suggests that pentoxifylline (PTX) may be useful in the treatment of sepsis. We examined effects of PTX in a conscious swine model of sepsis. Yucatan minipigs (20-30 kg) were anesthetized and instrumented with catheters in the vena cava, aortic arch, pulmonary artery (Swan-Ganz thermodilution catheter), and peritoneum. Twenty-four hours after surgery, sepsis was induced by intraperitoneal (ip) injection of Escherichia coli bacteria (2 x 10(10) cfu/kg). Nonseptic pigs received intraperitoneal saline (5 ml/kg). PTX treatment (3 mg/kg/hr, iv; 1 mg/ml in 0.9% saline) and maintenance fluid (5 ml/kg/hr, iv) were started with bacterial infusion. An additional 60 cc/kg 0.9% saline bolus was administered iv at 1 hr. Pigs were monitored before and 1, 2, 5, and 24 hr after bacterial injection. Intraperitoneal injection of bacteria led to significant reductions in blood pressure and cardiac output and elevations in pulmonary wedge pressure and pulmonary vascular resistance. These effects were attenuated by PTX treatment. All septic animals demonstrated elevated creatinine, blood urea nitrogen, circulating endotoxin (LPS), and tumor necrosis factor concentrations, reductions in white blood cell and platelet counts, and peritonitis. None of these responses was altered by PTX treatment. We conclude that PTX may prove to be a useful therapeutic tool in the early treatment of septic shock but is limited in the scope of its effects.

Animals↗

PubMed1991

Cardiovascular sequelae of endotoxin shock in diabetic dogs.

Diabetic patients exhibit a higher incidence of post-surgical sepsis, as well as a higher rate of mortality from sepsis, than their non-diabetic counterparts. This may be a result of cardiovascular deterioration associated with diabetes mellitus. This study was designed to characterize the cardiovascular sequelae associated with endotoxin shock in a canine model of diabetes. Diabetes was induced with alloxan (50 mg/kg) and streptozotocin (30 mg/kg) in dogs weighing 19-25 kg. Thirty days later, anaesthetized dogs were instrumented to obtain blood pressures, blood samples, left ventricular chamber diameter, circumflex arterial blood flow, and aortic blood flow. Metabolic parameters were calculated according to the Fick principle, and myocardial inotropic state assessed with the end-systolic pressure-diameter relationship. After stable baseline measurements, Escherichia coli endotoxin (1 mg/kg) was infused over 1 h, and measurements were obtained every 30 min. After endotoxin administration diabetic dogs became more hypotensive than the non-diabetic dogs. Cardiac performance parameters were also depressed to a greater degree. These changes could be attributed to depressions in vascular resistance and myocardial inotropic state in diabetic dogs. Cardiac dysfunction occurred in association with a relative decrease in the supply to demand ratio for oxygen in the diabetic dogs, suggesting functional ischemia. Data indicating a decrease in pre-load and vascular resistance in the diabetic group suggest a greater degree of vascular collapse, vascular pooling, or extravasation of fluid than occurred in the non-diabetic group. These data support the hypothesis that the cardiovascular system of diabetic subjects cannot tolerate a septic insult as well as their non-diabetic counterparts.

Analysis of Variance↗

PubMed1991

Adenosine enhances myocardial glucose uptake only in the presence of insulin.

Better understood in other tissues, the effects of adenosine on insulin-stimulated glucose uptake in the heart are poorly understood. Under pentobarbital anesthesia, we instrumented mongrel dogs to obtain general hemodynamics (blood pressure and heart rate), and arterial and coronary sinus blood samples for measuring oxygen and glucose concentrations. An electromagnetic blood flow probe around the circumflex coronary artery allowed determinations of blood flow, and calculation of substrate uptake by the heart (Fick principle). Somatostatin (SRIF) was infused intravenously (0.8 micrograms/kg/min) along with 0, 0.5, 1.0, 5.0, or 10 mU/kg/min regular insulin, and variable quantities of glucose to maintain euglycemia. Concomitant with the SRIF, insulin, and glucose infusions, adenosine was infused in logarithmically increasing rates (0, 0.01, 0.1, 1.0, 10 or 100 mumol/min) for 30 minutes each into the main left coronary arteries. Insulin infusions increased myocardial glucose uptake in a dose-dependent manner. The heart displayed exquisite sensitivity to insulin, with an ED50 of approximately 14 microU/mL (serum insulin). Adenosine infusions in the absence of insulin (SRIF infusion) increased coronary blood flow, but did not alter myocardial glucose uptake. In the presence of insulin, adenosine increased the maximal value for glucose uptake without changing sensitivity to insulin. These results indicate that adenosine enhances myocardial responsiveness to insulin, with respect to glucose uptake, independent of changes in blood flow. Since glucose can be used for anaerobic metabolism, and adenosine levels are known to increase under situations in which myocardial oxygenation is inadequate, these data have serious implications for conditions such as myocardial ischemia or hypoxia, when glycolytic substrate availability is vital.

Adenosine↗