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Endotoxin differentially impairs cyclic guanosine monophosphate-mediated relaxation in the pulmonary and systemic circulations.

OBJECTIVES: The purpose of this study was to determine the effect of endotoxin on alpha1-adrenergic receptor vasoconstriction and both endothelium-dependent and -independent cyclic guanosine monophosphate (cGMP)-mediated vasodilation in the pulmonary and systemic circulations. DESIGN: Prospective, multiple group, controlled experimental study. SETTING: Medical school research laboratory. SUBJECTS: Male Sprague-Dawley rats, weighing 250 to 350 g. INTERVENTIONS: Six hours after endotoxin (20 mg/kg intraperitoneally) or saline, the response to the a) alpha1-adrenergic receptor agonist, phenylephrine; b) endothelium-dependent vasodilator, acetylcholine; and c) the endothelium-independent vasodilator, sodium nitroprusside, was determined in isolated rat pulmonary artery and thoracic aortic rings. MEASUREMENTS AND MAIN RESULTS: Endotoxin caused a significant decrease in the response to phenylephrine in the aorta but did not affect the response in the pulmonary artery. Endotoxin caused significant impairment of relaxation to acetylcholine and sodium nitroprusside in the pulmonary circulation. In control rings, only 4 +/- 1% of the preconstricted tension remained in response to acetylcholine vs. 77 +/- 3% following endotoxin administration (p < .05). Similarly, sodium nitroprusside resulted in complete pulmonary ring relaxation in controls vs. 18 +/- 3% tension remaining following endotoxin administration (p < .05). On the other hand, only the response to acetylcholine was dysfunctional in the thoracic aorta. In thoracic aortic rings from control rats, acetylcholine caused complete relaxation; however, 23 +/- 5% of the preconstricted tension remained following endotoxin administration. The response to sodium nitroprusside in the thoracic aorta from endotoxin-treated rats was not different from control. CONCLUSIONS: From these data, we conclude that endotoxin causes organ-specific changes in vascular reactivity. These changes in vascular reactivity favor a decrease in vascular pressure and resistance in the systemic circulation, and an increase in vascular pressure and resistance in the pulmonary circulation in response to endotoxin.

Acetylcholine↗

Pulmonary circulation and burns and trauma.

The lung is a critical organ in victims of thermal injury or multiple trauma since the blood that drains injured organs circulates through the pulmonary circulation before passing through any other organ. The lung therefore will receive the first volley of cytotoxins released postinjury. In addition to being a target of injury, the lung may also contribute to the injury of systemic organs. This injury may be the result of a reduced delivery of oxygenated blood or the direct release of cytotoxins into the systemic circulation. The injury to the lung may be to the pulmonary microvasculature or the airway. The bronchial circulation responds to injury by a marked elevation in its blood flow and microvascular permeability. These latter effects may be important in mediating the changes which occur in the lung parenchyma.

Animals↗

Cerebrovascular tone rather than intracranial pressure determines the effective downstream pressure of the cerebral circulation in the absence of intracranial hypertension.

Cerebral perfusion pressure is commonly calculated from the difference between mean arterial pressure and intracranial pressure because intracranial pressure is known to represent the effective downstream pressure of the cerebral circulation. Studies of other organs, however, have shown that effective downstream pressure is determined by a critical closing pressure located at the arteriolar level. This study was designed to investigate the effects of PCO2-induced variations in cerebrovascular tone on the effective downstream pressure of the cerebral circulation. Sixteen patients recovering from head injury were studied. Intracranial pressure was assessed by epidural pressure transducers. Blood flow velocity in the middle cerebral artery was monitored by transcranial Doppler sonography. Effective downstream pressure was derived from the zero flow pressure as extrapolated by regression analysis of instantaneous arterial pressure/middle cerebral artery flow velocity relationships. PaCO2 was varied between 30 and 47 mm Hg in randomized sequence. Intracranial pressure decreased from 18.5+/-5.2 mm Hg during hypercapnia to 9.9+/-3.1 mm Hg during hypocapnia. In contrast, effective downstream pressure increased from 13.7+/-9.6 mm Hg to 23.4+/-8.6 mm Hg and exceeded intracranial pressure at hypocapnic PaCO2 levels. Our results demonstrate that, in the absence of intracranial hypertension, intracranial pressure does not necessarily represent the effective downstream pressure of the cerebral circulation. Instead, the tone of cerebral resistance vessels seems to determine effective downstream pressure. This suggests a modified model of the cerebral circulation based on the existence of two Starling resistors in a series connection.

Adult↗

Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best?

OBJECTIVE: To assess the effects of different doses of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in patients with septic shock. DESIGN: Prospective, randomized, open-label study. SETTING: A 31-bed, medicosurgical intensive care unit of a university hospital. PATIENTS: Convenience sample of 20 patients with septic shock, separated into two groups according to whether (moderate shock group, n = 10) or not (severe shock, n = 10) dopamine alone was able maintain mean arterial pressure >65 mm Hg. INTERVENTIONS: Dopamine was progressively withdrawn and replaced successively by norepinephrine and then epinephrine (the order of the two agents was randomly determined) to maintain mean arterial pressure constant (moderate shock) or to increase mean arterial pressure above 65 mm Hg (severe shock). MEASUREMENTS AND MAIN RESULTS: Systemic circulation (pulmonary artery catheter) and splanchnic circulation (indocyanine green dilution and hepatic vein catheter) and gastric mucosal Pco(2) (gas tonometry) were measured during dopamine (moderate shock only), norepinephrine, and epinephrine administration (both groups). Data were analyzed with nonparametric tests and are presented as median [percentiles 25-75]. In moderate shock, cardiac index was similar to dopamine and norepinephrine (3.1 [2.7-3.8] vs. 2.9 [2.7-4.1] L/min.m2, p = nonsignificant) but greater with epinephrine (4.1 [3.5-4.4] p <.01 vs. dopamine and norepinephrine). Splanchnic blood flow was similar with the three agents (732 [413-1483] vs. 746 [470-1401] vs. 653 [476-1832] mL/min.m, p = nonsignificant). The gradient between mixed-venous and hepatic venous oxygen saturations was lower with dopamine than with norepinephrine and epinephrine, but the Pco(2) gap was similar with the three agents. In severe shock, cardiac index was higher, but splanchnic blood flow was lower, with epinephrine than with norepinephrine (4.6 [3.7-5.3] vs. 3.4 [3.0-4.1] L/min.m2, p <.01 and 860 [684-1334] vs. 977 [806-1802] mL/min.m2, p <.05, respectively). Epinephrine increased the mixed-venous and hepatic venous oxygen saturation gradient but did not alter Pco(2) gap. CONCLUSIONS: Dopamine and norepinephrine have similar hemodynamic effects, but epinephrine can impair splanchnic circulation in severe septic shock.

Aged↗

Elevated numbers of circulating endothelial cells in renal transplant recipients.

BACKGROUND: Damage of microvascular endothelial cells is a salient feature of acute vascular rejection and chronic allograft nephropathy, yet specific blood markers of ongoing endothelial injury are currently unavailable. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders. METHODS: We studied 129 renal transplant recipients who underwent percutaneous graft biopsy. Circulating endothelial cells were isolated with immunomagnetic anti-CD146-coated Dynabeads. Cells were stained with acridine and counted. To verify their endothelial origin, staining for Ulex europaeus lectin 1 (UEA-1) was performed in parallel. Twenty-one healthy controls were also studied. RESULTS: On biopsy, seven patients had acute vascular rejection, 15 patients had acute tubulointerstitial rejection, 14 patients had borderline rejection, and 93 patients had no rejection. Patients with acute vascular rejection had the highest cell numbers (72+/-39 cells/mL) when compared with all other patients (P<0.02). Regardless of their biopsy findings, however, all other renal transplant recipients had significantly higher numbers of circulating endothelial cells (25+/-20 cells/mL) than healthy controls (7+/-5 cells/mL, P<0.001). Finally, there was a significant correlation of cell numbers and serum cyclosporine A trough levels. By contrast, there was no correlation with serum creatinine, age, or the number of immunosuppressive drugs. CONCLUSIONS: The number of circulating endothelial cells is a novel marker of endothelial damage in renal transplant recipients. Further studies must now evaluate the origin of these cells, corroborate the clinical significance of our findings, and delineate the influence of calcineurin inhibitors.

Acute Disease↗

Stimulatory cholinergic effect on the release of antiaggregatory activity into the circulation of cat and man and its modification by beta-adrenergic antagonists.

The release of PGI2-like activity into the circulation in response to cholinergic agonists and modification of this response by beta-adrenergic antagonists was investigated in anaesthetized cats and healthy humans. Antiaggregatory activity in the arterial blood was continuously assayed by measuring platelet aggregation on blood superfused collagen strip. In some of the human experiments, after the administration of the drugs, the conversion of [14C]-arachidonate to [14C]-prostaglandins in the pulmonary vascular bed was studied. Cholinergic agonists stimulated the release of PGI2-like activity into the circulation, which effect was potentiated in cats by beta-adrenergic antagonists. In humans the latter agents did not stimulate the conversion of [14C]-arachidonate to prostaglandins in the pulmonary circulation and, moreover, inhibited the stimulatory cholinergic effect. The results suggest that an interplay between cholinergic and beta-adrenergic mediators may be involved, although in a different way in cats and in humans, in the release of PGI2-like activity into the systemic circulation.

Acetylcholine↗

Central circulation during halothane-diethyl-ether azeotrope and isoflurane anaesthesia in the pig.

The fatal anaesthetic ratio (FAR) has been determined for halothane-diethyl-ether (HE) in pigs, and the central circulation during hypovolaemia has been investigated using a well-documented agent such as isoflurane as a standard. The fatal anaesthetic ratio for HE in pigs was (3.21/1.03) = 3.12. This is high compared to the FAR for halothane of 1.7. The central circulation was investigated in 12 pigs which were randomly allocated to either HE or isoflurance anaesthesia, respectively. Baseline values were recorded when they were stable at 1.3 MAC of the volatile anaesthetic used. The pigs were bled 30% of their blood volume, and measurements were made at 5 and 30 min. There was one significant difference between these groups in central circulation: the blood pressure was higher at baseline measurement in the HE group. At 5 min and 30 min, there were no significant differences between these groups. There was a general depression of central circulation without any sign of decreased contractility. HE anaesthesia is well tolerated during hypovolaemia in pigs.

Anesthesia, Inhalation↗

Estimation of total body fluid shifts between plasma and interstitium in man during extracorporeal circulation.

Fluid transport between plasma and interstitium during extracorporeal circulation was studied in seven patients undergoing aortocoronary bypass grafting. The absolute shifts in plasma volume during hypothermia were determined as the difference between input and loss of fluid and the changes in blood volume. The change in haemoglobin concentration due to acute haemodilution when starting extracorporeal circulation was used to calculate the absolute blood and plasma volume. The Starling equation for exchange across the capillary wall was used to describe fluid shifts. The total fluid filtered during the 60- to 90-min period of extracorporeal circulation averaged 34.1 +/- 11.1 (s.d.) ml/min. The total body filtration coefficient from the Starling relationship averaged 0.046 +/- 0.012 ml/kg.mmHg.min (0.354 +/- 0.092 ml/kg.kPa.min). Haemodilution, reducing colloid osmotic pressure in plasma (COPP) by approximately 10 mmHg (1.3 kPa) will result in a loss of plasma fluid of around 2 1 per hour. When corrected for lower fluid viscosity due to hypothermia during extracorporeal circulation, CFC would be about 40% higher, and a filtered volume of nearly 3 1 in a normothermic 70-kg person would be expected. Crystalloid haemodilution for shorter periods of time does not produce excessive oedema and thus may be well tolerated.

Aged↗

Effects of thoracic vs. lumbar epidural anaesthesia on systemic haemodynamics and coronary circulation in sevoflurane anaesthetized dogs.

BACKGROUND: Although many investigators reported changes in coronary circulation during thoracic epidural anaesthesia (TEA), no previous studies have attempted to compare it with lumbar epidural anaesthesia (LEA) concerning coronary circulation. Our aim was to compare effects of TEA on systemic haemodynamics and coronary circulation with those of LEA in anaesthetized dogs. METHODS: In dogs receiving 1.5% sevoflurane, 2% lidocaine (0.1 ml kg-1) was injected into the epidural space via an epidural catheter inserted at either the T7-T8 (TEA group, n = 8) or L5-L6 (LEA group, n = 8) interspace, and the same dose was repeated again 30 min later. RESULTS: Heart rate and maximum left ventricular dP/dt decreased in the TEA group but were unchanged in the LEA group. Decreases in mean arterial pressure were found for both groups, and they were more substantial in the TEA than in the LEA group. Decreases in left ventricular minute work index were found for both groups, and they tended to be more substantial in the TEA than in the LEA group. Coronary perfusion pressure and blood flow decreased in both groups. Calculated coronary vascular resistance increased in the TEA group but was unchanged in the LEA group. CONCLUSION: The most significant difference between TEA and LEA concerning coronary circulation was characterized by an increase in coronary vascular resistance in the TEA group, which was not present in the LEA group. The increase in coronary vascular resistance caused by TEA may be explained by a coronary vasoconstriction caused by a lower myocardial oxygen demand.

Anesthesia, Epidural↗

Intermittent vascular access for extracorporeal circulation in conscious rats: a new technique.

A new technique is described for repeated intermittent access to the systemic circulation in fully conscious rats for infusion or extracorporeal circulation. The femoral artery and vein of each rat were cannulated. The cannulas were then passed subcutaneously and exteriorized through the skin of the tail 2 cm from its base. The exposed cannulas were protected by a special plastic device. This new approach did not immobilize the rat except during access to the circulation; even then, only the distal portion of the tail was immobilized, thus allowing the animal to move freely. This way repeated access to the systemic circulation was easily achieved in the fully conscious rat.

Animals↗

Loss of anticoagulant effect of heparin during circulation of human blood in vitro.

Device-induced thrombogenesis was studied in an in vitro model using human blood circulated through an artificial ventricle. A new constant pressure filtration technique was used to detect circulating microemboli, the activated partial thromboplastin time (APTT) test was used to monitor the blood for the presence of anticoagulant activity of heparin, and hemolysis was quantified by measuring the plasma free hemoglobin level. Circulation of blood through a 20-ml stroke volume pneumatically driven ventricle for 6-9 h resulted in a significant reduction of APTT, indicating the loss of the anticoagulant effect of heparin. Microemboli concentration was minimal until the APTT decreased below 125 s, at which time the microemboli concentration increased rapidly. This was presumed to be due to the formation of thrombi following a decrease in heparin activity. A significant increase in hemolysis was also noted when blood was pumped. None of these changes was noted in the nonpumped control blood. Spontaneous loss of heparin activity in blood circulated by a pneumatically driven pump may have clinical implications and may help understanding of the problems associated with device-induced thrombogenesis.

Adult↗

Evaluation of left ventricular assist device performance and hydraulic force in a complete mock circulation loop.

Centrifugal pump performance characteristics are vital in determining the ability of a prototype left ventricular assist device (LVAD) to meet the physiological circulation requirements of the cardiovascular system. These characteristics influence the static hydraulic forces encountered by the pump impeller, which determine the required load stiffness of suspension type bearings to minimize impeller touchdown. Performance investigations were conducted on an LVAD design while characterizing the impeller static hydraulic forces of various impeller/volute configurations. The pumps were inserted into a complete systemic and pulmonary mock circulation rig configured to provide suitable nonpulsatile or simulated pulsatile left heart failure environments. The single volute and closed shroud impeller configuration exhibited lowest radial (0.01 N) and axial (3 N) force at nonpulsatile design flow conditions, respectively. Normal hemodynamic conditions of 5.1 L/min at 94 mm Hg were re-established upon inserting the device into the left heart failure environment, where the pump operated along the nonpulsatile characteristic curve for 2200 rpm. The operational limits on this curve were dictated by the required pressure differential across the pump during systolic and diastolic periods. The reduction of left atrial pressure (25 to 8 mm Hg) indicated the alleviation of pulmonary congestion. The ability for the LVAD to support circulation in a left heart failure environment was successfully demonstrated in the mock circulation loop. The impeller hydraulic force characteristics attained will aid the bearing designer to select the best volute and impeller configuration to minimize impeller touchdown in magnetic, hydrodynamic or mechanical type bearing applications.

Blood Pressure↗

Retrograde cerebral circulation for distal aortic arch surgery through a left thoracotomy.

We have devised a simple hypothermic retrograde cerebral circulation technique for protecting the brain during aortic arch surgery. The central venous pressure is simply elevated (15 to 18 mmHg) while the aortic arch is open and the descending aorta occluded, causing oxygen-saturated venous blood from the lower half of the body, which is undergoing deep hypothermic (15 degrees C to 18 degrees C) perfusion, to circulate in the brain in a retrograde fashion, supplying it with oxygen. Twenty-six cases of distal aortic arch aneurysm treated using this method, through a left thoracotomy with femoral vein cannulation, were evaluated. Retrograde cerebral circulation time was 59.6 +/- 13.1 minutes (40 to 93 min). Retrograde flow was 43.9 +/- 13.0 (25 to 62) mL/min. Significant oxygen and apparent lactate extraction were noted in the brain. Early death resulted in 3 of the first 14 cases (21.4%) from embolism, and in 1 of the other 12 cases (8.3%) from massive bleeding and multiple organ failure. Only one late death occurred. No death was attributed to the method itself. This method, with its simplified operative procedure using a lateral thoracotomy, supplied oxygen to the brain and protected it during interruption of the cerebral circulation. Careful management of the atherosclerotic aorta is needed.

Aged↗

Cross-circulation in experimental hepatic failure in the pig.

In experimental liver failure (pigs with totally devascularized liver) the effect of different types of extracorporeal hepatic assistance was evaluated. Group I (N = 6) were untreated controls, Group II (N = 6), simple cross-circulation, Group III (N = 6), cross-circulation with inflow in the donor directly into the portal vein and Group IV (N = 4), cross-perfusion with isolated perfused liver. The cross-circulation was started 20 h after devascularization. There was no change in survival time. Bilirubin was decreased by a factor of 2 and the prothrombin index increased by a factor of 2 after initiation of the cross-circulation due to the dilution. In contrast to this, ammonia was unchanged. During the perfusion no significant changes were found. In Group V (N = 4), extended cross-perfusion with isolated perfused liver for 20 h, starting just after exclusion of liver function in the recipient and with a new liver in the perfusion system every 6th hour, the survival time was significantly increased. Furthermore, changes in the biochemical variables were prevented. It is concluded that with a supply of quantitatively sufficient hepatic assistance it is possible to extend the survival time in experimental liver failure.

Ammonia↗

Biliary response to food in rabbits: role of the gall bladder and the enterohepatic circulation of bile salts.

The biliary response to feeding has been investigated in intact and cholecystectomized rabbits, with and without interruption of the enterohepatic circulation of bile salts. The relative contribution of the different secretory mechanisms involved in this process has been examined. Feeding induced an increase in the flow and bicarbonate concentration of the bile and a slight decrease in the bile salt content in rabbits with gall bladders and the enterohepatic circulation intact. Feeding with the enterohepatic circulation interrupted elicited a drop in bile flow and the bile salt concentration, but an increase in bicarbonate concentration. Interruption of the enterohepatic circulation thus dramatically modifies the feeding response: a response to food is still detectable after interruption, but is masked by the negative effects of drainage of the bile away from the duodenum.

Animals↗

Paramedic interventions increase the rate of return of spontaneous circulation in out of hospital cardiac arrests.

OBJECTIVE: To determine whether paramedic interventions increased the rate of return of spontaneous circulation in the victims of out of hospital cardiac arrest. METHODS: A retrospective analysis of 276 out of hospital cardiac arrests was made. Data analysed included age, sex, presenting rhythm, ambulance response time, presence of a pulse at any point, interventions performed by the ambulance crews, and survival to discharge. RESULTS: 146 patients were treated by paramedics and 130 by technicians. There was no difference in the rate of return of spontaneous circulation or survival to discharge in patients presenting in ventricular fibrillation (VF). In non-VF arrests there was no increase in survival to discharge, but 15% of patients in non-VF arrests achieved a return of spontaneous circulation when treated by paramedics compared to none treated by technicians. There were no other significant differences in any of the variables assessed. CONCLUSIONS: Out of hospital cardiac arrests presenting in VF are managed equally well by paramedics and technicians. However, in non-VF arrests there is a significantly increased rate of return of spontaneous circulation in those patients attended by paramedics.

Adult↗

Effect of central corticotropin releasing factor on hepatic circulation in rats: the role of the CRF2 receptor in the brain.

BACKGROUND: Corticotropin releasing factor (CRF) is distributed in the central nervous system and acts as a neurotransmitter to regulate gastric functions through vagal-muscarinic pathways. We have recently demonstrated that central CRF aggravates experimental acute liver injury in rats. In the present study, the central effect of CRF on hepatic circulation was investigated. METHODS: Hepatic surface perfusion was determined by laser Doppler flowmetry in urethane anaesthetised rats. Portal pressure and portal blood flow was simultaneously monitored. CRF (0.1-4 nmol), urocortin II (a selective CRF2 receptor agonist 2.5-100 pmol), or saline vehicle was injected intracisternally, and changes in hepatic circulation were observed for 120 minutes. We examined the effects of various pretreatments with K41498, a selective CRF2 receptor antagonist, atropine, 6-hydroxydopamine, hepatic plexus denervation, or hepatic branch vagotomy, respectively. RESULTS: Intracisternal injection of CRF (0.2-4 nmol) caused a dose dependent decrease in hepatic surface perfusion with a maximum response occurring 60 minutes post injection. Portal pressure was dose dependently elevated and portal blood flow was decreased by intracisternal CRF concurrently with the decrease in hepatic surface perfusion. These changes in hepatic circulation by intracisternal CRF were abolished by 6-hydroxydopamine and hepatic plexus denervation, but not by atropine or hepatic vagotomy. Urocortin II injected intracisternally decreased hepatic surface perfusion and elevated portal pressure at doses within the picomolar range. Intracisternal preadministration of K41498 inhibited the effect of central CRF on the hepatic circulation. CONCLUSION: These data suggest that CRF acts in the brain to decrease hepatic surface perfusion and elevate portal pressure through central CRF(2) receptor and sympathetic-noradrenergic pathways.

Adrenergic Agents↗

Detection of epithelial tumour RNA in the plasma of colon cancer patients is associated with advanced stages and circulating tumour cells.

BACKGROUND: Although circulating tumour DNA has been detected in patients with different types of cancer, little is known of free RNA in cancer patients. AIMS: We investigated the presence of RNA from epithelial tumours in plasma from patients with colorectal carcinomas, and its correlation with tumour characteristics and circulating tumour cells. METHODS: beta-actin mRNA was analysed to assess the viability of plasma RNA in samples from 53 patients with colonic cancer and 25 controls. Subsequently, nested primers were used to detect the presence of cytokeratin 19 (CK19) and carcinoembryonic antigen (CEA) RNA in the same samples. Nine clinicopathological parameters were studied to correlate the molecular and clinical parameters. Additionally, we investigated for micrometastases in blood in 18 of these patients and in 10 of the controls samples. RESULTS: All samples had detectable quantities of beta-actin RNA. In the controls, one case (4%) was positive for CEA and five (20%) for CK19 RNA; of the 53 patients, 17 cases (32%) were positive for CEA and 39 (73.6%) for CK19 RNA. This was statistically significant (p=0.000001). Advanced stages (p=0.03) and soluble CEA status (p=0.03) were associated with the presence of CEA, CK19, or both RNAs in plasma. Lymph node metastases (p=0.06) and vascular invasion (p=0.07) were almost significant. On the basis of these results, we examined the possible presence of micrometastases in blood in several of these patients. The presence of plasma tumour RNA was found to be associated with circulating tumour cells in blood (p=0.04). CONCLUSIONS: Epithelial tumour RNA is detectable in plasma from colon cancer patients. This molecular event is associated with advanced stages and circulating tumour cells. Our results could offer new approaches in the diagnosis and monitoring of colon cancer.

Actins↗