Shedding of the coronary endothelial glycocalyx: effects of hypoxia/reoxygenation vs ischaemia/reperfusion.

BACKGROUND: Vascular endothelium is covered by a glycocalyx. Damage to the glycocalyx after systemic inflammation or ischaemia/reperfusion contributes to increased vascular permeability and leucocyte adhesion. The underlying mechanisms leading to ischaemia/reperfusion-induced glycocalyx shedding are incompletely understood, in terms of lack of oxygen, absence of flow, or return of oxygen. METHODS: Isolated guinea pig hearts perfused with Krebs-Henseleit buffer at 37°C underwent 20 min of either stopped-flow ischaemia or hypoxic perfusion with subsequent reperfusion/reoxygenation (n = 6 each). Hearts perfused with normoxic buffer served as time controls. Epicardial transudate was collected to assess coronary net fluid filtration, colloid extravasation, and histamine release by mast cells. Syndecan-1 and heparan sulphate were measured in coronary effluent, together with lactate, purines, and the release of mast-cell tryptase ß. Additional hearts were perfusion-fixed to visualize the glycocalyx. RESULTS: Both ischaemia and hypoxia with reperfusion/reoxygenation resulted in significant increases in net fluid filtration (P < 0.05) and release of syndecan-1 and heparan sulphate in coronary effluent. These effects were already seen with the onset of hypoxic perfusion. Histamine was released during hypoxia and reoxygenation and also reperfusion, as was tryptase ß, and high concentrations of adenosine (>1 µmol litre⁻¹, hypoxia group) and inosine (> 7 µmol litre⁻¹, ischaemia group) were measured in effluent (P < 0.05). Damage to the coronary glycocalyx was evident upon electron microscopy. CONCLUSIONS: Both ischaemic and hypoxic hypoxia initiate glycocalyx degradation, promoting an increase in permeability. A contributing mechanism could be purine-mediated degranulation of resident mast cells, with liberated tryptase ß acting as potential 'sheddase'.

Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury.

BACKGROUND: Healthy vascular endothelium is coated by the glycocalyx, important in multiple endothelial functions, but destroyed by ischaemia-reperfusion. The impact of volatile anaesthetics on this fragile structure has not been investigated. We evaluated the effect of cardiac pre- and post-conditioning with sevoflurane on integrity of the endothelial glycocalyx in conjunction with coronary vascular function. METHODS: Isolated guinea pig hearts perfused with Krebs-Henseleit buffer underwent 20 min stopped-flow ischaemia (37 degrees C), either without or with 1 MAC sevoflurane. This was applied for 15 min before, for 20 min after, or both before and after ischaemia. Transudate was collected for assessing coronary net fluid extravasation and histamine release by mast cells. Coronary release of syndecan-1 and heparan sulphate was measured. In additional experiments with and without continuous sevoflurane, cathepsin B and tryptase beta-like protease activity were measured in effluent. Hearts were perfusion-fixed to visualize the endothelial glycocalyx. RESULTS: Ischaemia led to a significant (P<0.05) increase by 70% in transudate formation during reperfusion only in hearts without sevoflurane. This was accompanied by significant (P<0.05) increases in heparan sulphate (four-fold) and syndecan release (6.5-fold), with electron microscopy revealing massive degradation of glycocalyx. After ischaemia, histamine was released into transudate, and cathepsin B activity increased in effluent (P<0.05). Sevoflurane application attenuated all these changes, except for histamine release. CONCLUSIONS: Sevoflurane protects the endothelial glycocalyx from ischaemia-reperfusion-induced degradation, with both preconditioning and rapid post-conditioning being successful. The mechanism seems to involve attenuation of lysosomal cathepsin B release and to be independent from tissue mast cell degranulation.

[Methylnaltrexone. A new approach for therapy of opioid-induced obstipation]. / Methylnaltrexon. Ein neuer Ansatz zur Therapie der opioidinduzierten Obstipation.

Chronic pain patients using opioids frequently suffer from constipation which compromises well-being. Such an opioid-induced gastro-intestinal complication can occur regularly in patients in palliative care as well as in analgesic sedated intensive care patients or during prolonged perioperative pain therapy. Discomfort and distress in the affected patients can be so severely pronounced that they would rather suffer from the pain than from the side effect of constipation. Conventional therapy can be insufficient in providing satisfactory relief of constipation, mostly because this opioid-induced bowel hypomotility can be laxative-resistant. Moreover, constipation does not decrease during the course of therapy as do other side effects. It is well known that opioid-induced constipation is mediated via activation of micro-opioid receptors in the gastrointestinal tract. Selective peripheral micro-receptor antagonists (such as methylnaltrexone, Relistor) can effectively treat opioid-induced constipation. An interference with central analgesia does not occur as the molecules cannot pass the blood-brain barrier due to their charged states. A reduction of opioid therapy or the development of withdrawal symptoms can be avoided. Studies have shown that methylnaltrexone is not only safe and efficient for chronically constipated palliative care patients but offers promising therapeutic options for further patient collectives.

[Hypernatremic alkalosis. Possible counterpart of hyperchloremic acidosis in intensive care patients?]. / Hypernatriämische Alkalose. Pendant zur hyperchlorämischen Acidose in der Intensivmedizin?

BACKGROUND: With broad acceptance of Stewart's acid-base model "hyperchloremic acidosis" is regarded as an independent form of metabolic disorder. It is unknown whether hypernatremia plays a corresponding role with respect to the development of alkalosis. METHODS: A total of 201 artificially ventilated, critically ill patients were monitored for hypernatremic episodes. Inclusion criterion was a serum sodium concentration above 145 mmol/l. RESULTS: In 20 patients a total of 78 periods of elevated plasma sodium levels lasting at least 24 h were observed. In 86% of these cases sodium and chloride concentrations were simultaneously increased. The development of alkalosis correlated with the strong ion difference (r=0.80, p<0.01) but not with the serum sodium concentration (r=-0.031, p=0.78). In cases without accompanying hyperchloremia (13%) metabolic alkalosis regularly occurred and a correlation between serum sodium concentration and base excess could be verified (r=0.66, p=0.03). Alkalosis occurred in 84.8% of cases where the strong on difference exceeded 39 mmol/l. CONCLUSION: From the available data hypernatremic alkalosis could not be defined as an independent metabolic disorder. In would seem more appropriate to use the term "strong ion alkalosis" in this context.

Blood volume is normal after pre-operative overnight fasting.

BACKGROUND: Pre-operative fasting is assumed to cause a deficit in intravascular blood volume (BV), as a result of ongoing urine production and insensible perspiration. Standard regimes consist of volume loading prior or simultaneous to any anaesthetic procedure to minimise the risk of hypotension. However, fluid overload in the context of major abdominal surgery has been shown to deteriorate patient outcome. Our study aimed to quantify total intravascular BV after fasting by direct measurements and to compare it with calculated normal values in comparable non-fasted patients. METHODS: After 10 h of fasting, total plasma volume (PV) and red cell volume (RCV) were measured via the double-label technique (indocyanine green dilution and erythrocytes labelled with fluorescein, respectively) following induction of general anaesthesia in 53 gynaecological patients suffering from malignoma of the cervix. The corresponding normal values were calculated individually from age, body height and body weight. RESULTS: Measured BV, RCV and PV after fasting were 4123+/-589, 1244+/-196 and 2879+/-496 ml, respectively. The differences to the corresponding calculated normal values were not significant (3882+/-366, 1474+/-134 and 2413+/-232 ml, respectively). The measured haematocrit reflected a slight anaemic state (0.35+/-0.03). CONCLUSION: Our data suggest that even after prolonged pre-operative fasting, cardio-pulmonary healthy patients remain intravascularly normovolaemic. Therefore, hypotension associated with induction of general or neuraxial anaesthesia should perhaps be treated with moderate doses of vasopressors rather than with undifferentiated volume loading.

Lung injury following thoracic aortic occlusion: comparison of sevoflurane and propofol anaesthesia.

BACKGROUND: Halogenated anaesthetics have been shown to reduce ischaemia-reperfusion injuries in various organs due to pre- and post-conditioning mechanisms. We compared volatile and total intravenous anaesthesia with regard to their effect on remote pulmonary injury after thoracic aortic occlusion and reperfusion. METHODS: Eighteen pigs were randomized after sternotomy and laparotomy (fentanyl-midazolam anaesthesia) to receive either sevoflurane or propofol in an investigator-blinded fashion. Ninety minutes of thoracic aortic occlusion was induced by a balloon catheter. During reperfusion, a goal-directed resuscitation protocol was performed. After 120 min of reperfusion, the anaesthetic regimen was changed to fentanyl-midazolam again for another 180 min. The oxygenation index and intra-pulmonary shunt fractions were calculated. After 5 h of reperfusion, a bronchoalveolar lavage was performed. The total protein content and lactate dehydrogenase activity were measured in epithelial lining fluid (ELF). Alveolar macrophage oxidative burst was analysed. The wet to dry ratio was calculated and tissue injury was graded using a semi-quantitative score. Ten animals (n=5 for each anaesthetic) without aortic occlusion served as time controls. RESULTS: The oxygenation index decreased and the intra-pulmonary shunt fraction increased significantly in both occlusion groups. There were no significant differences between sevoflurane and propofol with respect to the oxygenation index, ELF composition, morphologic lung damage, wet to dry ratio and alveolar macrophage burst activity. Differences were, however, seen in terms of systemic haemodynamic stability, where catecholamine requirements were less pronounced with sevoflurane. CONCLUSION: We conclude that the severity of remote lung injury was not different between sevoflurane and propofol anaesthesia in this porcine model of severe lower-body ischaemia and reperfusion injury.

Impact of the time window on plasma volume measurement with indocyanine green.

Recent reports have questioned the accuracy of the indocyanine green dilution technique for measuring plasma volume. Our objective was to evaluate the impact of different time windows for monoexponential extrapolation. We retrospectively analysed 31 indocyanine green decay curves to investigate the problem in principle (group 1) and prospectively performed another 21 plasma volume measurements to estimate its practical impact (group 2). To monoexponentially extrapolate back to the specific extinction at the time of dye injection, two different time windows were applied to each decay curve, comparing the plasma volumes resulting from sampling within a short (5 min) period of time. Extrapolating back from the longer period led to a higher apparent plasma volume relative to the shorter period in both groups, the difference being 348 +/- 171 ml (group 1) and 384 +/- 131 ml (group 2; mean +/- SD; p < 0.05 each). This result was due to a reliable monoexponentiality of decay only up to the 5th min after dye injection. Thus, to estimate the initial distribution space of indocyanine green via monoexponential extrapolation, the first linear kinetic of indocyanine green decay should be taken.

[Expedition glycocalyx. A newly discovered "Great Barrier Reef"]. / Expedition Glykokalyx. Ein neu entdecktes "Great Barrier Reef."

Healthy vascular endothelium is luminally coated by an endothelial glycocalyx, which interacts with the bloodstream and assumes a filter function on the vascular wall. Although this structure was discovered nearly 70 years ago, its physiological importance has been underestimated for a long time. Recent findings indicate that the glycocalyx is, in addition to the endothelial cells themselves, a main constituent part of the vascular barrier. The existence of different colloid osmotic gradients within and beneath this structure has now led to a modification of the Starling equation. In many vascular beds the interstitial space features a protein concentration similar to that of the plasma. The inwardly directed gradient, which retains water and proteins in the vascular system, is generated beneath the glycocalyx by selective protein filtration over this structure. The endothelial glycocalyx, as an additional competent vascular permeability barrier has, therefore, not only a key role for perioperative fluid and protein shifts into the interstitial space, but it seems to be intimately involved in the pathophysiology of diabetes, arteriosclerosis, sepsis and ischemia/reperfusion, especially with respect to associated vascular dysfunctions. The fragile glycocalyx can be destroyed in the course of surgery, trauma, ischemia/reperfusion and sepsis and by inflammatory mediators such as TNF-alpha, causing leukocyte adhesion, platelet aggregation and edema formation. Recent studies have shown that protecting this structure not only maintains the vascular barrier, but constitutes an important component of a rational perioperative fluid therapy.

Application of the Bogossian formula for evaluation of the QT interval in pacemaker patients with stimulated left bundle branch block.

BACKGROUND: The presence of left bundle branch block (LBBB) represents a particular challenge in properly measuring the QT interval. Here we demonstrate the applicability of the "Bogossian formula" in pacemaker patients with LBBB due to apical or nonapical right ventricular (RV) pacing and preserved left ventricular function. METHODS: A total of 163 patients with a cardiac one- or two-chamber pacemaker were included in this prospective, multicentre observational study. Twelve-lead ECG recordings were obtained during both intrinsic rhythm and RV pacing with induced LBBB. The QT interval measured during LBBB was corrected using the Bogossian formula to obtain the "modified QT" (QTm). The QTmc interval was calculated with the Bazett formula, and this was compared with the QTc interval during intrinsic rhythm. RESULTS: Eighty-three patients (78 ± 9 years; male n = 83) with apical and eighty patients (71 ± 13 years; male n = 80) with non-apical RV pacing were included in this study. In the apical group the QTmc was determined to be 444 ± 39 ms in paced rhythm and the QTc interval 413 ± 36 ms in intrinsic rhythm. In the non-apical group these values were 430 ± 34 ms in paced and 416 ± 32 ms in intrinsic rhythm. CONCLUSION: The Bogossian formula is a reliable tool for QTc interval evaluation in pacemaker patients with LBBB due to apical or non-apical RV pacing. However, an overestimation of 30 ms should be included in the calculation.

No effect of the cyclooxygenase-2 inhibitor etoricoxib on pre-emptive and post-operative analgesia in visceral surgery: results of a randomized controlled trial.

BACKGROUND: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 × 2 factorial trial design. METHODS: According to the 2 × 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection. RESULTS: Eighty-six patients (female n = 42; mean age 53.82 ± 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre-emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups. CONCLUSIONS: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery.

Left ventricular surface tissue oxygen pressures determined by oxygen sensitive multiwire electrodes in pigs.

STUDY OBJECTIVE: Polarographic oxygen sensitive electrodes can be used to measure tissue oxygen pressures on the surface of the beating heart. The purpose of the study was to clarify the significance of these PO2 determinations. DESIGN: Changes in left ventricular surface oxygen pressures, subendocardial or subepicardial wall functions (ultrasonic dimension technique), and blood flow (radioactive microsphere technique) were correlated during different degrees of acute coronary artery stenoses in pigs. EXPERIMENTAL MATERIAL: 19 anaesthetised open chest pigs, 28-40 kg body weight, were studied during different degrees of constriction of the left anterior descending artery which did not influence overall left ventricular function or irreversibly damage the myocardium. MEASUREMENTS AND MAIN RESULTS: Highly significant (p less than 0.001) correlations (each % delta) were obtained for surface tissue oxygen pressures (y) with subepicardial (y = 0.002 e 0.10x; r = 0.89) and subendocardial (y = 1.44 e 0.04x; r = 0.98) blood flow values, as well as with subendocardial function (y = 82.4 + 0.22x; r = 0.89); a significant correlation was also obtained for subendocardial function (y) with subendocardial blood flow (y = 66.0 + 0.28x; r = 0.69). However, no significant correlation was obtained for polarographic tissue PO2 with subepicardial segment function, indicating that regional function was maintained when tissue PO2 recordings were not much above 0 kPa and when blood flow was reduced by 25 to 30%. CONCLUSIONS: Oxygen pressures of the superficial layers of the left ventricle are relatively high at normal values of oxygen consumption but decrease rapidly if blood supply is reduced. Regional wall function is preserved at low oxygen pressures. Polarographic surface PO2 electrodes hence can be used to study influences of experimental interventions on oxygenation of the normally perfused and of the moderately ischaemic myocardium.

Myocardial surface PO2--an indicator of myocardial tissue oxygenation?

The validity of myocardial surface tissue PO2 (PtO2) as a reliable indicator of transmural myocardial tissue oxygenation was studied in six anaesthetised, open chest pigs. Epicardial surface PtO2 was correlated with other variables of myocardial tissue oxygenation such as regional blood flow, coronary venous PO2, O2 saturation, PCO2 and regional myocardial lactate extraction. The study design was based on an experimental model in which the effects of a pacing induced tachycardia on tissue oxygenation of ischaemic and normally supplied myocardium were measured. Two platinum multiwire surface electrodes were placed on the epicardium, on the areas supplied by the left anterior descending coronary artery (LAD) and the left circumflex coronary artery (CX). The LAD was constricted to reduce mean surface PtO2 in the LAD area to about 50% of its baseline value. This did not affect surface PtO2 in the CX area. The reduction of surface PtO2 in the LAD area was associated with decreases in coronary venous PO2 and O2 saturation and with increases in coronary venous lactate and PCO2. Subendocardial regional blood flow and the subendocardial to subepicardial flow ratio were significantly lower than in the CX area. Increasing the heart rate by pacing (+45 beats.min-1) led to an increased degree of ischaemia as shown by fall in surface PtO2 in the LAD area to values around zero kPa, by marked increase in coronary venous lactate and PCO2, by reduction in total (-10%) and subendocardial (-40%) LAD flow and by deterioration of the subendocardial to subepicardial flow ratio. The increased degree of ischaemia was not accompanied by an increase in O2 extraction. The marked decrease in surface PtO2 occurred in spite of a slight increase in the subepicardial regional blood flow (+10%); thus the increase in O2 delivery was not sufficient to meet the increase in O2 demand. Total flow was increased by 27% in the CX area without changes in the subendocardial to subepicardial flow ratio and in the surface PtO2 values. When pacing was stopped, surface values of PtO2 in the LAD area returned to prepacing values, as did lactate extraction and coronary venous PCO2. Clear and close relationships with surface PtO2 were found for regional lactate extraction, coronary venous PCO2 and the normalised subendocardial RBF. Poor or no correlations were found for the normalised subepicardial regional blood flow, the coronary venous O2 saturation and the absolute values of subendocardial and subepicardial regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhancement of the leukocyte-endothelial cell interaction in collecting venules of skeletal muscle by protamine.

OBJECTIVE: A transient but severe systemic leukopenia regularly occurs after the antagonization of heparin by protamine in patients and in animals. The aim of the present study was to investigate the site and mechanisms of white blood cell retention during this transient leukopenia by studying the leukocyte-endothelial cell interaction in skeletal muscle venules. METHODS: Syrian golden hamsters were equipped with a dorsal skinfold chamber for intravital fluorescence microscopy and arterial and venous catheters for drug infusion, blood pressure measurement, and blood sampling. Microhemodynamic parameters and leukocyte-endothelial cell interactions were observed in one single collecting venule per animal after intravenous infusion of saline solution (control, n = 10), of protamine (n = 9), and after infusion of heparin followed by either intravenous protamine (n = 9) or intraarterial protamine (n = 9). RESULTS: All parameters remained unchanged in the control group. Whereas venular diameters remained unchanged, protamine transiently increased arterial blood pressure and venular erythrocyte velocity in all groups. Systemic leukocyte counts and the venular leukocyte discharge concentration decreased concurrently after protamine administration by about 60% to 70% at 2 minutes while the fraction of rolling leukocytes and the number of adherent leukocytes remained unchanged. Two and one-half minutes later, systemic leukocyte counts and venular discharge concentrations normalized while the fraction of leukocytes rolling slowly along or adhering firmly to the venular endothelial wall increased considerably and similarly in all groups receiving protamine. Myeloperoxidase (an indicator of polymorphonuclear leukocytes) determination in 20 separate hamsters 2 minutes after protamine infusion revealed increased myeloperoxidase activity exclusively in the lungs. CONCLUSION: The response of leukocytes to protamine infusion with or without prior heparinization is biphasic: initial retention of leukocytes in the lungs is followed by enhanced leukocyte-endothelial cell interaction in the systemic circulation.

Heparin-protamine reactions in pigs: role of oxygen-derived free radicals.

We tested the hypothesis that pulmonary hypertension and thromboxane A2 release after heparin neutralization by protamine are mediated by oxygen free radicals. Forty-five pigs in five groups were studied during general anesthesia. Group I animals received 250 IU heparin followed by 100 mg protamine after 15 min. Group II and group III animals received dimethyl sulfoxide (DMSO) and dimethylthiourea (DMTU) 30 min before heparin infusion. Group IV animals were given superoxide dismutase (SOD) 5 min before protamine. Group V served for testing the pulmonary vascular reactivity in DMTU-treated animals to a thromboxane A2 analogue (U-46619). Generation of oxygen free radicals by polymorphonuclear granulocytes (PMNs) was measured in vitro by chemiluminescence. Severe pulmonary hypertension and thromboxane A2 release after protamine were not prevented by either DMSO or SOD. DMTU reduced pulmonary vasoconstriction to U-46619 and protamine but not to TxA2 release, indicating that DMTU had unspecific vascular effects in group III. Heparin-protamine released no oxygen free radicals from isolated PMNs. The results indicate that oxygen free radicals do not have a key role in mediating pulmonary vasoconstriction after protamine neutralization of heparin.

Effect of leukopenia on pulmonary hypertension after heparin-protamine in pigs.

Heparin neutralization by protamine after cardiac surgery and cardiopulmonary bypass may be associated with complement activation, transient leukopenia, thromboxane A2 release, and severe pulmonary hypertension. The role of leukocytes in the heparin-protamine reaction was studied in leukopenic pigs (n = 9) and a control group (n = 8). Leukopenia was induced by pretreatment with cyclophosphamide (30 mg.kg-1.day-1) for 6-7 days. During general anesthesia and after catheterization, baseline recordings of hemodynamics were performed and blood samples were withdrawn. Heparin (250 IU/kg) was injected and measurements were repeated after 10 min. Protamine sulfate (100 mg) was then infused over 2 min and measurements were performed after 2, 5, and 15 min. Prostanoid concentrations were measured by radioimmunoassays. In additional in vitro experiments, the release of thromboxane B2 from washed platelets and leukocytes after heparin-protamine stimulation was measured. Pretreatment with cyclophosphamide reduced leukocyte counts by 95.5% and the number of neutrophils by greater than 99.9%. Protamine infusion increased mean pulmonary arterial pressure by 74 and 46% and pulmonary vascular resistance by 185 and 384% in control and leukopenic animals, respectively. Thromboxane B2 concentrations increased in both groups. Stimulation by heparin, protamine, or heparin and protamine in sequence did not induce any thromboxane A2 release from washed blood cells. It is concluded that leukocytes do not contribute to pulmonary hypertension after heparin-protamine.

Heterogeneous microvascular coronary vasodilation by adenosine and nitroglycerin in dogs.

We investigated the effects of adenosine and nitroglycerin (NTG) on coronary microvessel diameters (intravital fluorescence microscopy) and coronary perfusion (radioactive microspheres). Measurements were performed during baseline conditions (intravenous piritramid) and during controlled hypotension (mean arterial pressure approximately 60 mmHg) induced by halothane, adenosine, and NTG. Coronary vascular resistance (CVR) remained unchanged during halothane (-7%) but decreased during adenosine (-76%) and NTG (-29%). Coronary arteriolar diameters increased during all experimental steps. In the smallest vessels (20-40 microns), diameters increased by 14, 43, and 42% during halothane-, adenosine-, and NTG-induced hypotension, respectively. Diameter increases were less pronounced in larger vessels. The uniform action of adenosine and NTG in 20- to 500-microns arterial vessels is in contrast to the pronounced differences in reduction of CVR. Preferential dilation of arterioles < 20 microns or recruitment of coronary microvessels by adenosine might account for the more pronounced decrease of CVR during adenosine. Intracoronary application of adenosine (0.8 mg.kg-1.h-1) and NTG (1, 5, and 25 micrograms.kg-1.h-1) equally caused near-maximum dilation of coronary arterioles > 100 microns. However, NTG dilation of arterioles < 100 microns was dose dependent and exceeded large-vessel dilation only with the highest concentration of NTG.

Heparin reversal by protamine in humans--complement, prostaglandins, blood cells, and hemodynamics.

Fourteen noncardiac surgical patients received heparin (10,000 IU), which was neutralized by 100 mg protamine injected within 2 min during steady-state anesthesia. After protamine application, plasma complement C3a, thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha) and KH2PGF2 alpha increased significantly, whereas prostacyclin (6-keto-PGF2 alpha) levels did not change. This mediator response was associated with transient leukopenia and thrombocytopenia. Arterial pressure, pulmonary arterial pressure, and transpulmonary pressure gradient increased significantly. Heart rate, cardiac output, pulmonary capillary wedge pressure, and arterial PO2 remained constant. Positive correlations of plasma C3a were observed with pulmonary leukosequestration and plasma TxB2. Inverse correlations of C3a were noted with the counts of leukocytes and of platelets. A positive correlation was found between TxB2 and pulmonary arterial pressure. Our results indicate that marked activation of the complement system and the cyclooxygenase pathway is common after heparin reversal by protamine in anesthetized patients. This is in contrast to previous human studies performed after cardiopulmonary bypass but agrees well with results obtained in animal experiments. The mediator response in our patients, however, was not accompanied by hemodynamic instability, suggesting appropriate compensatory mechanisms.

Biological effects of shock waves: induction of arrhythmia in piglet hearts.

During lithotripsy by electrohydraulic or electromagnetic lithotripters, the application of extracorporeal shock waves has to be synchronized with the electrocardiogram to reduce the induction of arrhythmias. The relation between the refractory period of the cardiac cycle and arrhythmia induction by shock waves, and the underlying mechanism have so far not been examined. In this experiment, the cardiac response to shock waves administered at 20 kV by an electrohydraulic lithotripter was assessed in nine piglets. The focus was positioned 5, 10 and 15 cm caudal to the apex of the left ventricle, and in some piglets also at the apex. The interval following the R-wave was determined during which the heart was refractory to shock wave stimulation by either single discharges or shock-wave bursts, i.e., groups of discharges separated by 10 ms intervals. This mechanical refractory period was compared to its electrical counterpart, which was determined by transvenous intracardiac atrial stimulation. As a result, mechanical refractory periods following the R-wave were at 5 cm distance 60 ms for single discharges and 70 ms for bursts (medians; range 10-180 ms); both stimulation modes were highly correlated (r = 0.88). While a similar result was obtained with the focus positioned directly at the cardiac apex, at 10 cm distance from it, bursts elicited a cardiac response significantly more often (in nine vs. two piglets). At 15 cm distance, no response was obtained at all. Both mechanical and electrical atrial refractory periods were in a similar range.(ABSTRACT TRUNCATED AT 250 WORDS)