Biomedical subjects

M Kleen

Publications and source records attributed to M Kleen.

48 records · Page 3Linked to original sources

PubMed1996

Inhalation of prostacyclin (PGI2) for 8 hours does not produce signs of acute pulmonary toxicity in healthy lambs.

OBJECTIVE: To study the potential side effects and toxicity of inhaling prostacyclin (PGI2) aerosol for 8 h. DESIGN: In a prospective, randomized study 14 healthy lambs received either PGI2 (n = 7) or 0.9% NaCl (n = 7) as an aerosol for 8 h. SETTING: Institute for Surgical Research of the Ludwig-Maximilians-University of Munich. INTERVENTIONS: All animals were studied under general anesthesia in a prone position. They were first intubated endotracheally and later tracheotomized. PGI2 solution (median dose 28 ng/kg per min) or 0.9% NaCl was administered with a jet nebulizer (delivery rate 4-10 ml/h; mass median diameter of aerosol particles 3.1 microns). Bronchoalveolar lavage was performed before and after the inhalation period to collect epithelial lining fluid of alveoli. MEASUREMENTS AND RESULTS: Hemodynamic and respiratory parameters, systemic resorption (plasma levels of 6-keto-prostaglandin-F 1 alpha), in vitro bleeding time, collagen-induced platelet aggregation and global biochemical and cellular composition of the epithelial lining fluid were examined in order to assess the side effects and signs of acute pulmonary toxicity induced by inhaled PGI2. No statistically significant differences were found between the PGI2 and the control groups for any of the parameters examined. CONCLUSION: Inhalation of PGI2 (28 ng/kg per min) over a period of 8 h in healthy lambs does not produce major side effects or acute pulmonary toxicity.

Acute Disease↗

PubMed1996

Hypovolemic shock and cardiac contractility: assessment by end-systolic pressure-volume relations.

The end-systolic pressure-volume relation (ESPVR) is accepted as a load-independent measure of cardiac contractility. Potential curvilinearity of the ESPVR, dependency on coronary perfusion pressure (CPP) and sensitivity to the type of loading intervention might limit its use in hemorrhagic shock. This study compared ESPVRs obtained by caval and aortic occlusion under physiological loading conditions at baseline with those obtained during hemorrhagic shock (mean arterial pressure 45 mmHg). The left ventricular (LV) pressure (tip manometer) and volume (conductance catheter) were measured in ten anesthetized pigs. ESPVRs were fitted to linear and quadratic models. Within end-systolic pressure (Pes) ranges obtained under baseline conditions, ESPVR displayed only minimal curvilinearity (second-order coefficient a < 0.007) and could be accurately described by a linear model. However, nonlinearity of ESPVRs obtained over wider load ranges is suggested by negative volume axis intercepts of the linear model. Steeper ESPVR with aortic than with caval occlusion (2.28 +/- 0.22 vs 3.41 +/- 0.51 mmHg/ml, ns) could not be proven owing to the large interindividual variance of ESPVR slopes with both loading interventions. During shock the Pes range obtained by caval occlusion decreased to very low levels (from 49 +/- 2 to 34 +/- 1 mmHg), ESPVR did not adequately fit either of the two models (mean R < 0.66), and critical reduction of CPP induced negative ESPVR slope in four of ten experiments. In contrast, aortic occlusion at shock resulted in linear ESPVR (R = 0.927 +/- 0.029), Pes ranges (92 +/- 3 to 58 +/- 4 mmHg) comparable to the ones obtained by caval occlusion at control (113 +/- 5 to 73 +/- 6 mmHg), and steeper ESPVR than at control (3.41 +/- 0.51 to 7.38 +/- 1.0 mmHg/ml, P < 0.05). Interpretation of the increased ESPVR slope obtained with aortic occlusion as due to increased contractility in shock is, however, complicated by different Pes ranges. It is concluded that within Pes ranges obtained with caval or aortic occlusion in situ the ESPVR can be adequately fitted to a linear model. For assessment of the inotropic response to shock the ESPVR is of limited value because (1) caval occlusion is not suitable to generate ESPVR during shock, and (2) Pes ranges obtained with identical loading interventions differ greatly between baseline and shock and, therefore, apparent ESPVR changes are influenced by the potential nonlinearity of the ESPVR. Combining caval occlusion at baseline with aortic occlusion at shock would result in comparable Pes ranges. Interpretation of results is, however, complicated by diverging effects of the different loading interventions on the shape and slope of the ESPVR.

Animals↗

PubMed1996

Effects of hemodilution on gastric regional perfusion and intramucosal pH.

UNLABELLED: Acute normovolemic hemodilution (ANH) has been shown to be a cost-effective method of reducing allogenic blood transfusion during elective surgery. ANH has been implicated with impaired oxygenation in isolated canine gastric flaps. The present study was designed to investigate the effects of ANH on gastric mucosal oxygenation using a model closely imitating the clinical situation. Sixteen splenectomized anesthetized beagles were isovolemically hemodiluted to a hematocrit of 20 +/- 1% (6% hydroxyethyl starch; mol wt 200,000; substitution ratio 0.45-0.55). Blood volume (indocyanine green), cardiorespiratory parameters, gastric intramucosal pH (pHi), and gastric regional blood flow (radioactive microspheres; 15 microns) were measured before and after ANH. RESULTS: blood volume was unchanged (87 +/- 8 ml/kg before and 88 +/- 7 ml/kg after ANH). Median total gastric mucosal blood flow at baseline was 0.51 +/- 0.35 ml.min-1.g-1 and did not change significantly upon ANH. The mean pHi was 7.29 +/- 0.05 before and 7.28 +/- 0.05 after hemodilution. There was a homogenization of blood flow distribution in gastric mucosa. Severe hemodilution to a hematocrit of 20% does not impair gastric mucosal oxygenation and poses no risk to gastric mucosal integrity.

Animals↗

PubMed1996

Determination of regional pulmonary blood flow with systemically injected nonentrapped microspheres.

Radioactive microspheres (MS) injected into the systemic circulation shunt to the venous side of the circulation and are trapped in the lung vasculature. We hypothesized that regional pulmonary perfusion could be determined by using systemically injected shunted MS. In seven anesthetized mechanically ventilated foxhounds, regional pulmonary perfusion was measured at baseline and during experimental acute respiratory distress syndrome with MS injected into both the right and left atrium (protocol 1). Methodological error of the MS technique was assessed by simultaneous injection of two different batches of MS into the right atrium (protocol 2). Measurement of perfusion during baseline and during experimental acute respiratory distress syndrome with shunted MS had a mean bias of 0.8 and 5.6% and mean precision of 19.2 and 34.7% (r = 0.94 and r = 0.95), respectively, compared with data from nonshunted MS. Simultaneous perfusion measurements displayed bias of -2.7 and 6% and precision of 8.2 and 5.3% (r = 0.98 and r = 0.99), respectively. Systemic shunt should be high for this method to prevent bronchial circulation from imposing significant error. We conclude that systemically injected MS can be used for simultaneous measurement of regional systemic and regional pulmonary perfusion, provided that MS that shunted in the first pass are measured in lung tissue.

Animals↗

PubMed1996

Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome.

Inhalation of nitric oxide (NO) and prostacyclin (PGI2) may induce selective pulmonary vasodilation and-by improving ventilation-perfusion ratio in ventilated areas of the lung-increase Pao2 in patients with acute lung injury. To assess the therapeutic efficacy of both compounds, dose-response curves were established in patients with adult respiratory distress syndrome (ARDS). Patients received both PGI2 (doses of 1, 10, and 25 ng/kg/min) and NO (concentrations of 1, 4, and 8 ppm). Cardiorespiratory parameters were assessed at control, at each drug concentration, and after withdrawal of NO and PGI2. PGI2 resulted in a significant, dose-dependent and selective reduction of pulmonary artery pressure (PAP) from 35.1 +/- 6.3 mm Hg at control to 33.1 +/- 4.8 (1 ng/kg/min), 31.3 +/- 4.8 mm Hg (10 ng/kg/min) and 29.6 +/- 4.5 mm Hg (25 ng/kg/min), respectively. Inhaled NO reduced PAP from 34.5 +/- 5.6 to 32.1 +/- 5.9 mm Hg at 4 ppm, and to 31.8 +/- 6.1 mm Hg at 8 ppm, respectively, with no effect at 1 ppm. Pao2/Flo2 ratio increased from 105 +/- 37 to 125 +/- 56 mm Hg (range of increase: 0 to 57 mm Hg) at PGI2 10 ng/kg/min and to 131 +/- 63 mm Hg (range: -5 to 89 mm Hg) at 25 ng/kg/min with no effect at 1 ng/kg/min. NO improved Pao2 (e.g., from 116 +/- 47 to 167 +/- 86 mm Hg at 8 ppm) and reduced intrapulmonary shunt at all doses tested. We conclude that both inhaled PGI2 and NO may induce selective pulmonary vasodilation and increase Pao2 in severe ARDS.

APACHE↗

PubMed1995

Inhaled sodium nitroprusside. Non-selective reduction of thromboxane analogue-induced pulmonary vasoconstriction in healthy sheep.

Both inhaled nitric oxide (NO) and inhaled prostacyclin have been shown to selectively decrease pulmonary hypertension of various origin. The aim of the present study was to assess the potential of the NO donor sodium nitroprusside (SNP) to elicit selective pulmonary vasodilation. SNP spontaneously liberates nitric oxide in the presence of reducing substances like cysteine or glutathione, ubiquitous in many different tissues. Inhaled as an aerosol in 3 healthy lambs presenting pulmonary hypertension induced by infusion of a thromboxane analogue, low concentrations of SNP (0.02-0.6 mg/ml) revealed no effect at all. In contrast, high concentrations of SNP (1.0-20.0 mg/ml) lowered pulmonary artery pressure in conjunction with systemic arterial hypotension, suggesting systemic resorption of SNP with subsequent release of its nitroso-group. Selective pulmonary vasodilation was never observed. In conclusion, the present results do not support a selective effect of inhaled SNP in the pulmonary circulation.

Administration, Inhalation↗

PubMed1995

Effects of inhaled prostacyclin as compared with inhaled nitric oxide in a canine model of pulmonary microembolism and oleic acid edema.

OBJECTIVE: Recently, it has been shown that the inhalation of nitric oxide (NO) and of prostacyclin (PGI2) elicits selective pulmonary vasodilation in a canine model of pulmonary hypertension induced by hypoxic pulmonary vasoconstriction. The present study was designed to investigate whether inhaled NO or PGI2-aerosol, respectively, is also effective in decreasing pulmonary artery pressure in a canine model of acute pulmonary microembolism and oleic acid edema. DESIGN: Prospective, randomized, cross-over design. SETTING: University animal research laboratory. PARTICIPANTS: Eight anesthetized, mechanically ventilated dogs (28 +/- 1 kg). INTERVENTIONS: Acute pulmonary microembolization (PME) was induced using glass microbeads (mean diameter: 100 microns) and 0.01 mL/kg of oleic acid. Subsequently, inhaled PGI2 (concentration: 10 micrograms/mL) or NO (50 ppm), respectively, was randomly administered for 15 minutes each and then withdrawn. MEASUREMENTS AND MAIN RESULTS: Central hemodynamics (heart rate [HR], cardiac output [CO], stroke volume [SV], mean arterial pressure [MAP], systemic vascular resistance [SVR], mean pulmonary artery pressure [PAP], pulmonary vascular resistance [PVR]) and gas exchange (PaO2/FIO2 ratio, intrapulmonary shunt [Qs/Qt], alveolar-arterial oxygen difference, [AaDO2]) were assessed. Measurements were performed at control, after PME, and during administration of PGI2 and NO, respectively. PME induced a significant increase (p < 0.001) of MAP (+9%), PAP (+68%), and PVR (+163%), whereas HR, CO, and SV remained unchanged and lung function deteriorated. Inhalation of NO slightly decreased PAP (-10%; p < 0.05) and PVR (-26%; p < 0.01) and improved AaDO2 and PaO2/FIO2. In contrast, inhalation of PGI2 had no consistent effect on pulmonary vascular tone or gas exchange. CONCLUSION: The data demonstrate that inhaled NO may elicit selective pulmonary vasodilation and improve gas exchange in a canine model of pulmonary microembolism and respiratory insufficiency. However, the degree of these effects was relatively small. The aerosolization of PGI2 under conditions of positive-pressure ventilation did not exert a significant vasodilatory effect on pulmonary vessels and did not improve pulmonary gas exchange in this model.

Administration, Inhalation↗

PubMed1995

Prostacyclin aerosol and inhaled nitric oxide fail to reverse pulmonary vasoconstriction induced by thromboxane analogue in dogs.

Inhalation of either prostacyclin (PGI2) as an aerosol or nitric oxide (NO) has been shown to elicit selective pulmonary vasodilation during hypoxic pulmonary vasoconstriction in dogs. Hypoxia may produce cardiovascular changes confounding interpretation of drug effects. Therefore, we investigated the effects of PGI2-aerosol and inhaled NO (50 p.p.m.) on pulmonary pressure-flow relationships (P/Q plots) during thromboxane analogue (U46619) induced pulmonary vasoconstriction. In eight anaesthetized dogs infusion of U46619 (0.33 +/- 0.18 micrograms kg-1 min-1) increased the slope (3.5 +/- 1.1 to 8.4 +/- 1.7 mmHg L-1 min-1, P < 0.001) and the intercept (4.4 +/- 2.3 to 10.2 +/- 4.6 mmHg, P < 0.01) of P/Q plots indicating pulmonary vasoconstriction. Inhalation of both aerosolized PGI2 solution (10 micrograms mL-1) and NO (50 p.p.m.) reduced neither the slope nor the intercept of the P/Q plots. Increasing the concentration of the aerosolized PGI2 solution to 50 micrograms mL-1 (n = 3) did not enhance the effect on pulmonary circulation but systemic vascular resistance fell by 23%. Oxygenation and intrapulmonary shunt remained unchanged during both PGI2-aerosol and inhaled NO. The failure of PGI2-aerosol to induce pulmonary vasodilation indicates that during aerosolization PGI2-concentrations at receptor sites on pulmonary vessels were insufficient to surmount U46619 induced vasoconstriction; this notion is supported by unchanged arterial plasma concentrations of the PGI2 degradation product 6-keto-PGF1 alpha. Considering that NO inhaled at comparable concentrations in sheep reversed U46619 induced pulmonary vasoconstriction, species differences may account for the failure of both PGI2-aerosol and NO to dilate pulmonary vessels in dogs.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMedDate not supplied

Hyperoxia in extreme hemodilution.

Intraoperative surgical blood loss is initially replaced by infusion of red cell-free, cristalloidal or colloidal solutions. When normovolemia is maintained the ensuing dilutional anemia is compensated by an increase of cardiac output and of arterial oxygen extraction. In the ideal case, a surgical blood loss can entirely be 'bridged' without transfusion by intraoperative normovolemic hemodilution. However major blood loss results in extreme hemodilution and the transfusion of red blood cells may finally become necessary to increase arterial oxygen content and to preserve tissue oxygenation. When transfusion has to be started before surgical control of bleeding has been achieved, parts of the red blood cells transfused will get lost, thereby increasing intraoperative transfusion needs. Beside red blood cell transfusion, arterial oxygen content can be rapidly increased by ventilating the patient with 100% oxygen (hyperoxic ventilation), thus enhancing the amount of physically dissolved oxygen in plasma (hyperoxia). In experimental and clinical studies hyperoxic ventilation has emerged as a simple, safe and effective intervention to enlarge the margin of safety for hemodynamic compensation and tissue oxygenation in hemodiluted subjects experiencing major bleeding. The hyperoxia-associated microcirculatory dysregulation and impaired tissue oxygenation known to take place in the presence of a physiologic hemoglobin concentration are not encountered in hemodiluted subjects. Hyperoxic hemodilution i.e. the combination of intraoperative extreme hemodilution and hyperoxic ventilation may therefore be considered a cost-effective, safe and efficient supplement to reduce allogeneic transfusion during surgical interventions associated with high blood losses. The vast majority of the experimental and clinical investigations this new concept is based on was initiated and performed under the guidance of Prof. Konrad Messmer.

Blood Loss, Surgical↗

PubMedDate not supplied

Searching the ideal inhaled vasodilator: from nitric oxide to prostacyclin.

Today, the technique to directly administer vasodilators via the airway to treat pulmonary hypertension and to improve pulmonary gas exchange is widely accepted among clinicians. The flood of scientific work focussing on this new therapeutic concept had been initiated by a fundamental new observation by Pepke-Zaba [1]and Frostell in 1991 [2]: Both scientists reported, that inhalation of exogenous nitric oxide (NO) gas selectively dilates pulmonary vessels without a concomittant systemic vasodilation. No more than another decade ago NO was identified as an important endogenous vasodilator [3]while having merely been regarded an environmental pollutant before that time. Although inhaled NO proved to be efficacious, alternatives were sought-after due to NO's potential side-effects. In search for the ideal inhaled vasodilator another group of endogenous mediators -- the prostanoids -- came into the focus of interest. The evidence for safety and efficacy of inhaled prostanoids is -- among a lot of other valuable work -- based on a series of experimental and clinical investigations that have been performed or designed at the Institute for Surgical Research under the guidance and mentorship of Prof. Dr. med. Dr. h.c. mult. K. Messmer [4-19]. In the following, the current and newly emerging clinical applications of inhaled prostanoids and the experimental data which they are based on, will be reviewed.

Administration, Inhalation↗

PubMedDate not supplied

Diaspirin cross-linked hemoglobin fails to improve left ventricular diastolic function after fluid resuscitation from hemorrhagic shock.

In severe hemorrhagic shock, left ventricular (LV) diastolic dysfunction is an early sign of cardiac failure due to compromised myocardial oxygenation. Immediate fluid replacement or, in particular, administration of a hemoglobin-based oxygen carrier (diaspirin cross-linked hemoglobin; DCLHb) improves myocardial oxygenation; therefore, positive effects on LV diastolic function could be expected. The effects of fluid resuscitation from severe hemorrhagic shock with DCLHb were investigated in 20 anesthetized domestic pigs. After generation of a critical left anterior descending coronary artery stenosis (narrowing of the artery until disappearance of reactive hyperemia after a 10-second complete vessel occlusion), hemorrhagic shock (mean arterial blood pressure 45 mm Hg) was induced within 15 min by controlled blood withdrawal and maintained for 60 min. Fluid resuscitation consisted of replacement of the plasma volume withdrawn during hemorrhage by infusion of either 10% DCLHb (DCLHb group, n = 10) or 8% human serum albumin (HSA) oncotically matched to DCLHb (HSA group, n = 10). After completion of resuscitation, an observation period of 60 min elapsed. Measurements of central hemodynamics, myocardial oxygenation, and LV diastolic function were performed at baseline, after induction of critical coronary artery stenosis, after 60 min of hemorrhagic shock, immediately after resuscitation, and 60 min later. While 5 out of 10 animals treated with HSA died within the first 20 min after fluid resuscitation from acute LV pump failure, all DCLHb-treated animals survived until the end of the protocol (p < 0.05). Despite superior myocardial oxygenation due to augmentation of the arterial O(2) content as well as of coronary perfusion pressure, no beneficial effects on LV diastolic function were observed after infusion of DCLHb. Peak velocity of LV pressure decrease (dp/dt(min)) did not reveal significant differences between the two groups. Immediately after completion of fluid resuscitation with DCLHb, the time constant of LV diastolic relaxation (tau) was prolonged when compared with HSA-treated animals (p < 0.05), indicating retardation of early LV diastolic relaxation. Our data suggest that DCLHb fails to improve LV diastolic function after fluid resuscitation from severe hemorrhagic shock. However, positive effects on myocardial perfusion and oxygenation result in a significant reduction of the mortality of severe hemorrhagic shock.

Animals↗

PubMedDate not supplied

Comparison of regional blood flow values measured by radioactive and fluorescent microspheres.

Fluorescent microspheres (FM) have become an attractive alternative to radioactive microspheres (RM) for the measurement of regional blood flow (RBF). The aim of the present study was to investigate the comparability of both methods by measuring RBF with FM and RM. Eight anaesthetised pigs received simultaneous, left atrial injections of FM and RM with a diameter of 15 microm at six different time points. Blood reference samples were collected from the descending aorta. RBF was determined in tissue samples of the myocardium, spleen and kidneys of all 8 animals. After radioactivity of the tissue samples was determined, the samples were processed automatically for measuring fluorescence using a recently developed filter device (SPU). RBF was calculated with both the isotope and spectrometric data of both methods for each sample resulting in a total of 10,512 blood flow values. The comparison of the RBF values yielded high linear correlation (mean r(2) = 0.95 +/- 0.03 to 0.97 +/- 0.02) and excellent agreement (bias 5.4-6.7%, precision 9.9- 16.5%) of both methods. Our results indicate the validity of MS and of the automated tissue processing technique by means of the SPU.

Animals↗