Development of acute tolerance to the EEG effect of propofol in rats.

BACKGROUND: A previous study in rats with propofol suggested the development of acute tolerance to the EEG effect. The aim of this study was to evaluate acute tolerance by means of EEG-controlled closed-loop anaesthesia as this approach allows precise determination of drug requirement to maintain a defined drug effect. METHODS: Ten male Sprague-Dawley rats [weight 402 (40) g, mean (SD)] were included in the study. The EEG was recorded with occipito-occipital needle electrodes and a modified median frequency (mMEF) of the EEG power spectrum was used as a pharmacodynamic control parameter. The propofol infusion rate was controlled by a model-based adaptive algorithm to maintain a set point of mMEF=3 (0.5) Hz for 90 min. The performance of the closed-loop system was characterized by the prediction error PE=(mMEF-set point)/set point. Plasma propofol concentrations were determined from arterial samples by HPLC. RESULTS: The chosen set point was successfully maintained in all rats. The median (SE) and absolute median values of PE were -5.0 (0.3) and 11.3 (0.2)% respectively. Propofol concentration increased significantly from 2.9 (2.2) microg ml(-1) at the beginning to 5.8 (3.8) microg ml(-1) at 90 min [mean (SD), P<0.05]. The cumulative dose increased linearly, with a mean infusion rate of 0.60 (0.16) mg kg(-1) min(-1). The minimum value of the mean arterial pressure during closed-loop administration of propofol was 130 (24) mm Hg, compared with a baseline value of 141 (12) mm Hg. CONCLUSIONS: The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.

EEG-controlled closed-loop dosing of propofol in rats.

BACKGROUND: Based on previous pharmacokinetic and pharmacodynamic studies, we have developed an EEG-controlled closed-loop system for the i.v. hypnotic agent propofol in rats. METHODS: Seven adult male Sprague-Dawley rats (weight 423-584 g) were included in the study. EEG was recorded with occipito-occipital needle electrodes and the EEG power spectrum was estimated. The median frequency (MEF) was extracted from the power spectrum and was modified MEF (mMEF) to account for the occurrence of spikes and burst suppression patterns in the EEG. Propofol infusion was controlled by a model-based adaptive control algorithm to maintain a set point of mMEF=3.0 (sd 0.5) Hz. The performance of the feedback system was characterized by the median performance error MDPE=median[(mMEF-set point)/set point] and the median absolute performance error (MDAPE). The effective therapeutic infusion (ETI) to maintain the set point was determined from the resulting infusion rates. RESULTS: In all rats a feedback period of 90 min could be performed. Mean MDPE was 1.2 (se 0.4)% and MDAPE was 13.9 (0.3)%. The ETI was 0.73 (sd 0.20) mg kg(-1) min(-1). Mean arterial pressure before propofol infusion was 148 (14) mm Hg, with the lowest value during closed-loop infusion being 110 (20) mm Hg. CONCLUSIONS: The feedback system presented here may be a useful tool not only for automatic drug control to maintain a defined hypnotic effect but may also be a powerful device in pharmacological studies such as the determination of dose requirements or the assessment of drug-drug interactions.

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats.

BACKGROUND AND OBJECTIVE: We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan injection), a new water-soluble prodrug metabolized to propofol by hydrolysis. METHODS: Nine adult male Sprague-Dawley rats (398 +/- 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum. RESULTS: A maximum propofol concentration of 7.1 +/- 1.7 microg mL(-1) was reached 3.7 +/- 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 +/- 0.2 and 23.9 +/- 9.9 min), an elimination rate constant of 0.18 +/- 0.01 min(-1) and a central volume of distribution of 0.25 +/- 0.02 L kg(-1). For propofol, the half-life was 1.9 +/- 0.1 and 45 +/- 7 min, the elimination rate constant was 0.15 +/- 0.02 min(-1) and the central volume of distribution was 2.3 +/- 0.6 L kg(-1). The maximum effect on the electroencephalogram (EEG)--EEG suppression for >4 s--occurred 6.5 +/- 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 +/- 7.9 Hz, EC50 = 2.6 +/- 0.8 microg mL(-1), ke0 = 0.35 +/- 0.04 min(-1)). CONCLUSIONS: Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects.

BACKGROUND AND OBJECTIVE: Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance. METHODS: Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg(-1) min(-1). Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect. RESULTS: Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 microg mL(-1) min(-1), Km = 2.65 microg mL(-1), k12 = 0.30 min(-1), k21 0.063 min(-1), Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 microg mL(-1), gamma = 2.3, ke0 = 0.36 min(-1)) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment. CONCLUSIONS: For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.

A polyhydroxybutyrate biodegradable stent: preliminary experience in the rabbit.

PURPOSE: The lifelong persistence of foreign bodies within the arteries may contribute to restenosis. Thus, biodegradable devices might decrease recurrence rates. METHODS: Eleven polyhydroxybutyrate biodegradable stents and 13 tantalum stents were implanted into the iliac arteries of New Zealand white rabbits for up to 30 weeks. After killing the animals, the specimens were harvested, fixed in formalin, processed in paraffin, and stained. RESULTS: Polyhydroxybutyrate instigated intense inflammatory and proliferative reactions with an increase in collagen (2.4- to 8-fold vs native segments), thrombosis and in-stent lumen narrowing (375.5-606.6 mm vs 655.6 +/- 268.8 mm in native segments). The elastic membranes were destroyed in all specimens. The tantalum stents increased the in-stent lumen progressively (769.7 +/- 366.6 mm vs 1309.9 +/- 695.3 mm), penetrated the external elastic membrane, and increased mural collagen content (6- to 8.6-fold vs native segments). Neither restenoses nor thromboses occurred. CONCLUSIONS: In the rabbit iliac artery, polyhydroxybutyrate stents caused intensive inflammatory vascular reactions which ban them from clinical use.

[First results in an animal model on stents sheathed with a polytetrafluoroethylene membrane]. / Erste tierexperimentelle Ergebnisse eines von einer Polytetrafluoroethylenmembran umhüllten Koronarstents.

OBJECTIVES: Mechanisms of restenosis after coronary stent implantation include marked intimal proliferation as well as vascular tissue protrusion through the meshes. Thus, stent sheathed with membranes may be an alternative to improve the long-term outcome. METHODS: Seventeen cylindric serpentine shaped 316L stainless steel stents (nominal diameter 3.0 mm, length 15 mm) lined and covered by a polytetrafluoroethylene (PTFE) membrane and 10 unsheathed devices were implanted into the iliac arteries of 14 New Zealand White Rabbits for an observation period of 1 - 10, 11 - 20, and 21 - 30 weeks. After sacrificing the animals, specimens were harvested, fixed in formalin, processed in paraffin, serially sliced into 5 microm thick preparations, and stained (hematoxylin & eosin, elastica von Gieson). RESULTS: The polytetrafluoroethylene membrane stents increased the vascular lumen significantly (p < 0.04) to 1185.3 - 1620.4 microm compared with the native segments (655.6 +/- 268.8 microm). In the stainless steel stents the lumen decreased from 1873.1 microm to 719.1 microm. None of the devices penetrated the internal elastic membrane. There was no inflammatory vascular reaction. Compared to the native segments, the amount of elastic fibres was slightly less (native: 8.9 %, PTFE: 2.3 - 3.5 %, without PTFE: 1.9 - 5.5 %) whereas the collagen fibres increased marginally (native: 5.1 %, PTFE: 6 - 6.9 %, without PTFE: 6.4 - 8.4 %). CONCLUSIONS: In the rabbit iliac artery, stents sheathed with a microporous polytetrafluoroethylene membrane showed good tissue compatibility with no restenosis. These results warrant clinical trials.

Fish oil-supplemented parenteral diets normalize splanchnic blood flow and improve killing of translocated bacteria in a low-dose endotoxin rat model.

OBJECTIVE: Intestinal ischemia decreases barrier function of the gut and enhances translocation of bacteria and toxins. Several studies indicate that fish oil can modulate prostaglandin formation and thus, regional blood flow and immune function. This study was performed to determine the effects of parenteral diets with omega-3 fatty acids on microcirculation and barrier function of the gut.0 DESIGN: Prospective, randomized, controlled animal study. SETTING: University laboratory. SUBJECTS: A total of 64 male Sprague-Dawley CD rats. INTERVENTIONS AND MEASUREMENTS: For 48 hrs, eight groups of eight rats each received total parenteral nutrition with four different types of lipids. The source of fat in group L was soybean oil only and in group L-M a mixture of soybean oil and medium-chain triglycerides. In groups FO-20 and FO-40, 20% or 40%, respectively, of the soybean oil in group L-M was replaced by fish oil. The other four groups received an additional continuous infusion of endotoxin (0.1 mg/100 g body weight per day) for the last 24 hrs. Blood flow was measured with microspheres, and translocation was determined by microbiological methods and instillation of radioactive-marked bacteria into the gut. MAIN RESULTS: In the animals without fish oil, the endotoxin application reduced the blood flow to the intestine approximately 25%. Animals with fish oil in their diets showed normal values. Translocation of gut bacteria was increased significantly in all endotoxin groups. However, less-viable bacteria could be detected in the animals with fish oil diets in their mesenteric lymph nodes and livers. CONCLUSIONS: In this model, diets enriched with fish oil abolish the endotoxin-induced decrease of nutritive blood flow to the gut and ameliorate the bactericidal defense of the splanchnic region. The lower count of viable bacteria in the fish oil groups is more related to an improved killing of translocated bacteria than a reduction of the translocation rate.

Influence of pyrrolidine dithiocarbamate on the inflammatory response in macrophages and mouse endotoxin shock.

To analyze the immunomodulatory effect of pyrrolidine dithiocarbamate (PDTC) on the endotoxin (LPS) stimulated inflammatory response, we measured the LPS-stimulated cytokine and NO production in murine peritoneal macrophages, J774A.1 cells and human whole blood in the presence of PDTC (60 microM). PDTC significantly inhibited the production of nitrite, IL-1beta and IL-6 in these cells. TNFalpha release was stimulated in murine cells, but suppressed in human whole blood. We further investigated the influence of PDTC on mortality and cytokine release in mouse endotoxin shock. PDTC was i.p. injected 30 min prior to the induction of endotoxin shock in female NMRI-mice and survival was significantly improved as compared to controls (48% vs 20%, n=25 per group). Plasma concentrations of TNFalpha were slightly augmented while IL-6 levels were decreased in PDTC-treated animals as compared to controls, however, without reaching significance. We conclude that PDTC is a potent immunomodulatory substance that modulates the inflammatory response in vitro and reduces mortality in mouse endotoxin shock. The pathophysiological mechanisms of the protective effect of PDTC in vivo, however, appears to be pluripotent, comprising both antioxidative properties and the inhibition of NF-kB.

Effects of PEEP ventilation on liver metabolism.

OBJECTIVE: To study the influence of positive endexpiratory pressure (PEEP) ventilation on metabolic parameters with specific regard to liver metabolism. DESIGN: Prospective experimental study on the effects of PEEP ventilation on hemodynamic and gas exchange as well as metabolic parameters, i.e. hepatic glucose production, arterial, hepatic and portal venous insulin, glucagon, free fatty acid (FFA), glycerol, beta-hydroxybutyrate and lactate concentrations. SETTING: Experimental Laboratory Unit of the University Hospital. ANIMALS: 10 Labrador Beagle dogs (18-22 kg) were studied. INTERVENTIONS: Animals were ventilated with PEEP of 0, 7.5, 15, and 0 mm Hg, each level lasting 2 h. RESULTS: PEEP 15 significantly increased heart rate from 110(70) to 220(55) beats/min and decreased cardiac output from 2.5 (2.0) to 1.5 (0.8) l/min. This was associated with significant increases in mean pulmonary artery pressure, pulmonary artery occlusion pressure, portal and hepatic venous pressure, whereas mean systemic pressure did not change. While whole-body oxygen consumption and respiratory quotient remained constant, whole-body oxygen delivery significantly decreased from 456(266) to 294(168) ml/min during PEEP 15 concomitant to augmented whole-body oxygen extraction (from 27(34) to 51(33)%). Oxygen extraction from the splanchnic organs increased from 41(31) to 81(30)%. Hepatic venous oxygen tension (PhvO2) and hemoglobin oxygen saturation (ShvO2) during PEEP 15 decreased from 41(18) to 28(47) mm Hg and from 60(31) to 18(66)%, respectively. Hepatic glucose production was significantly stimulated from 3.44(1.44) to 3.92(1.83) mg/kg/min at PEEP 15. Arterial and portalvenous glucagon/insulin ratios did not change. FFA and glycerol concentrations depending on PEEP levels were significantly higher in the hepatic artery and portal vein than in the hepatic vein. Compared to portal venous and arterial hepatic concentrations, hepatic venous beta-hydroxybutyrate significantly increased with rising PEEP levels. CONCLUSIONS: Low values of PhvO2 and ShvO2 during PEEP 15 gave evidence for hypoxia of the liver. This was associated with a stimulated hepatic glucose production rate accompanied by enhanced hepatic uptake and utilization of FFA serving as fuel substrates. As the rate of gluconeogenesis is a major determinant of hepatic oxygen consumption these metabolic effects of PEEP ventilation have to be considered during states of critical illness.

[Measuring cardiac output in infants with the Fick principle via oxygen consumption: animal experiment and clinical results]. / Ermittlung des Herzzeitvolumens bei Kleinkindern mittels des Fickschen Prinzipes über den Sauerstoffverbrauch: Tierexperimentelle und klinische Ergebnisse.

UNLABELLED: The aim of this investigation was the validation of cardiac output measurement in children using the method of Fick with the help of a new equipment for the determination of oxygen uptake. METHODS: We compared the cardiac output measured with thermodilution with the calculated cardiac output using the method described by Fick in an animal model (11 dogs, mean weight 20 kg). For determining the cardiac output on Fick's principle oxygen uptake and oxygen content of the arterial and pulmonary-arterial blood was measured in the ventilated dogs. To examine the method of Fick in clinical routine we also determined oxygen uptake and arterial and central venous oxygen content in 5 children in the postoperative period after cardiac surgery with a mean weight of 8.5 kg. Cardiac output in the patients was calculated with the central venous and the pulmonary-arterial oxygen content. The two results were compared. RESULTS: The animal model showed a good correlation of cardiac output measurement on thermodilution and on Fick's method (alpha = 0.001, t-test of significance of correlation). With the method of Fick we found also reliable results at follow up in the clinical routine in the 5 children. The comparison of cardiac output calculated with the central venous oxygen content versus the pulmonary-arterial oxygen content shows a good correlation over all (r = 0.92). In some cases however we found profound differences.

[Drug induced prevention of the acid aspiration syndrome in non-elective cesarean section]. / Die medikamentöse Prophylaxe des Säure-Aspirations-Syndroms bei nicht elektiver Sectio Caesarea.

Pulmonary aspiration of gastric content with a subsequent aspiration syndrome is a major cause of maternal mortality. Since regurgitation in patients undergoing general anaesthesia cannot reliably be excluded, a prophylaxis with specific drugs is recommendable. In a prospective investigation on patients undergoing nonelective Caesarean section, the H2-receptor antagonist famotidine (fam), the antacid sodium citrate (cit) and the dopamine antagonist metoclopramide (met) were evaluated with respect to volume and acidity of gastric juice. When indicated, a group of 255 patients received 20 mg famotidine i.v., with a randomised subgroup of 126 of these patients also receiving 10 mg metoclopramide i.v. A second group of 171 patients received 20 ml 0.3 M sodium citrate p.o., with a randomised subgroup of 75 of these patients receiving 10 mg metoclopramide i.v. in addition. After induction of anaesthesia the gastric content was evacuated via a gastric tube. Mean volume and pH of the gastric juice as well as the percentage of patients at risk for the development of an aspiration syndrome (juice volume > 0.4 ml/kg and pH < 2.5) were determined. Already in the first hour after drug administration a lower percentage of patients at risk could be observed compared to data from patients without prophylaxis published in recent studies (fam 18.2%, fam + met 12.0%, cit 1.9%, cit + met 2.2%). Treatment with sodium citrate was most effective because of a rapid increase in pH (cit vs. fam: p < 0.05, cit vs. fam + met: p < 0.1, cit + met vs. fam: p < 0.05, cit + met vs. fam+met: p < 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

[A comparison of the two anticholinergic agents atropine and glycopyrrolate during antagonism of a muscle relaxation with pyridostigmine]. / Vergleich der beiden Anticholinergika Atropin und Glycopyrrolat bei der Antagonisierung einer Muskelrelaxation mit Pyridostigmin.

Central, peripheral and cardiac side-effects of both anticholinergic drugs atropine and glycopyrrolate were compared during the antagonism of muscle relaxation with pyridostigmine. In a randomized, double-blind fashion 50 patients were given 10 micrograms/kg of atropine and 50 were given 5 micrograms/kg of glycopyrrolate with 125 micrograms/kg pyridostigmine intravenously. Continuous Holter ECG-monitoring over 3 hours was performed. The procedure was divided into the following phases: control (5 minutes before application of antagonists), phase I (application of antagonists and the following 5 minutes), phase II (subsequent 30 minutes), phase III (until 3 hours had passed). The first 32 minutes were subdivided into periods of 4 minutes. Analysed were: 1st: The number of patients with supraventricular, junctional and ventricular beats, 2nd: The mean heart rate per period, 3rd: The incidence of central-anticholinergic syndromes and the peripheral antimuscarinic side-effects. Supraventricular beats were found after atropine in 42 patients and after glycopyrrolate in 18 patients (p < 0.001). The differences mainly occurred during phase I (atropine 15 vs. glycopyrrolate 4 p < 0.05) and III (atropine 38 vs. glycopyrrolate 18, p < 0.01). Junctional beats were found after both drugs (atropine 7 vs. glycopyrrolate 10), above all during phase III. Ventricular beats were observed after atropine (21) and glycopyrrolate (18). Atropine as well as glycopyrrolate caused an increased heart rate within the first 4 minutes (atropine 47% vs. glycopyrrolate 27%, p < 0.01). During phase III after atropine, the heart rate decreased below the control value (p < 0.05). None of the patients showed central anticholinergic syndromes after either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraorgan differences of blood flow, oxygen supply and glycogen content in the multilobular liver of normal and hemorrhagic rats.

In order to characterize intraorgan differences in blood supply of the rat liver, hepatic blood flow (HBF), surface oxygen tension (sPO2) and glycogen content of the largest and smallest lobi have been determined for normal and hemorrhagic rats (N = 68) in ketamin-xylazine anesthesia. 1. Mean HBF +/- SD of lobus sinister measured 1.07 +/- 0.23 ml/g min (n = 119 determinations, N = 9 rats); HBF of lob. caudatus dexter showed a left-shifted histogram (mean value = 0.77 ml/g.min, median = 0.72 ml/g.min, modul = 0.63 ml/g.min, p less than 0.005). 2. Mean sPO2 +/- SD of lob. sin. measured 23 +/- 6.8 mm Hg (n = 168, N = 16). The histograms of lob. caudat. dext. and sin. were left-shifted (mean value of l.c.d. = 9 mm Hg, median = 4 mm Hg, modul = 0 mm Hg, mean value of l.c.s. = 16 mm Hg, median = 17 mm Hg, modul = 0 mm Hg). Under hemorrhage sPO2 became almost zero in 91% of the measurements. 3. In response to an arterial bolus of fluorescence stained gamma-globulins, spreading of the dye showed a pronounced front and marked periportal area within lob. sin., while an irregular convective front and a much smaller area were detected within both of the lobi caudati. Under hemorrhage, intersinusoidal staining and undefined, irregular contours were observed within all lobes. 4. Compared with lob. sin. preferential glycogen depletion and partial centrilobular necrosis were detected within both of the lob. caudati while under hemorrhage the glycogen stores were empty and severe group necroses have been observed especially within the small lobi. From the data it is concluded that in comparison to lob. sin. an insufficient supply and pronounced vulnerability against hepatic ischemia exists within the small lobi caudati.

[Atropine versus glycopyrrolate in eye surgery. A comparison of rhythm disorders and heart frequency using Holter-ECG]. / Atropin versus Glycopyrrolat bei ophthalmochirurgischen Eingriffen. Vergleich der Rhythmusstörungen und der Herzfrequenz mit Holter-EKG.

Anticholinergics are indicated in ophthalmic surgery to inhibit oculocardiac reflexes (OCR). Although all anticholinergics exert an arrhythmic effect, comparative data on occurrence and severity of arrhythmias are not available. The aim of this investigation was to compare atropine (A) and glycopyrrolate (G) in adults undergoing ophthalmic surgery. One hundred patients (ASA class I and II, age range 20-60 yrs.) were given equipotent doses of either A (10 micrograms.kg-1) or G (5 micrograms.kg-1) in a randomized, double-blind fashion, before induction of anaesthesia. Continuous Holter monitoring was performed. The procedure was divided into the following phases: O (5 min before drug), I (5 min after drug), II (up to induction), III (induction until intubation), IV (intubation until operation), V (operation). Supraventricular, junctional, and ventricular arrhythmias were analyzed. Severe arrhythmia was judged to be greater than 5 events per min, or ventricular beats Lown classes III-V. The beat to beat analog signal was digitalized. The heart rate (HR) and the occurrence rate of OCR (greater than 20% decrease in heart rate, arrhythmias) was calculated by a computerized program. Analysed were: 1. the frequency of OCR, 2. the mean HR for each phase, 3. the frequency of all the various arrhythmias during the whole period, 4. as well as for each phase. The number of patients with severe arrhythmias 5. either for all the time or 6. for the individual phase were registered separately. There were no differences 1. in the frequency of OCR and 2. in mean HR during all phases between A and G.(ABSTRACT TRUNCATED AT 250 WORDS)

Redistribution of local hepatic blood flow during acute bleeding and prolonged hemorrhagic hypotension studied using fluorochromed plasma proteins and surface PO2 measurements.

The present study was performed in order to study the development of sinusoidal blood flow heterogeneity during stepwise bleeding and during prolonged hemorrhagic hypotension. Two methods have been applied: Hepatic surface oxygen tension was measured by a multi-gold-wire-cathode. Sinusoidal perfusion patterns were demonstrated by use of fluorochromed plasma proteins. During stepwise bleeding the relative decrease of the five individual sPO2 curves showed different slopes in the same rat thus indicating a flow dependent heterogeneity. The corresponding perfusion patterns were characterized by an irregular convection front. Time dependent flow heterogeneity resulted in a perfusion pattern showing predominantly perfused sinusoids and low or no flow sinusoids, whereby the predominantly perfused sinusoids might be taken as sinusoidal shunts. It is concluded that stepwise bleeding results in a functional redistribution depending upon the degree of reduced flow, while long time induced microcirculatory changes result in sinusoidal shunt flow depending upon morphological alterations.

Response of spinal cord oxygen tension to aortic occlusion.

In order to study the factors influencing spinal cord injury resulting from occlusion of the descending aorta, the local surface PO2 (sPO2) was measured in the lumbar region (L4-5) of the exposed spinal cord after laminectomy in the pig. This is the area supplied by the arteria radicularis magna anterior (ARMA). The following aspects were considered: duration of occlusion, blood supply by the ARMA, distribution and width of spinal cord collaterals. The animals were divided into two groups. In group I (n = 7) the descending aorta was occluded immediately below the left subclavian artery; in group II (n = 7) the abdominal aorta was occluded immediately superior to the ARMA. Occlusion induced a rapid sPO2 decrease in all animals, from 29 to 3 mm Hg in group I (-14 mm Hg/min) and from 28 to 8 mm Hg in group II (-12 mm Hg/min). After 45 minutes of occlusion the blood flow through the aorta was released giving a pronounced sPO2 overshoot (36 mm Hg) about 10 minutes later. After 20 minutes there had been a return to initial sPO2 values. The results of this study confirm the hypothesis that spinal cord injury during occlusion of the descending aorta is primarily due to ischemic hypoxia/anoxia.