N. Lund

Autonomic modulation of heart rate variability during endotoxin shock in rabbits

OBJECTIVE Gram-negative septic shock is associated with severe hypotension and autonomic cardiovascular dysfunction. We hypothesized that in an anesthetized rabbit model of endotoxin shock, autonomic modulation of cardiac activity, as measured by power spectral analysis of heart rate (HR) variability, would be decreased compared with the anesthetized control rabbits. DESIGN Experimental, comparative study. SETTING Laboratory of a university hospital. SUBJECTS Fourteen adult male New Zealand white rabbits (2.7 to 3.1 kg body weight) were studied under anesthesia. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We studied the absolute and temporal changes in HR power spectra and plasma catecholamine concentrations in eight experimental and six control New Zealand white rabbits during Escherichia coli endotoxin-induced shock. HR, respirations, arterial blood pressure (BP), HR power spectra, and plasma catecholamine concentrations were measured at 5- to 10-min intervals for 60 mins in control rabbits or until the mean arterial pressure (MAP) decreased by > or = 20 mm Hg in experimental rabbits. There were no differences in basal HR, respiratory rate, BP, HR power spectra, or catecholamine concentrations between groups. After endotoxin administration, MAP decreased (82 +/- 7 vs. 62 +/- 5 mm Hg; p < .05) as did log low-frequency HR power (-2.14 +/- 2.46 vs. -2.20 +/- 2.48 beats/min2; p < .05). Low-frequency HR power and MAP remained unchanged in control animals. Log high-frequency HR power decreased in control and experimental rabbits (-1.02 +/- 1.34 vs. -1.69 +/- 2.12 [control], p < .05; -1.53 +/- 2.19 vs. -2.19 +/- 2.85 beats/min2 [experimental], p < .05). While there was an inverse relationship between low- and high-frequency HR power and MAP, the direction of change was opposite in six of six rabbits in the control group and in six of eight rabbits in the experimental group. Plasma catecholamine concentrations did not change during the experiment in either group. CONCLUSIONS Sympathetic modulation of cardiac activity decreased, while the sympathomedullary response remained unchanged during endotoxin shock. We speculate that a concomitant decrease in low-frequency HR power as MAP decreases may prove to be an early marker for impending shock.

Beneficial effect of glycoprotein IIb/IIIa inhibitor (AZ-1) on endothelium in Escherichia coli endotoxin-induced shock.

Objective To investigate the effects of AZ-1, a murine monoclonal antiglycoprotein-IIb/IIIa antibody, on endothelium and on hemostasis in a rabbit endotoxic shock model. Design Prospective laboratory study. Setting University laboratory. Subjects Thirty-five male New-Zealand rabbits. Interventions In vitro vascular reactivity, endothelium CD31-PECAM1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor determination were performed 1 day and/or 5 days after onset of endotoxic shock (0.5 mg/kg, intravenous bolus, Escherichia coli lipopolysaccharide) with or without treatment by AZ-1 (0.5 mg/kg intravenously) given 1 hr after lipopolysaccharide injection. Measurements and Main Results Metabolic acidosis and coagulation activation confirmed the presence of shock. AZ-1 treatment improved endothelial-dependent relaxation at 1 day (maximal effect = 87.2 ± 4.0% vs. 60.9 ± 5.2% in the nontreated group, p < .05) and at 5 days (maximal effect = 84.5 ± 3.5% vs. 56.6 ± 8.2% in the nontreated group, p < .05). Endotoxin-induced endothelial injury was decreased significantly by AZ-1 at 1 day (6.4 ± 1.9% vs. 10.3 ± 0.8% in the nontreated group, p < .05) and at 5 days (6.3 ± 2.0% vs. 20.2 ± 1.2% in the nontreated group, p < .05). Monocyte tissue factor expression was significantly reduced at 5 days. Conclusions These data indicate that potent inhibition of platelet function via antiglycoprotein-IIb/IIIa receptor blockade can inhibit coagulation activation and protect against endothelial dysfunction and histologic injury in endotoxin-induced shock.

Dopexamine hydrochloride in septic shock : effects on oxygen delivery and oxygenation of gut, liver, and muscle

It has been suggested that septic shock is a disorder of microvascular autoregulation. Tissue blood flow is modulated by the state of activation of upstream endothelial receptors controlling the vascular smooth muscle tone. Because vascular receptor populations vary between organs, it should be expected that vasoactive drugs affect tissue oxygenation differently in different organs. We studied the effects of dopexamine HCl (a novel inotrope) and septic shock on oxygen delivery as well as tissue Po2 in gut, liver, and skeletal muscle in anesthetized rabbits. Employing the thermodilution technique, cardiac output was measured across the pulmonary bed and used to calculate oxygen delivery. Three eight-channel Mehrdraht Dortmund Oberfläche oxygen electrodes were placed on gut serosa, liver, and skeletal muscle surfaces, respectively, and sufficient readings were obtained to calculate tissue Po2 distributions. During septic shock mean arterial pressure, cardiac output, oxygen delivery, and mean tissue Po2 decreased in all organs. Our results suggest that the observed changes in tissue oxygenation during septic shock were caused by defective regulation of microvascular blood flow. In conclusion, during baseline conditions dopexamine HCl caused no statistically significant changes in tissue oxygenation in any organ, except in skeletal muscle at 10 micrograms/kg/min when tissue Po2 increased. During septic shock, however, dopexamine HCl improved oxygenation in all three organs in a dose-dependent manner.

Skeletal Muscle Oxygen Pressure Fields in Healthy Human Volunteers: A Study of the Normal State and the Effects of Different Arterial Oxygen Pressures

The MDO (Mehrdraht Dortmund Oberfläche) oxygen electrode was used for studies of tissue oxygen pressure fields (presented as histograms) in healthy human volunteers breathing room air and gas mixtures with different oxygen concentrations. Forearm blood flow measurements were performed with strain gauge plethysmography, and local blood flow and permeability‐surface area product (PS) were studied by the clearances of 133xenon and 51Cr‐EDTA. At ordinary arterial oxygen pressure levels the histograms were normal, i.e. their distribution type was approximately Gaussian. Higher arterial oxygen pressures caused changes in tissue oxygenation. However, at arterial oxygen pressure levels above 31 kPa two types of abnormal histogram distribution types were distinguished: scattered multi‐population histograms (type a) and a type with predominantly low values (type b). Mean forearm blood flow showed only minor variations, whereas the clearances of 133xenonand and 51Cr‐EDTA were higher with higher PaO2. A parallel increase was also seen in PS.

Skeletal Muscle Oxygen Pressure Fields in Artificially Ventilated, Critically 111 Patients

The MDO (Mehrdraht Dortmund Oberfläche) oxygen electrode was used in a study of skeletal muscle oxygen pressure fields. presented as histograms, in critically ill patients artificially ventilated with gas mixtures of different oxygen concentrations. The histograms were compared with forearm blood flow measurements performed with strain gauge plethysmography. Local blood flow and permeability‐surface area product (PS) were also studied by the simultaneous clearances of 133xenon and 51 Cr‐EDTA. The histogram distribution type was normal, i.e. approximately Gaussian, at arterial oxygen pressure levels between 10 and 18 kPa. At arterial oxygen pressures outside this range the histogram distribution types were abnormal, i.e. they showed a nonsymmetrical distribution of oxygen pressure values, but their mean was approximately the same as in the normal histogram. However, there were significantly higher tissue oxygen pressure mean values in the patients (3.43 kPa) than in a group of healthy human volunteers (2.25 kPa). Mean forearm blood flow and the clearances of 133 xenon and 51 Cr‐EDTA showed marked variations during the measurements both intraindividually and interindividually. Mean forearm blood now and mean clearances of133 xenon showed opposite trends compared with arterial oxygen pressures. Mean clearances of 51 Cr‐EDTA and mean PS showed only minor variations at the different arterial oxygen pressure levels.

Skeletal Muscle Oxygen Pressure Fields in Rats: A Study of the Normal State and the Effects of Local Anesthetics, Local Trauma and Hemorrhage

The MDO (Mehrdraht Dortmund Oberflache) oxygen electrode was used for studies of oxygen pressure fields in rat skeletal muscle. With this multiwire oxygen electrode, the three‐dimensional oxygen pressure field was measured and presented as a two‐dimensional frequency distribution, i.e. a histogram. Statistical analysis of the histograms was carried out with the two‐sample Kolmogorov‐Smirnov test. This eliminated the influence of mean values, since these do not always represent the actual biological situation. The oxygen pressure fields in skeletal muscle of anesthetized normal rats breathing air spontaneously were investigated. When the oxygen pressure in the inspired gas was changed (50% and 95%), changes were seen in muscle oxygen pressure curves. The normal oxygen pressure field histograms were compared with those obtained after local anesthesia, after local trauma to the muscle and after hemorrhage. After local anesthesia the histograms were unchanged. Significant changes in the distribution types of the histograms were found after trauma in all rats studied. After hemorrhage significant changes, similar to those seen after trauma, were found in 15 of the 23 rats studied. Local blood flow was also measured with the 133xenon‐clearance method in the hemorrhage experiments. No correlation was found between the changes in the mean oxygen tension values and the changes in 133xenon‐clearance.

The use of pressure-controlled inverse ratio ventilation in the surgical intensive care unit.

A key element in the treatment of Adult Respiratory Distress Syndrome (ARDS) is improvement in oxygen delivery to match metabolic demands. Conventional modes of ventilation have decreased mortality (50%) very little. We have done a retrospective analysis of 30 surgical patients who were treated with pressure-controlled inverse ratio ventilation. Mortality was 10%. Arterial oxygenation improved from 40.8 +/- 12.2 mm Hg to 138 +/- 47.2 mm Hg, while PCO2 decreased from 37.8 +/- 7.6 mm Hg to 31.1 +/- 5.9 mm Hg. Simultaneously, with the use of pressure-controlled inverse ratio ventilation, minute ventilation could be decreased by 30%, which may be secondary to increased O2 delivery to the tissue. Our data indicate that pressure-controlled inverse ratio ventilation may be beneficial to surgical patients with ARDS.

Effects of increases in the inspired oxygen fraction on brain surface oxygen pressure fields in pig and man

In six patients undergoing neurosurgical operation, brain surface oxygen pressure was studied during an increase of the inspired oxygen fraction (Fio2). The eight‐channel oxygen surface electrode (MDO‐electrode) was placed directly on the brain cortex. Fio2 was increased to four levels, from baseline level 0.21 to 0.3, 0.5, 0.7 and 1.0, respectively. During these four stages and Fio2 0.21, brain surface oxygen pressure (Pto2) was measured. The physiological variables such as blood pressure, Paco2, pH and temperature were stable throughout the study. The results are presented as mean values ± s.d. and a Pto2 histogram for each Fio2‐level. Already at an Fio2 of 0.3 (at a Pao2 of 16.3 ± 3.4 kPa) scattered histograms were seen in five of six patients. A scattered histogram indicates disturbed microcirculation. At the Fio2 levels of 0.5, 0.7 and 1.0, all histograms were scattered. The Pto2 values did not increase proportionally to Pao2 at Fio2 levels 0.3, 0.5 or 0.7. But at Fio2 1.0 four patients had normal mean Pto2 values and two patients very high mean Pto2 values. It is possible that the four patients with normal Pto2 values succeeded in regulating the cerebral microcirculation as a response to the high Fio2 leading to a high Pao2 (60.1 ± 6.4 kPa). The same study was initially done on six pigs in which the regional cerebral blood flow (rCBF) was also measured. MDO‐electrode measurements at different Fio2‐levels gave the same results as in the patients. rCBF decreased when Fio2 was increased.

Skeletal and Cardiac Muscle Oxygenation

Tissue oxygenation is accomplished through a long chain of complex, interrelated factors. The end result is heterogeneity (in time and space) of local oxygen pressures (see e.g. Duling 1981, Longmuir 1981, Silver 1981).

Anaphylactoid reaction to infusion of polygelatin (Haemaccel). A study in pregnant women.

A series of allergic reactions to infusion of polygelatin (Haemaccel®) in six pregnant women is reported. These women and a control group of five pregnant women were studied with analysis of complement, ELISA and skin tests. No differences were found between the groups in the factors studied. It is concluded that the reactions to polygelatin were caused through direct liberation of histamine, that is, an anaphylactoid reaction.