Staffan Holbeck

Effects on capillary fluid permeability and fluid exchange of albumin, dextran, gelatin, and hydroxyethyl starch in cat skeletal muscle.

Objective: To evaluate the peripheral hemodynamic effects in a skeletal muscle in vivo model of the four commercially available colloid solutions, 20% human albumin, 6% dextran‐70, 6% hydroxyethyl starch 200/0.5 (HES), and 3.5% urea‐linked gelatin. Design: Controlled laboratory study. Setting: University research laboratory. Subjects: Fifteen adult cats. Interventions: The isolated, autoperfused, and denervated calf muscles of the cat hindlimb were placed in a plethysmograph. The colloids tested were given intra‐arterially to the muscles in increasing rates of clinically relevant doses. Measurements and Main Results: Arterial blood flow, arterial and venous blood pressures, total vascular resistance, tissue volume changes, and capillary filtration coefficient were measured before, during, and after the colloid infusions. The altered capillary filtration coefficient reflects a change in capillary fluid permeability. The capillary filtration coefficient was decreased by albumin and dextran, not affected by HES, and increased by urea‐linked gelatin. Albumin induced transcapillary fluid absorption, gelatin induced transcapillary filtration, and no transcapillary fluid exchange was observed with dextran and HES. After discontinuation of the infusions, HES and gelatin induced a rebound transcapillary filtration. No such effect was seen after dextran and albumin. All colloids increased muscle blood flow. Conclusion: We conclude that capillary fluid permeability is decreased by albumin and dextran, unchanged by HES, and increased by gelatin. This and the differences in the rebound effect may contribute to the differences in the plasma volume expanding properties of the respective colloid. The increased blood flow induced by the colloids was more an effect of reduced vascular tone than of lowered blood viscosity.

Endotoxin increases both protein and fluid microvascular permeability in cat skeletal muscle

ObjectiveTo evaluate effects of lipopolysaccharide (endotoxin) on protein and fluid permeability in a whole organ skeletal muscle preparation. DesignControlled, prospective laboratory study. SettingUniversity research laboratory. SubjectsEleven adult male cats. InterventionsThe study was performed on the autoperfused and denervated calf muscles of the cat hindlimb placed in a fluid-filled plethysmograph. The endotoxin-induced change in the osmotic reflection coefficient for albumin was used as a measure of alteration in protein permeability of the microvascular wall, and the simultaneous change in capillary filtration coefficient was used as a measure of alteration in fluid permeability. Endotoxin as a bolus infusion (1 mg/kg iv) was given to six cats, and another five cats given only the vehicle (NaCl) were used as control. Measurements and Main ResultsArterial blood flow, arterial and venous blood pressures, total vascular resistance, and tissue volume changes were measured continuously. The ratio between the osmotic reflection coefficients for albumin on two occasions (before and about 1.5 hr after endotoxin infusion) was calculated from the Starling fluid equilibrium equation. This was performed by measurement of the maximum absorption rate from an isovolumetric state by an intravenous bolus infusion of 20% human albumin (0.6 g/kg) and the capillary filtration coefficient. Albumin concentrations were measured before and after the albumin infusion to correct for effects of difference in plasma volume on the induced increase in colloid osmotic pressure. We found that the osmotic reflection coefficient for albumin was reduced by 30% (p < .05), and the capillary filtration coefficient was increased by 31% (p < .05) by endotoxin. No changes were seen in the vehicle experiments. ConclusionEndotoxin causes a significant increase in both protein and fluid microvascular wall permeability. These effects may explain the marked leakage of plasma to the interstitium that is often seen in critically ill patients with sepsis and systemic inflammatory response syndrome.

Dextran, gelatin, and hydroxyethyl starch do not affect permeability for albumin in cat skeletal muscle

ObjectiveTo evaluate the effects of the three commercially available colloid solutions, 6% dextran 70, 6% hydroxyethyl starch (HES) 200/0.5, and 3.5% urea-linked gelatin on permeability for human albumin in a skeletal muscle in vivo model by evaluating their effects on the reflection coefficient for albumin. DesignControlled laboratory study. SettingUniversity research laboratory. SubjectsEighteen adult cats. InterventionsThe autoperfused and denervated calf muscles of the cat hindlimb were placed in a plethysmograph. The transvascular fluid absorption induced by an increase in the colloid osmotic pressure following a fixed intravenous bolus of human albumin was analyzed, first before start of, and then during an intra-arterial infusion to, the muscle preparation of the synthetic colloid to be analyzed. Capillary filtration coefficient as a measure of microvascular fluid permeability (conductance) was analyzed before and after start of the synthetic colloid. Measurements and Main Results Arterial blood flow, arterial and venous blood pressures, total vascular resistance, tissue volume changes, capillary filtration coefficient, and plasma volume were measured before and during the colloid infusion. According to the Starling fluid equilibrium, the ratio between the reflection coefficients for albumin on two occasions (before and after infusion of the synthetic colloid) can be calculated from the maximum osmotic absorption rates induced by a fixed intravenous bolus infusion of albumin and from the capillary filtration coefficients. Obtained data were adjusted for different plasma volume at the two occasions. We found that none of the three synthetic colloids analyzed had any significant effect on the reflection coefficient for albumin. ConclusionAn effect on albumin microvascular permeability of the synthetic colloids dextran 70, HES 200/0.5, and urea-linked gelatin could not be shown by a method analyzing their effect on the reflection coefficient for albumin.

Hypovolemia is a main factor behind disturbed perfusion and metabolism in the intestine during endotoxemia in cat.

Disturbances in intestinal metabolism and perfusion during SIRS can be direct effects of toxic substances, and/or effects secondary to hypovolemia. An attempt to evaluate the significance of hypovolemia for intestinal disturbances during SIRS was made in the present study on feline by evaluating the degree to which the intestinal alterations following endotoxin infusion were restored by a clinically relevant volume infusion. The results were compared with control animals treated identically except that they were not given a volume infusion. We analyzed effects of a colloid infusion during endotoxemia on intestinal perfusion, and on the metabolites lactate, pyruvate, glucose, and glycerol in the intestinal wall, the latter by a microdialysis technique. Arterial and central venous blood pressures, and superior mesenteric artery blood flow were measured, and intestinal oxygen delivery and uptake were calculated. To evaluate to what extent a restoring effect of a colloid infusion was dependent on the type of colloid solution used, three different colloids with about the same volume expanding effects (6% albumin, 6% dextran 70 and 6% hydroxyethyl starch, n = 3 × 6) were tested randomly and blinded. Four hrs after start of endotoxin (1 mg/kg + 1 mg/kg/h), the colloid was infused at a rate of 5 mL/kg for 30 min followed by 2.5 mL/kg/h. Endotoxin caused a marked deterioration of perfusion and metabolic parameters. Most of these parameters turned towards normalization, though not fully reaching baseline values within 4 hrs after start of the colloid infusion. In the control experiments (n = 4), the endotoxin-induced deteriorations persisted or were aggravated during the corresponding time period. The results indicated that hypovolemia is an essential factor but not the only one behind alterations in metabolism and perfusion in the intestine during SIRS, and the alterations can be significantly reduced by adequate volume substitution. In this respect no differences could be seen between the three colloids tested.

Prostacyclin Reduces Microvascular Fluid Conductivity in Cat Skeletal Muscle through Opening of ATP-Dependent Potassium Channels

Prostacyclin is suggested to reduce microvascular permeability, but the cellular mechanisms mediating this response in the microvascular endothelial cells are still unknown. Considering that prostacyclin relaxes vascular smooth muscle cells via opening of ATP-dependent potassium channels, and opening of ATP-dependent potassium channels in the endothelial cells is suggested to influence microvascular permeability, this study was designed to test (1) if ATP-dependent potassium channels are involved in the regulation of microvascular hydraulic permeability, (2) if the permeability-reducing effect of prostacyclin is mediated through opening of ATP-dependent potassium channels, and (3) if cAMP is involved in this process. An autoperfused cat calf hindlimb was used as experimental model, and microvascular hydraulic permeability (conductivity) was estimated by a capillary filtration coefficient (CFC) technique. The potassium channel opener PCO-400 (0.5 μg·min–1 per 100 g muscle, intra-arterially), prostacyclin (1 ng·min–1 per kg body weight, intravenously) and the cAMP analogue dibutyryl-cAMP (24 μg·min–1 per 100 g muscle, intra-arterially), decreased CFC to 77, 72 and 69% compared to control, respectively (p < 0.01). The decrease in CFC obtained by these substances was completely restituted after the start of a simultaneous infusion of the ATP-dependent potassium channel blocker glibenclamide (6 μg·min–1 per 100 g muscle, intra-arterially; p < 0.01). Infusion of glibenclamide alone increased CFC to 107% of control (p < 0.05). In conclusion, the ATP-dependent potassium channels contribute to the regulation of microvascular hydraulic conductivity, and the prostacyclin permeability-reducing effect may act through this mechanism via increase in intracellular cAMP.

Effects of hypertonic saline, mannitol, and urea with regard to absorption and rebound filtration in cat skeletal muscle.

Objective To study the effects of the hypertonic solutions 15% mannitol, 3% and 7.5% saline, and 30% urea at clinically relevant plasma concentrations with regard to absorption and rebound effects on tissue volume in skeletal muscle. Design A prospective, experimental study. Setting University laboratory. Subjects Twenty-eight anesthetized cats. Interventions The study was performed on an autoperfused and denervated cat calf muscle placed in a fluid-filled plethysmograph. Muscle volume changes and capillary filtration coefficient (reflecting capillary fluid conductivity) were measured before, during, and after intra-arterial infusion (4 mL/hr) of the hypertonic solutions. Mannitol and 3% saline have the same osmolality and were compared specifically in an attempt to distinguish osmotic effects from those specific to the compound. Measurements and Main Results All solutions reduced muscle volume during the infusion (p < .05). The maximum volume reduction persisted after 2 hrs of infusion for 3% and 7.5% saline, whereas there was a tendency for volume recovery during the urea infusion and a complete recovery back to control for mannitol. After discontinuation of the infusions, the muscle volume increased for all four solutions, stabilizing at the initial control for 3% and 7.5% saline, whereas it increased to levels above control for mannitol and urea (p < .05). Capillary filtration coefficient was increased by hypertonic saline (p < .05) but was unaffected by mannitol and urea. Conclusions The effectiveness of a hypertonic solution in reducing tissue volume and its tendency to cause a rebound volume increase depends not only on the osmolality of the solution. Hypertonic saline may in the long run be superior to mannitol and urea to increase plasma volume or decrease tissue volume of an organ, because it lacks rebound effects. Alterations in capillary filtration coefficient (fluid conductivity) may reflect volume changes of the capillary endothelial cell and thereby differences in cell membrane permeability for the hypertonic solutions, also consistent with the obtained differences in tissue volume effects.

Internet Discussion Forum

The study by Steeds et al. [1] was selected for this forum since it investigates not only the association between polymorphisms and diseases but also the possible functional consequences. Specifically, the authors investigate two gene polymorphisms of components of the renin angiotensin system (RAS) which have been previously associated with cardiovascular disorders. The D allele of the angiotensin converting enzyme (ACE) I/D polymorphism as well as the C allele of the A1166-C-polymorphism of the angiotensin II (AT1) receptor gene have been previously associated with myocardial infarction and changes in vascular structure. The authors ask the important question whether these associations between genotype and disease have a functional correlate at the level of the vascular wall. For the study, resistance arteries were obtained after colon surgery and studied in a small vessel wire myograph. Vascular function was characterized using a number of stimuli and the genotypes of the individual samples were determined. Results revealed no significant effect of the ACE I/D polymorphism on vascular function. The AT1 polymorphism was only associated with an increase to prostaglandin F2alpha but not with any other changes. The authors conclude that neither polymorphisms are associated with any significant functional vascular changes in mesenteric resistance arteries in subjects without cardiovascular disease.