Per-Olof Grände

Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice.

In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, the physiological role of GPR30 in vivo is unknown, and it remains to be determined whether GPR30 is an estrogen receptor also in vivo. To this end, we studied the effects of disrupting the GPR30 gene in female and male mice. Female GPR30((-/-)) mice had hyperglycemia and impaired glucose tolerance, reduced body growth, increased blood pressure, and reduced serum IGF-I levels. The reduced growth correlated with a proportional decrease in skeletal development. The elevated blood pressure was associated with an increased vascular resistance manifested as an increased media to lumen ratio of the resistance arteries. The hyperglycemia and impaired glucose tolerance in vivo were associated with decreased insulin expression and release in vivo and in vitro in isolated pancreatic islets. GPR30 is expressed in islets, and GPR30 deletion abolished estradiol-stimulated insulin release both in vivo in ovariectomized adult mice and in vitro in isolated islets. Our findings show that GPR30 is important for several metabolic functions in female mice, including estradiol-stimulated insulin release.

A new therapy of post-trauma brain oedema based on haemodynamic principles for brain volume regulation.

ObjectiveTo evaluate a new therapy of posttraumatic brain oedema, with the main concept that opening of the blood-brain barrier upsets the normal brain volume regulation, inducing oedema formation. This means that transcapillary fluid fluxes will be controlled by hydrostatic capillary and colloid osmotic pressures, rather than by crystalloid osmotic pressure. If so, brain oedema therapy should include reduction of hydrostatic capillary pressure and preservation of normal colloid osmotic pressure.Patients11 severely head injured comatose patients with brain swelling, raised intracranial pressure (ICP), and impaired cerebrovascular response to hyperventilation.InterventionsTo reduce capillary hydrostatic pressure the patients were given hypotensive therapy (β1-antagonist, metoprolol and α2-agonist, clonidine) and a potential precapillary vasoconstrictor (dihydroergotamine). The latter may also decrease cerebral blood volume through venous capacitance constriction. Colloid osmotic pressure was maintained by albumin infusions. The concept implies the need of a negative fluid balance with preserved normovolaemia.ResultsICP decreased significantly within a few hours of treatment with unaltered perfusion pressure in spite of lowered blood pressure. Of 11 patients 9 survived with good recovery/moderate disability, 2 died. This was compared to outcome in a historical control group with identical entry criteria, given conventional brain oedema therapy, where mortality/vegetativity/severe disability was 100%.ConclusionThe results indicate that the therapy should focus on extracellular rather than intracellular oedema and that ischemia is not the main triggering mechanism behind oedema formation. We suggest that our therapy is superior to conventional therapy by preventing herniation during the healing period of the blood-brain barrier.

Volume-targeted therapy of increased intracranial pressure: the Lund concept unifies surgical and non-surgical treatments

Opinions differ widely on the various treatment protocols for sustained increase in intracranial pressure (ICP). This review focuses on the physiological volume regulation of the intracranial compartments. Based on these mechanisms we describe a protocol called ‘volume‐targeted’ (‘Lund concept’) for treatment of increased ICP.

An outcome study of severe traumatic head injury using the "Lund therapy" with low-dose prostacyclin

Background: There are two independent head injury outcome studies using the “Lund concept”, and both showed a mortality rate of about 10%, and a favourable outcome (Glasgow outcome scale, GOS 4 and 5) of about 70%. The Lund concept aims at controlling intracranial pressure, and improving microcirculation around contusions. Intracranial pressure is controlled by maintaining a normal colloid osmotic pressure and reducing the hydrostatic capillary pressure. Microcirculation is improved by ensuring strict normovolaemia and reducing sympathetic discharge. The endogenous substance prostacyclin with its antiaggregatory/antiadhesive effects may further improve microcirculation, which finds support from a microdialysis‐based clinical study and an experimental brain trauma study. The present clinical outcome study aims at evaluating whether the previously obtained good outcome with the Lund therapy can be reproduced, and whether the addition of prostacyclin has any adverse side‐effects.

Low-dose prostacyclin in treatment of severe brain trauma evaluated with microdialysis and jugular bulb oxygen measurements

Background: The endogenous substance prostacyclin is a substance with the potential to improve microcirculation and oxygenation around contusions in the brain following a head trauma by its vasodilatory, antiaggregatory and antiadhesive effects. Microdialysis measurements of local concentrations of selected interstitial substances in the brain, and measurements of venous jugular bulb oxygenation reflecting overall brain oxygenation, might be useful to evaluate possible therapeutic effects of a specific therapy, such as treatment with prostacyclin.

Effects of hypotensive treatment with α2‐agonist and β1‐antagonist on cerebral haemodynamics in severely head injured patients

Therapy of post‐traumatic brain oedema often includes preservation of high arterial blood pressure to avoid secondary ischaemic injuries to the brain. This practice can be questioned since high arterial blood pressure may aggravate brain oedema through raised hydrostatic capillary pressure, causing fluid filtration across the damaged blood‐brain barrier. This latter view is in agreement with our clinical experience and therefore hypotensive therapy with an α2‐adrenergic agonist (clonidine) and a β1‐adrenergic antagonist (metoprolol) has become part of our treatment protocol for severely head injured patients to decrease the post‐traumatic brain oedema. The present study is an attempt to analyse whether there are any direct local cerebrovascular effects of the hypotensive agents used, which also might influence intracranial pressure. Severely head injured patients were investigated. Heart rate, mean arterial blood pressure, intracranial pressure, cerebral blood flow and arterio‐venous difference in oxygen content were measured before and after a bolus dose of clonidine (six patients) and metoprolol (nine patients).

Infusion of prostacyclin following experimental brain injury in the rat reduces cortical lesion volume.

Endothelial-derived prostacyclin is an important regulator of microvascular function, and its main actions are inhibition of platelet/leukocyte aggregation and adhesion, and vasodilation. Disturbances in endothelial integrity following traumatic brain injury (TBI) may result in insufficient prostacyclin production and participate in the pathophysiological sequelae of brain injury. The objective of this study was to evaluate the potential therapeutic effects of a low-dose prostacyclin infusion on cortical lesion volume, CA3 neuron survival and functional outcome following TBI in the rat. Anesthetized animals (sodium pentobarbital, 60 mg/kg, i.p.) were subjected to a lateral fluid percussion brain injury (2.5 atm) or sham injury. Following TBI, animals were randomized to receive a constant infusion of either prostacyclin (1 ng/kg x min(-1) i.v.) or vehicle over 48 h. All sham animals received vehicle (n = 6). Evaluation of neuromotor function, lesion volume, and CA3 neuronal loss was performed blindly. By 7 days postinjury, cortical lesion volume was significantly reduced by 43% in the prostacyclin-treated group as compared to the vehicle treated group (p < 0.01; n = 12 prostacyclin, n = 12 vehicle). No differences were observed in neuromotor function (48 h and 7 days following TBI), or in hippocampal cell loss (7 days following TBI) between the prostacyclin- and vehicle-treated groups. We conclude that prostacyclin in a low dose reduces loss of neocortical neurons following TBI and may be a potential clinical therapeutic agent to reduce neuronal cell death associated with brain trauma.

Treatment of intracranial hypertension and aspects on lumbar dural puncture in severe bacterial meningitis

Background: Brain stem herniation due to raised intracranial pressure (ICP) is a common cause of mortality in severe bacterial meningitis, but continuous measurements of ICP and the effects of ICP‐reducing therapy in these patients have, to our knowledge, not been described.

Plasma volume expansion and transcapillary fluid exchange in skeletal muscle of albumin, dextran, gelatin, hydroxyethyl starch, and saline after trauma in the cat*

Objective:To compare 5% albumin, 6% dextran 70, 3.5% gelatin, 6% hydroxyethyl starch 130/0.4, and saline regarding their plasma volume expanding effect after a surgical skeletal muscle trauma and their simultaneous effects on transvascular fluid exchange in skeletal muscle. Design:Controlled, prospective, randomized laboratory study. Setting:University research laboratory. Subjects:Thirty-six adult cats. Interventions:Systemic arterial pressure and tissue volume variations of and blood flow to a surgically isolated and autoperfused calf muscle placed in a plethysmograph were recorded. Arterial and venous pressures to the muscle were kept constant. After preparation, plasma volumes were determined by a 125I albumin tracer technique just before and 3 hrs after a bolus infusion of the plasma expander (25 mL/kg). Measurements and Main Results:Plasma volume was 20.9 ± 2.9 mL/kg (n = 36) just before infusion of the plasma expander (normal plasma volume for the cat is 34–37 mL/kg). The remaining volume expansion of the infusion after 3 hrs was 6.8 mL/kg for albumin, 11.2 mL/kg for dextran, 1.8 mL/kg for gelatin, 2.2 mL/kg for hydroxyethyl starch, and 0.9 mL/kg for saline. Plasma volume decreased by 1.1 mL/kg when no solution was given (n = 6 per group). Colloid osmotic pressure was better preserved with dextran and albumin than with the other solutions. Albumin and dextran reduced muscle volume by absorption after 3 hrs, whereas the initial absorption turned to net filtration in the gelatin and hydroxyethyl starch groups. Saline infusion increased muscle volume by filtration for about 20 mins, followed by an approximately constant volume. Conclusion:The relatively poor plasma expansion for all solutions analyzed can most likely be explained by increased transcapillary leakage due to increased microvascular permeability following trauma. Under such circumstances, for equal volumes, plasma expansion was better preserved with 6% dextran 70 than with 5% albumin, which was better than 3.5% gelatin, 6% hydroxyethyl starch 130/0.4, and saline.

Effects on Brain Edema of Crystalloid and Albumin Fluid Resuscitation after Brain Trauma and Hemorrhage in the Rat

Background:It has been hypothesized that resuscitation with crystalloids after brain trauma increases brain edema compared with colloids, but previous studies on the subject have been inconclusive. To test this hypothesis, the authors compared groups resuscitated with either colloid or crystalloid. Methods:After fluid percussion injury, rats were subjected to a controlled hemorrhage of 20 ml/kg and were randomized to 5% albumin at 20 ml/kg (A20), isotonic Ringers acetate at 50 ml/kg (C50), or 90 ml/kg (C90). After 3 or 24 h, water content in the injured cortex was determined using a wet/dry weight method. Blood volume was calculated from plasma volume, measured by 125I-albumin dilution, and hematocrit. Oncotic pressure and osmolality were measured with osmometers. Results:At 3 h, blood volume was equal in the A20 and C90 groups and lower in the C50 group. Oncotic pressure was reduced by 35–40% in the crystalloid groups and unchanged in the albumin group. Cortical water content in the A20 group was lower than in the C90 group (81.3 ± 0.5% vs. 82.1 ± 1.1%, P < 0.05), but it was not different from the C50 group (81.8 ± 1.1%). At 24 h, oncotic pressure and blood volume were normalized in all groups, and cortical water content was significantly lower in the albumin group than in the crystalloid groups. Osmolality and arterial pressure were equal in all groups throughout the experiment. Conclusions:When given to the same intravascular volume expansion, isotonic crystalloids caused greater posttraumatic brain edema than 5% albumin at 3 and 24 h after trauma.