Nils Dahlgren

Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model

ABSTRACT— A model is described in which transient ischemia is induced in rats anaesthetized with N2O:O2 (70:30) by bilateral carotid artery clamping combined with a lowering of mean arterial blood pressure to 50 mm Hg, the latter being achieved by bleeding, or by bleeding supplemented with administration of trimetaphan or phentolamine. By the use of intubation, muscle paralysis with suxamethonium chloride, and insertion of tail arterial and venous catheters, it was possible to induce reversible ischemia for long‐term recovery studies.

Severe Neurological Complications after Central Neuraxial Blockades in Sweden 1990–1999

Background:Central neuraxial blockades find widespread applications. Severe complications are believed to be extremely rare, but the incidence is probably underestimated. Methods:A retrospective study of severe neurologic complications after central neuraxial blockades in Sweden 1990–1999 was performed. Information was obtained from a postal survey and administrative files in the health care system. During the study period approximately 1,260,000 spinal blockades and 450,000 epidural blockades were administered, including 200,000 epidural blockades for pain relief in labor. Results:The 127 complications found included spinal hematoma (33), cauda equina syndrome (32), meningitis (29), epidural abscess (13), and miscellaneous (20). Permanent neurologic damage was observed in 85 patients. Incidence of complications after spinal blockade was within 1:20–30,000 in all patient groups. Incidence after obstetric epidural blockade was 1:25,000; in the remaining patients it was 1:3600 (P < 0.0001). Spinal hematoma after obstetric epidural blockade carried the incidence 1:200,000, significantly lower than the incidence 1:3,600 females subject to knee arthroplasty (P < 0.0001). Conclusions:More complications than expected were found, probably as a result of the comprehensive study design. Half of the complications were retrieved exclusively from administrative files. Complications occur significantly more often after epidural blockade than after spinal blockade, and the complications are different. Obstetric patients carry significantly lower incidence of complications. Osteoporosis is proposed as a previously neglected risk factor. Close surveillance after central neuraxial blockade is mandatory for safe practice.

Cerebral Blood Flow and Oxygen Consumption in the Rat Brain during Extreme Hypercarbia

The effects of hypercapnia (PaCO2 80, 160 and 300 torr) on cerebral metabolic rate for oxygen (CMRO2) and blood flow (CBF) were evaluated in paralyzed, mechanically ventilated rats by use of a 133Xe modification of the Kety-Schmidt inert-gas technique. Hypercapnic rats (PaCO, 80 torr) maintained on N2O, 70 per cent, had a sixfold increase in CBF and a 25 per cent increase in CMRO2, which were not prevented by adrenalectomy or decreases in tissue O2 tensions to near-normal values. Further increases in arterial blood CO2 tensions were associated with decreases in CMRO2 to normal (PaCO2 160 torr) or subnormal values (PaCO2 300 torr). In the last situation there was only a threefold increase in CBF. In rats with PaCO2 about 80 torr that were given propranolol, 2.5 mgċkg-1, during N2O anesthesia, there was only a threefold increase in CBF, while CMRO2 decreased to below normocapnic control values. Rats with PaCO2 80 torr given sedative or anesthetic doses of diazepam (ventilated with O2, 30 per cent, in N2) also had decreased CMRO2 values and had a twofold increase in CBF. It is concluded that hypercapnia activates catecholaminergic neurons in the brain, and that this activation increases oxygen consumption. The increase in flow that occurs with hypercapnia is markedly influenced by activity in catecholaminergic neurons.

Influence of Nitrous Oxide on Local Cerebral Blood Flow in Awake, Minimally Restrained Rats

In order to evaluate the effect of 70–80% N2O on local cerebral blood flow (l-CBF) in the rat brain, we developed a procedure for measuring CBF by an autoradiographic [14C]iodoantipyrine technique in awake, minimally restrained animals. Results on l-CBF, as measured in 22 different structures, showed little variability between animals. In the majority of structures analyzed, 70–80% N2O failed to alter l-CBF. These included all cerebral cortical and most subcortical structures. However, nitrous oxide reduced CBF in the the inferior colliculus and the superior olive, in two of the limbic structures analyzed, and in the hypothalamus. In no structure, except the striatum (p < 0.05), was a significant increase in l-CBF obtained in N2O-breathing animals. However, the results suggest that CBF may have been increased in the auditory cortex. Immobilization was found to reduce l-CBF in the cerebellum, inferior colliculus, superior olive, hippocampus, and septal nuclei. The results also suggest that the procedure somewhat increased CBF in frontal and parietal cortex. When the results obtained in awake, air-breathing animals were compared with those obtained in immobilized animals ventilated on N2O, there was no significant increase in any of the structures analyzed, although there were suggested increases in all cortical areas except the visual cortex. However, the data showed that ventilation with 70–80% N2O significantly decreased CBF in several structures (inferior colliculus, superior olive, hippocampus, amygdala, septal nuceli, and hypothalamus). In some of these, the effects of 70–80% N2O and of immobilization were obviously additive.

Cerebral functional, metabolic and circulatory effects of intravenous infusion of adrenaline in the rat

Abstract Cerebral functional, metabolic and circulatory effects of intravenous infusion of adrenaline (8 μg/kg/min) were evaluated in paralyzed, artificially ventilated and lightly anesthetized rats. At 5, 10 and 15 min following the start of infusion cerebral oxygen consumption (CMRO2) increased 1.6- to 2-fold and cerebral blood flow (CBF) 3- to 4-fold. If the increase in arterial blood pressure was prevented or minimized, adrenaline infusion had no effect on CMRO2 or CBF. In the absence of adrenaline infusion, a precipitous rise in blood pressure (induced by cross-clamping the aorta) likewise failed to alter CMRO2 or CBF. It is concluded that the cerebral metabolic and circulatory effects required the presence of both high concentrations of adrenaline and a marked rise in pressure, the latter presumably allowing translocation of the amine from blood to cerebral extracellular fluids. Changes in EEG were recorded in animals in which the blood pressure was allowed to rise and in those in which it was servo-controlled. In the former, 5 of 6 animals showed an increased incidence of slow (4–5 Hz) waves, but the records failed to show signs of EEG arousal. In servo-controlled animals, 5 of 6 animals showed similar changes but with longer latency and shorter duration. Measurements of tissue metabolites failed to show alterations in cerebral cortical concentrations of glycogen, lactate, ATP, ADP, AMP or cyclic AMP. The lack of perturbation of cerebral metabolic state in spite of a doubling of CMRO2 hints at the operation of an unusual metabolic effect of adrenaline on brain cells.

Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus coeruleus system

The effect of lesions of the locus coeruleus neuron system on cerebral metabolic rate for oxygen (CMRO2) and blood flow (CBF) was evaluated in paralyzed and mechanically ventilated rats, using a 133xenon modification of the Kety-Schmidt inert gas technique. Bilateral electrothermic lesions of its ascending bundle caused no significant change in CBF or CMRO2. The 6-hydroxydopamine lesions did not influence the CBF and CMRO2 responses to hypercapnia and hypoxia. It is concluded that the locus coeruleus does not exert any resting tone on CBF and CMRO2 and that no influence on the CBF and CMRO2 responses to hypercapnia and hypoxia is mediated via its ascending projections.

Effects of Indomethacin on Cerebral Blood Flow and Oxygen Consumption in Barbiturate-Anesthetized Normocapnic and Hypercapnic Rats

Although results obtained in baboons and rats have demonstrated that the fatty acid cyclo-oxygenase inhibitor indomethacin reduces cerebral blood flow (CBF) under control conditions and markedly attenuates the CBF response to hypercapnia, nonconfirmatory results have been obtained in rabbits and cats. Since these latter studies were carried out under barbiturate anesthesia, we tested the effect of indomethacin (10 mg kg−1) on CBF and cerebral oxygen consumption in rats anesthetized with 150 mg kg−1 of phenobarbital. At normocapnia the barbiturate reduced CBF, measured with a 133Xe modification of the Kety-Schmidt technique, to about 50% of nitrous oxide control values as previously determined with a similar technique. At this CBF level, indomethacin induced a small, albeit highly significant decrease in CBF. We suggest that a reduction of this magnitude will escape detection with some CBF techniques in current use. Indomethacin induced a highly significant decrease in CBF during hypercapnia, demonstrating that the barbiturate does not eliminate the effect of indomethacin on CO2 responsiveness. The magnitude of the reduction in CO2 response was so large that it should be detected with most methods for measuring CBF. A comparison with previous data on animals under 70% N2O demonstrated that phenobarbital reduced the CO2 responsiveness, defined as the ratio ΔCBF/ΔPco2, to 39% of that observed under nitrous oxide analgesia. With both types of anesthesia, indomethacin curtailed the CO2 responsiveness 4- to 5-fold.

Effect of propranolol on local cerebral blood flow under normocapnic and hypercapnic conditions.

The effect of propranolol (2.5 mg kg−1, i.v.) on local cerebral blood flow (CBF) in normocapnia was studied in rats maintained artificially ventilated on 70% N2O and 30% O2. The method used was autoradiography with [14C]iodoantipyrine. Although a single dose of propranolol, given 30 min prior to CBF measurements, somewhat reduced mean CBF values in all of the 22 structures analysed, none of the changes were significant. The results confirm previous ones, in which overall CBF was measured, in showing that β-adrenergic mechanisms have little effect on normal cerebrovascular tone. Following a single dose of propranolol, results obtained in hypercapnia were equally negative; neither did CBF fall significantly when propranolol was given by constant infusion during 15 min. Furthermore, local CBF did not differ between animals infused with dl-propranolol and d-propranolol. It is concluded that in the rat, propranolol has but small effects on the CBF response to hypercapnia, if any. The results reveal that local CO2 responsiveness, calculated as ΔCBF/ΔPco2, varies with normocapnic flow rates.

Cerebral circulatory response to hypercapnia: Effects of lesions of central dopaminergic and serotoninergic neuron systems

The present study explores the possibility that the central dopaminergic and serotoninergic neuron systems influence CBF under normocapnic and hypercapnic conditions. In the first part of the study the effect of unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway on local cerebral blood flow (1-CBF) was measured autoradiographically with [14C]iodoantipyrine as the diffusible tracer. The lesion caused no major effect on CBF under normocapnic or hypercapnic conditions. However, the circulatory response to hypercapnia was slightly enhanced (about 10%) in the denervated caudate-putamen. It is suggested that under hypercapnic conditions the pronounced increase in blood flow in the caudate-putamen is normally modulated by a slight vasoconstriction caused by dopamine release from the nigrostriatal system. In the second part of the study the effect of intraventricular 5,7-dihydroxytryptamine on cerebral metabolic rate for oxygen (CMRO2) and CBF was evaluated using a 133xenon modification of the Kety-Schmidt inert gas technique. The lesion, which removed about 90% of cortical 5-hydroxytryptamine, had no effect on the circulatory response to hypercapnia, not did it alter CMRO2. Under normocapnic conditions, though, the lesion seemed to induced a minor increase in CMRO2, which indicates that the serotoninergic system exerts a depressant resting tone on metabolic rate in the brain.

Effect of Indomethacin on Local Cerebral Blood Flow in Awake, Minimally Restrained Rats:

The effect of indomethacin (10 mg kg−1) on local CBF (l-CBF) was studied with autoradiographic techniques in awake, minimally restrained rats. When compared with uninjected awake control animals, those given indomethacin showed a reduction of l-CBF by 25–45%. This reduction is somewhat less pronounced than that previously obtained in paralyzed animals maintained on 70% N2O (a reduction by 30–60%). An enhancement of the indomethacin response during nitrous oxide anesthesia was mainly observed in structures which show a maintained or increased CBF during anesthesia.