https://www.chpso.org/sites/main/files/file-attachments/chest-2008-geerts-381s-453s.pdf

Prevention of Venous Thromboembolism* American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition)

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

https://rapm.bmj.com/content/rapm/43/3/263.full.pdf

Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition).

The density and distribution of brain damage after 2-10 min of cerebral ischemia was studied in the rat. Ischemia was produced by a combination of carotid clamping and hypotension, followed by 1 week recovery. The brains were perfusion-fixed with formaldehyde, embedded in paraffin, subserially sectioned, and stained with acid fuchsin/cresyl violet. The number of necrotic neurons in the cerebral cortex, hippocampus, and caudate nucleus was assessed by direct visual counting. Somewhat unexpectedly, mild brain damage was observed in some animals already after 2 min, and more consistently after 4 min of ischemia. This damage affected CA4 and CA1 pyramids in the hippocampus, and neurons in the subiculum. Necrosis of neocortical cells began to appear after 4 min and CA3 hippocampal damage after 6 min of ischemia, while neurons in the caudoputamen were affected first after 8-10 min. Selective neuronal necrosis of the cerebral cortex worsened into infarction after higher doses of insult. Damage was worst over the superolateral convexity of the hemisphere, in the middle laminae of the cerebral cortex. The caudate nucleus showed geographically demarcated zones of selective neuronal necrosis, damage to neurons in the dorsolateral portion showing an all-or-none pattern. Other structures involved included the amygdaloid, the thalamic reticular nucleus, the septal nuclei, the pars reticularis of the substantia nigra, and the cerebellar vermis.

The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia

Selective vulnerability of the hippocampus in brain ischemia.

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. CENTRAL neuraxial blockades (CNB) find widespread application in anesthesia as well as in postoperative and labor analgesia. Recent studies also suggest a reduction in postoperative mortality when CNB are used in major surgery. 1 The use of CNB will probably increase in the future, as serious complications have been reported to be extremely rare. 2 Studies are scarce, and their results difficult to compare. 3– 8 Many complications are known through case reports, and these rare events might not be evenly distributed within the patient population. Because the enormous number of patients needed to perform prospective studies exceeds feasibility, it is important that retrospective studies try to minimize the inherent weakness of such study designs. Underreporting is common in retrospective studies, causing underestimation of risk. In recent years, interest has focused on spinal hematoma after administration of low molecular weight heparin (LMWH). 9 –12 To investigate the incidence of serious neurologic complications after CNB in Sweden from 1990 to 1999, all available sources of information were searched. The aim was also to identify subgroups of patients with higher or lower prevalence of risk factors.

Severe Neurological Complications After Central Neuraxial Blockades in Sweden 1990-1999:

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. Autoradiographic measurements of local CBF showed that the procedure reduced CBF in neocortical areas, hippocampus, and caudoputamen to near-zero values, flow rates in a number of subcortical areas being variable. Administration of trimethaphane or phentolamine did not affect ischemic and postischemic flow rates, nor did they alter recovery of EEG and sensory-evoked responses, but trimetaphan blunted the changes in plasma concentrations of adrenaline and noradrenaline. Recovery experiments showed that 10 min of ischemia gave rise to clear signs of permanent brain damage, with a small number of animals developing postischemic seizures that led to the death of the animals in status epilepticus. After 15 min of ischemia, such alterations were more pronounced, and the majority of animals died. It is concluded that the short revival times noted are explained by the fact that the model induces near-complete ischemia, and that recovery following forebrain ischemia is critically dependent on residual flow rates during the period of ischemia.

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

The effect of the fatty acid cyclo-oxygenase inhibitor indomethacin on cerebral blood flow (CBF) and the metabolic rate for oxygen (CMRO2) was studied in paralyzed and artificially ventilated rats. In normocapnic animals, the drug (10 mg.kg-1i.v.) reduced CBF to 50% of control without a measurable effect on CMRO2. During hypercapnia (PaCO2 70-80 mmHg) the increase in CBF was reduced by about 80% but CMRO2 remained unchanged. Autoradiographic evaluation of local CBF in 20 brain structures indicated that the reduction in CBF was relatively uniform throughout the brain. Dose response curves showed that an effect on CBF was evident already at an indomethacin dose of 1 mg.kg-1 and maximal effects were obtained with 3-5 mg.kg-1. Following i.v. injection of the drug reduction in CBF was observed already after 10 s and the full response occurred after 1-2 min. It is concluded that metabolites of arachidonic acid, possibly mainly prostacyclin, are powerful modulators of normal cerebrovascular tone, and help to mediate the CBF response to increased CO2 tensions. However, since indomethacin does not modify the circulatory response in other conditions with increased CBF these substances do not qualify as general coupling factors controlling CBF in physiological or pathological states.

The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at normal and increased carbon dioxide tensions.

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.

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

In order to study effects of catecholamines on cerebral oxygen consumption (CMRo2) and blood flow (CBF), rats maintained on 75% N2O and 25% O2 were infused i.v. with noradrenaline (2, 5, or 8 microgram.kg-1.min-1) or adrenaline (2 or 8 microgram.kg-1.min-1) for 10 min before CBF and CMRo2 were measured. In about 50% of animals infused with 2--8 microgram.kg-1.min-1 of noradrenaline, CMRo2 (and CBF) rose. However, there was no dose-dependent response, and CMRo2 did not exceed 150% of control. The effects of noradrenaline in a dose of 5 microgram.kg-1.min-1 on CMRo2 and CBF were blocked by propranolol (2.5 mg.kg-1). In animals infused with adrenaline (8 microgram.kg-1.min-1) CMRo2 was doubled and, in many, CBF rose 4- to 6-fold. It is concluded that, when given in sufficient amounts, catecholamines have pronounced effects on cerebral metabolism and blood flow, the effects of adrenaline on CMRo2 and CBF resembling those observed in status epilepticus.

Nils Dahlgren

Papers

Severe Neurological Complications After Central Neuraxial Blockades in Sweden 1990-1999:

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

The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at normal and increased carbon dioxide tensions.

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

Influence of intravenously administered catecholamines on cerebral oxygen consumption and blood flow in the rat.