Should general anaesthesia be avoided in the elderly?

Surgery and anaesthesia exert comparatively greater adverse effects on the elderly than on the younger brain, manifest by the higher prevalence of postoperative delirium and cognitive dysfunction. Postoperative delirium and cognitive dysfunction delay rehabilitation, and are associated with increases in morbidity and mortality among elderly surgical patients. We review the aetiology of postoperative delirium and cognitive dysfunction in the elderly with a particular focus on anaesthesia and sedation, discuss methods of diagnosing and monitoring postoperative cognitive decline, and describe the treatment strategies by which such decline may be prevented.

Evaluation of two delirium screening tools for detecting post-operative delirium in the elderly.

BACKGROUND: Postoperative delirium in the elderly is common and associated with poor outcomes, but often goes unrecognized. Delirium screening tools, validated in postoperative settings are lacking. This study compares two screening tools [Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Nursing Delirium Symptom Checklist (NuDESC)] with a DSM-IV-based diagnosis of delirium, conducted by neuropsychiatric examination in postoperative settings. METHODS: Consecutive English-speaking patients, ≥70 yr, undergoing surgery with general anaesthesia and capable of providing informed consent, were recruited. Diagnostic test characteristics were compared for each screening tool vs neuropsychiatric examination, both in the Post-Anaesthesia Care Unit (PACU), and daily during inpatient hospitalization, adjusting for repeated measures. RESULTS: Neuropsychiatric examination identified delirium in 45% of 91 patients evaluated in the PACU and in 32% of 166 subsequent delirium assessments on the ward in the 58 admitted patients. The sensitivity [95% confidence interval (CI)] of delirium detection of the CAM-ICU in the PACU, and in all repeated assessments was 28% (16-45%) and 28% (17-42%), respectively; for the NuDESC (scoring threshold ≥2), 32% (19-48%) and 29% (19-42%), respectively, and the NuDESC (threshold ≥1), 80% (65-91%) and 72% (60-82%), respectively. Specificity was >90% for both the CAM-ICU and the NuDESC (threshold ≥2); specificity for the NuDESC (threshold ≥1), in the PACU was 69% (54-80%) and 80% (73-85%) for all assessments. CONCLUSIONS: While highly specific, neither CAM-ICU nor NuDESC (threshold ≥2) are adequately sensitive to identify delirium post-operatively; NuDESC (threshold ≥1) increases sensitivity, but reduces specificity.

Does intraoperative fluid management in spine surgery predict intensive care unit length of stay?

STUDY OBJECTIVE: To determine whether intraoperative fluid management in spine surgery predicts postoperative intensive care unit length of stay (ICU LOS). DESIGN: Retrospective case series. SETTING: University-affiliated medical center. PATIENTS: 103 adult ASA physical status I, II, and III patients undergoing spine surgery. INTERVENTIONS: Patients were divided into three LOS groups: no ICU stay (LOS0) (n = 26), 1 day ICU stay (LOS1) (n = 48), and ICU stay > 1 day (LOS2) (n = 29). Measurements were analyzed by groups using the Kruskal-Wallis and Mann-Whitney tests, and linear regression. MEASUREMENTS: Demographics, comorbidity, length of surgery, surgical procedure, and intraoperative fluids were recorded. MAIN RESULTS: The important differences in perioperative fluid management among the three groups included estimated blood loss (612 +/- 480 mL, 1853 +/- 1175 mL, 2702 +/- 1771 mL, means +/- SD); total crystalloid administration (2715 +/- 1396 mL, 5717 +/- 2574 mL, 7281 +/- 3417 mL); and total blood administration (92 +/- 279 mL, 935 +/- 757 mL, 1542 +/- 1230 mL) in LOS0, LOS1, and LOS2, respectively. The mixture of surgical procedures was similar in LOS1 and LOS2; and differed from LOS0. Predictors of ICU LOS included age, ASA physical status, surgical procedure, total crystalloid administration, and platelet administration. Surgical procedure and total crystalloid administration correlated (Pearson correlation coefficient = 0.441; p = 0.000) and were not related to age or ASA physical status. CONCLUSIONS: Total crystalloid administration during spine surgery does predict ICU LOS. In addition, total crystalloid administration is closely related to the surgical procedure. Given that the mixture of surgical procedures was similar in LOS1 and LOS2, but differed in estimated blood loss, total crystalloid administration, and total blood administration; intraoperative fluid management during spine surgery only predicts ICU LOS insofar as total crystalloid administration is related to the surgical procedure.

Estrogen decreases infarct size after temporary focal ischemia in a genetic model of type 1 diabetes mellitus.

BACKGROUND AND PURPOSE: It is unclear how genetic type 1 diabetes mellitus (DM) influences infarct size when blood glucose is tightly controlled. The aim of this study was to determine the effect of genetic type 1 DM, as occurs in BB rats, on infarct size after transient unilateral middle cerebral artery occlusion (MCAO) in male and female rats. In addition, studies suggest that male type 1 DM rats have a higher incidence of end-organ complications than do females. A second aim of this study was to determine the effect of chronic 17beta-estradiol (E(2)) administration on infarct size in male BB rats. METHODS: Diabetic male (MDiab, n=14) and female (FDiab, n=8) BB rats were studied and compared with background strain Wistar rats (MWist, n=16; FWist, n=14). Two additional male cohorts (MWist+E(2), n=15; MDiab+E(2), n=14) received subcutaneous 25 microg E(2) implants 7 to 10 days before MCAO. Rats underwent 1 hour of MCAO followed by 22 hours of reperfusion. Physiological variables were controlled among groups, and the intraischemic laser Doppler flow signal was reduced similarly in all animals. Infarction volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining and image analysis. RESULTS: Preischemic blood glucose was 94+/-5, 127+/-13, 90+/-15, 63+/-18, 122+/-8, and 81+/-14 mg/dL in MWist, FWist, MDiab, FDiab, MWist+E(2), and MDiab+E(2) rats, respectively (mean+/-SE). Intraischemic laser Doppler flow was reduced to 20% to 25% of baseline in all groups. Striatal infarct size (percentage of ipsilateral caudate putamen) was increased in male diabetic rats relative to nondiabetic MWist rats (41+/-3% versus 28+/-3%). Striatal injury was not increased in FDiab rats, and infarction volume was smaller than that in FWist rats (23+/-4% in FWist versus 13+/-3% in FDiab). Chronic estrogen treatment reduced cortical and striatal infarction in MDiab+E(2) rats compared with untreated MDiab rats. CONCLUSIONS: Type 1 DM is associated with increased infarct size after temporary MCAO, despite tight control of blood glucose. The deleterious effect of DM is evident only in males rats; female diabetic BB rats sustain small infarcts. Chronic E(2) treatment reduced injury in the male BB rat, providing neuroprotection even in the presence of DM. These data suggest that genetic diabetes even with mild glucose elevation plays a role in determining neuropathology in experimental stroke. However, factors such as reproductive steroids also determine outcome in DM stroke.

Apoptosis and necrosis occur in separate neuronal populations in hippocampus and cerebellum after ischemia and are associated with differential alterations in metabotropic glutamate receptor signaling pathways.

It was evaluated whether postischemic neurodegeneration is apoptosis and occurs with alterations in phosphoinositide-linked metabotropic glutamate receptors (mGluRs) and their associated signaling pathways. A dog model of transient global incomplete cerebral ischemia was used. The CA1 pyramidal cells and cerebellar Purkinje cells underwent progressive delayed degeneration. By in situ end-labeling of DNA, death of CA1 and Purkinje cells was greater at 7 days than 1 day after ischemia, whereas death of granule neurons in dentate gyrus and cerebellar cortex was greater at 1 than at 7 days. Ultrastructurally, degenerating CA1 pyramidal neurons and cerebellar Purkinje cells were necrotic; in contrast, degenerating granule neurons were apoptotic. In agarose gels of regional DNA extracts, random DNA fragmentation coexisted with internucleosomal fragmentation. By immunoblotting of regional homogenates, mGluR1alpha, mGluR5, phospholipase Cbeta (PLCbeta), and Galphaq/11 protein levels in hippocampus at 1 and 7 days after ischemia were similar to control levels, but in cerebellar cortex, mGluR1alpha and mGluR5 were decreased but PLCbeta was increased. By immunocytochemistry, mGluR and PLCbeta immunoreactivity dissipated in CA1 and cerebellar Purkinje cell/ molecular layers, whereas immunoreactivities for these proteins were enhanced in granule neurons. It was concluded that neuronal death after global ischemia exists as two distinct, temporally overlapping forms in hippocampus and cerebellum: necrosis of pyramidal neurons and Purkinje cells and apoptosis of granule neurons. Neuronal necrosis is associated with a loss of phosphoinositide-linked mGluR transduction proteins, whereas neuronal apoptosis occurs with increased mGluR signaling.

Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis.

In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult-onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N-methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitotoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in nonneuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.

Protein kinase C expression and activity after global incomplete cerebral ischemia in dogs.

BACKGROUND AND PURPOSE: Studies suggest that protein kinase C (PKC) activation during ischemia plays an important role in glutamate neurotoxicity and that PKC inhibition may be neuroprotective. We tested the hypothesis that elevations in the biochemical activity and protein expression of Ca2+-dependent PKC isoforms occur in hippocampus and cerebellum during the period of delayed neurodegeneration after mild brain ischemia. METHODS: We used a dog model of 20 minutes of global incomplete ischemia followed by either 6 hours, 1 day, or 7 days of recovery. Changes in PKC expression (Western blotting and immunocytochemistry) and biochemical activity were compared with neuropathology (percent ischemically damaged neurons) by means of hematoxylin and eosin staining. RESULTS: The percentage of ischemically damaged neurons increased from 13+/-4% to 52+/-10% in CA1 and 24+/-11% to 69+/-6% in cerebellar Purkinje cells from 1 to 7 days, respectively. The occurrence of neuronal injury was accompanied by sustained increases in PKC activity (240% and 211% of control in hippocampus and cerebellum, respectively) and increased protein phosphorylation as detected by proteins containing phosphoserine residues. By Western blotting, the membrane-enriched fraction showed postischemic changes in protein expression with increases of 146+/-64% of control in hippocampal PKCalpha and increases of 138+/-38% of control in cerebellar PKCalpha, but no changes in PKCbeta and PKCgamma were observed. By immunocytochemistry, the neuropil of CA1 and CA4 in hippocampus and the radial glia in the molecular layer of cerebellum showed increased PKCalpha expression after ischemia. CONCLUSIONS: This study shows that during the period of progressive ischemic neurodegeneration there are regionally specific increases in PKC activity, isoform-specific increases in membrane-associated PKC, and elevated protein phosphorylation at serine sites.

The neurologic implications of diabetic hyperglycemia during surgical procedures at increased risk for brain ischemia.

The neurologic implications of diabetic hyperglycemia depend on whether the ischemic insult is permanent or temporary. Laboratory studies show that following permanent focal ischemia, a situation analogous to stroke, diabetic hyperglycemia is protective in the penumbral region, whereas it may slightly increase infarct size. In addition, clinical studies cannot unequivocally attribute poor outcome in diabetic stroke patients to hyperglycemia. Thus, both laboratory and clinical studies have been unable to define a cause and effect relationship between diabetic hyperglycemia and neurologic outcome following stroke. On the other hand, diabetic hyperglycemia is an important determinant of neurologic outcome following temporary focal ischemia (analogous to temporary occlusion of a cerebral vessel) and global ischemia (analogous to circulatory arrest). Based on laboratory studies, aggressive insulin-based blood glucose management with the goal of euglycemia is imperative prior to temporary ischemia. However, intraoperative ischemic events are overwhelmingly of a permanent focal nature, and the neurologic implications of diabetic hyperglycemia for the vast majority of surgical procedures at increased risk for brain ischemia are minimal. It is only in circumstances where temporary focal or global ischemia are used as part of the surgical procedure that aggressive insulin-based blood glucose management is warranted.

Delayed neuronal death after global incomplete ischemia in dogs is accompanied by changes in phospholipase C protein expression.

Activation of phospholipase C (PLC) increases intracellular Ca2+ and may play a role in delayed neuronal death after ischemia. Because changes in intracellular Ca2+ are believed to participate in ischemic neuronal injury, we tested the hypothesis that PLC beta protein levels are temporally altered in brain regions that undergo neurodegeneration after global incomplete ischemia. Dogs (n = 12) were subjected to 20 minutes of global incomplete ischemia followed by recovery of either 1 (n = 5) or 7 days (n = 7). Six sham-operated animals were used as nonischemic controls. In hematoxylin and eosin-stained brain sections, neuronal density at 1 day after ischemia was unchanged relative to nonischemic controls in hippocampus CA1, caudate, and cerebellar cortex (anterior lobule). However, at 7 days after ischemia, neuronal densities were decreased to 56 +/- 15% (mean +/- SD) and 75 +/- 17% of control in CA1 and caudate, respectively. At 1 and 7 days after ischemia, the percentage of neurons showing ischemic injury increased from 13 +/- 10 to 40 +/- 35% in CA1, 24 +/- 25 to 59 +/- 16% in cerebellum, and 4 +/- 2 to 18 +/- 12% in caudate. Densitometric analysis of immunocytochemically stained brain sections from controls (n = 3). 1 day after ischemia (n = 3), and 7 days after ischemia (n = 5) revealed that PLC beta immunoreactivity was increased in cerebellum at 1 day (0.274 +/- 0.013 v 0.295 +/- 0.005 optical density units [OD] in control and 1 day, respectively) and 7 days (0.108 +/- 0.009 v 0.116 +/- 0.005 O.D. in control and 7 days, respectively). PLC beta immunoreactivity was unchanged after ischemia in caudate and hippocampus. Western blot analysis of PLC beta immunoreactivity in the cerebellar cortex and hippocampus in the control (n = 3), 1 day (n = 2), and 7 days after ischemia (n = 2) groups showed that PLC beta levels were increased after ischemia in cerebellum 266% and 227% above control at 1 and 7 days, respectively. However, in hippocampus, PLC expression after ischemia was unchanged at 97% and 84% of control at 1 and 7 days, respectively. These results show that delayed neuronal degeneration after global incomplete ischemia is accompanied by regional abnormalities in PLC levels. Elevated PLC levels early may represent an aberrant signal transduction mechanism resulting in delayed cell damage, whereas decreased PLC levels later after ischemia may reflect ongoing neurodegeneration.

Diabetic chronic hyperglycemia and neurologic outcome following global ischemia in dogs.

We tested the hypothesis that the neuropathologic outcome following recovery from incomplete ischemia is similar in normoglycemia and diabetes. Incomplete global ischemia was induced for 20 min in two groups of dogs: (a) normoglycemic, nondiabetic controls (n = 11) and (b) chronic (3 months), diabetic hyperglycemic subjects (n = 12). Animals were allowed to recover from surgery for 7 days after which they were perfusion-fixed for neuropathology. On paraffin processed tissue stained with hematoxylin and eosin (H&E), ischemic neurons were counted and the per cent of cell damage determined. All control animals survived for 7 days postischemia. Four of 12 diabetic animals survived for 7 days, with the remaining eight diabetic dogs dying within the first 3 days. On day 7, the percentage of neurons showing ischemic cell change in the four diabetic survivors and the 11 nondiabetic controls was similar in the cerebellum, CA1, superior temporal gyrus, and caudate. However, diabetic dogs that did not survive the 7-day recovery period showed cerebellar swelling, reduced Purkinje cell densities, and herniation. During the 3 months prior to ischemia, morning (10.7 +/- 4.4 versus 11.2 +/- 5.2 mM) and afternoon (8.8 +/- 5.0 versus 9.4 +/- 5.3 mM) blood glucose levels in the four surviving and eight nonsurviving diabetic animals, respectively, were similar. However, preischemic blood glucose was significantly elevated in animals that did not survive (7.8 +/- 2.8 versus 15.8 +/- 7.3 mM in survivors and nonsurvivors, respectively). This study shows that diabetic animals surviving 7 days postischemia and nondiabetic controls have similar neuropathology. However, diabetic animals in which glucose control deteriorated during the 24-h prior to ischemia did not survive, possibly due to severe hindbrain edema. These results show that in diabetes, blood glucose control immediately prior to incomplete global brain ischemia is an important determinant of morbidity and neuropathology.

Global incomplete cerebral ischemia produces predominantly cortical neuronal injury.

BACKGROUND AND PURPOSE: We determined the neuropathologic damage in a canine model of global incomplete ischemia commonly used in a variety of physiological experiments. METHODS: We induced 20 minutes of incomplete ischemia in dogs (n = 9) by increasing intracranial pressure via intraventricular infusion of artificial cerebrospinal fluid to maintain a cerebral perfusion pressure of 10 mm Hg while keeping body temperature at 38 degrees C during and immediately after ischemia. After a 7-day recovery period, animals were perfusion-fixed for neuropathology. In hematoxylin and eosin preparations, ischemic neuronal injury was assessed, neurons were counted, and percentage of cell damage was determined. RESULTS: No focal neurological deficits or overt seizures were observed during the 7-day recovery period. In superior temporal gyrus, 49 +/- 11% and 70 +/- 10% damage (mean +/- SEM) was observed in layer III pyramidal cells in the crown and sulcus, respectively. All neocortical regions examined showed neuronal damage in layers III and/or V. In hippocampus, 59 +/- 11% damage of pyramidal neurons occurred in CA1, with dorsal (septal) hippocampus showing more injury than ventral (temporal) portions. The caudate nucleus (head) exhibited 27 +/- 7% neuronal injury. In cerebellar cortex (anterior lobule), 70 +/- 7% damage of Purkinje cells occurred, but different folia of cerebellum showed varying degrees of injury. Brain stem and thalamus were minimally affected despite reduced blood flow. Inflammatory changes (leukocytic infiltration and neuronal incrustations) were observed, but only when neuronal degeneration was severe. Pancellular necrosis and infarction did not occur. CONCLUSIONS: This animal model of ischemia causes reproducible neuronal injury primarily in cortical regions without pancellular necrosis and infarction. Damage to subcortical areas is less severe than to cortical areas, despite comparable reductions in regional cerebral blood flow. Therefore, in the presence of regionally uniform but incomplete cerebral ischemia, neocortical and hippocampal pyramidal neurons and cerebellar cortical Purkinje cells are more likely than subcortical neurons to degenerate; alternatively, pyramidal and Purkinje neurons degenerate before neostriatal neurons in this model. This neuronal degeneration may represent an intrinsic cellular mechanism without major contribution of cytotoxic pathways associated with inflammation.

Poor hemodynamic and metabolic recovery after global incomplete cerebral ischemia associated with short-term diabetes in dogs.

We determined the effect of 4-5 weeks of diabetes on ATP recovery following global incomplete cerebral ischemia. 31P magnetic resonance spectra of ATP, intracellular pH (pHi), and CBF (radiolabeled microspheres) were measured in three groups of anesthetized dogs (n = 8/group): chronic hyperglycemic diabetes (pancreatectomy followed by blood glucose of > 10 mM for 4-5 weeks); acute hyperglycemia (blood glucose of > 10 mM) during ischemia and reperfusion in nondiabetic dogs; and normoglycemic controls. Twenty minutes of incomplete ischemia was produced by ventricular fluid infusion to keep cerebral perfusion pressure (CPP) at 10 mm Hg during spontaneous variations in MABP. Intracranial pressure was increased initially to similar levels, resulting in a similar Cushing response among the groups. However, during the final 8 min of ischemia, MABP decreased to a greater extent in diabetic (86 +/- 42 mm Hg) than in hyperglycemic (162 +/- 30 mm Hg) and normoglycemic (135 +/- 54 mm Hg) groups and remained lower throughout 3 h of reperfusion. CPP was kept constant during ischemia, but was lower throughout reperfusion in diabetic dogs. During ischemia CBF was reduced similarly among groups: 5 +/- 3 ml.min-1 x 100 g-1 in hyperglycemic and normoglycemic and 4 +/- 3 ml.min-1 x 100 g-1 in diabetic dogs. During reperfusion early hyperemia was attenuated and delayed hypoperfusion was augmented (7 +/- 17 ml.min-1 x 100 g-1 by 180 min) as a result of low perfusion pressure in diabetics. However, medullary blood flow was similar among groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetic chronic hyperglycemia and cerebral pH recovery following global ischemia in dogs.

BACKGROUND AND PURPOSE: We determined the effect of chronic hyperglycemia associated with diabetes on recovery of cerebral pH after global incomplete cerebral ischemia. METHODS: 31P magnetic resonance spectra and cerebral blood flow (radiolabeled microspheres) were measured in three groups of dogs: (1) chronic hyperglycemic diabetes (pancreatectomy followed by blood glucose > 10 mmol/L for 3 months; n = 8); (2) acute hyperglycemia during ischemia and reperfusion in nondiabetic dogs (n = 8); and (3) normoglycemic controls (n = 8). Incomplete ischemia was produced for 20 minutes by ventricular fluid infusion followed by 3 hours of reperfusion. RESULTS: Cerebral blood flow was reduced to approximately 5 mL/min per 100 g in all groups during ischemia with individual values ranging from 1 to 11 mL/min per 100 g. Blood flow returned to preischemic values by 30 minutes of reperfusion in the normoglycemia group but remained elevated during reperfusion in the acute hyperglycemia and diabetes groups. Cerebral pH at the end of ischemia was lower in acute hyperglycemia (5.94 +/- 0.05; +/- SE) and diabetes (5.97 +/- 0.08) groups than in the normoglycemia group (6.27 +/- 0.02). However, recovery of pH through 90 minutes of reperfusion in the normoglycemia (7.08 +/- 0.05) and diabetes (7.00 +/- 0.04) groups was significantly greater than in the acute hyperglycemia group (6.74 +/- 0.11). Persistent acidosis in the acute hyperglycemia group was associated with a delayed reduction of cerebral oxygen consumption and high-energy phosphates and with greater cortical water content and impairment of somatosensory evoked potentials compared with the diabetes group. CONCLUSIONS: This study shows that cerebral pH recovery after global incomplete ischemia is improved in chronic hyperglycemia compared with acute hyperglycemia, despite similar decreases in blood flow and pH during ischemia and similar levels of blood flow and glucose levels during ischemia and reperfusion. In addition, cerebral pH recovery in chronic hyperglycemic dogs was not different from that in normoglycemic controls. These results suggest that an adaptation occurs with chronic hyperglycemia that improves recovery of cerebral pH during reperfusion and that is associated with better maintenance of energy metabolism and evoked potentials and with less edema over 3 hours of reperfusion compared with acute hyperglycemia.

Cerebral blood flow and metabolism in dogs with chronic diabetes.

BACKGROUND: Previously, the authors found that anesthetized diabetic dogs had increased cerebral blood flow (CBF) and oxygen consumption (CMRO2). These results may have been influenced by anesthesia or surgery. The aim of this study was to determine whether CBF and CMRO2 are increased in the awake or anesthetized state in the absence of acute surgical stress in diabetic dogs. A second aim was to determine whether increased CBF and CMRO2 in diabetic dogs are mediated through beta-adrenergic mechanisms. METHODS: Diabetic dogs (n = 8) underwent total surgical pancreatectomy followed by 4 months of insulin management (16 +/- 0.4 units/day, mean +/- SE) to maintain fasting and 3 PM blood glucose 10-17 mM. Control dogs (n = 8) underwent sham operation followed by a 4-month convalescence. Using previously inserted catheters, CBF (radiolabelled microspheres) and CMRO2 (sagittal sinus sampling) were measured before and after propranolol (2 mg/kg) in both the awake and anesthetized states. RESULTS: During the 4 months before CBF studies, the fasting blood glucose was greater in diabetic group than in the control group (11.0 +/- 0.3 vs. 4.0 +/- 0.1 mM, respectively). No difference occurred between groups in CBF or CMRO2. In the awake state, propranolol administration caused no CBF or CMRO2 changes. However, during anesthesia with 50 micrograms/kg fentanyl plus 10 mg/kg pentobarbital, propranolol administration decreased CBF in control, but not in diabetic, dogs. CONCLUSIONS: The authors' previous results showing increased CBF and CMRO2 with diabetes may be secondary to a differential response to acute surgical stress, a factor that was eliminated in this study. These results indicate that diabetes is associated with changes in the beta-adrenergic system that become evident under fentanyl/pentobarbital anesthesia.

Extracellular potassium activity and cerebral blood flow during moderate hypoglycemia in anesthetized dogs.

Moderate hypoglycemia (MH) may be associated with blunting of cerebral hypocapnic vasoconstriction. Coincident with this change, electroencephalogram (EEG) flattening occurs. Previous reports show that brain extracellular potassium activity ([K+]o) increases in association with the onset of isoelectricity during severe hypoglycemia and that K+ increases cause pial vessel vasodilation. Using a model of MH, we tested the hypothesis that increases in [K+]o (approximately 15 mM) correlate with blunting of cerebral hypocapnic vasoconstriction. Cerebral blood flow (CBF), [K+]o, and EEG were measured during normocapnia [arterial Pco2 (Paco2) = 35 Torr)] and hypocapnia (PaCO2 = 15 Torr) in MH (< 2 mM) and normoglycemic dogs. During MH, increases in [K+]o occurred in association with EEG flattening (from 4.2 +/- 0.5 to 13.8 +/- 3.8 mM). During normoglycemia and MH without [K+]o elevations, hypocapnic vasoconstriction occurred. [K+]o elevations with MH were associated with increased CBF and decreased vascular resistance (146 +/- 5 and 42 +/- 2% of control, respectively) during normocapnia, and blunting of cerebral hypocapnic vasoconstriction (93 +/- 16% normocapnic control) when [K+]o increased during hypocapnia. This study shows that increases in [K+]o during MH are necessary for both normocapnic increases in CBF and blunting of cerebral hypocapnic vasoconstriction. Increases in [K+]o may represent a mechanism for decreases in cerebral vascular resistance during MH.

Cerebral blood flow responsivity to CO2 in anesthetized chronically diabetic dogs.

The effect of diabetes mellitus on the cerebrovascular response to CO2 is unclear. We examined the effects of diabetes on cerebral blood flow (CBF) and cerebral oxygen uptake (CMRO2) during CO2 alterations. Four groups of dogs were studied: nondiabetic, normoglycemic controls; non-diabetic acute hyperglycemia; diabetic (pancreatectomy) with high-dose insulin treatment to maintain blood glucose between 4.0 and 6.0 mM; and diabetic with low-dose insulin treatment to maintain blood glucose at 13.2 +/- 0.4 mM. Six weeks after either sham surgery or pancreatectomy, dogs were anesthetized with fentanyl (50 micrograms/kg) plus pentobarbital (10 mg/kg), and microsphere determinations of CBF were made during normo-, hypo-, and hypercapnia. On the day of the study, arterial glucose levels in the control, acute hyperglycemia, and high- and low-dose insulin diabetic groups were 4.0 +/- 0.3, 14.9 +/- 2.5, 3.3 +/- 0.8, and 13.3 +/- 0.7 mM, respectively, at control. The corresponding baseline CMRO2 levels were 2.8 +/- 0.2, 3.0 +/- 0.2, 4.1 +/- 0.4, and 4.0 +/- 0.3 ml O2.100 g-1 x min,1, and the values in both diabetic groups were higher than control. Normocapnic CBF in the acute hyperglycemia, high-dose insulin, and low-dose insulin groups was elevated from control (54 +/- 3, 50 +/- 3, 51 +/- 3 vs. 36 +/- 1 ml x 100 g-1 x min-1) and cerebrovascular resistance was lower (2.24 +/- 0.15, 2.51 +/- 0.14, 2.38 +/- 0.21 vs. 3.35 +/- 0.18 mmHg.ml-1 x 100 g.min). CBF responses to both hypercapnia and hypocapnia were similar among groups. Thus both acute hyperglycemia and diabetes decrease cerebrovascular resistance and increase CBF.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypocapnic-hypoglycemic interactions on cerebral high-energy phosphates and pH in dogs.

With a level of hypoglycemia (1-1.5 mM) that does not alter cerebral O2 uptake and glucose uptake in dogs, induction of hypocapnia may cause severe electroencephalographic (EEG) abnormalities. The aim of this study was to determine the effect of hypoglycemia (blood glucose = 1.1 +/- 0.1 mM) and hypocapnia (arterial PCO2 = 15 +/- 1 mmHg) on cerebral ATP, phosphocreatine, and intracellular pH (pHi; 31P magnetic resonance spectroscopy), cerebral blood flow (CBF; radiolabeled microspheres), global O2 uptake, and glucose uptake in anesthetized dogs. Neither hypoglycemia nor hypocapnia alone altered brain high-energy phosphates, pHi, O2 or glucose uptake or caused major EEG abnormalities. Hypocapnia alone decreased CBF to 62 +/- 4% of control. The combination of hypoglycemia and hypocapnia did not decrease CBF (85 +/- 6% of control), and O2 and glucose uptake were unchanged. During hypocapnic hypoglycemia, isoelectric EEG was seen in 40% of animals, ATP and phosphocreatine decreased to 38 +/- 12 and 43 +/- 12% of control, respectively, while pHi increased from 7.13 +/- 0.05 to 7.43 +/- 0.09. The increase in pHi was related reciprocally to the decrease in venous PCO2, indicating little change in intracellular bicarbonate concentration ([HCO3-]i). With normoglycemic hypocapnia, in contrast, estimated [HCO3-]i decreased 57 +/- 1%. These data suggest that active regulation of pHi during normoglycemic hypocapnia is impaired during hypoglycemic hypocapnia associated with decreased ATP.

Preoperative risks predict neurological outcome of carotid endarterectomy related stroke.

The aim of this study was to determine if preoperative risk factors are predictors of poor stroke outcome after carotid endarterectomy. In addition, the effect of other stroke risk factors on stroke severity was determined. A retrospective review of carotid endarterectomy results spanning 10 years, encompassing 561 patients, and reporting the combined results of all surgeons at our institution was performed. Patients were assigned to one of four groups. There were 227 patients with no preoperative risks (Group 1), 61 with angiographic risks (Group 2), 196 with medical risks with or without angiographic risks (Group 3), and 77 with neurological risks with or without medical/angiographic risks (Group 4). Other risks associated with stroke occurrence were recorded including: intraoperative risks (cross-clamp time, use of shunt, use of glucose solutions), surgical complications (carotid occlusion/thrombus or ligation), and medical complications (hypoxia, myocardial infarct). Stroke incidence was 5% with 2% (11 patients) and 3.4% (19 patients) having good and poor outcomes, respectively. Stroke incidence was highest in Groups 2 and 4 (10 and 14%, respectively), and Group 4 had the highest incidence of poor-outcome stroke (12%). Cross-clamp time, intraoperative shunt placement, and intraoperative glucose administration were similar among preoperative risk groups and were not primary determinants of stroke severity. The most common medical complication was myocardial infarction, which had the highest incidence in Groups 3 and 4 (6.1 and 5%, respectively). The highest incidence of surgical complications occurred in Groups 2 and 4, carotid thrombosis being the most common event (16 patients). Surgical complications were more commonly associated with stroke than were medical complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Special issues: glucose and the brain.

PURPOSE: This review focuses on the neurologic issues concerning the treatment of hypo- or hyperglycemia in the critically ill patient. DATA SOURCES: Articles written in English and identified through the Bibliographic Retrieved Service Colleague database. STUDY SELECTION: Articles chosen on the basis of their relevance to the issue of blood glucose management and its neurologic effects in critically ill patients. DATA EXTRACTION: Data from articles were analyzed to obtain a scientific foundation and rationale for treating abnormal blood glucose levels. DATA SYNTHESIS: Moderate hypoglycemia may evoke a significant stress response, behavioral changes, and alterations in cerebral blood flow and metabolism. It is unclear what effect prolonged or repeated episodes of moderate hypoglycemia may have on patient outcome. However, alterations in cerebral vascular physiology must be addressed when caring for patients with cerebral ischemia or intracranial compliance problems. Depending on its severity, hypoglycemia has varying influences on neurologic damage after ischemia. Hyperglycemia may impair neuronal recovery following cerebral ischemia. However, the detrimental effects of hyperglycemia vary depending on the types of brain ischemia sustained (focal or global). Evidence suggests that hyperglycemia during global and incomplete global ischemia events is detrimental to neurologic outcome. However, the relationship between hyperglycemia and outcome after focal ischemia is controversial. CONCLUSION: Because both hypo- and hyperglycemia may produce neurologic changes, aggressive management of abnormal glucose values is warranted.