H. Mayumi Homi

The Neuroprotective Effect of Xenon Administration during Transient Middle Cerebral Artery Occlusion in Mice

Background Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion. Methods C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated. Results The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 ± 17 mm3versus 59 ± 11 mm3, respectively; P = 0.0009). Conclusions In this model of transient focal cerebral ischemia, xenon administration improved both functional and histologic outcome.

Cognitive Dysfunction After Cardiac Surgery: Revisiting Etiology

Cognitive dysfunction remains a frequent complication of cardiac surgery. Despite many years of research, few preventive strategies and no definitive therapeutic options exist for the management of this troublesome clinical problem. This shortcoming may be secondary to an incomplete understanding of the pathophysiology and etiology of cognitive loss after cardiac surgery; a better understanding of the etiology is essential to finding new therapies. The etiology of cognitive dysfunction after cardiac surgery is multifactorial and includes cerebral microembolization, global cerebral hypoperfusion, systemic and cerebral inflammation, cerebral temperature perturbations, cerebral edema, and possible blood-brain barrier dysfunction, all superimposed on genetic differences in patients that may make them more susceptible to injury or unable to repair from injury once it has occurred. This review expands on these potential etiologies in detailing the evidence for their existence.

Cerebral ischemia/stroke and small ubiquitin-like modifier (SUMO) conjugation--a new target for therapeutic intervention?

Transient cerebral ischemia/stroke activates various post‐translational protein modifications such as phosphorylation and ubiquitin conjugation that are believed to play a major role in the pathological process triggered by an interruption of blood supply and culminating in cell death. A new system of post‐translational protein modification has been identified, termed as small ubiquitin‐like modifier (SUMO) conjugation. Like ubiquitin, SUMO is conjugated to the lysine residue of target proteins in a complex process. This review summarizes observations from recent experiments focusing on the effect of cerebral ischemia on SUMO conjugation. Transient global and focal cerebral ischemia both induced a rapid, dramatic and long‐lasting rise in levels of SUMO2/3 conjugation. After transient focal cerebral ischemia, SUMO conjugation was particularly prominent in neurons located at the border of the ischemic territory where SUMO‐conjugated proteins translocated to the nucleus. Many SUMO conjugation target proteins are transcription factors and sumoylation has been shown to have a major impact on the activity, stability, and cellular localization of target proteins. The rise in levels of SUMO‐conjugated proteins is therefore likely to have a major effect on the fate of post‐ischemic neurons. The sumoylation process could provide an exciting new target for therapeutic intervention.

Intraischemic Nitrous Oxide Alters Neither Neurologic Nor Histologic Outcome: A Comparison with Dizocilpine

N-Methyl-d-aspartate receptor antagonism contributes to the anesthetic action of nitrous oxide (N2O). We examined the effects of the N-methyl-d-aspartate antagonists N2O and dizocilpine on outcome from filament occlusion of the middle cerebral artery (MCAO). Rats breathed 70% nitrogen/30% oxygen or 70% N2O/30% oxygen during MCAO. A third group breathed 70% nitrogen/30% oxygen and was given dizocilpine (0.25 mg/kg IV). After 75 min of MCAO, the rats recovered for 3 or 14 days. Pericranial temperature was maintained at 37.5°C ± 0.2°C during ischemia and for 20 h postischemia. N2O did not alter neurologic scores at 3 days (N2O, 21 ± 6; nitrogen, 22 ± 8; P = 0.95; 0 = normal; 48 = maximal deficit; mean ± sd; n = 15) or 14 days (N2O, 13 ± 6; nitrogen, 12 ± 6; P = 0.93; n = 15–16) postischemia. N2O had no effect on infarct size at 3 days (N2O, 162 ± 45 mm3; nitrogen, 162 ± 61 mm3; P = 0.99) or 14 days (N2O, 147 ± 56 mm3; nitrogen, 151 ± 62 mm3; P > 0.99) postischemia. Dizocilpine treatment caused smaller infarcts (3 days: 66 ±49 mm3, P < 0.0001 versus nitrogen; 14 days: 84 ± 50 mm3, P < 0.006 versus nitrogen) and reduced the neurologic deficit (3 days: 10 ±10, P =0.002 versus nitrogen; 14 days: 6 ± 7, P = 0.006 versus nitrogen). N2O (70%) had no effect on either behavioral or histologic outcome from transient focal cerebral ischemia when compared with results in rats breathing 70% nitrogen. These results indicate that normobaric N2O does not alter the response of rat brain to a focal ischemic insult.

Hemodilution during cardiopulmonary bypass increases cerebral infarct volume after middle cerebral artery occlusion in rats.

Although the optimal hematocrit during cardiopulmonary bypass (CPB) is not defined, excessive hemodilution may lead to organ ischemia via a reduction in oxygen-carrying capacity uncompensated by autoregulatory and/or rheologic increases in organ blood flow. As a result, the consequences of hemodilution in patients at risk for cerebral ischemia are not clearly understood. We designed this study to evaluate the effects of hemodilution in the setting of focal cerebral ischemia during CPB. Wistar rats surgically prepared for CPB were randomized to either hemodilution (hemoglobin (Hb), 6 g/dL; n = 9) or control (Hb, 11 g/dL; n = 8) groups and subsequently exposed to focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Immediately after the onset of MCAO (maintained for 90 min), 65 min of hypothermic (28°C) CPB was initiated. Twenty-four hours later, functional neurological outcome and cerebral infarct volume were determined. Compared with controls, the hemodilution group had worse neurological performance (new score = 8 [2], hemodilution; versus 10 [2], control; P = 0.030) and larger total cerebral infarct volumes (182 ± 84 mm3, hemodilution; versus 103 ± 58 mm3, control; P = 0.043). In this experimental model of CPB with reversible MCAO-induced focal cerebral ischemia, hemodilution worsened neurological function and increased cerebral infarct volume.

Severe Hypotension Is Not Essential for Isoflurane Neuroprotection against Forebrain Ischemia in Mice

Background Volatile anesthetics provide protection in experimental models of global cerebral ischemia. To date, all models evaluated have included profound systemic arterial hypotension as a component of the ischemic insult. This study was designed to determine if isoflurane protection persists in a global insult devoid of hypotension. Methods C57BL/6J mice having a high incidence of posterior communicating artery atresia were anesthetized with isoflurane (1.2%) or fentanyl/N2O and subjected to bilateral carotid artery occlusion for 15 min or 20 min with normotension (80–110 mmHg mean arterial pressure) or for 10 min with hypotension (35 mmHg mean arterial pressure). Three days later, neurologic function and histologic damage were assessed. Other mice underwent measurement of intraischemic cerebral blood flow (4-iodo-N-methyl-[14C]antipyrine autoradiography) or plasma norepinephrine. Results Isoflurane reduced the percentage of hippocampal CA1 dead neurons (e.g., 10 min bilateral carotid occlusion + hypotension: 43 ± 18 (isoflurane) vs. 67 ± 20 (fentanyl/N2O), P = 0.003; 20 min bilateral carotid occlusion + normotension: 49 ± 27 (isoflurane) vs. 71 ± 22 (fentanyl/N2O), P = 0.003). Isoflurane also reduced CA3 damage and improved neurologic function under all conditions. Intraischemic forebrain blood flow was similar during bilateral carotid occlusion plus normotension for the two anesthetic states. Plasma norepinephrine values were greater when hypotension was added to the ischemic insult. Conclusions Isoflurane resulted in improved neurologic function and reduced histologic damage regardless of the presence or absence of systemic hypotension during the ischemic insult. This indicates that beneficial effects of isoflurane are most likely attributable to direct effects at the neuronal level as opposed to indirect effects resulting from interactions with profound hypotension.

“Other” Neurologic Complications After Cardiac Surgery

Compared to the neurologic morbidity of stroke and cognitive dysfunction, “other” neurologic complications involving injuries to the brachial plexus, phrenic nerve, cranial nerves, other peripheral nerves, as well as the visual pathways, have been disproportionately underrepresented in the cardiac surgery and anesthesiology literature. These injuries are often missed in the early postoperative period when attention is focused principally on recovery from the acute trespass of cardiac surgery and cardiopulmonary bypass. However, when these problems do become apparent, they can cause considerable discomfort and morbidity. An overview of the current concepts of injury mechanisms/etiology, diagnosis, prognosis, and when possible, prevention of these injuries is presented.

Exacerbation of systemic inflammation and increased cerebral infarct volume with cardiopulmonary bypass after focal cerebral ischemia in the rat

OBJECTIVE Stroke remains a significant contributor to morbidity and mortality after cardiac surgery. Cardiopulmonary bypass is known to induce a significant inflammatory response, which could adversely influence outcomes. We hypothesized that cardiopulmonary bypass, through an enhanced systemic inflammatory response, might affect outcomes after focal cerebral ischemia. METHODS Wistar rats (275-300 g) were anesthetized, surgically prepared for cardiopulmonary bypass and right middle cerebral artery occlusion, and randomly allocated to 2 groups: focal cerebral ischemia alone (n = 9) and focal cerebral ischemia combined with normothermic cardiopulmonary bypass (n = 8). Serum cytokines (tumor necrosis factor alpha and interleukins 1beta, 6, and 10) were measured at baseline, at end of bypass, and at 2, 6, and 24 hours after bypass. On postoperative day 3, animals underwent neurologic testing, after which the brains were prepared for assessment of cerebral infarct volume. Data were compared between groups by Mann-Whitney U test. RESULTS Compared with the ischemia-alone group, the ischemia plus bypass group had significantly higher levels of circulating tumor necrosis factor alpha and interleukins 1beta and 10 at the end of bypass and 2 hours after bypass. In addition, the ischemia plus bypass animals had larger total cerebral infarct volumes (286 +/- 125 mm(3)) than did those with ischemia alone (144 +/- 85 mm(3), P = .0124). CONCLUSIONS Cardiopulmonary bypass increased cerebral infarct size after focal cerebral ischemia in rats. This worsening of outcome may in part be related to an augmented inflammatory response that accompanies cardiopulmonary bypass.

Aprotinin improves functional outcome but not cerebral infarct size in an experimental model of stroke during cardiopulmonary bypass.

BACKGROUND: Aprotinin, a nonspecific serine protease inhibitor, has been used to decrease bleeding and reduce the systemic inflammatory response after cardiopulmonary bypass (CPB). Studies have variably linked aprotinin administration with both improved as well as adverse cerebral consequences after cardiac surgery. We designed this study to determine whether an antiinflammatory dose of aprotinin could improve the histologic and functional neurologic outcome in a rat model of focal cerebral ischemia during CPB. METHODS: After surgical preparation, the animals were randomized into 2 groups: an aprotinin group (60,000 kIU/kg IV) and a control group (0.9% NaCl IV). Normothermic CPB was performed for 60 minutes during which time a partial overlapping 60 minutes of right middle cerebral artery occlusion was induced. Cytokines (tumor necrosis factor-&agr;, interleukin [IL]-1&bgr;, IL-6, and IL-10) were measured at baseline, the end of CPB, then 2 and 24 hours after CPB. On postoperative day 3, the animals underwent functional neurologic testing and histologic assessment of cerebral infarct volume. RESULTS: There was a reduction in systemic inflammation in the aprotinin group compared with the control group, demonstrated by lower levels of IL-1&bgr; (P = 0.035) and IL-6 (P = 0.047). The aprotinin group also had a better functional neurologic performance (median [interquartile range]: aprotinin 27 [8] vs control 32 [6]; P = 0.042). However, there was no difference in cerebral infarct volume (aprotinin 306 [27] mm3 vs control 297 [52] mm3; P = 0.599). CONCLUSIONS: In this experimental model of stroke occurring during CPB, aprotinin decreased the systemic inflammatory response to CPB. Although there was no difference in the cerebral infarct volume, there was a small improvement in the short-term functional neurologic outcome in the aprotinin group.

Longitudinal assessment of neurocognitive function in rats after cardiopulmonary bypass: evidence for long-term deficits.

OBJECTIVE(S) Neurologic and neurocognitive dysfunction after cardiopulmonary bypass (CPB) have been shown in both clinical and experimental settings. Although short-term outcome has been evaluated in rats, the assessment of neurocognitive dysfunction with long-term follow-up has not been reported in experimental CPB models. The objective of this study was to evaluate the effects of CPB on long-term neurocognitive function in the rat. DESIGN Prospective, interventional study. SETTING A university research laboratory. PARTICIPANTS Male Sprague-Dawley rats. INTERVENTIONS Sprague-Dawley rats were randomized to either CPB (n = 19) or sham-operated groups (n = 17). On days 3, 7, and 14 and at 6 weeks after surgery, the rats were submitted to standardized neurologic testing (Neuroscore). In addition, the animals underwent cognitive testing in the Morris water maze (MWM), including basic, probe, and reversal trial protocols during the first 19 postoperative days (short-term cognitive outcome) and then repeated 6 weeks after surgery (long-term cognitive outcome). MEASUREMENTS AND MAIN RESULTS The CPB group had worse Neuroscores (day 3, 5[2]; day 7, 7[2]; day 14, 5[1]; 6 weeks, 5[1]) compared with the sham group (day 3, 7[2]; day 7, 7[1]; day 14, 7[1]; 6 weeks, 7[1]) at all time points tested (p < 0.05). In the MWM, the CPB group showed both short-term and persistent long-term neurocognitive dysfunction. CONCLUSIONS Compared with sham-operated controls, rats undergoing CPB showed worse neurologic and neurocognitive outcome early after surgery. Importantly, long-term deficits also persisted at 6 weeks after surgery.