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Gregory M T Hare

Publications and source records attributed to Gregory M T Hare.

13 recordsLinked to original sources
PubMed2007

Increased cerebral and renal endothelial nitric oxide synthase gene expression after cardiopulmonary bypass in the rat.

OBJECTIVE: Hemodilution and endothelial nitric oxide synthase genetic polymorphism may contribute to cerebral and renal injury after cardiopulmonary bypass. This study tested the hypothesis that cardiopulmonary bypass and anemia stimulate an increase in cerebral and renal endothelial nitric oxide synthase gene expression in an experimental model of cardiopulmonary bypass. METHODS: Anesthetized rats underwent a sham procedure without cardiopulmonary bypass (sham, n = 5), normothermic bypass for 1 hour (CPB, n = 7), or bypass plus hemodilutional anemia (CPB anemia, n = 9). After 24 hours of recovery, RNA was extracted from the cerebral cortex, renal cortex, and renal medulla. Quantitative reverse transcriptase polymerase chain reaction was used to assess endothelial nitric oxide synthase messenger RNA levels in brain and kidney tissues. RESULTS: The hemoglobin concentration of anemic CPB rats was significantly lower than that of nonanemic rats on bypass (64 +/- 5 vs 99 +/- 8 g x L(-1), P < .001). Cerebral cortical endothelial nitric oxide synthase messenger RNA levels were increased after cardiopulmonary bypass relative to those of the sham group (11.2 +/- 4.2 vs 6.3 +/- 1.5 fg, P = .031), without a further increase in anemic rats. Renal medullary endothelial nitric oxide synthase messenger RNA levels were significantly higher in the CPB anemia group than in the sham and CPB groups (7.1 +/- 4.4 fg vs 1.8 +/- 0.4 fg vs 3.0 +/- 0.6 fg, P < .001). Renal cortical endothelial nitric oxide synthase messenger RNA levels did not change significantly. CONCLUSIONS: Normothermic cardiopulmonary bypass was associated with higher endothelial nitric oxide synthase messenger RNA levels in kidney and brain than was the sham procedure 24 hours after cardiopulmonary bypass. Anemia accentuated the increase in renal medullary, but not cerebral cortical, endothelial nitric oxide synthase expression. These data provide an approach for exploring potential mechanisms by which endothelial nitric oxide synthase may contribute to renal and cerebral dysfunction after cardiopulmonary bypass and anemia.

Animals↗
PubMed2006

Increased expression of HIF-1alpha, nNOS, and VEGF in the cerebral cortex of anemic rats.

This study tested the hypothesis that specific hypoxic molecules, including hypoxia-inducible factor-1alpha (HIF-1alpha), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF), are upregulated within the cerebral cortex of acutely anemic rats. Isoflurane-anesthetized rats underwent acute hemodilution by exchanging 50% of their blood volume with pentastarch. Following hemodilution, mean arterial pressure and arterial Pa(O(2)) values did not differ between control and anemic rats while the hemoglobin concentration decreased to 57 +/- 2 g/l. In anemic rats, cerebral cortical HIF-1alpha protein levels were increased, relative to controls (1.7 +/- 0.5-fold, P < 0.05). This increase was associated with an increase in mRNA levels for VEGF, erythropoietin, CXCR4, iNOS, and nNOS (P < 0.05 for all), but not endothelial NOS. Cerebral cortical nNOS and VEGF protein levels were increased in anemic rats, relative to controls (2.0 +/- 0.2- and 1.5 +/- 0.4-fold, respectively, P < 0.05 for both). Immunohistochemistry demonstrated increased HIF-1alpha and VEGF staining in perivascular regions of the anemic cerebral cortex and an increase in the number of nNOS-positive cerebral cortical cells (3.2 +/- 1.0-fold, P < 0.001). The nNOS-positive cells costained with the neuronal marker, Neu-N, but not with the astrocytic marker glial fibrillary acidic protein (GFAP). These nNOS-positive neurons frequently sent axonal projections toward cerebral blood vessels. Conversely, VEGF immunostaining colocalized with both neuronal (NeuN) and astrocytic markers (GFAP). In conclusion, acute normotensive, normoxemic hemodilution increased the levels of HIF-1alpha protein and mRNA for HIF-1-responsive molecules. nNOS and VEGF protein levels were also increased within the cerebral cortex of anemic rats at clinically relevant hemoglobin concentrations.

Anemia↗
PubMed2006

Case report: profound hypotension associated with labetalol therapy in a patient with cerebral aneurysms and subarachnoid hemorrhage.

PURPOSE: Labetalol is an effective antihypertensive medication frequently used to treat systemic hypertension in acute care settings, including the management of hypertension associated with a subarachnoid hemorrhage. We present a case of profound hypotension, refractory to inotropic and vasopressor therapy following an iv infusion of labetalol. CLINICAL FEATURES: Initiation of an iv labetalol infusion resulted in good blood pressure control in a patient suffering from a Fisher grade 3 subarachnoid hemorrhage with an initial Glascow coma scale of 14/15 and mild hydrocephalus. Progressive deterioration of neurological symptoms and evidence of worsening hydrocephalus preceded the sudden development of profound hypotension (60/35 mmHg) and bradycardia with a minimum heart rate of 40 beats.min(-1). Initial resuscitative efforts included administration of intravascular fluid, hypertonic saline, atropine, adrenalin (more than 10 mg in divided doses) and noradrenalin. These measures restored the blood pressure to 80/45 with a HR of 98 beats.min(-1). Intraoperative placement of an intraventricular drain released cerebrospinal fluid under pressure with an initial intracranial pressure of 15 cm H(2)O. A combination of adrenalin, noradrenalin, dopamine and vasopressin infusions were required to restore the blood pressure to 130/65 mmHg after an additional two hours. All inotropic and vasopressor support was weaned off after the 14th hr (about two drug half-lives). The patient was awake and responsive the following day, with no obvious neurological consequences. No evidence of neurological injury, drug administration error or myocardial dysfunction was documented. CONCLUSION: The episode of profound hypotension which occurred after initiating a labetolol infusion required maximal combined vasopressor therapy to restore the blood pressure suggesting that this patient demonstrated an extreme sensitivity to labetalol. Combination therapy with adrenergic and nonadrenergic agonists may be required for optimal treatment of profound hypotension associated with labetalol-induced vasoplegia.

Antihypertensive Agents↗
PubMed2006

Effect of oxygen affinity and molecular weight of HBOCs on cerebral oxygenation and blood pressure in rats.

PURPOSE: This study assessed the effect of oxygen affinity and molecular weight (MW) of o-raffinose cross-linked hemoglobin based oxygen carriers (HBOCs) on cerebral oxygen delivery and mean arterial blood pressure (MAP) following hemorrhage and resuscitation in rats. METHODS: Isoflurane anesthetized rats (n = 6-7 per group) underwent 30% hemorrhage and resuscitation with an equivalent volume of one of three different HBOCs: 1) High P50 Poly o-raffinose hemoglobin (Poly OR-Hb, P50 = 70 mmHg); 2) High P50 > 128 Poly OR-Hb (MW > 128 kDa, P50 = 70 mmHg) and 3) Low P50 > 128 Poly OR-Hb (MW >128 kDa, P50 = 11 mmHg). Hippocampal cerebral tissue oxygen tension, regional cerebral blood flow (rCBF), MAP, total hemoglobin concentration and arterial blood gases were measured. Data analysis by two-way ANOVA and post hoc Tukey tests determined significance (P < 0.05, mean +/- SD). RESULTS: Hippocampal tissue oxygen tension increased in all HBOC groups following resuscitation. The rCBF remained unchanged after HBOC resuscitation in all groups. Following resuscitation, the peak MAP was higher in the High P50 Poly OR-Hb group (152 +/- 13 mmHg) when compared to either the Low or High P50 large MW, (> 128 kDa) HBOC group (119 +/- 15 mmHg or 127 +/- 18 respectively, P < 0.05 for both). CONCLUSIONS: O-raffinose polymerized HBOC, with or without lower MW components, maintained cerebral tissue oxygen delivery following hemorrhage and resuscitation in rats. The higher MW HBOCs showed a decrease in peak MAP, which did not alter oxygen delivery. No significant effect of oxygen affinity on cerebral tissue oxygen tension or blood flow was observed.

Animals↗
PubMed2006

Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury.

OBJECTIVE: To compare a restrictive versus a liberal transfusion strategy in patients with moderate to severe closed head injury following multiple trauma in 13 Canadian intensive care units (ICUs). METHODS: This is a subgroup analysis of a multicenter randomized controlled clinical trial involving sixty-seven critically ill patients from the Transfusion Requirements in the Critical Care trial who sustained a closed head injury. Patients had a hemoglobin concentration less than 9.0 g/dL within 72 hours of admission to the ICU. Patients were randomized to a restrictive allogeneic red blood cell transfusion strategy (hemoglobin 7.0 g/dL and maintained between 7.0 and 9.0 g/dL) or a liberal strategy (hemoglobin 10.0 g/dL and maintained between 10.0 and 12.0 g/dL). RESULTS: Baseline characteristics in the restrictive ( n = 29) and the liberal ( n = 38) transfusion groups were comparable. Average hemoglobin concentrations and red blood cell units transfused per patient were significantly lower in the restrictive compared to the liberal group. The 30-day all-cause mortality rates in the restrictive group were 17% as compared to 13% in the liberal group (risk difference 4.1 with 95% confidence interval [CI], 13.4 to 21.5, p = 0.64). Presence of multiple organ dysfunction (12.1 +/- 6.4 versus 10.6 +/- 6.3, p = 0.35) and changes in multiple organ dysfunction from baseline scores adjusted for death (4.5 +/- 6.2 versus 3.4 +/- 6.2, p = 0.49) were similar between the restrictive and liberal transfusion groups, respectively. Median length of stay in ICU (10 days, interquartile range 5 to 21 days versus 8 days, interquartile range 5 to 11 days, p = 0.26) and hospital (27 days, interquartile range 14 to 39 days versus 30.5 days, interquartile range 17 to 47 days, p = 0.72) were similar between the restrictive and liberal transfusion groups. CONCLUSIONS: We were unable to detect significant improvements in mortality with a liberal as compared to restrictive transfusion strategy in critically ill trauma victims with moderate to severe head injury.

Adult↗
PubMed2005

Hypocapnia attenuates mesenteric ischemia-reperfusion injury in a rat model.

PURPOSE: Hypocapnia, a recognized complication of high frequency oscillation ventilation, has multiple adverse effects on lung and brain physiology in vivo, including potentiation of free radical injury. We hypothesized that hypocapnia would potentiate the effects of mesenteric ischemia-reperfusion on bowel, liver and lung injury. METHODS: Anesthetized male Sprague-Dawley rats were ventilated with high frequency oscillation and were randomized to one of four groups, exposed to either mesenteric ischemia-reperfusion or sham surgery, and to either hypocapnia or normocapnia. RESULTS: All animals survived the protocol. Ischemia-reperfusion caused significant histologic bowel injury. Bowel 8-isoprostane generation was greater in ischemia-reperfusion vs sham, but was attenuated by hypocapnia. Laser-Doppler flow studies of bowel perfusion confirmed that hypocapnia attenuated reperfusion following ischemia. Plasma alanine transaminase, reflecting overall hepatocellular injury, was not increased by ischemia-reperfusion but was increased by hypocapnia; however, hepatic isoprostane generation was increased by ischemia-reperfusion, and not by hypocapnia. Oxygenation was comparable in all groups, and compliance was impaired by ischemia-reperfusion but not by hypocapnia. CONCLUSION: Hypocapnia, although directly injurious to the liver, attenuates ischemia-reperfusion induced lipid peroxidation in the bowel, possibly through attenuation of blood flow during reperfusion.

Animals↗
PubMed2004

Anaemia and the brain.

PURPOSE OF REVIEW: This article reviews the physiological and pathophysiological effects of anaemia on the brain, focusing on the hypothesis that anaemia-induced cerebral hypoxia contributes to anaemic cerebral dysfunction and injury. It also reviews evidence that the regulated increase in cerebral blood flow observed during anaemia represents a compensatory neuroprotective mechanism invoked to optimize cerebral oxygen delivery, thereby protecting the brain from hypoxic injury. RECENT FINDINGS: Severe anaemia, or low haematocrit, has been associated with cognitive dysfunction, impaired cerebral vascular regulation, neurological injury, and increased mortality, which suggests that the brain is vulnerable to anaemia-induced injury. Reduced cerebral tissue oxygen tension has been measured directly at haemoglobin concentrations near 35 g/l, suggesting that hypoxia may contribute to anaemic cerebral injury. A demonstration of increased hypoxic cerebral gene expression, including neuronal nitric oxide synthase, may provide a more sensitive means of determining the minimum haemoglobin concentration at which anaemia-induced cerebral hypoxia can be detected. The measurement of increased cerebral cortical neuronal nitric oxide synthase messenger RNA and protein levels in rats, at haemoglobin concentrations between 50 and 60 g/l, suggests that cerebral hypoxia occurred at these higher haemoglobin concentrations. Mechanisms regulating anaemic cerebral vasodilation and increased cerebral oxygen delivery, including nitric oxide, require further elucidation to establish their role in protecting the brain during anaemia. SUMMARY: Characterization of mechanisms of anaemia-induced cerebral injury will contribute to the development of optimal therapeutic strategies for anaemic patients. Such strategies would include a clearer definition of transfusion triggers based on physiological endpoints. The overall goal of these efforts would be to minimize morbidity and mortality associated with anaemia.

Journal Article↗
PubMed2004

Increased cerebral tissue oxygen tension after extensive hemodilution with a hemoglobin-based oxygen carrier.

Transfusion of anemic patients with hemoglobin-based oxygen carriers (HBOCs) may improve cerebral oxygen delivery. Conversely, cerebral vasoconstriction, associated with HBOC transfusion, could limit optimal cerebral tissue oxygenation. We hypothesized that hemodilution with a HBOC would maintain cerebral tissue oxygenation, despite the occurrence of cerebral vasoconstriction. Isoflurane-anesthetized rats (100% oxygen) underwent direct measurement of mean arterial blood pressure (MAP), caudate tissue oxygen tension (P(Br)o(2)), and regional cortical cerebral blood flow (rCBF) before and after 50% of the estimated blood volume (30 mL/kg) was exchanged with either an HBOC (hemoglobin raffimer; Hemolink) or pentastarch (n = 6). Hemodilution with hemoglobin raffimer caused a transient increase in P(Br)o(2) from 24.9 +/- 13.3 mm Hg to 32.2 +/- 19.1 mm Hg (P < 0.05), a sustained increase in MAP, and no change in rCBF. Arterial blood oxygen content was maintained despite an increase in methemoglobin and reduced oxygen saturation. Hemodilution with pentastarch caused a transient increase in MAP, no change in P(Br)o(2), and a sustained increase in rCBF (P < 0.05), whereas the hemoglobin concentration and oxygen content were significantly reduced. Hemodilution with hemoglobin raffimer augmented P(Br)o(2) and prevented the increase in rCBF observed after similar hemodilution with pentastarch. These data suggest that transfusion with hemoglobin raffimer may help to maintain cerebral oxygenation during severe anemia.

Animals↗
PubMed2003

Hemodilutional anemia is associated with increased cerebral neuronal nitric oxide synthase gene expression.

Severe hemodilutional anemia may reduce cerebral oxygen delivery, resulting in cerebral tissue hypoxia. Increased nitric oxide synthase (NOS) expression has been identified following cerebral hypoxia and may contribute to the compensatory increase in cerebral blood flow (CBF) observed after hypoxia and anemia. However, changes in cerebral NOS gene expression have not been reported after acute anemia. This study tests the hypothesis that acute hemodilutional anemia causes cerebral tissue hypoxia, triggering changes in cerebral NOS gene expression. Anesthetized rats underwent hemodilution when 30 ml/kg of blood were exchanged with pentastarch, resulting in a final hemoglobin concentration of 51.0 +/- 1.2 g/l (n = 7 rats). Caudate tissue oxygen tension (Pbr(O(2))) decreased transiently from 17.3 +/- 4.1 to 14.4 +/- 4.1 Torr (P < 0.05), before returning to baseline after approximately 20 min. An increase in CBF may have contributed to restoring Pbr(O(2)) by improving cerebral tissue oxygen delivery. An increase in neuronal NOS (nNOS) mRNA was detected by RT-PCR in the cerebral cortex of anemic rats after 3 h (P < 0.05, n = 5). A similar response was observed after exposure to hypoxia. By contrast, no increases in mRNA for endothelial NOS or interleukin-1beta were observed after anemia or hypoxia. Hemodilutional anemia caused an acute reduction in Pbr(O(2)) and an increase in cerebral cortical nNOS mRNA, supporting a role for nNOS in the physiological response to acute anemia.

Anemia↗
PubMed2003

Hypercapnia increases cerebral tissue oxygen tension in anesthetized rats.

PURPOSE: To test the hypotheses that deliberate elevation of PaCO(2) increases cerebral tissue oxygen tension (PBrO(2)) by augmenting PaO(2) and regional cerebral blood flow (rCBF). METHODS: Anesthetized rats were exposed to increasing levels of inspired oxygen (O(2)) or carbon dioxide (CO(2); 5%, 10% and 15%, n = 6). Mean arterial blood pressure (MAP), PBrO(2) and rCBF were measured continuously. Blood gas analysis and hemoglobin concentrations were determined for each change in inspired gas concentration. Data are presented as mean +/- standard deviation with P < 0.05 taken to be significant. RESULTS: The PBrO(2) increased in proportion to arterial oxygenation (PaO(2)) when the percentage of inspired O(2) was increased. Proportional increases in PaCO(2) (48.7 +/- 4.9, 72.3 +/- 6.0 and 95.3 +/- 15.4 mmHg), PaO(2) (172.2 +/- 33.1, 191.7 +/- 42.5 and 216.0 +/- 41.8 mmHg), and PBrO(2) (29.1 +/- 9.2, 49.4 +/- 19.5 and 60.5 +/- 23.0 mmHg) were observed when inspired CO(2) concentrations were increased from 0% to 5%, 10% and 15%, respectively, while arterial pH decreased (P < 0.05 for each). Exposure to CO(2) increased rCBF from 1.04 +/- 0.67 to a peak value of 1.49 +/- 0.45 (P < 0.05). Following removal of exogenous CO(2), arterial blood gas values returned to baseline while rCBF and PBrO(2) remained elevated for over 30 min. The hypercapnia induced increase in PBrO(2) was threefold higher than that resulting from a comparable increase in PaO(2) achieved by increasing the inspired O(2) concentration (34.9 +/- 14.5 vs 11.4 +/- 5.0 mmHg, P < 0.05). CONCLUSION: These data support the hypothesis that the combined effect of increased CBF, PaO(2) and reduced pH collectively contribute to augmenting cerebral PBrO(2) during hypercapnia.

Animals↗
PubMedDate not supplied

Successful treatment using recombinant factor VIIa for severe bleeding post cardiopulmonary bypass.

PURPOSE: To describe a case of persistent and excessive bleeding following an aortic valve and ascending aorta replacement that was successfully managed with recombinant factor VIIa (rFVIIa). The postulated mechanisms for rFVIIa are discussed. CLINICAL FEATURES: A 75-yr-old female with no preoperative coagulopathy underwent a tissue aortic valve replacement and supracoronary ascending aorta replacement for severe aortic stenosis and an ascending aortic aneurysm. Following surgery, she bled in excess of 200 mL x hr(-1) despite a nearly normal platelet count and nearly normal coagulation parameters. The patient was surgically re-explored twice in seven hours, and despite the presence of near normal in vitro coagulation parameters, the patient continued to bleed. Multiple units of fresh frozen plasma, platelets and cryoprecipitate were administered empirically. We then administered a single 6-mg (107 microg x kg(-1)) iv dose of rFVIIa. Following the administration of rFVIIa, blood loss decreased to a total of 440 mL over the next 12 hr. CONCLUSIONS: This case describes the use of rFVIIa for intractable bleeding postcardiovascular surgery in the presence of nearly normal laboratory markers of coagulation. Further controlled laboratory and clinical studies are required to define the role of rFVIIa in patients undergoing cardiovascular surgery.

Aged↗