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Biomedical subjects

Hilary P Grocott

Publications and source records attributed to Hilary P Grocott.

At least 19 recordsLinked to original sources
PubMed2006

Central nervous system injury associated with cardiac surgery.

Millions of individuals with coronary artery or valvular heart disease have been given a new chance at life by heart surgery, but the potential for neurological injury is an Achilles heel. Technological advancements and innovations in surgical and anaesthetic technique have allowed us to offer surgical treatment to patients at the extremes of age and infirmity-the group at greatest risk for neurological injury. Neurocognitive dysfunction is a complication of cardiac surgery that can restrict the improved quality of life that patients usually experience after heart surgery. With a broader understanding of the frequency and effects of neurological injury from cardiac surgery and its implications for patients in both the short term and the long term, we should be able to give personalised treatments and thus preserve both their quantity and quality of life. We describe these issues and the controversies that merit continued investigation.

Cognition Disorders↗
PubMed2006

Cardiopulmonary bypass and long-term neurocognitive dysfunction in the rat.

Neurologic and neurocognitive complications after cardiac surgery with cardiopulmonary bypass (CPB) have been reported repeatedly. To better understand its etiology and design protective strategies, an appropriate animal model may prove useful. Although impaired short-term neurocognitive function has been recently demonstrated after CPB in rats, the demonstration of persistent long-term neurocognitive changes would be more relevant from a clinical perspective. We hypothesized that CPB results in long-term impairment of neurocognitive performance in rats. Male rats were exposed to either 60 min of normothermic non-pulsatile CPB, using a roller-pump and a neonatal membrane oxygenator, or to cannulation only (sham animals). Long-term neurocognitive function was assessed at 4 to 7 weeks after CPB (Can test), and again after 12 weeks (Morris water maze) in both operated groups and in a non-operated control group, followed by histologic evaluation of the hippocampus. In separate groups of CPB and sham animals, we also measured TNF-alpha and IL-6 in plasma. There were no significant differences in long-term neurocognitive performance or histological outcome between the three groups. Cytokine patterns were also similar in both operated groups. We conclude that CPB did not appear to cause long-term neurocognitive dysfunction in this model of CPB in young healthy rats. The lack of long-term deficits may be due to the absence of clinically important etiologic factors such as atheromatous and gaseous embolization in this model. Similar cytokine patterns in both operated groups suggest that surgical trauma rather than exposure of blood to extra-corporeal circuit was probably responsible for the inflammatory response.

Animals↗
PubMed2006

Genetic influences on cerebral outcome after cardiac surgery.

Just as the influence of genetic variation on patient outcomes is being discussed in many other areas of medicine, so too are its effects on cerebral outcome after cardiac surgery now being described. Whereas early studies focused on neurocognitive outcome, where the single nucleotide polymorphisms of APOE4 and PL(A2) were the first investigated genetic targets, stroke is now being elaborated on with related single and multi-gene single nucleotide polymorphisms having been identified. Our work has established key links between post-cardiac surgery stroke and C-reactive protein (3'UTR 1846C/T) and interleukin-6 (-174 G/C) single nucleotide polymorphisms.

Antigens, Human Platelet↗
PubMed2006

Reduction in air bubble size using perfluorocarbons during cardiopulmonary bypass in the rat.

BACKGROUND: Perfluorocarbon (PFC) emulsions are artificial oxygen-carrying compounds with a high solubility for gases that have experimentally been shown to ameliorate cerebral air embolism. Cerebral air embolism has been associated with adverse cerebral outcomes after cardiac surgery using cardiopulmonary bypass (CPB). We designed this study to test whether PFC emulsions could reduce the volume of bubbles within the CPB circuit. METHODS: Male Sprague-Dawley rats undergoing 60 min of normothermic nonpulsatile CPB were randomized to one of the three groups. The PFC group (n = 10) received 60% O(2)/36% N(2)/4% CO(2) via the membrane oxygenator and 2.7 g/kg (4.5 mL/kg) of PFC into the venous reservoir; the control group (n = 10) received the same gas mixture and 4.5 mL/kg of saline; the N(2)O group (n = 6) was exposed to 36% N(2)O/60% O(2)/4% CO(2) and received 4.5 mL/kg of saline. After 10 min and 35 min of CPB, 400 microL of air was injected into a bubble chamber in the CPB circuit. After 20 min, the bubble was removed for volumetric analysis. RESULTS: Compared with baseline, the bubble decreased 13% +/- 5% in size in the PFC group and increased 46% +/- 9% in the nitrous oxide group, both of these changes significantly different from the control group (P < 0.0001). CONCLUSION: The results suggest that PFC administration may be useful in reducing the volume of gaseous bubbles present during CPB.

Animals↗
PubMed2005

Genetic polymorphisms and the risk of stroke after cardiac surgery.

BACKGROUND AND PURPOSE: Stroke represents a significant cause of morbidity and mortality after cardiac surgery. Although the risk of stroke varies according to both patient and procedural factors, the impact of genetic variants on stroke risk is not well understood. Therefore, we tested the hypothesis that specific genetic polymorphisms are associated with an increased risk of stroke after cardiac surgery. METHODS: Patients undergoing cardiac surgery utilizing cardiopulmonary bypass surgery were studied. DNA was isolated from preoperative blood and analyzed for 26 different single-nucleotide polymorphisms. Multivariable logistic regression modeling was used to determine the association of clinical and genetic characteristics with stroke. Permutation analysis was used to adjust for multiple comparisons inherent in genetic association studies. RESULTS: A total of 1635 patients experiencing 28 strokes (1.7%) were included in the final genetic model. The combination of the 2 minor alleles of C-reactive protein (CRP; 3'UTR 1846C/T) and interleukin-6 (IL-6; -174G/C) polymorphisms, occurring in 583 (35.7%) patients, was significantly associated with stroke (odds ratio, 3.3; 95% CI, 1.4 to 8.1; P=0.0023). In a multivariable logistic model adjusting for age, the CRP and IL-6 single-nucleotide polymorphism combination remained significantly associated with stroke (P=0.0020). CONCLUSIONS: We demonstrate that common genetic variants of CRP (3'UTR 1846C/T) and IL-6 (-174G/C) are significantly associated with the risk of stroke after cardiac surgery, suggesting a pivotal role of inflammation in post-cardiac surgery stroke.

Aged↗
PubMed2005

G alpha(q)-coupled receptors in human atrium function through protein kinase C epsilon and delta.

Cardiac G alpha(q)-coupled receptors (such as endothelin, angiotensin, and alpha1-adrenergic receptors) mediate cardiac inotropy and chronotropy, as well as the development of hypertrophy. These receptors signal through protein kinase C (PKC), a family of 12 isozymes including PKC alpha, beta I, beta II, gamma, delta, epsilon, theta, eta, lambda, iota, zeta, and mu. Of these PKC isozymes, alpha, beta II, gamma, epsilon, delta, and zeta have been implicated in signaling through cardiac G alpha(q)-coupled receptors in various animal models. However, the profile of which isozymes are activated by a given G alpha(q)-coupled receptor varies among animal species. Thus, these results can not be extrapolated to human heart. In this study, we examine PKC isozymes activated by three different G alpha(q)-coupled receptors in human atrial tissue. Live atrial appendages obtained from the operating room were sliced and treated with agonists of G alpha(q)-coupled receptors, and cellular redistribution of PKC isozymes was examined by immunoblotting. We find that stimulation of G alpha(q)-coupled receptors in human atrium activates PKC epsilon and delta only, under both acute (5 min) and longer (35 min) stimulations. Further, PKC epsilon and delta exhibit distinct subcellular redistribution patterns; while both translocate to the plasma membrane upon G alpha(q) stimulation, PKC delta also redistributes to mitochondria. We conclude that PKC epsilon and delta are the main PKC isozymes involved in G alpha(q)-mediated signaling in human atria.

Adult↗
PubMed2005

Cerebral physiology of cardiac surgical patients treated with the perfluorocarbon emulsion, AF0144.

BACKGROUND: Perfluorooctyl bromide is a biologically inert compound with short biologic retention and high oxygen solubility. The purpose of this study was to assess the effect of the perfluorocarbon emulsion, AF0144 (Perflubron, Alliance Pharmaceutical Corp, San Diego, CA), used in conjunction with acute normovolemic hemodilution on cerebral blood flow and cerebral emboli measurements during coronary artery bypass grafting with cardiopulmonary bypass. METHODS: Thirty-six adult cardiac surgical patients were enrolled in a single-institution, randomized, controlled, single-blind dose escalation trial. Autologous whole blood was harvested from each patient to target an on-bypass hematocrit of 20% to 22%. Placebo, low dose (1.8 g/kg) or high dose (2.7 g/kg) AF0144 was administered. Transcranial Doppler ultrasonography was used to quantitate cerebral emboli and xenon-133 clearance was used to measure cerebral blood flow. RESULTS: Cerebral blood flow was increased in both AF0144-treated groups compared with placebo (p = 0.006, low dose vs control; p = 0.036, high dose vs control). Numbers of cerebral emboli were greater in the high-dose AF0144-treated group versus control during the time periods from aortic cannulation through aortic cross-clamp placement (p = 0.026) and from aortic cross-clamp placement through cross-clamp removal (p = 0.008). CONCLUSIONS: The perfluorocarbon emulsion, AF0144, increased cerebral blood flow during cardiopulmonary bypass. In addition, total cerebral emboli load during bypass was greater in patients receiving high-dose AF0144.

Adult↗
PubMed2005

Differential cardiac gene expression during cardiopulmonary bypass: ischemia-independent upregulation of proinflammatory genes.

OBJECTIVE: Cardiac surgery with cardiopulmonary bypass induces both systemic and local inflammatory responses implicated in the pathogenesis of myocardial dysfunction. Multifactorial perioperative sources of myocardial injury complicate understanding of the molecular mechanisms involved. By using microarray technology, this study examines myocardial gene expression responses to cardiopulmonary bypass in the absence of cardioplegic arrest and ischemia-reperfusion injury. METHODS: We used a unique rat model of cardiopulmonary bypass in which sternotomy, direct operations on the heart, aortic crossclamping, and cardioplegic arrest were not performed. Hearts from 6 animals randomized to either 90 minutes of cardiopulmonary bypass or sham control animals were used to perform cDNA microarray analyses of 2343 genes. Real-time quantitative polymerase chain reaction was used to confirm the microarray results for a subset of genes. RESULTS: Compared with sham-operated control animals, myocardium from animals undergoing cardiopulmonary bypass revealed 42 differentially expressed genes. Upregulated genes include the transcription activator nuclear factor kappaB, adhesion molecules (vascular cell adhesion molecule 1 and P-selectin), and interleukin 6 receptor subunits; downregulated genes include transforming growth factor beta receptor 2, tissue inhibitor of metalloproteinase 3, and mitogen-activated protein kinase 1. Distinct proinflammatory gene cascades were confirmed by means of category overrepresentation analysis. CONCLUSIONS: This study represents an initial report on the use of microarray technology to elucidate cardiac transcriptional programs in response to cardiopulmonary bypass-specific injury in vivo. These preliminary findings, combined with future functional genomic studies superimposing ischemia and reperfusion and other inflammatory stimuli, should improve our understanding of the molecular regulatory networks involved in myocardial responses to injury and aid in the development of novel cardioprotective and perfusion strategies.

Animals↗
PubMed2005

Postoperative hyperthermia following off-pump versus on-pump coronary artery bypass surgery.

OBJECTIVE: Hyperthermia is common in the first 24 hours following coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB). An inflammatory response to CPB is often implicated in the pathophysiology of this fever. Unlike CABG with CPB, the temperature pattern after off-pump CABG (OPCAB), where CPB is avoided, has not yet been described. The purpose of this study was to describe the postoperative temperature pattern following OPCAB and to compare it with that following on-pump cardiac surgery. DESIGN: Retrospective, observational study. SETTING: Tertiary care university hospital. PARTICIPANTS: Consenting patients undergoing CABG or OPCAB procedures. INTERVENTIONS: Observational. MEASUREMENTS AND MAIN RESULTS: Of the CABG patients, 89% had temperature elevations above 38 degrees C, versus 44% of the OPCAB patients (P = 0.04). Peak body temperature was higher in the on-pump patients (CABG 38.5 degrees C +/- 0.4 degrees C versus OPCAB 37.9 degrees C +/- 0.5 degrees C; P = 0.002), as was the area under the curve for temperatures greater than 38 degrees C (CABG 1.6 +/- 1.7 degrees C/hr versus OPCAB 0.4 +/- 1.2 degrees C/hr; P = 0.02). CONCLUSIONS: Off-pump CABG surgery patients experience less hyperthermia compared with on-pump CABG patients. The reasons for a lower incidence and severity of hyperthermia after OPCAB surgery are not known, but may be related to a reduced inflammatory response.

Body Temperature↗
PubMed2005

Preoperative statin therapy does not reduce cognitive dysfunction after cardiopulmonary bypass.

OBJECTIVE: The purpose of this study was to determine if patients receiving statin therapy before coronary artery bypass grafting surgery would have less cognitive dysfunction after cardiopulmonary bypass as a consequence of a diminished inflammatory response. DESIGN: Retrospective observational study of patients undergoing coronary artery bypass grafting surgery. SETTING: Referral center for cardiothoracic surgery at a university hospital. PARTICIPANTS: Four hundred forty patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-five percent of patients received statins in the preoperative period. Multivariable analysis revealed no effect of preoperative statin therapy on cognitive function (p = 0.67). Post hoc analysis revealed that statin therapy at hospital discharge was associated with less improvement in cognitive performance at 6 weeks after surgery (p = 0.011). No significant differences were found between statin therapy groups in either range or maximum value of any of the cytokines (p > 0.05). CONCLUSIONS: Preoperative statin therapy did not decrease the inflammatory response to cardiopulmonary bypass or the cognitive dysfunction commonly seen after cardiac surgery.

C-Reactive Protein↗
PubMed2005

Xenon and the inflammatory response to cardiopulmonary bypass in the rat.

OBJECTIVE: The purpose of this study was to investigate the effect of xenon on the inflammatory response to cardiopulmonary bypass. DESIGN: Prospective, randomized experimental study. SETTING: University research laboratory. PARTICIPANTS: Sprague-Dawley rats. INTERVENTIONS: After surgical preparation, rats were randomly divided into 4 groups: (1) SHAM rats were cannulated but did not undergo cardiopulmonary bypass; (2) cardiopulmonary bypass rats were subjected to 60 minutes of cardiopulmonary bypass using an oxygenator receiving a 30% O(2), 65% N(2), and 5% CO(2) gas mixture; (3) MK801 rats received MK801 (0.15 mg/kg intravenous) 15 minutes before 60 minutes of cardiopulmonary bypass with the same gas mixture; and (4) xenon rats underwent 60 minutes of cardiopulmonary bypass receiving a 30% O(2), 60% xenon, 5% N(2), and 5% CO(2) gas mixture. MEASUREMENTS AND MAIN RESULTS: All bypass groups showed elevations in both cytokines compared with the SHAM-operated group. However, the inflammatory response to cardiopulmonary bypass in the group receiving xenon was no different from the other bypass groups. CONCLUSIONS: Xenon appears to have no effect on the inflammatory response to cardiopulmonary bypass, making its previously described neuroprotective effect during cardiopulmonary bypass likely independent of any inflammation modulation.

Anesthesia, Inhalation↗