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Objectives: Risk scoring models (RSMs) are commonly used for estimation of postoperative-mortality risk in patients undergoing cardiac surgery, but their prediction accuracy may vary in different populations and clinical situations. The prognostic accuracies of some RSMs have not yet been fully evaluated in the Australian population. In this retrospective observational study, our aims were to assess the performance of four contemporary RSMs, to identify the best RSMs for prediction of postoperative-mortality in the single-centre cohort, and to determine a statistical threshold for classification of patients with increased or "higher" mortality risk., Methods: The study population included patients who underwent cardiac surgery at Liverpool Hospital between January 2013 and December 2014. Demographic information was collected, and mortality risks were estimated with the ES2 (EuroSCORE II), STS (Society of Thoracic Surgeons Score), AS (AusSCORE total) and ASMR (AusSCORE multi-risk) RSMs. (Additive EuroSCORE) (AES) and LES (logistic EuroSCORE) were included for historical interest. Discrimination, the ability to stratify patients between mortality and no mortality outcomes, and calibration, the comparison of risk score estimated and observed outcome in the population, were evaluated for each RSM, to determine their predictive accuracy in the study population. Discrimination was assessed by the AUC (area under the receiver operating characteristic curve), and acceptable calibration by the p-value greater than 0.05 for the Hosmer-Lemeshow (H-L) test. The best AUCs in contempory models were compared using the DeLong test. For ES2 and STS risk scores, cut-off points, or thresholds, for patients at increased risk of mortality were derived using Youden's J-statistics, calculated from sensitivity and specificity of models in predicting mortality., Results: From a total study population of 898 patients, 738 had scores for all six RSMs. The three EuroSCORE risk models and Youden's J-statistics analysis included the total population. Of the models in contemporary use, ES2 had higher discrimination (AUC=0.850) in this population than ASMR (AUC=0.767, p=0.024) and AS (AUC=0.739) and non-significantly higher discrimination than STS (AUC=0.806, p=0.19). All contemporary models had acceptable calibration but the older LES (H-L p=0.024) did not. Estimated mortality was closest to observed mortality with the ES2 model. Both AES and LES over predicted mortality. The RSM with the highest discrimination in isolated coronary artery bypass graft surgery (CAGs) (AUC=0.847), isolated valves (AUC=0.830), and females (AUC=0.784) was the ES2 model. STS discrimination was highest in CAGs plus valve procedures (AUC 0.891), and males (STS AUC=0.891). Cut-off points for risk scores to define increased risk populations were 3.0% for ES2 and 1.7% for STS. Similar proportions of patients in each RSM (ES2-26% to STS-32%) were defined as higher risk by the model threshold score depending on type of procedure., Conclusion: Among RSMs in contemporary use, ES2 and STS showed the best discrimination and acceptable calibration. Caution is recommended in specific subgroups. Increased mortality risk score cut-off points could be identified for these two RSMs in this single-centre cohort., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To assess predictive factors of postoperative stroke in cardiac surgery using cardiopulmonary bypass (CPB)., Design: This study was a retrospective observational study., Setting: This study was conducted at a single institution (Liverpool Hospital, NSW, Australia)., Participants: All patients with CPB treated surgically at Liverpool Hospital, NSW, between January 2016 and December 2018 INTERVENTIONS: Patients underwent cardiac surgery with CPB., Measurements and Main Results: The primary outcome was cerebrovascular accident, or stroke. Univariate and multivariate analyses via Firth's logistic regression with regard to stroke were performed. The study comprised 1,092 patients over a three-year period. In this cohort, the stroke rate was 3.1%. Via univariate analysis of factors in relation to stroke post-CPB, recent or past stroke (odds ratio [OR] 5.43 v 2.32), diabetes mellitus (OR 1.92), dialysis dependence (OR 5.67), elective procedures (OR 0.34), aortic procedures (OR 4.02), bypass and cross-clamp times (OR 1.02 and 1.04), postoperative atrial fibrillation (OR 2.28), and hypoperfusion times all reached the significance level of p ≤ 0.1 to be included in the multivariate analysis. Multivariate analysis to find independent factors in relation to stroke yielded diabetes mellitus (OR 2.49; p = 0.025), dialysis dependence (OR 3.82; p = 0.03), aortic procedures (OR 3.93; p = 0.014), and elective procedures (OR 0.24; p = 0.026) as independently predictive or protective with regard to postoperative stroke., Conclusions: Independent predictors of stroke in this single center cohort included dialysis dependence, diabetes, and aortic procedures. Elective procedures were shown to be an independent protective factor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cardiac surgery results in complications for some patients that lead to a longer hospital stay and higher costs. This study identified the presurgery characteristics of patients that were associated with the cost of their hospital stay and estimated how much of that cost could be attributed to a bleeding event, defined as requiring 3 units or more of packed red blood cells or returning to the operating room for bleeding. We also identified the presurgery characteristics that were associated with the bleeding event., Methods: This prospective cohort of patients (n = 1459) underwent cardiac surgery at 3 tertiary referral hospitals in Australia during 2014 and 2015. Clinical data included the variables held by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons registry. Cost data were collected as part of a state-level hospital data collection., Results: Many of the baseline patient characteristics were associated with the total cost of cardiac surgery. After adjusting for these characteristics, the cost of cardiac surgery was 1.76 (confidence interval, 1.64-1.90) times higher for patients who had a bleeding event (P < .001), thus resulting in a median increase in costs (in Australian dollars) of $33,338 (confidence interval, $21,943-$38,415). Several baseline characteristics were strongly associated with a bleeding event., Conclusions: The impact of a bleeding event on the cost of cardiac surgery is substantial. This study identified a set of risk factors for bleeding that could be used to identify patients for discussion at the heart team level, where measures to minimize the risk of transfusion may be initiated., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Identifying predictors of bleeding in patients before coronary artery bypass grafting surgery is important, given the complications of bleeding and finite supply of blood. Patient response to aspirin is heterogeneous and can be evaluated using point-of-care platelet function tests. We postulated that patients who hyper-respond to aspirin given preoperatively, as identified by VerifyNow® Aspirin assay (Accumetrics, Inc., San Diego, CA, USA), are at increased risk of bleeding and transfusion., Methods: This prospective pilot study examined response to aspirin in patients undergoing coronary artery bypass grafting surgery (n = 61) from 2009 to 2013. Patients with aspirin reaction unit (ARU) values in the lower 50 th percentile as identified by VerifyNow® assays were defined as aspirin hyper-responders. The proportion of patients transfused and the median adjusted indexed drop in haemoglobin were compared between aspirin hyper-responders and non-hyper-responders. Logistic regression was performed to determine factors associated with increased risk of transfusion., Results: Seventy per cent (70%) of aspirin hyper-responders were transfused perioperatively compared with 39% of patients who did not hyper-respond, (OR 3.694, 95% CI 1.275-10.706, p = 0.014). VerifyNow® Aspirin hyper-responders had a greater median adjusted indexed drop in haemoglobin compared to non-hyper-responders (34.1 g/L versus 26.6 g/L respectively, p = 0.032). Multivariate analysis also showed VerifyNow® Aspirin hyper-response to be an independent predictor of transfusion (p = 0.016). Other variables such as age, gender, body mass index, renal insufficiency, and cross clamp and bypass times were not predictors of postoperative bleeding in this pilot cohort., Conclusions: VerifyNow® Aspirin is able to preoperatively identify aspirin hyper-responders at an increased risk of bleeding and subsequent transfusion in the context of coronary artery bypass graft surgery., (Copyright © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-Vessel Disease (FREEDOM) clinical trial randomized only a proportion of screened patients with diabetes mellitus (DM) and multi-vessel disease (MVD)., Methods and Results: We determined late rates of death, non-fatal myocardial infarction (MI) and stroke in all 430 patients with DM who had MVD identified on angiographic screening for the FREEDOM Trial, which recruited from June 2006 -March 2010 at Liverpool Hospital, Sydney, Australia. Mortality at 6 years [median] was 23% among 192 FREEDOM-eligible patients and 26% among 238 FREEDOM-ineligible patients, of whom 139 [58%] had prior. CABG (mortality 31%). Overall, 196 (45%) had percutaneous coronary intervention (PCI), 127 (30%) underwent coronary artery bypass grafting (CABG) (who were 4 years younger; p = 0.003), and 107 (25%) had neither procedure of whom 80 were considered unsuitable for revascularization. Mortality was 26% post-PCI 16%, post-CABG and 33% among those who did not undergo revascularization (p = 0.01). On multivariable analyses, factors associated with late mortality were older age, hypertension and not undergoing CABG (all p < 0.05). Factors associated with late MI were presented with an acute coronary syndrome, whereas patients that underwent treatment with either PCI or CABG had less late MI (all p < 0.05)., Conclusion: Among consecutive diabetic patients with MVD, at a median of 6-years CABG was associated with better survival and fewer non-fatal MI outcomes compared to PCI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the effects of continuous infusion of ropivacaine compared to sham infusion or usual care on pain scores before and after physiotherapy treatment, distance walked and time to discharge from physiotherapy, after coronary artery bypass graft (CABG) surgery., Design: Prospective, randomised, double blind controlled trial., Setting and Participants: Seventy-five participants who underwent CABG surgery with left internal mammary artery grafts were allocated, to the ropivacaine group (n=26), the sham group (n=25), or usual care group (n=24). Participants in the ropivacaine group received 0.5% ropivacaine and participants in the sham group received normal saline, both as continuous infusions via two parasternally tunnelled catheters for 96hours continuously. The usual care group did not receive a device. All groups had patient-controlled analgesia and/or oral analgesia., Results: Seventy-two participants completed the study. There was no significant between-group differences in pain scores, distance walked on any post operative day (POD) or number of participants discharged from physiotherapy by POD 4. For the group as a whole there was a significant linear decrease in pain score from mean (SD) 42 (24) mm on POD1 to 15 (16) mm on POD4 (p<0.001), (MD 27mm, 95% CI 22 to 32) and walking distance increased from 1 (5) m on POD1 to 183 (239) m on POD4 (p<0.001) MD 181m, 95% CI 126 to 236)., Conclusion: Infusion of ropivacaine post CABG surgery was unable to reduce pain, increase distance walked or reduce time to physiotherapy discharge compared to sham or usual care. Trial registration number ACTRN12612001243808., (Copyright © 2017 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Aims: The Warfarin Self-Management Anticoagulation Research Trial (Warfarin SMART) was designed to determine whether patients self-managing warfarin (PSM) using the CoaguChek device and a dosing algorithm developed for the trial could keep the INR (International Normalised Ratio) test in target range at least as often as patients managed by usual care by the family doctor or hospital clinic., Methods and Results: 310 patients were randomly assigned to PSM or usual care. The PSM group was trained to perform home INR testing and warfarin dosing using a validated ColourChart algorithm. The primary endpoint was the proportion of times over 12 months that a monthly, blinded "outcome INR test", measured in a central laboratory, was outside the patient's target therapeutic range. The rate of out-of-range outcome INRs was lower in PSM, and non-inferior to the usual care group (PSM: 36% vs. usual care: 41%, P<0.001 for non-inferiority; P=0.08 for superiority in closed-loop testing). The deviations from the patient's midpoint of target INR range (P=0.02) and number of extreme INRs (P=0.03) were significantly less in the PSM group than the usual-care group. There was no significant difference between groups in rates of bleeding or thrombotic adverse events., Conclusion: Patient self-management performed at least as well as usual care in maintaining the INR within the target range, without any safety concerns. This treatment modality for the long-term use of warfarin has the potential to change current local and international practice., (© 2013.)

There is little information on whether identification of multi-vessel disease (MVD) in patients with diabetic mellitus (DM) affects risk factor management. From 1125 consecutively screened patients between June 2006 and March 2010, we examined 227 diabetic patients with MVD on coronary angiography. Diabetic control and cholesterol levels were assessed by glycated haemoglobin (HbA1c) and total cholesterol (TC) respectively which were evaluated at baseline and at 1-year follow-up. Patients were grouped by age into <55(n=33), 55-65(n=75), 66-75(n=75) and >75(n=44). Target levels were defined as HbA1c<7% and TC<4.0 mmol/L. Patients <55 years had the highest HbA1c at 9.1[7.6-11.2]% with the lowest proportion of patients (n=3; 11.1%) within target at baseline, while 66-75 years had the best HbA1c at 7.1[6.4-7.8]% with the highest proportion (n=28, 45.2%) reaching target (p<0.0001). At 1-year, the poorest HbA1c control was again observed in the age <55 with fewer patients achieving target compared to the 66-75 age group (HbA1c: 8.5% vs 6.9%; % of patients at target: 20.7% vs 54.5%; p<0.0001). Furthermore, the group <55 years demonstrated the worst TC control at 1-year with a significant increase compared to the baseline TC (p=0.01). Patients with a lower body mass index (BMI) were likely to have an improvement in HbA1c and reach target (p=0.01). Paradoxically, patients who were current smokers demonstrated a beneficial effect on optimal TC control (29.2% vs 15.4%, p=0.027). In younger diabetic patients, risk factor modification at 1-year was poor despite identification of MVD. Developing an effective education and monitoring programme to improve glycaemic control in this high risk group should be a priority., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Clinical outcomes in patients with diabetes mellitus and multivessel disease (MVD) undergoing coronary revascularization have not been extensively evaluated, we sought to examine outcomes in a diabetic cohort of 195 consecutive patients with MVD characterized by SYNTAX scores (SSs) undergoing nonrandomized revascularization, 102 (52%) by percutaneous intervention (PCI) and 93 (48%) by coronary artery bypass grafting (CABG) at Liverpool Hospital (Sydney, Australia) from June 2006 to March 2010. Clinical outcomes were assessed at a median term of 14 months. The overall median SS was 44, with significantly higher SSs in CABG- than PCI-treated patients (48 vs 39, p <0.0001). There was a similar incidence of all-cause death, nonfatal myocardial infarction and stroke in PCI- and CABG-treated patients (6.1% vs 8.3%, p = 0.383; 12% vs 4.9%, p = 0.152; 3.1% vs 3.5%, p = 0.680 respectively). However, the rates of target vessel revascularization and major adverse coronary and cerebral event were significantly higher in PCI-treated patients than in those undergoing CABG (20% vs 1.2%, p <0.0001; 29% vs 15%, p = 0.034). Despite a much higher SS, patients who underwent PCI achieved comparable outcomes at 1 year to those with diabetes mellitus and a SS ≥ 33 as reported in the SYNTAX trial. In conclusion, in this single-center nonrandomized observational study, coronary revascularization by PCI is associated with increased major adverse coronary and cerebral events at 1-year follow-up, predominantly driven by a high rate of target vessel revascularization. Thus, CABG should remain the revascularization procedure of choice for diabetic patients with MVD and high SSs., (Copyright © 2012. Published by Elsevier Inc.)

Background and Aim of the Study: The association between aortic valve allograft dysfunction in patients with long-term follow up and human leukocyte class 2 antigen donor/recipient mismatch suggests that elements of the anti-donor immune response penetrate and damage the aortic valve allograft. An aortic valve allograft recipient cohort was studied to determine whether presence of recipient antibodies to donor human leukocyte class 1 or 2 antigen was associated with shorter time to aortic valve allograft dysfunction., Methods: Both donor and recipient human leukocyte antigen (HLA) type, HLA antibody information and echocardiography data were available for 148 recipients of cryopreserved aortic valve allografts between 1986 and 1998. Structural deterioration of the aortic valve allograft was defined as at least moderate aortic stenosis or regurgitation by echocardiography. Recipient sera were assayed for anti-HLA (class 1 and 2) antibodies using three assays: complement-dependent cytotoxicity (CDC) on T- and B-lymphocyte panels (CDC PRA); flow cytometry using HLA-coated beads (Flow PRA); and an ELISA using HLA-coated microwells. The donor specificity of anti-class 1 and 2 HLA antibodies was determined on T- and B-cell panels using CDC. Associations between the results of the three assays and donor-specific class 1 and 2 antibodies and time to structural deterioration were analyzed using Kaplan-Meier curves of freedom from structural deterioration. Cox proportional-hazards were used to determine independent predictors of time to structural deterioration., Results: Patients highly positive for HLA class 2 antibodies using an ELISA had a significant association (p = 0.007) with shorter time to aortic valve allograft structural deterioration using both a log rank test and Cox proportional-hazards analysis. Patients (n = 15) with donor-specific antibodies to class 2 antigen (DR antigens) had significantly more structural deterioration (p = 0.035) than those without specific antibodies., Conclusion: The association between aortic valve allograft structural deterioration and high titer human leukocyte class 2 antigen antibodies, a subset detected by ELISA adds further information about the link between HLA class 2 mismatch and structural deterioration. Further studies are needed to confirm the importance of class 2 antibodies on outcome, and to determine by which method these antibodies should be detected. Potential recipients with pre-existing antibodies of these specific types might be expected to sustain accelerated allograft damage.

A 47-year-old man had an ICD system with epicardial and endocardial components and an abdominal generator placed in 1990 following a cardiac arrest. Ten years later his BT10 lead was amputated due to an insulation defect, and he received a new pectoral generator with transvenous leads. A few months later he developed fevers, chills, and bacteremia. Evaluation demonstrated migration of the entire BT10 lead into the right atrium. Complete surgical explantation was required and the bacteremia resolved. This case illustrates the importance of solid anchoring of distal lead components following generator removal and the potential complication of intravascular lead migration.

Penetrating wounds to the heart represent a significant surgical challenge because of their unique clinical course and the need for emergent operative care. This operative care, which may include cardiopulmonary bypass (CPB), must be initiated in a prompt yet careful fashion to optimize outcome, while minimizing morbidity. Trauma, because of its unpredictable and non-routine nature, may present many challenges to the perfusionist in an attempt to anticipate surgical needs and requirements. In this case report, we describe the successful surgical repair of a cardiac nail gun injury, as well as strategies we feel are essential for the safe, successful, and timely application of emergent CPB.

Background: The recommended dose of aprotinin has been shown to reduce blood loss and need for blood transfusions, but the cost precludes its routine use. This study was designed to determine whether a less expensive, ultra-low dose of aprotinin is effective when used in coronary artery bypass grafting with left internal mammary artery., Methods: Patients (n = 202) were randomized to receive either placebo or aprotinin, 0.5 million KIU before incision and 0.5 million KIU during initiation of cardiopulmonary bypass. Differences in quantity of blood transfused were analyzed. Further groups were analyzed to account for the effect of aspirin. Multivariable analysis was performed to determine risk factors for transfusion. Direct costs of blood products and aprotinin were tabulated for each group., Results: There was an important reduction in the proportion of patients transfused, and number of blood units transfused when aprotinin was given before coronary artery bypass grafting. These differences were even more important in patients on aspirin preoperatively. Independent predictors for increased number of transfusions were aspirin continued before operation, smaller body surface area, and the use of placebo instead of ultra-low dose aprotinin. There was no difference in morbidity between treatment groups. There was a reduction in direct costs associated with the use of aprotinin., Conclusions: These data support the routine use of aprotinin 1 million KIU in coronary artery bypass grafting with left internal mammary artery to reduce cost and transfusion requirements.

Background and Aim of the Study: Evidence suggests that the implanted aortic valve homograft suffers eventual loss of function due to early donor-specific antibody and T cell-mediated responses to human leukocyte antigens (HLA). The association between rejection/dysfunction and donor/recipient HLA mismatch for vascularized organ homografts has not been revealed for aortic valve homografts. An aortic valve homograft recipient cohort was studied to determine whether HLA mismatch and associated factors predicted homograft dysfunction., Methods: Both donor and recipient HLA type was obtained for 162 recipients of cryopreserved aortic valve homografts between 1986 and 1998. Structural deterioration of the homograft was defined by echocardiography as at least moderate aortic stenosis or regurgitation. Patients' records were searched for postoperative fever, ABO blood type disparity, and other associated factors. HLA class 1 (A and B antigens) were typed serologically, and HLA class 2 (DR antigens) by molecular genotyping. Associations were analyzed using chi-square tests and Kaplan-Meier curves of freedom from structural deterioration in all patients, and in those with > or =5 years of follow up. Cox regression was used to determine independent predictors of structural deterioration., Results: Class 2 antigen mismatch had a significant association (p = 0.04) with decrease in cryopreserved aortic valve homograft freedom from structural deterioration in patients with long-term follow up (> or =5 years). In addition, there was an important difference in frequency of postoperative fever in recipients with two DR mismatches (31.2%), and in those with no or one DR mismatch (16.9%; p = 0.051). Significant associations were not found between homograft dysfunction and HLA mismatch at the class-1 loci. Young age at operation and short time (<4 h) between homograft procurement and cryopreservation were associated with an increase in structural deterioration., Conclusion: The association between aortic valve homograft dysfunction and HLA DR mismatch suggests that elements of the anti-donor immune response penetrate and damage the homograft. A similar link to postoperative fever indicates that immune stimulation may be an early event. Further investigation will reveal the exact pathways by which this occurs and by which therapy (immunosuppression of the recipient, genetic engineering of the donor graft, or other techniques) this recipient anti-donor response can be modified.

Background: Pulmonary hypertension after cardiopulmonary bypass is a common problem in pediatric cardiac operations. This study tested the hypothesis that there is a difference between adult and immature pulmonary artery constrictor and dilator responses., Methods: Reactivity of pulmonary artery ring segments from 22 mature (15 to 19 weeks) and 15 immature pigs (4 to 5 weeks) was tested in a vessel myograph. Potassium as a receptor-independent vasoconstrictor and phenylephrine as an alpha-receptor-mediated vasoconstrictor were used to assess smooth-muscle vasoconstriction. To assess endothelial cell function (nitric oxide production and secretion), we used increasing concentrations of bradykinin or acetylcholine. Sodium nitroprusside was used to produce maximum smooth-muscle relaxation at the end of each experiment., Results: The data demonstrated maturation-independent endothelium and smooth-muscle-mediated vasodilation. Pulmonary artery ring segments from immature pigs had significantly less KCl constriction compared with mature pigs (p < 0.05). In contrast, pulmonary ring segments from immature pigs demonstrated enhanced alpha-receptor-mediated constriction compared with mature pigs., Conclusions: These data may explain perioperative pulmonary vasoconstriction in pediatric patients.

A substantial increase in pulmonary vascular resistance is associated with sepsis and its sequelae (sepsis syndrome and septic shock). It is postulated that increased resistance may result from sepsis-induced endothelial cell injury or altered vasoreactivity secondary to pulmonary hypertension. We, therefore, tested the hypothesis that sepsis causes endothelial cell injury and that increased pulmonary pressure alters vascular reactivity. Young swine (15-25 kg) were anesthetized and ventilated. Septic animals received a 1-hr infusion of live Pseudomonas aeruginosa (n = 11), and the control cohort received 0.9% NaCl (n = 7). All animals were studied for 300 min following the infusion. Postmortem branches of peripheral pulmonary arteries were prepared and tested in a vessel myograph. Ring segments were set to 90% of the circumference the vessels would have at pressures of 20, 30, 40, or 50 mmHg (L90), corresponding to varying pulmonary pressures observed in sepsis. A high dose of potassium was used to obtain maximum possible contraction. Prostaglandin was used to precontract the vessels before testing endothelial cell responses to acetylcholine or bradykinin. Sodium nitroprusside was added at the end of each experiment to obtain maximum possible smooth muscle relaxation. No differences in contraction or relaxation were observed when vessels were set to different pressures (i.e., 20 vs 50 mmHg). Maximum possible contraction to KCl was significantly decreased after 300 min of sepsis compared to control. No differences between groups were found in contractility to prostaglandin. Bradykinin-induced EDRF/NO production, mediated by BK2 receptors, was not altered in Pseudomonas sepsis (97-98% of total relaxation control and 91-95% septic cohort). Response to acetylcholine was significantly decreased after sepsis (89-95% of total relaxation control and 51-61% of septic cohort relaxation). Decreased response to acetylcholine could not be attributed to decreased smooth muscle sensitivity to nitric oxide because the response to bradykinin plus sodium nitroprusside was not altered following sepsis. Vessel reactivity was not altered by increasing pressure settings reflective of changing pulmonary pressure in vivo. These results strongly suggest a sepsis-induced alteration in pulmonary artery endothelial cell receptor sensitivity to acetylcholine, independent of changing pulmonary arterial pressures. This is the first time this decrease has been shown in pseudomonas sepsis.

Endothelium-mediated relaxation and smooth muscle function in large coronary arteries are resistant to prolonged global ischemia. We used a small-vessel myograph to test the hypothesis that small intramyocardial artery endothelium and smooth muscle function have greater sensitivity to ischemic injury than large artery endothelium and smooth muscle. Normothermic global ischemia was induced in 15 porcine hearts. Intramyocardial arterial ring segments were assessed at 0, 30, 60, 90, and 120 minutes of ischemia in vitro with a small-vessel myograph. Potassium determined smooth muscle contraction, bradykinin endothelium-mediated relaxation, and sodium nitroprusside direct smooth muscle relaxation. Endothelium-mediated relaxation after 30 minutes of ischemia was similar to control (56% versus 66%) but was impaired at 60, 90, and 120 minutes of ischemia (32%, 11%, and 6%). Smooth muscle contraction was unchanged at 30 and 60 minutes compared with control (56 and 53 versus 63 mm Hg) but was significantly decreased at 90 and 120 minutes (33 and 13 mm Hg). Direct smooth muscle relaxation was significantly decreased at 120 minutes of ischemia compared with control (58% versus 95%). In a previous study, epicardial coronary artery endothelium-mediated smooth muscle vasodilation and direct smooth muscle vasodilation were preserved until 160 minutes of ischemia. After 160 minutes of ischemia, endothelium-mediated relaxation was lost and only direct smooth muscle vasodilation was preserved. In contrast to vasodilation, vasoconstriction was significantly reduced at 140 minutes of ischemia. These data indicate a greater and earlier adverse effect of ischemia on intramyocardial arterial endothelium-mediated relaxation than smooth muscle contraction or relaxation. These data support the hypothesis that there is an early functional endothelial cell injury associated with global ischemia. Relaxation that is endothelium-dependent in intramyocardial arteries is more sensitive to ischemic injury than in epicardial arteries. Unique to this study was the evaluation of small intramyocardial arteries (281 +/- 29 microns) that are the primary sites of coronary vascular resistance. Microvascular endothelial dysfunction after ischemia, therefore, may contribute to the "no-reflow phenomenon" seen during reperfusion injury.

Activated neutrophils have been implicated in reperfusion injury and the no-reflow phenomenon of intramyocardial arterioles. This study tested the hypothesis that ischemia and activated neutrophils impair coronary endothelial and smooth muscle cell function of epicardial and intramyocardial coronary arteries. Alteration of smooth muscle and endothelial cell function in epicardial coronary arteries (3 mm diameter) and intramyocardial coronary arteries (0.3 mm diameter) was compared by means of a myograph after exposure to ischemia (epicardial, 160 minutes, intramyocardial, 30 minutes), activated neutrophils, and combined ischemia and activated neutrophils. Morphologic studies at the ultrastructural level were done by means of scanning electron microscopy. Epicardial coronary artery function was normal after ischemia, storage with activated neutrophils, and ischemia followed by storage with activated neutrophils. Intramyocardial artery function, however, was altered. Contraction to a 45 mmol/L concentration of potassium chloride after ischemia and storage with activated neutrophils was increased (p = 0.06). Smooth muscle relaxation was significantly decreased after ischemia, but storage with activated neutrophils did not further decrease smooth muscle relaxation. Endothelium-dependent relaxation to bradykinin was significantly decreased after combined ischemia and incubation with activated neutrophils (p < 0.05). Sensitivity to bradykinin was decreased after both ischemia alone (p < 0.05) and activated neutrophils alone (p < 0.05). Similar morphologic alterations were found in epicardial and intramyocardial arteries after ischemia. Activated neutrophils alone minimally damaged endothelial cells of nonischemic intramyocardial and epicardial arteries. Endothelial cells of both arteries exposed to ischemia alone showed evidence of ischemic damage, including endothelial cell blebbing, nuclear bulging, and appearance of large holes in the cell surface. Severe endothelial cell damage was found after combined ischemia and storage with neutrophils: total destruction of cells and exposure of the basal lamina. Endothelial damage, therefore, correlated with artery function in intramyocardial but not in epicardial arteries. These results indicate that ischemia is a prerequisite for severe neutrophil injury of intramyocardial artery endothelium-mediated relaxation. This may explain no-reflow phenomenon in arterioles concurrent with myocardial reperfusion injury.

Orotic acid accelerates compensatory myocardial hypertrophy after regional ischemia and improves left ventricular function acutely after global ischemia. In this study, the effect of orotic acid on left ventricular function was investigated 4 days after global ischemia (75 minutes, 21 degrees C) using heterotopically transplanted rabbit hearts (n = 18). Experimental animals received daily 100-mg/kg doses of intraperitoneally administered orotic acid, starting 1 day before transplantation, and showed a threefold increase in the serum level of orotic acid by 4 days. After 1 hour of reperfusion, the developed pressure was equally depressed in both the control and experimental groups; however, 4 days later, the developed pressure in control animals was decreased by 3 +/- 3 mm Hg (versus the developed pressure measured at 1 hour) while the developed pressure in experimental animals was significantly increased by 25 +/- 8 mm Hg. Heterotopically transplanted hearts manifested diminished systolic function (stemming from ischemia and unloading) as well as decreased expression of adult myosin. Because orotic acid has been observed to produce an increase in protein synthesis in other models, we investigated whether this improvement in systolic function resulted from an orotic acid-mediated augmentation (or preservation) or normal adult myosin expression. Both orotic acid-treated and untreated hearts manifested decreased expression of the beta-myosin heavy chain protein and steady-state messenger RNA levels. Because function improved with decreased beta-myosin heavy chain expression, an alternate mechanism underlying orotic acid-mediated improvement in function is implicated. Nevertheless, orotic acid may be a therapeutic agent facilitating long-term recovery from global ischemia.

Cardiopulmonary bypass causes a "euthyroid-sick" state characterized by low levels of circulating triiodothyronine. Triiodothyronine supplementation in this setting has been postulated to improve postischemic left ventricular function by increasing the availability of myocardial high-energy phosphates. These postulates have not been substantiated, however, using load-independent parameters of left ventricular function and analysis of high-energy phosphate metabolism. To test these hypotheses, 14 healthy pigs (30 to 40 kg) were placed on cardiopulmonary bypass and instrumented with left ventricular minor-axis ultrasonic crystals and micromanometer-tipped pressure catheters. Hearts were subjected to 30 minutes of global, normothermic ischemia. Triiodothyronine (0.1 mg/kg; n = 7) or placebo (n = 7) was administered in a random, investigator-blinded fashion at the removal of the aortic cross-clamp and after 60 minutes of reperfusion. Hemodynamic, metabolic, and ultrastructural data were obtained before ischemia and after 30, 60, 90, and 120 minutes of reperfusion. By 90 minutes of reperfusion left ventricular contractility had returned to preischemic levels in hearts supplemented with triiodothyronine, despite postischemic myocardial adenosine triphosphate levels of 50% to 60% of baseline in both groups. Ultrastructurally, the sarcoplasmic reticulum and mitochondria were significantly better preserved in the group treated with triiodothyronine. This study suggests that triiodothyronine supplementation significantly enhances postischemic left ventricular functional recovery and that this recovery is due to mechanisms other than enhanced availability of myocardial high-energy phosphates.

The marked edema observed in neonatal cardiopulmonary bypass is thought to result from pathologic increases in capillary permeability. Pentafraction is a subfraction of hydroxyethyl starch that is thought to be of appropriate size and shape to be retained by leaking capillaries and seal endothelial gaps in capillary basement membranes. To test the hypothesis that pentafraction would reduce edema in neonatal cardiopulmonary bypass, we established a model of edema formation in neonatal bypass in which neonatal piglets underwent 2 hours of normothermic cardiopulmonary bypass with crystalloid prime and no myocardial ischemia. Before initiation of bypass, experimental animals (n = 11) received intravenous pentafraction, 3 gm/kg. Control animals (n = 10) received an equivalent volume of saline. Hemodynamic parameters, animal weight, fluid redistribution, and percent tissue water of individual organs were assessed during and after bypass. Pentafraction treatment resulted in significant differences in (1) lowered percent body weight gain from baseline (11% versus 48%), (2) lowered volume requirement to maintain venous reservoir during cardiopulmonary bypass (148 ml/kg versus 581 ml/kg), (3) less fluid loss from the peritoneum (11 ml/kg versus 115 ml/kg), and (4) lowered percent tissue water of kidney, pancreas, stomach, jejunum, colon, and skeletal muscle (p less than 0.05 by unpaired t test). Pentafraction had no effect on hemodynamic parameters during bypass nor in percent tissue water of heart, lung, liver, spleen, skin, or brain. In summary, pentafraction lessened weight gain and fluid requirements during cardiopulmonary bypass, favorably influencing the percent tissue water of certain organs. If pentafraction functions as proposed, it may have wide applicability not only in cardiopulmonary bypass (or extracorporeal membrane oxygenation) but also in other clinical scenarios with altered capillary permeability.

We tested the hypothesis that 3,4,5,-trihydroxybenzamidoxime (VF 233), a demonstrated hydroxyl radical scavenger and an effective Fe3+ chelator, attenuates reperfusion injury and improves isovolumic left ventricular function. Eighteen isolated, perfused rabbit hearts with intracavitary balloons were subjected to normothermic, global ischemia until the initiation of ischemic contracture. Effects on the adenine nucleotide pool metabolites were determined by high-pressure liquid chromatography from right ventricular biopsy specimens before ischemia and at 15-minute intervals throughout reperfusion. In the experimental group (n = 9), a 5-mL bolus of 1 mol/L VF 233 was given immediately before reperfusion and followed by a continuous infusion (0.125 mumol/min). The control group (n = 9) received the vehicle solution at identical times. Rabbits treated with VF 233 had significant improvement in left ventricular function (expressed as percent return of left ventricular peak developed pressure) within 15 minutes of reperfusion (55.0 +/- 3.0 versus 66.2 +/- 4.1; p less than 0.05 by analysis of variance) after global ischemia and remained significantly improved throughout the reperfusion period. Myocardial adenine nucleotide pool intermediates were not significantly different between groups. These results demonstrate that administration of VF 233 significantly improves ventricular function but does not affect adenine nucleotide metabolism after ischemia and reperfusion.

Internal mammary arteries (IMAs) from women and the elderly have been postulated to be smaller and more reactive than IMAs from men and younger patients and, therefore, not as reliable for coronary artery bypass grafting in the short term. This study tests the physiologic basis for that hypothesis. Trimmed IMA segments were obtained from patients aged 50 to 76 years at coronary artery bypass grafting. Eighteen ring segments from 12 women and 35 ring segments from 17 men were mounted on a strain-gauge apparatus, and internal diameter at a transmural pressure of 100 mm Hg was determined from length-tension curves. Contractions to potassium chloride and a dose-response curve to norepinephrine or serotonin were obtained to simulate physiologic vasospasm. Sodium nitroprusside determined arterial relaxation. Linear regression was used to determine correlation of these parameters with age. Internal mammary arteries from women and men were of equal size. They had equal strength of contraction to potassium chloride and norepinephrine, but female IMAs had greater strength of contraction to serotonin. Female IMAs had weaker contraction to norepinephrine as a percent of maximum contraction to potassium chloride than IMAs from men. Internal mammary arteries from women had equal relaxation to sodium nitroprusside compared with IMAs from men. There was no correlation between age and arterial reactivity to vasoconstrictors, relaxation to sodium nitroprusside, or size. These data suggest that IMAs from women and the elderly are not more susceptible to reduction in flow due to smaller size. Postoperatively, it may be important that women be kept on platelet inhibitors because of their greater absolute contraction to serotonin and men on nitrovasodilators because of their greater relative contraction to norepinephrine.

Myocardial dysfunction and subendocardial ischemia have been described during hemorrhagic shock, but technical limitations have precluded the in vitro examination of coronary reactivity following hemorrhage. We tested the hypothesis that in vitro coronary artery contraction and relaxation are impaired by hemorrhagic shock (HS). HS was produced in awake rats (n = 6) 24 hr after surgery for arterial cannulation, by bleeding to a mean arterial pressure of 50 mm Hg for 2 hr followed by reinfusion of shed blood. Using a small vessel myograph, reactivity of coronary arterial ring segments from three groups of rats not undergoing HS were compared to coronaries harvested from rats after HS (Group 4). The three nonshock treatments included normal rats without pretreatment (Group 1), rats undergoing prior surgical cannulation alone (Group 2), and rats undergoing prior surgical cannulation followed by nonhypotensive hemorrhage (Group 3). Responses to 125 mM potassium (KCl) and to 10(-6) M serotonin (STN) determined smooth muscle contraction. Acetylcholine administration determined endothelium-mediated smooth muscle relaxation, whereas acetylcholine plus nitroprusside combined determined maximum smooth muscle relaxation. Rats following HS demonstrated impaired coronary arterial smooth muscle contraction to KCl when compared to normal rats, but the response to STN did not differ among groups. Maximum smooth muscle relaxation was significantly lower in rats following HS as compared to rats in Groups 1 and 2. Endothelium-dependent relaxation was significantly impaired when compared to each of the three nonshock groups. Thus, in coronary arteries isolated from neurohumoral influences, HS was associated with diminished smooth muscle contraction and relaxation as well as impaired endothelium-mediated relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

We hypothesized that coronary artery endothelial cell function and smooth muscle function are modified by global myocardial ischemia and used bradykinin-induced secretion of endothelium-derived relaxing factor as a marker of endothelial cell function. Bradykinin and sodium nitroprusside together determined maximum smooth muscle relaxation. Potassium chloride-induced contraction determined smooth muscle contractility. Endothelium-mediated smooth muscle relaxation expressed as a ratio of total coronary smooth muscle relaxation before and after ischemia quantified endothelial cell function. The effect of global normothermic ischemia on in situ coronary arteries from 7 swine hearts was studied. Coronary arterial rings taken from 0 to 220 minutes of ischemia at 20-minute intervals were studied in vitro. The data revealed unexpected tolerance of endothelium-mediated relaxation to ischemia. Endothelium-derived relaxing factor function was maintained to 160 minutes and smooth muscle function, to 120 minutes of ischemia. Coronary artery dysfunction seen in other studies after less ischemia may be the result of injury introduced during reperfusion, may be the consequence of myocardial injury, or may be due to events operative at the level of small arterioles.

The gastroepiploic artery is an alternate conduit for coronary artery bypass grafting. To test the hypothesis that its vasoreactive properties are different from those of the internal mammary artery, we obtained gastroepiploic artery segments from human gastrectomy specimens. Trimmed internal mammary artery segments were obtained during coronary artery bypass. Ring segments were mounted on a strain gauge and stretched to optimum resting length (90% of the internal circumference at 100 mm Hg). Potassium chloride, serotonin, and norepinephrine were chosen to simulate physiologic vasospasm induced by depolarization, platelet aggregation, or adrenergic stimulation, respectively. Contractions to potassium and a concentration-response curve to serotonin or norepinephrine were obtained. Sodium nitroprusside was used to assess relaxation. Gastroepiploic artery segments had stronger contractions to the depolarizing agent (potassium chloride), adrenergic stimulation (norepinephrine), and product of platelet aggregation (serotonin). The gastroepiploic and internal mammary arteries showed equal sensitivity, measured by concentration causing half-maximal contraction to norepinephrine and serotonin. There was no difference in relaxation to sodium nitroprusside. These data suggest that prevention of platelet-, adrenergic-, or potassium-induced contraction may be more important when the gastroepiploic artery is used as an alternate conduit for coronary artery bypass, reinforcing consideration of nitrovasodilators and platelet inhibitors in the perioperative interval.

Inotropic support for the dilated, failing ventricle results in complex hemodynamic changes affecting preload, afterload, contractility, and heart rate, each of which affects myocardial oxygen consumption. Appreciation of a hierarchy of hemodynamic determinants of myocardial oxygen consumption may be helpful to the clinician trying to balance oxygen demands and hemodynamic performance. We tested the hypothesis that epinephrine alters the hierarchy of hemodynamic determinants of myocardial oxygen consumption in a canine model of dilated cardiomyopathy created by rapid ventricular pacing. Dogs (n = 10) were instrumented to record left ventricular pressure and dimension, and a modified right heart bypass preparation was used to control left ventricular workload. Coronary sinus effluent was quantitatively collected and analyzed for oxygen content and used to calculate myocardial oxygen consumption. Epinephrine administration significantly increased myocardial oxygen consumption in the empty, beating heart; however, when the relationships of multiple determinants of left ventricular work and load were compared before and after epinephrine administration, no oxygen wasting effect was observed. Using multivariate linear regression analysis, a hierarchy of hemodynamic determinants of myocardial oxygen consumption was created. In the untreated heart, stroke work and cardiac output were the primary hemodynamic determinants of oxygen consumption; epinephrine significantly altered the determinants such that wall stress became the dominant hemodynamic determinant of myocardial oxygen consumption. Focused manipulation of wall stress in the treated, failing heart may limit the potentially deleterious effects of inotropic stimulation in this setting.

We tested the hypothesis that dynamic cardiomyoplasty produces beneficial changes in the functional mechanics of the dilated, failing left ventricle. Chronic dilated cardiomyopathy was induced in seven mongrel dogs by rapid ventricular pacing (260 beats/min) for 3 to 4 weeks. After completion of the induction period, dynamic cardiomyoplasty was performed with the left latissimus dorsi muscle, paced synchronously with the R waves of the electrocardiogram (Medtronic SP1005). Instruments included an aortic flow probe, a left ventricular Millar pressure catheter, and piezoelectric sonomicrometric crystals on the left ventricle for measurements of wall thickness and minor and major axis dimensions. Data were obtained with the stimulator off and on. Statistical comparisons were made with Student's t test for paired data. Dynamic cardiomyoplasty increased the cardiac output of the failing heart (966 +/- 124 versus 1166 +/- 112 ml/min; p less than 0.01). Systolic shortening of both minor and major axis dimensions increased (3.1 +/- 0.3 versus 4.7 +/- 0.3 mm, p less than 0.01, and 4.6 +/- 0.3 versus 7.3 +/- 0.9 mm, p less than 0.05, respectively). Left ventricular end-diastolic pressure decreased by 16% (18 +/- 1 versus 15 +/- 1 mm Hg, p less than 0.01). Although skeletal muscle contraction increased the pressure development in the left ventricular chamber, mean systolic wall stress was diminished by concomitant changes in left ventricular dimensions (116,144 +/- 11,530 versus 101,268 +/- 7464 dynes/cm2, p less than 0.05). At end-systole, wall thickness increased (11.8 +/- 1.1 versus 12.7 +/- 1.1 mm, p less than 0.01), minor axis dimension decreased (51.3 +/- 1.4 versus 49.2 +/- 1.8 mm, p less than 0.01), and major axis dimension also decreased (85.6 +/- 3.3 versus 79.0 +/- 2.3 mm, p less than 0.05). Our detailed evaluation of left ventricular chamber mechanics suggests that dynamic cardiomyoplasty may have a role in ameliorating the functional and mechanical derangements associated with progression of dilated cardiomyopathy both by augmenting cardiac performance and by diminishing determinants of myocardial oxygen consumption. (All values are expressed as mean +/- standard error of the mean.)

Two hundred and fifty-eight patients with juvenile polyps were reviewed. Ten patients less than 20 years of age were found to have adenomas. The points to be presented can, therefore, be emphasized. Juvenile polyps are a distinct pathologic entity and can occur at any age and in either sex. Adenomas do exist in pediatric patients. We should not assume that every polyp in patients less than 20 years of age is automatically a juvenile polyp and, therefore, benign. Barium enema is recommended for any child or adolescent in whom one or more polyps are found. In multiple polyposis, the finding that one polyp is of the juvenile type does not necessarily rule out the presence of adenoma. Any patient with a solitary adenoma who has multiple polyps, whether adenoma or juvenile polyps, should be observed at appropriate intervals by sigmoidoscopic, roentgenographic and, possibly, colonoscopic examination. Finally, we hope that this study will inspire others to investigate further this interesting pathologic condition.

The ultimate goal of the cone method of colostomy irrigation is to return patients with colostomies to their former role in society with confidence in themselves to the extent that having a colostomy is not considered a handicap. The results have generally been excellent. We believe all patients with stomas should be afforded the opportunity to attempt colostomy irrigation.