Jason M. Budde

One hundred pulmonary valve replacements in children after relief of right ventricular outflow tract obstruction

BACKGROUND Surgical repair of obstructive lesions of the right ventricular outflow tract (RVOT) in children commonly creates pulmonary valve incompetence that may eventually require pulmonary valve replacement (PVR). We reviewed our experience with PVR late after RVOT reconstruction. METHODS We performed 100 PVRs in 93 children 1.1 months to 22.4 years (median 8) after RVOT reconstruction. Children with right ventricular to pulmonary artery conduits and primary PVRs were excluded. Age at PVR was 4.5 months to 27.9 years (median 9.5 years). Initial diagnosis was tetralogy of Fallot and variants, 62; critical pulmonary stenosis, 15; pulmonary atresia with intact ventricular septum, 7; and others, 9. Eleven patients had a redo PVR. A total of 62 PVRs were homografts; 38 were porcine valves. RESULTS There was one early death. On follow-up of 5 months to 12.4 years (mean 4.9 years) there were no late deaths although 1 child underwent cardiac transplantation. Actuarial freedom from redo PVR at 8 years was 100% for porcine valves but 70% for homograft valves (p = 0.17). For children younger than 3 years at PVR, freedom from reoperation was 76% at 1 year and 39% at 8 years compared with freedom from redo PVR at 8 years of 100% for children older than 3 years. On latest echocardiogram 97% of porcine valves had mild or no pulmonary regurgitation compared with 72% of homograft valves. CONCLUSIONS PVR after RVOT reconstruction can be performed with low risk. Porcine valves may be superior to homograft valves although this advantage may be due to older age at time of PVR.

Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion

OBJECTIVE Myocardial apoptosis is primarily triggered during reperfusion (R) through various mechanisms that may involve endonuclease to cleavage genomic DNA in the internucleosomal linker regions. However, the relative contribution of myocardial apoptosis to development of myocardial injury during R remains unknown. In the present study, we examined whether inhibition of apoptosis with aurintricarboxylic acid (ATA), an endonuclease inhibitor, during R reduces infarct size and improves regional contractile function. METHODS AND RESULTS In two groups of chronically-instrumented dogs, 1 h of left anterior descending (LAD) coronary occlusion was followed by 24 h of R with infusion of saline (control, n=8) or ATA (1 mg/kg/h, n=8) into the left atrium starting 5 min before R and continuing for 2 h. ATA significantly reduced apoptotic cells (TUNEL staining) in the peri-necrotic myocardium (12+/-1%* vs. 36+/-4%), consistent with the absence of DNA laddering. To confirm inhibition of apoptosis with ATA, densitometrically, Bcl-2 (% of normal myocardium) was significantly increased vs. control (102+/-12* vs. 68+/-9) and Bax as well as the activated caspase-3 were significantly reduced vs. control (108+/-17* vs. 194+/-42 and -29+/-4* vs. 174+/-43, respectively). ATA significantly improved segmental shortening (3.3+/-1.2* vs. -1.8+/-0.7%) and segmental work (79.3+/-11.3* vs. 7.1+/-5.8 mmHg/mm) in area at risk myocardium, and reduced infarct size (TTC staining, 27+/-0.2* vs. 37+/-0.5%), confirmed by lower plasma creatine kinase activity. In addition, myocardial blood flow (0.9+/-0.1* vs. 0.4+/-0.1 ml/min/g) and endothelial-dependent maximal vascular relaxation (119+/-6* vs. 49+/-8%) were significantly improved. Myeloperoxidase activity in area at risk myocardium, a marker for neutrophil accumulation, was also significantly reduced (17+/-4* vs. 138+/-28 Delta Abs/min). CONCLUSIONS These data suggest that the inhibition of apoptosis during R is associated with a reduction in infarction, improvement in regional contractile and vascular endothelial functions as well as augmentation in myocardial blood flow. *P<0.05 vs. control group.

Tumors of the small intestine

Abstract. This collective review includes all available case reports and series of smooth muscle (stromal) tumors of the small intestine in the world literature from 1881 to 1996. We identified 1074 patients with leiomyoma (LM) and 1689 with leiomyosarcoma (LMS). Our purpose was to update our previous review, which encompassed case reports and series from 1881 to 1959, which included 350 LMs and 257 LMSs. The peak incidence of smooth muscle tumors in the small intestine in both male and female patients was between the ages of 50 and 59. Most commonly, the presenting complaint was gastrointestinal bleeding. Computed tomography was found to detect LM and LMS most successfully and had the additional advantage of locating metastatic disease. The jejunum contained the highest numbers of smooth muscle tumors, followed by the ileum and then the duodenum, with malignant lesions in all locations typically attaining larger diameters than benign tumors. The overall rate of metastatic spread of LMS ranged from 24% to 50%, with the liver being most commonly involved. Unlike other sarcomas, both hematogenous and lymphatic spread were common. The 5-year survival of 705 patients with LMS from 22 series was 27.8%. For both benign and malignant smooth muscle tumors of the small intestine, surgery remains the treatment of choice, with little efficacy reported for irradiation, chemotherapy, or both.

Predictors of outcome in thymectomy for myasthenia gravis

BACKGROUND Factors determining predictability of response to thymectomy for myasthenia gravis (MG) vary in the literature. METHODS A 25-year retrospective review (1974 to 1999) of all thymectomies performed at a single institution was undertaken. RESULTS In 113 consecutive thymectomies for MG, women comprised 79% (89 of 113 patients), and mean age was 40+/-15 years. Complications occurred in 14% of patients (16 of 113). In-hospital mortality was 0, but 90-day hospital mortality was 0.88% (1 of 113 patients). Follow-up was obtained in 81% (92 of 113 patients) at a mean of 51+/-59 months postoperatively. Complete remission was achieved in 21% of patients (19 of 92), and marked improvement of MG in 54% (50 of 92), for a total benefit rate of 75%. Fourteen percent (13 of 92) were unchanged, and 11% (10 of 92) were worse. Using univariate analysis, sex, age, and pathology correlated significantly with outcome (p < 0.05): 80% of women (57 of 70) benefited from the procedure, versus 57% of men (12 of 21). Eighty percent (57 of 70) of patients less than 51 years of age were improved or in remission, versus 57% (12 of 22) older than 50. Twenty-three percent (5 of 22) of patients with thymoma deteriorated, versus 7.1% (5 of 70) without thymoma. Sex did not significantly correlate in the multivariate model. CONCLUSIONS Sex, age, and thymic pathology are potential predictors of outcome in thymectomy for MG, and may shape treatment decisions and target higher-risk patients.

Comparative study of AMP579 and adenosine in inhibition of neutrophil-mediated vascular and myocardial injury during 24 h of reperfusion

OBJECTIVE The purpose of this study was to compare protective effects of AMP579 and adenosine (Ado) at reperfusion (R) on inhibition of polymorphonuclear neutrophil (PMN) activation, PMN-mediated injury to coronary artery endothelium, and final infarct size. METHODS In anesthetized dogs, 1 h of left anterior descending coronary artery occlusion was followed by 24 h R and drugs were administered at R. Control (n=8, saline control), AMPI (n=7, AMP579, 50 microg/kg i.v. bolus followed by 3 microg/kg/min for 2 h), AMPII (n=7, AMP579, 50 microg/kg i.v. bolus), AMPIII (n=7, AMP579, 3 microg/kg/min i.v. for 2 h), and Ado (n=7, adenosine, 140 microg/kg/min i.v. for 2 h). RESULTS AMP579 in vitro directly inhibited superoxide radical (O(-)(2)) generation (nM/5x10(6) PMNs) from PMNs dose-dependently (from 17+/-1* at 10 nM to 2+/-0.2* at 10 microM vs. activated 30+/-2). However, inhibition of O(-)(2) generation by Ado at each concentration was significantly less than for AMP579. The IC(50) value for AMP579 (0.09+/-0.02 microM) on O(-)(2) generation was significantly less than that of Ado (3.9+/-1. 1 microM). Adherence of unstimulated PMN to postischemic coronary artery endothelium (PMNs/mm(2)) was attenuated in AMPI and AMPIII vs. Control (60+/-3* and 58+/-3* vs. Control 110+/-4), while Ado partially attenuated PMN adherence (98+/-3*). Accordingly, endothelial-dependent vascular relaxation was significantly greater in AMPI and AMPIII vs. Ado. At 24 h R, myocardial blood flow (MBF, ml/min/g) in the area at risk (AAR), confirmed by colored microspheres, in AMPI and AMPIII was significantly improved (0.8+/-0. 1* and 0.7+/-0.1* vs. Control 0.3+/-0.04). Infarct size (IS, TTC staining) in AMPI and AMPIII was significantly reduced from 38+/-3% in Control to 21+/-4%* and 22+/-3%*, respectively, confirmed by lower plasma creatine kinase activity (I.U./g protein) in these two groups (27+/-6* and 32+/-2* vs. 49+/-3). Cardiac myeloperoxidase activity (MPO, Abs/min) in the AAR was significantly reduced in AMPI and AMPIII vs. Control (36+/-11* and 35+/-10* vs. 89+/-10). However, changes in MBF, IS and MPO were not significantly altered by Ado. CONCLUSIONS These data suggest that continuous infusion of AMP579 at R is more potent than adenosine in attenuating R injury, and AMP579-induced cardioprotection involves inhibition of PMN-induced vascular and myocardial tissue injury. *P<0.05 vs. Control.

Adenosine in myocardial protection in on-pump and off-pump cardiac surgery

Adenosine is most well known for its potent vasodilation of the vasculature. However, it also promotes glycolysis, and activates potassium-sensitive adenosine triphosphate (K(ATP)) channels. Adenosine also strongly inhibits neutrophil function such as superoxide anion production, protease release, and adherence to coronary endothelial cells. Hence adenosine attenuates ischemic injury as well as neutrophil-mediated reperfusion injury. Adenosine has also been implicated in the cardioprotective phenomenon of ischemic preconditioning. Accordingly experimental evidence shows that adenosine reduces postischemic injury when administered before ischemia and at the onset of reperfusion. Clinical studies in cardiology and cardiac surgery show cardioprotective trends with adenosine treatment but the effects are not as dramatic as those reported by experimental studies.

Palliative management of malignant airway obstruction

BACKGROUND Obstruction of the airway due to unresectable malignant disease is a frightening condition that portends a poor prognosis. Endobronchial treatment modalities were reviewed to determine the most effective management strategy. METHODS A 12-year retrospective review (1988 to 1999) of 121 consecutive patients with inoperable malignant airway obstruction (MAO) was performed. Sixty-five patients received high-dose-rate brachytherapy (HDR) alone, 32 received HDR plus neodymium:yttrium-aluminum garnet laser (YAG) therapy, 16 received YAG only, 4 patients were stented, and 4 received photodynamic therapy (PDT). Follow-up was obtained by chart review and contact. RESULTS Seventy-seven men and 44 women, median age 62 years (range 30 to 86 years), underwent 378 endobronchial procedures for relief of MAO. Good to excellent results were achieved in 77% (93/121) of patients. Seventy-two percent (23/32) of patients undergoing HDR plus YAG received a good to excellent result. All 8 patients receiving either stents or PDT had good to excellent palliation. There were no intraoperative deaths, but there were two in-hospital deaths. Complications occurred in 4% (5/121) of patients. Forty-four percent (53/121) of our patients were lost to follow-up. Mean survival was 6.7 months after the last treatment. CONCLUSIONS Temporary relief of inoperable MAO can be accomplished with a number of endobronchial treatments used either singularly or in combination. The majority of patients managed with HDR, YAG, or HDR plus YAG received good to excellent short-term palliation.

Pretreatment with phenoxybenzamine attenuates the radial artery's vasoconstrictor response to α-adrenergic stimuli

BACKGROUND Although the radial artery bypass conduit has excellent intermediate-term patency, it has a proclivity to vasospasm. We tested the hypothesis that brief pretreatment of a radial artery graft with the irreversible adrenergic antagonist phenoxybenzamine attenuates the vasoconstrictor response to the vasopressors phenylephrine and norepinephrine compared with the currently used papaverine/lidocaine. METHODS Segments of human radial artery grafts were obtained after a 30-minute intraoperative pretreatment with a solution containing 20 mL of heparinized blood, 0.4 mL of papaverine (30 mg/mL), and 1.6 mL of lidocaine (1%). The segments were transported to the laboratory and placed into a bath containing Krebs-Henseleit solution and 10, 100, or 1000 micromol/L phenoxybenzamine or vehicle. The segments were tested in organ chambers for contractile responses to increasing concentrations of phenylephrine and norepinephrine (0.5-15 micromol/L). RESULTS Contractile responses to 15 micromol/L phenylephrine in control radial artery segments averaged 44.2% +/- 9.1% of the maximal contractile response to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated contraction to 15 micromol/L phenylephrine (32.1% +/- 5.9%; P =.22), but 1000 micromol/L phenoxybenzamine completely abolished radial artery contraction (-7.2% +/- 4.4%; P <.001). The effect of 10 and 100 micromol/L phenoxybenzamine on attenuating vasocontraction was intermediate between 1000 micromol/L phenoxybenzamine and papaverine/lidocaine. Responses to 15 micromol/L norepinephrine in control radial artery segments averaged 54.7% +/- 7.5% of maximal contraction to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated the contraction response of radial artery segments (35.6% +/- 5.1%; P =.04). In contrast, 1000 micromol/L phenoxybenzamine showed the greatest attenuation of norepinephrine-induced contraction (-10.5% +/- 2.0%; P <.001). CONCLUSIONS A brief pretreatment of the human radial artery bypass conduit with 1000 micromol/L phenoxybenzamine completely attenuates the vasoconstrictor responses to the widely used vasopressors norepinephrine and phenylephrine. Papaverine/lidocaine alone did not block vasoconstriction to these alpha-adrenergic agonists.

Reduction of infarct size and preservation of endothelial function by multidose intravenous adenosine during extended reperfusion

It has been proposed that infarct extension is developed from the early to the late phase of reperfusion (R). This study compares the protective effect of single or multidose administration of adenosine (Ado) on infarct size during early and late phases of R by attenuating neutrophil (PMN) recruitment. Forty-one dogs underwent 60-min left anterior descending artery (LAD) ischemia followed by 6, 24, and 48 h of R, respectively. Infarct size (%) increased over 6 to 24 h (27 +/- 2 to 38 +/- 4; P < 0.05 24 h versus 6 h group), with a corresponding increase in creatine kinase activity. Transmural myocardial blood flow (mL/min/g) decreased from 6 to 24 h (0.47 +/- 0.02 to 0.29 +/- 0.02; P < 0.05 24 h versus 6 h group). PMN localization (mm(2) myocardium) in the perinecrotic tissue detected by immunohistochemistry with anti-CD18 antibody, and accumulation detected by myeloperoxidase (MPO, DeltaAbs/min/g) increased from 6 to 24 h (292 +/- 25 to 605 +/- 44; P < 0.05 24 h versus 6 h group; and 55 +/- 7 to 96 +/- 5; P < 0.05 24 h versus 6 h group), respectively. In in vitro analysis, PMN adherence (mm(2) endothelium) to postischemic LAD increased from 98 +/- 2 to 125 +/- 3 (P < 0.05 24 h versus 6 h group) and maximal LAD endothelium-dependent relaxation (%) impaired from 6 to 24 h (74 +/- 7 to 42 +/- 10; P < 0.05 24 h versus 6 h group). Intravenous Ado (140 microg/kg/min) for 2 h at R reduced infarct size (17 +/- 2; P < 0.05 Ado versus 6 h group), CD18 positive cells (130 +/- 10; P < 0.05 Ado versus 6 h group), MPO (14 +/- 3; P < 0.05 Ado versus 6 h group), PMN adherence (57 +/- 2; P < 0.05 Ado versus 6 h group), and augmented LAD vascular relaxation (102 +/- 5 versus 74 +/- 7; P < 0.05 Ado versus 6 h group). However, this protection by Ado was lost when R was extended to 24 h. Treatment with multiple infusion of Ado at 2, 6, 12, and 18 h R significantly preserved protective effects seen at 6 h R in the Ado group. Protection by multidose Ado was still preserved when R was extended to an additional 24 h. These data suggest that interventions aiming at permanently reducing R injury may thus need to be administered not only at early R, but also during late phase. A slow wave of PMN accumulation at late R may be involved in the extension of infarction and endothelial dysfunction.

Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury

BACKGROUND In clinical trials, perioperative intravenous Na(+)/H(+) exchange isoform-1 (NHE1) inhibitors were only moderately effective in high-risk patients undergoing surgical reperfusion (GUARDIAN trial). However, effective myocardial concentrations of NHE1 inhibitor may not have been achieved by parenteral administration alone. We tested the hypothesis that increasing doses of NHE1 inhibitor EMD 87580 ((2-methyl-4,5-di-(methylsulfonyl)-benzoyl)-guanidine) delivered in blood cardioplegia (BCP) and by parenteral route at reperfusion reduce myocardial injury after surgical reperfusion of evolving infarction. METHODS Twenty-six anesthetized dogs underwent 75 minutes of left anterior descending coronary artery occlusion, followed by cardiopulmonary bypass and 60 minutes of arrest with multidose 10 degrees C BCP. In the control group (n = 8), BCP was not supplemented. In the three EMD-BCP groups, BCP was supplemented with 10 micromol/L EMD 87580 (EMD-10, n = 5), 20 micromol/L EMD 87580 (EMD-20, n = 5), or 20 micromol/L EMD 87580 combined with an immediate reperfusion bolus (5 mg/kg intravenously) (EMD-20R, n = 8). The left anterior descending coronary artery occlusion was released just before the second infusion of BCP. Reperfusion continued for 120 minutes after discontinuation of cardiopulmonary bypass. RESULTS Postischemic systolic and diastolic function in the area at risk was dyskinetic in all groups. Infarct size (percentage of area at risk) was not significantly reduced in the EMD-10 (26.2% +/- 3.6%) and EMD-20 (22.5% +/- 2.4%) groups versus control (30.7% +/- 2.4%); however, infarct size was significantly reduced in the EMD-20R group (16.1% +/- 2.8%, p = 0.003). Edema in the area at risk in the EMD-10 (81.1% +/- 0.5% water content), EMD-20 (81.7% +/- 0.3%), and EMD-20R (81.9% +/- 0.3%) groups was less than in controls (83.2% +/- 0.2%), (p < 0.056). Neutrophil accumulation (myeloperoxidase activity) in postischemic area-at-risk myocardium was less in the EMD-20R group versus the control group (5.3 +/- 0.7 versus 8.7 +/- 1.4 absorbance units x min(-1) x g(-1); p = 0.05), which suggests an attenuated postischemic inflammatory response. CONCLUSIONS Optimal delivery of NHE1 inhibitor to the heart through combined cardioplegia and parenteral routes significantly attenuates myocardial injury after surgical reperfusion of regional ischemia. Timing, dose, and mode of delivery of NHE1 inhibitors are important to their efficacy.