Testosterone supplementation does not worsen lower urinary tract symptoms.

PURPOSE: Testosterone replacement therapy is commonly used to treat men with hypogonadism. However, there has been caution in using testosterone replacement therapy in men with moderate to severe lower urinary tract symptoms for fear of worsening the symptoms. In this study we examine the effect of testosterone replacement therapy on lower urinary tract symptoms in hypogonadal men. MATERIALS AND METHODS: We retrospectively reviewed our outpatient database and identified patients with a diagnosis of hypogonadism who received testosterone replacement therapy from 2002 to 2012. Lower urinary tract symptoms were assessed using the AUASI (American Urological Association symptom index) before and after testosterone replacement therapy. Testosterone and prostate specific antigen were also continuously measured, and all patients were closely monitored for side effects of testosterone replacement therapy. Patients who had progression of lower urinary tract symptoms to the point of requiring surgery were included in the study. RESULTS: We identified 120 hypogonadal men who received testosterone replacement therapy, the majority of whom had topical therapy or a combination of topical and pellet based therapy (57.5% and 20.8%, respectively). Mean baseline AUASI (±SD) was 10.8 (±7.8) and mean duration of testosterone replacement therapy was 692 days (±773). Mean change in AUASI was -1.07 (±6.06). Mean baseline prostate specific antigen was 1.6 ng/dl (±1.9) and mean change in prostate specific antigen was 0.44 (±2.2). Of the patients 8.1% had a baseline prostate specific antigen greater than 4.0 ng/dl, and these patients had greater improvement in AUASI than those with a baseline prostate specific antigen less than 4.0 ng/dl (-1.9 vs -1.0, p not significant). Overall 45.8% of patients had a less than 3-point change in AUASI in either direction. Of the 120 patients 38 (31.7%) had improvement in AUASI 3 or more points while 27 (22.5%) had worsening of AUASI 3 or more points. Patients with an improved AUASI had a mean prostate specific antigen change of 0.3 (±3.4), while those who had worsening of AUASI had a mean prostate specific antigen change of 0.7 (±2.2) (p not significant). Approximately 9 of 120 (7.5%) of these men initiated new medications for lower urinary tract symptoms during the course of the study. There was no significant change in AUASI compared to patients without any use of lower urinary tract symptoms medications. In addition, 4 (3.3%) patients had progression of lower urinary tract symptoms and required transurethral resection of the prostate. CONCLUSIONS: We demonstrate that initiating testosterone replacement therapy in hypogonadal men involves a low risk of worsening lower urinary tract symptoms. In fact, many men experience symptom improvement while changes in prostate specific antigen appear minor. Future research should focus on larger patient population studies to further examine this relationship.

Glucocorticoids improve calcium cycling in cardiac myocytes after cardiopulmonary bypass.

BACKGROUND: Glucocorticoids can reduce myocardial dysfunction associated with ischemia and reperfusion injury following cardiopulmonary bypass (CPB) and circulatory arrest. The hypothesis was that maintenance of cardiac function after CPB with methylprednisolone therapy results, in part, from preservation of myocyte calcium cycling. METHODS: Piglets (5-7 kg) underwent CPB and 120 min of hypothermic circulatory arrest with (CPB-GC) or without (CPB) methylprednisolone (30 mgkg(-1)) administered 6h before and at CPB. Controls (No-CPB) did not undergo CPB or receive glucocorticoids (n=6 per treatment). Myocardial function was monitored in vivo for 120 min after CPB. Calcium cycling was analyzed using rapid line-scan confocal microscopy in isolated, fluo-3-AM-loaded cardiac myocytes. Phospholamban phosphorylation and sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a) protein levels were determined by immunoblotting of myocardium collected 120 min after CPB. Calpain activation in myocardium was measured by fluorometric assay. RESULTS: Preload recruitable stroke work in vivo 120 min after reperfusion decreased from baseline in CPB (47.4±12 versus 26.4±8.3 slope of the regression line, P<0.05), but was not different in CPB-GC (41±8.1 versus 37.6±2.2, P=0.7). In myocytes isolated from piglets, total calcium transient time remained unaltered in CPB-GC (368±52.5 ms) compared with controls (434.5±35.3 ms; P=0.07), but was prolonged in CPB myocytes (632±83.4 ms; P<0.01). Calcium transient amplitude was blunted in myocytes from CPB (757±168 nM) compared with controls (1127±126 nM, P<0.05) but was maintained in CPB-GC (1021±155 nM, P>0.05). Activation of calpain after CPB was reduced with glucocorticoids. Phospholamban phosphorylation and SERCA2a protein levels in myocardium were decreased in CPB compared with No-CPB and CPB-GC (P<0.05). CONCLUSIONS: The glucocorticoid-mediated improvement in myocardial function after CPB might be due, in part, to prevention of calpain activation and maintenance of cardiac myocyte calcium cycling.

Role of FimW, FimY, and FimZ in regulating the expression of type i fimbriae in Salmonella enterica serovar Typhimurium.

Type I fimbriae in Salmonella enterica serovar Typhimurium are surface appendages that facilitate binding to eukaryotic cells. Expression of the fim gene cluster is known to be regulated by three proteins--FimW, FimY, and FimZ--and a tRNA encoded by fimU. In this work, we investigated how these proteins and tRNA coordinately regulate fim gene expression. Our results indicate that FimY and FimZ independently activate the P(fimA) promoter which controls the expression of the fim structural genes. FimY and FimZ were also found to strongly activate each other's expression and weakly activate their own expression. FimW was found to negatively regulate fim gene expression by repressing transcription from the P(fimY) promoter, independent of FimY or FimZ. Moreover, FimW and FimY interact within a negative feedback loop, as FimY was found to activate the P(fimW) promoter. In the case of fimU, the expression of this gene was not found to be regulated by FimW, FimY, or FimZ. We also explored the effect of fim gene expression on Salmonella pathogenicity island 1 (SPI1). Our results indicate that FimZ alone is able to enhance the expression of hilE, a known repressor of SPI1 gene expression. Based on our results, we were able to propose an integrated model for the fim gene circuit. As this model involves a combination of positive and negative feedback, we hypothesized that the response of this circuit may be bistable and thus a possible mechanism for phase variation. However, we found that the response was continuous and not bistable.

Modulation of nuclear factor-kappaB improves cardiac dysfunction associated with cardiopulmonary bypass and deep hypothermic circulatory arrest.

OBJECTIVE: The hypothesis is that partial nuclear factor-kappaB (NF-kappaB) inhibition can alleviate cardiopulmonary dysfunction associated with ischemia and reperfusion injury following cardiopulmonary bypass and deep hypothermic circulatory arrest (CPB/DHCA) in a pediatric model. DESIGN: Animal case study. SUBJECTS: Two-week-old piglets (5-7 kg). INTERVENTIONS: Piglets received 100 microg/kg of SN50, a peptide inhibitor of NF-kappaB translocation and activation, 1 hour before CPB. The control group received saline. Animals were cooled to 18 degrees C with CPB, the piglets were in DHCA for 120 minutes, and the piglets were then rewarmed on CPB to 38 degrees C and maintained for 120 minutes after CPB/DHCA. MEASUREMENTS: Sonomicrometry and pressure catheters collected hemodynamic data. Transmural left and right ventricular tissues were obtained at the terminal time point for determination of NF-kappaB activity by enzyme-linked immunosorbent assay. Data are expressed as mean +/- sd. MAIN POINTS: Oxygen delivery was maintained at 76 +/- 13 mL/min at baseline and 75 +/- 5 mL/min at 120 minutes after CPB/DHCA (p = 0.75) in SN50-treated animals vs. 99 +/- 26 mL/min at baseline and 63 +/- 20 mL/min at 120 minutes in the untreated group (p = 0.0001). Pulmonary vascular resistance (dynes.sec.cm) increased from 124 +/- 59 at baseline to 369 +/- 104 at 120 minutes in the untreated piglets (p = 0.001) compared with SN50-treated animals (100 +/- 24 at baseline and 169 +/- 88 at 120 minutes, p = 0.1). NF-kappaB activity was reduced by 74% in left ventricles of SN50-treated compared with SN50-untreated animals (p < 0.001). Plasma endothelin-1 (pg/mL), an important vasoconstrictor regulated by NF-kappaB, increased from 2.1 +/- 0.4 to 14.2 +/- 5.7 in untreated animals (p = 0.004) but was elevated to only 4.5 +/- 2 with SN50 treatment (p = 0.005). CONCLUSIONS: Improvement of cardiopulmonary function after ischemia/reperfusion was associated with the reduction of NF-kappaB activity in piglet hearts. Maintenance of systemic oxygen delivery and alleviation of pulmonary hypertension after CPB/DHCA in piglets administered SN50, possibly through a reduction of circulating endothelin-1, suggest that selective inhibition of NF-kappaB activity may reduce ischemia and reperfusion injury after pediatric cardiac surgery.

Computed tomographic appearance of Prolene Hernia System and polypropylene mesh plug inguinal hernia repair.

PURPOSE: To describe the normal postoperative computed tomographic (CT) appearance of inguinal hernia repair with the Prolene (polypropylene) Hernia System and polypropylene mesh plug. MATERIALS AND METHODS: The medical records for 480 consecutive patients who underwent inguinal mesh hernioplasty were reviewed to identify posthernioplasty pelvic CT scans. The presence or absence of the appearance and size of focal inguinal findings at CT for each groin was recorded by 2 radiologists in consensus. The CT scan reports and medical records were reviewed to determine prospective interpretations of these inguinal findings. FINDINGS: Posthernoplasty CT scans were identified in 26 patients, of whom, 20 had Prolene Hernia System (unilateral, n = 20; bilateral, n = 1) or mesh plug (unilateral, n = 5; bilateral, n = 1) repairs. These patients consisted of 23 men and 3 women with a mean age of 63 years (range, 36-89 years). For Prolene Hernia System hernioplasty patients, ipsilateral focal inguinal findings were found at CT in 21 of 22 groins. These focal findings had a mean size of 2.6 +/- 0.4 by 2.0 +/- 0.5 cm and were ringlike in 9, nodular in 7, and feathery in appearance in 5 groins. For mesh-plug hernioplasty, ipsilateral nodular focal inguinal findings were found in all 6 of 6 groins at CT. In 2 patients, nodular focal inguinal findings were mistaken for lymphadenopathy on the prospective CT report. CONCLUSION: Focal inguinal findings from mesh plug inguinal hernioplasty are common, have characteristic appearances at CT, and should not be mistaken as lymphadenopathy.

Patient Frailty and Discharge Disposition Following Radical Cystectomy.

BACKGROUND: Patients with bladder cancer who are treated with cystectomy are at high risk for complications and prolonged length of stay. This population tends to be of advanced age with underlying comorbidities, and thus more likely to have decreased physiologic reserve (ie, frailty). Our objective was to evaluate the relationship between frailty and discharge disposition for patients with bladder cancer treated with cystectomy. MATERIALS AND METHODS: Using data from the National Surgical Quality Improvement Program, we identified patients with bladder cancer undergoing cystectomy (2011-2014). Our exposure of interest was frailty, based on the 11-point modified Frailty Index (mFI). Patients were deemed robust (mFI = 0), pre-frail (mFI = 0.09-0.18), or frail (mFI ≥ 0.27). Our outcome of interest was discharge disposition defined as home, skilled nursing facility, and rehabilitation dichotomized as home versus non-home for multivariable logistic regression analysis. We then generated predicted probabilities of non-home discharge based on frailty and in-hospital complications. RESULTS: Among 4330 patients treated with radical cystectomy, 32.8% were robust, 65.1% were pre-frail, and 2.2% were frail. Overall, 86.2% were discharged home, 4.4% to a rehabilitation facility, and 9.4% to a skilled nursing facility. Frail patients were more likely to be discharged to non-home care (vs. robust, odds ratio, 2.33; 95% confidence interval, 1.34-4.03), which was independent of whether they experienced a major complication prior to discharge. CONCLUSION: Frailty is a significant predictor of non-home discharge following radical cystectomy. This finding was independent of inpatient complications. These data will assist providers in setting patient expectations and have important implications for allocating postoperative resources.

A novel preoperative inflammatory marker prognostic score in patients with localized and metastatic renal cell carcinoma.

OBJECTIVE: Several inflammatory markers have been studied as potential biomarkers in renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score (RISK) could serve as a rigorous prognostic indicator of overall survival (OS) in patients with clear cell and non-clear cell RCC. METHODS: Combination of preoperative C-reactive protein (CRP), albumin, erythrocyte sedimentation rate (ESR), corrected calcium, and aspartate transaminase to alanine transaminase (AST/ALT) ratio was used to develop RISK. RISK was developed using grid-search methodology, receiver-operating-characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. Prognostic value of RISK was analyzed using the Kaplan-Meier method and Cox proportional regression models. Predictive accuracy was compared with RISK to Size, Size, Grade, and Necrosis (SSIGN) score, University of California-LOS Angeles (UCLA) Integrated Staging System (UISS), and Leibovich Prognosis Score (LPS). RESULTS: Among 391 RCC patients treated with nephrectomy, area under the curve (AUC) for RISK was 0.783, which was comparable to SSIGN (AUC 0.776, p = 0.82) and UISS (AUC 0.809, p = 0.317). Among patients with localized disease, AUC for RISK and LPS was 0.742 and 0.706, respectively (p = 0.456). On multivariate analysis, we observed a step-wise statistically significant inverse relationship between increasing RISK group and OS (all p < 0.001). CONCLUSION: RISK is an independent and significant predictor of OS for patients treated with nephrectomy for clear cell and non-clear cell RCC, with accuracy comparable to other histopathological prognostic tools.

Bilateral semilunar valve disease in a child with partial deletion of the Williams-Beuren syndrome region is associated with elastin haploinsufficiency.

Elastin is an extracellular matrix protein that is the primary component of elastic fibers, and is expressed in the great vessels as well as the semilunar and atrioventricular valves. Elastin haploinsufficiency, resulting from mutation or deletion of the elastin gene, is an important clinical problem that is typically characterized by arteriopathy. Herein is described a patient with elastin haploinsufficiency due to partial deletion of the Williams-Beuren syndrome region, resulting in bilateral semilunar valve disease and arteriopathy. Histochemical analysis of the aortic valve revealed decreased and disorganized elastin with loss of the normal trilaminar cusp organization. These findings suggest that elastin has a role in the pathogenesis of semilunar valve disease.

Implementation of a Tele-urology Program for Outpatient Hematuria Referrals: Initial Results and Patient Satisfaction.

OBJECTIVE: To report on results from a new tele-urology pathway for managing hematuria consults, including a survey of patient attitudes and satisfaction with such a program. Recent guideline changes have relaxed the definition of microscopic hematuria and may have significantly increased the number of hematuria evaluations. MATERIALS AND METHODS: Patients referred to the Atlanta Veterans Administration Medical Center with hematuria were scheduled for a tele-urology clinic encounter utilizing a telephone call to obtain hematuria-related clinical information via a standardized algorithm. At subsequent cystoscopy, patients were evaluated with a 29-question survey regarding overall acceptance and satisfaction of the clinic (8 questions) and impact factors (21 questions). RESULTS: One hundred fifty veterans participated in the survey. Median time from consult request to appointment was 12 days and thereafter to cystoscopy was 16 days. Patients reported high acceptance and overall satisfaction with telephone evaluation; mean scores exceeded 9 out of 10 for overall satisfaction, efficiency, convenience, friendliness, care quality, understandability, privacy, and professionalism. When presented with a choice, nearly all patients (98%) preferred telephone-based encounters to face-to-face clinic visits. Underlying negative factors responsible for patients' preferences included transportation-related issues (97%) and logistical clinic issues (65%). Ninety-seven percent of patients reported high-quality evaluation. CONCLUSION: Patients report high acceptance and satisfaction with telephone clinics as a mechanism for expedited hematuria evaluation, primarily due to avoiding barriers related to transportation and clinical operations, as well as a perceived high quality of evaluation. Telephone appointments have potential to positively impact healthcare access and productivity.

Heparin-induced thrombocytopenia complicating support by the Berlin Heart.

Since 1992, miniaturized pulsatile air-driven ventricular assist devices (VADs), "Berlin Heart," have been used at many institutions (36 cases in North America in 19 different institutions) for pediatric use. Heparin-induced thrombocytopenia (HIT II) is a significant complication rarely reported in the setting of adult VAD support; no similar report exists concerning pediatric VAD support. We report on a 13-month-old, 8.1 kg girl who required LVAD support for cardiogenic shock of unclear etiology. The patient had a history of multiple surgical repairs for correction of complex congenital heart disease consisting of a series of left heart obstructive lesions (Shone's complex). Despite aggressive ventilatory and inotropic support, the patient continued to deteriorate and subsequently required extracorporeal life support. After 7 days of conventional venoarterial extracorporeal membrane oxygenation, a 10 ml Berlin Heart VAD was implanted. After implantation, the patient developed persistent low-grade fever of unclear etiology, gradual thrombocytopenia, and deterioration of renal function. On postimplant day 10, the pump required replacement because of concerns about an inlet valve thrombus; the explanted device demonstrated a nearly occlusive clot not appreciable from external inspection. Simultaneously, HIT II was diagnosed as a result of hematology workup for persistent thrombocytopenia. We discuss the unique challenges posed by HIT II complicating pediatric VAD support and in relation to the heparin coating of the device.

Iatrogenic urinary tract injuries: etiology, diagnosis, and management.

Iatrogenic injury to the urinary tract, including the kidneys, ureters, bladder, and urethra, is a potential complication of surgical procedures performed in or around the retroperitoneal abdominal space or pelvis. While both diagnostic and interventional radiologists often play a central and decisive role in the identification and initial management of a variety of iatrogenic injuries, discussions of these injuries are often directed toward specialists such as urologists, obstetricians, gynecologists, and general surgeons whose procedures are most often implicated in iatrogenic urinary tract injuries. Interventional radiologic procedures can also be a source of an iatrogenic urinary tract injury. This review describes the clinical presentation, risk factors, imaging findings, and management of iatrogenic renal vascular and urinary tract injuries, as well as the radiologist's role in the diagnosis, treatment, and cause of these injuries.

Risk of recoarctation should not be a deciding factor in the timing of coarctation repair.

To determine whether early coarctation repair is a significant risk for recoarctation in the modern era, 120 patients, including 87 infants, who underwent isolated coarctation repair at a single institution, were reviewed. At a mean follow-up of 44.4 months, there have were no late reoperations, and 2 patients required balloon aortoplasty. The overall incidence of late reintervention was 1.7%, with only 2.4% (2 of 83) in those <1 year old.

Impaired systemic ventricular relaxation affects postoperative short-term outcome in Fontan patients.

OBJECTIVES: Systemic ventricular end-diastolic pressure has been used as a predictor of outcome in patients undergoing the Fontan operation. However, this index only evaluates late diastolic function and does not assess active ventricular relaxation during the phase of early diastole, a key component of systemic venous pathway flow. This study sought to examine whether impaired preoperative systemic ventricular relaxation, expressed as the time constant of isovolumic relaxation (tau), affects short-term postoperative outcome in Fontan patients. METHODS: All patients who underwent Fontan operation between May 1998 and November 2001 were enrolled. Tau was calculated from digitized preoperative systemic ventricular pressure tracings. Standard preoperative invasive indices were also recorded and analyzed. These independent variables were then entered into a multiple stepwise regression model, with length of intensive care unit stay, length of hospital stay, and prolonged pleural effusion as outcome variables. RESULTS: Twenty-seven patients fulfilled inclusion criteria. Systemic left ventricle predominated, and all patients had undergone prior staged palliation. Extracardiac Fontan was the commonest operative technique. Of the independent variables examined, tau was the only statistically significant predictor of length of intensive care unit stay (P <.001) and length of hospital stay (P =.002). None of the independent variables predicted pleural effusion greater than 10 days. CONCLUSIONS: Tau was the only significant preoperative invasive predictor of short-term outcome in the Fontan patients. This illustrates the importance of systemic ventricular relaxation and highlights the need for a more comprehensive assessment of diastolic function before the Fontan operation.

Biventricular repair after Norwood palliation.

BACKGROUND: In general, neonates with severe left ventricular outflow tract obstruction, aortic valvar stenosis or atresia, and arch hypoplasia with either interruption or coarctation, and a small left ventricle undergo Norwood palliation followed classically by a bidirectional cavopulmonary shunt and eventual modified Fontan. However, a subset of patients, usually neonates with a ventricular septal defect, may have adequate left ventricle and mitral valve sizes making them candidates for future biventricular repair (BVR). In view of the long-term advantage of BVR, the feasibility and outcome of this approach was studied. Additionally, echocardiographic data were reviewed in an attempt to develop objective prognostic criteria for selection of patients suitable for BVR. METHODS: During a 4-year period, 8 of 58 infants undergoing Norwood palliation were identified as potential two-ventricle candidates. Their mean age was 6 days. Diagnoses included aortic atresia (n = 1), or aortic valve stenosis and subaortic stenosis (n = 7), with an interrupted aortic arch in 3 and coarctation in 4. All patients had a ventricular septal defect and a left ventricle that was considered to be apex forming. Mean mitral valve size was 11 mm (z-score = -1.7). Mean aortic valve size was 4.1 mm (mean z-score = -8.4). RESULTS: All 8 patients survived Norwood palliation. Six subsequently underwent BVR with ventricular septal defect closure and a right ventricle to pulmonary artery conduit at a mean age of 7 months. One patient is awaiting repair, and 1 underwent a cavopulmonary shunt. At the time of BVR, mean mitral valve z-score was essentially unchanged at -1.4 (14 mm). No early deaths or late deaths occurred during a mean follow-up of 32 months. CONCLUSIONS: A small subset of patients requiring Norwood palliation as newborns may be candidates for eventual BVR with low risk. In general, patients suitable for BVR have a mitral valve z-score of more than -3 and a normal-sized left ventricle. Recognition of neonatal BVR candidates enables consideration of complete neonatal repair. However, single-stage repair needs to be compared with the excellent results obtainable with the staged approach.

First-stage palliation for hypoplastic left heart syndrome in the twenty-first century.

Improved understanding of the postoperative physiology and experience with the surgical techniques and perioperative care of patients with hypoplastic left heart syndrome have resulted in improved outcomes. Over the past few years, numerous modifications to the intraoperative and postoperative management of these patients have been described. It is likely that in combination, these modifications and better understanding of the unique physiology after the Norwood procedure are responsible for decreasing early mortality. This review describes and discusses the current surgical and medical management of patients undergoing first-stage palliation for hypoplastic left heart syndrome and its variants.

Early failure of the Shelhigh pulmonary valve conduit in infants.

BACKGROUND: The ideal valved conduit for right-sided (pulmonary) reconstruction in infants and children remains elusive. Desired characteristics include availability, ease of implantation, and longevity. Cryopreserved homografts are most commonly used, but availability of small sizes and limited durability remain problematic. The Shelhigh porcine-valved conduit (SPVC) with its No-React anticalcification properties was developed as a potential alternative to homografts. METHODS: During a 10-month period, 8 patients underwent seven successful SPVC implantations. Median age was 9.5 days. Six conduits were less than 12 mm in diameter (range, 9 to 19 mm). RESULTS: The early and late survival rates were 100%. During a mean follow-up of 18 months, five conduits were replaced at 6, 10, 12, 12, and 13 months for severe obstruction. Actuarial conduit failure at 12 months was 72%. Explanted SPVCs demonstrated marked pseudointimal peel formation along the original intima with an intense granulomatous inflammatory reaction. The intimal reaction was severely fibrogenic, but calcification was not present. For comparison, we retrospectively reviewed the cases of 23 infants receiving cryopreserved homografts during an overlapping period. Twelve patients, 6 of them neonates, were less than 90 days old. Mean homograft size was 13 mm (range, 8 to 15 mm), with nine less than 13 mm. During a mean follow-up of 26 months, six conduits were replaced at 7, 12, 12, 16, 20, and 35 months (sizes 13, 17, 14, 12, 10, and 12 mm, respectively). Only three of nine homografts less than 13 mm in size were replaced during a mean follow-up of 12 months. The overall homograft replacement rate was 17% at 22 months (p = 0.005) compared with the SPVC). CONCLUSIONS: Although the SPVC appears to resist calcification, a marked foreign-body type of reaction results in pseudointimal peel formation and early conduit stenosis. In its present configuration, the SPVC in not a suitable valved conduit for use in infants. Although not ideal, the cryopreserved homograft has superior longevity to the SPVC.

Preoperative glucocorticoids decrease pulmonary hypertension in piglets after cardiopulmonary bypass and circulatory arrest.

BACKGROUND: Glucocorticoids during cardiopulmonary bypass benefit pediatric patients undergoing repair of congenital heart defects and are routine therapy, but underlying mechanisms have not been fully examined. The hypothesis was that glucocorticoids could improve cardiopulmonary recovery after cardiopulmonary bypass and deep hypothermic circulatory arrest. METHODS: Crossbred piglets (5 to 7 kg) were cooled with cardiopulmonary bypass, followed by 120-min deep hypothermic circulatory arrest. Animals were then warmed to 38 degrees C, removed from bypass, and maintained for 120 min. Methylprednisolone (60 mg/kg) was administered in the cardiopulmonary bypass pump prime (intraoperative glucocorticoids) or 6 hours before bypass (30 mg/kg) in addition to the intraoperative dose (30 mg/kg; preoperative and intraoperative glucocorticoids). Controls (no glucocorticoids) received saline. RESULTS: Pulmonary vascular resistance in controls increased from a baseline of 152 +/- 40 to 364 +/- 29 dynes. s/cm(5) at 2 hours of recovery (p < 0.001). Intraoperative glucocorticoids did not alleviate the increase in pulmonary vascular resistance (301 +/- 55 dynes. s/cm(5) at 2 hours of recovery, p < 0.001). However, animals receiving pre and intraoperative glucocorticoids had no increase in pulmonary vascular resistance (155 +/- 54 dynes. s/cm(5)). Plasma endothelin-1 in controls increased from 1.3 +/- 0.2 at baseline to 9.9 +/- 2.0 pg/mL at 2 hours recovery (p < 0.01), whereas glucocorticoid-treated animals had lower endothelin-1 levels (4.5 +/- 2.1 pg/ml, preoperative and intraoperative glucocorticoids; 4.9 +/- 1.7 pg/mL, intraoperative glucocorticoids) at the end of recovery (p < 0.05). Intracellular adhesion molecule-1 in lung tissue was lower in animals receiving pre and intraoperative glucocorticoids (p < 0.05). Myeloperoxidase activity was elevated in control lungs at 2 hours of recovery compared with glucocorticoid-treated groups (p < 0.05). Inhibitor kappaBalpha, the inhibitor of nuclear factor-kappaB, was higher in lungs of animals receiving glucocorticoids compared with controls (p < 0.05). CONCLUSIONS: Glucocorticoids prevented pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest, which was associated with reduced plasma endothelin-1. Glucocorticoids also reduced pulmonary intercellular adhesion molecule-1 and myeloperoxidase activity. Inhibition of nuclear factor-kappaB, along with reduced neutrophil activation, contributed to glucocorticoid alleviation of pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest.

Glucocorticoids reduce ischemia-reperfusion-induced myocardial apoptosis in immature hearts.

BACKGROUND: Transient myocardial dysfunction often occurs after ischemia-reperfusion with immature myocardium appearing particularly susceptible. Neutrophil adhesion and activation contribute to ischemia-reperfusion injury after cardiopulmonary bypass (CPB), possibly resulting in cell death. The hypothesis was that glucocorticoids could prevent reperfusion-induced myocardial dysfunction by blunting leukocyte-mediated injury. METHODS: Neonatal piglets were cooled with CPB followed by 2 hours of circulatory arrest. Animals were rewarmed, removed from CPB, and allowed to recover for 2 hours. Methylprednisolone (60 mg/kg) was administered in the CPB priming solution to one group (intraoperative glucocorticoids). In another group (preoperative glucocorticoids), 30 mg/kg methylprednisolone was administered 6 hours before CPB in addition to the intraoperative dose (30 mg/kg). Control animals received no glucocorticoids. RESULTS: Apoptotic myocardial cells measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and caspase-3 activity were reduced in animals administered glucocorticoids compared with controls (p < 0.05). Animals receiving either intraoperative or preoperative glucocorticoids had 0.10 +/- 0.07 and 0.13 +/- 0.05 apoptotic cells per high-power field, respectively, whereas 0.33 +/- 0.15 apoptotic cells were detected with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling in control animals. Glucocorticoid administration reduced myocardial intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 mRNA expression compared with control piglets. Maximum rate of increase of left ventricular pressure was 62% +/- 9% of baseline in control animals at 120 minutes of recovery compared with 96% +/- 6% and 95% +/- 10% of baseline in animals receiving intraoperative and preoperative glucocorticoids, respectively (p < 0.05). CONCLUSIONS: The reduction of neutrophil adhesion and activation proteins in neonatal myocardium was associated with less apoptotic cell death after glucocorticoid administration. The blunting of apoptosis in glucocorticoid-treated animals was also associated with improved recovery of left ventricular systolic function in neonatal animals after CPB and circulatory arrest. Glucocorticoid attenuation of myocardial apoptosis might have important implications for maintaining long-term ventricular function after ischemia and reperfusion.

Sildenafil citrate alleviates pulmonary hypertension after hypoxia and reoxygenation with cardiopulmonary bypass.

BACKGROUND: Sudden reoxygenation of hypoxic neonates undergoing cardiac operation exacerbates the systemic inflammatory response to cardiopulmonary bypass secondary to reoxygenation injury, worsening cardiopulmonary dysfunction. Reports suggest sildenafil decreases pulmonary hypertension and may affect myocardial function. Sildenafil's efficacy for treating postbypass cardiopulmonary dysfunction remains unknown. STUDY DESIGN: Fourteen neonatal piglets (5 to 7 kg) underwent 90 minutes of hypoxia, 60 minutes of reoxygenation with cardiopulmonary bypass, and 120 minutes of recovery. Six animals received 50 mg oral sildenafil and eight received saline at hypoxia. Data are presented as mean +/- SD. RESULTS: Sildenafil prevented the high pulmonary vascular resistance observed in controls (controls baseline 81 +/- 37 dynes. s/cm(5) versus recovery 230 +/- 93 dynes. s/cm(5), p = 0.004; sildenafil baseline 38 +/- 17 dynes. s/cm(5) versus recovery 101 +/- 60 dynes. s/cm(5), p = 0.003). Despite lower pulmonary vascular resistance after sildenafil, arterial endothelin-1 (ET-1) was increased in both groups (control baseline 1.3 +/- 0.5 pg/mL versus recovery 4.5 +/- 3.7 pg/mL, p = 0.01; sildenafil baseline 1.3 +/- 0.3 pg/mL versus recovery 9.8 +/- 4.9 pg/mL, p = 0.003). Intravenous nitric oxide (NO) levels were preserved after sildenafil treatment (sildenafil baseline 340 +/- 77 nM versus recovery 394 +/- 85 nM). IV NO levels in controls were decreased when compared with baseline (control baseline 364 +/- 83 nM versus recovery 257 +/- 97 nM, p = 0.028). Although levels of exhaled NO decreased in both groups, the sildenafil-treated animals had higher levels of exhaled NO when compared with controls at the end of recovery (0.6 +/- 0.4 parts per billion versus 1.8 +/- 0.9 parts per billion, respectively, p = 0.029). CONCLUSIONS: Sildenafil alleviated pulmonary hypertension after reoxygenation with cardiopulmonary bypass. Despite increased ET-1 levels, pulmonary vascular resistance was lower with sildenafil treatment, suggesting sildenafil's effect on the pulmonary vasculature is capable of countering vasoconstriction by ET-1. Further study into the role of sildenafil in perioperative therapy and its interactions with ET-1 are warranted.

Glucocorticoids reduce cardiac dysfunction after cardiopulmonary bypass and circulatory arrest in neonatal piglets.

OBJECTIVE: The hypotheses were that glucocorticoid administration could improve ventricular recovery by reducing cardiopulmonary bypass (CPB)-induced inflammatory response and that presurgical administration might be more effective than intraoperative dosing. DESIGN: Animal case study. SUBJECTS: Crossbred piglets (5-7 kg). INTERVENTIONS: Piglets were cooled with CPB, followed by 120 mins of deep hypothermic circulatory arrest (DHCA). Animals were rewarmed to 38 degrees C, removed from CPB, and maintained for 120 mins. Methylprednisolone (60 mg/kg) was administered in the CPB pump prime (intraoperative glucocorticoid [intraop GC]) or 6 hrs before CPB (30 mg/kg) in addition to the intraoperative dose (30 mg/kg; pre- and intraop GC). Controls (no GC) received saline. MEASUREMENTS AND MAIN RESULTS: In no GC, left ventricle (LV) positive change in pressure in time (+dP/dt) (mm Hg/sec) had a mean +/- SD of 1555 +/- 194 at baseline vs. 958 +/- 463 at 120 mins after CPB, p=.01). LV +dP/dt was maintained in glucocorticoid-treated animals (1262 +/- 229 at baseline vs. 1212 +/- 386 in intraop GC and 1471 +/- 118 vs. 1393 +/- 374 in pre-intraop GC). Glucocorticoids reduced myocardial interleukin-6 messenger RNA expression, measured by ribonuclease protection assay, at 120 mins after CPB compared with animals receiving saline (p<.05), although interleukin-6 plasma and LV protein concentrations were not affected. Interleukin-10 myocardial protein concentrations were elevated after CPB-DHCA with higher concentrations in glucocorticoid-treated animals (p<.05). Glucocorticoid treatment maintained myocardial concentrations of the inhibitor of nuclear factor-kappaB in the cytosol and decreased nuclear factor-kappaB concentrations detected in the nucleus in a DNA/protein interaction array. CONCLUSIONS: Glucocorticoids improved recovery of LV systolic function in neonatal animals undergoing CPB-DHCA. Animals receiving glucocorticoids before CPB had better postoperative oxygen delivery than those receiving only intraoperative treatment. Maintenance of cardiac function after glucocorticoids might be due, in part, to alterations in the balance of pro- and anti-inflammatory proteins, possibly through nuclear factor-kappaB-dependent pathways.