Sulindac sulfide, but not sulindac sulfone, inhibits colorectal cancer growth.

Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice.

Magnetic resonance imaging and two-dimensional echocardiography. Alternative approach to aortography in diagnosis of aortic dissecting aneurysm.

Unrecognized acute dissection of the aorta requires rapid and accurate diagnosis for appropriate management. The "gold standard" for diagnosis has been invasive angiography, but this diagnosis can be achieved noninvasively via two-dimensional echocardiography, computed tomographic scanning, and magnetic resonance imaging. Two patients are described in whom echocardiography and magnetic resonance imaging were complementary diagnostic aids. The advantages and disadvantages of echocardiography, computed tomographic scanning, magnetic resonance imaging, and aortography in aortic dissection are discussed. It is anticipated that a combination of noninvasive diagnostic aids will eliminate the need for invasive angiography in many instances in the future.

Four patterns of response to inhaled nitric oxide for persistent pulmonary hypertension of the newborn.

OBJECTIVE: To determine the clinical role of inhaled nitric oxide (iNO) in the treatment of persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: Prospective open observational clinical study. SETTING: A regional cardiac and pediatric intensive care unit. METHODS: Twenty-five consecutive near-term neonates (> 35 weeks gestation) with severe PPHN (oxygenation index [OI] > 25) were given a trial of iNO of 20 ppm for 20 minutes. Neonates who showed a greater than 20% improvement in PaO2 as well as a decrease in the OI to below 40 were defined as responders and continued on this therapy. RESULTS: Four patterns of response emerged to the iNO therapy: Pattern 1 neonates (n = 2) did not respond to the initial trial of iNO-one survived. Pattern 2 neonates (n = 9) responded to the initial trial of iNO, but failed to sustain this response over 36 hours, as defined by a rise in the OI to > 40. Six survived, five with extracorporeal membrane oxygenation. Pattern 3 neonates (n = 11) responded to the initial trial of iNO, sustained this response, and were successfully weaned from iNO within 5 days--all survived to discharge. Pattern 4 neonates (n = 3) responded to the initial trial of iNO, but developed a sustained dependence on iNO for 3 to 6 weeks. All three died and lung histology revealed severe pulmonary hypoplasia and dysplasia. These neonates (pattern 4) not only required iNO for a longer period of time than did the sustained responders (pattern 3), but they required significantly higher doses of iNO during their first 5 days of iNO therapy. CONCLUSIONS: Early responses to iNO may not be sustained. Neonates with pulmonary hypoplasia and dysplasia may have a decreased sensitivity and differing time course of response to iNO when compared with patients who have PPHN in fully developed lungs.

Echocardiographic analysis of left ventricular filling in isolated pure chronic aortic regurgitation.

Left ventricular (LV) diastolic filling was assessed using digitized M-mode echocardiography in 12 patients with aortic regurgitation (AR) and in 12 normal subjects. Ten patients with AR were asymptomatic and 2 patients had congestive heart failure. LV chamber dimensions, fractional shortening and the rate of change of LV dimensions during systole and diastole were determined. In addition, the timing of the rate of change of LV dimensions in diastole (peak dD/dt, 50% peak dD/dt and 20% peak dD/dt) was also measured. Patients with AR had a significant reduction in dD/dt (12.2 +/- 3.5 cm/s in patients with AR vs 15.9 +/- 1.9 cm/s in normal subjects, p less than 0.01) and a delay in the timing of peak dD/dt (160 +/- 35.2 ms in patients with AR vs 86 +/- 17.6 ms in normal subjects, p less than 0.01) from the minimum LV dimension. These diastolic abnormalities were present in patients with symptomatic as well as those with asymptomatic AR, occurred even when the fractional shortening and peak systolic emptying rate (peak -dD/dt) were normal, and showed no correlation with the calculated LV mass (r = 0.14). The delay in the diastolic filling velocities (peak dD/dt, 50% and 20% peak dD/dt) was associated with a decreased rate of change of LV dimension in diastole, suggesting delayed early LV filling. These findings indicate an abnormality of LV diastolic filling in patients with symptomatic as well as asymptomatic AR and suggest that diastolic abnormalities may precede echocardiographic indexes of systolic LV dysfunction.

Contribution of echocardiography and immediate surgery to the management of severe aortic regurgitation from active infective endocarditis.

The timing of surgery in patients with severe aortic regurgitation and left ventricular (LV) failure, particularly when associated with active infective endocarditis (IE), is of the utmost importance. From July 1982 to May 1984, 34 patients, aged 15 to 60 years, with severe aortic regurgitation underwent immediate (within 24 hours of diagnosis) aortic valve surgery. All patients were in New York Heart Association class IV for LV failure. Eighteen patients had right-sided heart failure. Decision for immediate surgery was based on the echocardiographic demonstration of diastolic closure of the mitral valve or of vegetations on the aortic valve. Premature closure of the mitral valve was demonstrated echocardiographically in 17 patients, 13 of whom had diastolic crossover of LV and left atrial pressure tracings recorded at surgery. IE of the aortic valve was confirmed at surgery in 29 patients, 27 of whom had vegetations on echocardiography. Seven patients required replacement of both aortic and mitral valves. Antibiotic therapy for IE was started immediately after blood cultures were taken and continued for 4 to 6 weeks postoperatively. The mortality rate within 30 days of surgery was 6% for the group as a whole and 7% for those with IE. Mean follow-up period for the 32 survivors was 10.6 months. There were 2 late deaths. No patient had periprosthetic regurgitation or persistence of endocarditis. Procrastination in referral for surgery of these extremely ill patients is not justified and is likely to be associated with higher risks of morbidity and mortality.

Early response to inhaled nitric oxide and its relationship to outcome in children with severe hypoxemic respiratory failure.

OBJECTIVE: To examine whether the early response to inhaled nitric oxide (iNO) is a measure of reversibility of lung injury and patient outcome in children with acute hypoxemic respiratory failure (AHRF). DESIGN: Retrospective review study. SETTING: Pediatric ICUs. PATIENTS: Thirty infants and children, aged 1 month to 13 years (median, 7 months) with severe AHRF (mean alveolar arterial oxygen gradient of 568+/-9.3 mm Hg, PaO2/fraction of inspired oxygen of 56+/-2.3, oxygenation index [OI] of 41+/-3.8, and acute lung injury score of 2.8+/-0.1). Eighteen patients had ARDS. INTERVENTIONS: The magnitude of the early response to iNO was quantified as the percentage change in OI occurring within 60 min of initiating 20 ppm iNO therapy. This response was compared to patient outcome data. MEASUREMENTS AND RESULTS: There was a significant association between early response to iNO and patient outcome (Kendall tau B r=0.43, p < 0.02). All six patients who showed < 15% improvement in OI died; 4 of the 11 patients (36%) who had a 15 to 30% improvement in OI survived, while 8 of 13 (61%) who had a > 30% improvement in OI survived. Overall, 12 patients (40%) survived, 9 with ongoing conventional treatment including iNO, and 3 with extracorporeal support. CONCLUSIONS: In AHRF in children, greater early response to iNO appears to be associated with improved outcome. This may reflect reversibility of pulmonary pathophysiologic condition and serve as a bedside marker of disease stage.

Nitric oxide is superior to prostacyclin for pulmonary hypertension after cardiac operations.

BACKGROUND: Severe pulmonary hypertension is still a cause of morbidity and mortality in children after cardiac operations. The objective of this study was to compare the vasodilator properties of inhaled nitric oxide, a novel pulmonary vasodilator, and intravenous prostacyclin in the treatment of severe postoperative pulmonary hypertension. METHODS: Thirteen children (aged 3 days to 12 months) with severe pulmonary hypertension after cardiac operations were given inhaled nitric oxide (20 ppm x 10 minutes) and intravenous prostacyclin (20 ng.kg-1.min-1 x 10 minutes) in a prospective, randomized cross-over study. RESULTS: Both nitric oxide and prostacyclin resulted in a reduction in pulmonary arterial pressure, although the mean pulmonary arterial pressure was significantly lower during nitric oxide therapy (28.5 +/- 2.9 mm Hg) than during prostacyclin therapy (35.4 +/- 2.1 mm Hg; p < 0.05). The mean pulmonary to systemic arterial pressure ratio was also significantly lower during nitric oxide than prostacylin administration (0.46 +/- 0.04 versus 0.68 +/- 0.05; p < 0.01), due mainly to only prostacyclin lowering systemic blood pressure. CONCLUSIONS: Inhaled nitric oxide was a more effective and selective pulmonary vasodilator than prostacyclin and should be considered as the preferred treatment for severe postoperative pulmonary hypertension.

The uses of two-dimensional Doppler echocardiographic techniques preoperatively and postoperatively in a ventricular septal defect caused by penetrating trauma.

Doppler echocardiography was used to determine the site and size of a ventricular septal defect in a patient with a penetrating wound of the heart. Additional physiological measurements by Doppler study, including pulmonary artery pressure and degree of left-to-right shunting, were helpful in deciding on surgical closure of the defect as the definitive therapy in this patient. Associated intracardiac defects (e.g., mitral or tricuspid regurgitation) can be excluded by Doppler echocardiography.

Role of echocardiography/Doppler in cardiogenic shock: silent mitral regurgitation.

Two cases of cardiogenic shock and pulmonary edema due to acute, severe, silent mitral regurgitation are discussed. The mechanism for the mitral regurgitation was papillary muscle rupture in the setting of acute myocardial infarction. Echocardiography established the presence, severity, and cause of the mitral regurgitation and the associated hyperdynamic left ventricular function in the setting of cardiogenic shock. Transesophageal echocardiography is excellent for assessing the mitral valve in critically ill patients in whom transthoracic echocardiography may be inadequate or misleading. This allowed for emergency mitral valve replacement without prolonged attempts at medical stabilization.

Nitric oxide might reduce the need for extracorporeal support in children with critical postoperative pulmonary hypertension.

BACKGROUND: Postoperative pulmonary hypertension is a life-threatening, yet reversible complication of congenital heart operations. Although inhaled nitric oxide (iNO), a selective pulmonary vasodilator, has been shown extensively to improve short-term oxygenation and hemodynamic indices in these patients, its influence on patient outcome has not been evaluated. The purpose of this study was to assess retrospectively whether patients who fulfilled our criteria for extracorporeal life support (ECLS) for critical postoperative pulmonary hypertension still required ECLS after the administration of iNO therapy. METHODS: Since January 1992, 10 patients (age 3 days to 10 months) fulfilled the criteria at our institution for ECLS for postoperative pulmonary hypertension. Of these, 5 could not be separated from cardiopulmonary bypass because of pulmonary hypertension, and 5 had critical pulmonary hypertension (pulmonary arterial pressure approaching systemic arterial pressure) causing severe cardiopulmonary compromise. RESULTS: Six of the 10 ECLS candidates had a sustained response to iNO and survived to discharge from the hospital, without the need for rescue ECLS. Three patients still required ECLS after 30 minutes, 4 hours, and 8 hours of beginning iNO because of failing cardiac output, and 2 survived. The remaining patient died after 5 days of iNO therapy, but was no longer a candidate for ECLS because of sepsis and multiorgan system failure. CONCLUSIONS: Children with critical pulmonary hypertension unresponsive to maximal conventional treatment may be managed successfully with iNO without the need for rescue ECLS. A trial of iNO should therefore be given before the use of ECLS in these patients.

High risk percutaneous transluminal coronary angioplasty in the treatment of severe coronary artery disease.

We report on 27 "high risk" patients out of 171 consecutive patients undergoing percutaneous transluminal coronary angioplasty from June 1984 to August 1985. The ages ranged from 31-80 years (mean 62.7 +/- 10) years. High risk percutaneous transluminal coronary angioplasty was defined as: salvage cases (3 patients) where the patients presented in cardiogenic shock or the vessels were not bypassable; multivessel coronary artery disease (22 patients) where a large area of jeopardized myocardium was dependent on the angioplasty vessel(s); left ventricular dysfunction (7 patients) as defined by two of the three criteria: left ventricular end-diastolic volume index greater than 100 ml/m2; ejection fraction less than 30%; and left ventricular end-diastolic pressure greater than 20 mm Hg. The initial success rate in the high risk patients was 85.2%. Emergency coronary artery bypass surgery in these patients was 7.4%. There was one death in the high risk group, as one of the salvage cases died 24 hours after successful percutaneous transluminal coronary angioplasty due to severe underlying myocardial disease. In conclusion percutaneous transluminal coronary angioplasty can be successfully performed in high risk patients with a low complication rate and should be considered as an alternative to coronary artery bypass graft surgery in selected high risk patients.

Predicting outcome in ex-premature infants supported with extracorporeal membrane oxygenation for acute hypoxic respiratory failure.

OBJECTIVE: To identify predictors of outcome in ex-premature infants supported with extracorporeal membrane oxygenation (ECMO) for acute hypoxic respiratory failure. METHODS: Retrospective review of ex-premature infants with acquired acute hypoxic respiratory failure requiring ECMO support in the United Kingdom from 1992 to 2001. Review of follow up questionnaires completed by general practitioners and local paediatricians. RESULTS: Sixty four ex-premature infants (5-10 each year) received ECMO support, despite increased use of advanced conventional treatments over the decade. The most common infective agent was respiratory syncytial virus (85% of cases). Median birth gestation was 29 weeks and median corrected age at the time of ECMO support was 42 weeks. Median ECMO support duration was relatively long, at 229 hours. Survival to hospital discharge and to 6 months was 80%, remaining similar throughout the period of review. At follow up, 60% had long term neurodisability and 79% had chronic pulmonary problems. Of pre-ECMO factors, baseline oxygen dependence, younger age, and inpatient status were associated with non-survival (p < or = 0.05). Of ECMO related factors, patient complications were independently associated with adverse neurodevelopmental outcome and death (p < 0.01). CONCLUSIONS: Survival rates for ex-premature infants after ECMO support are favourable, but patients suffer a high burden of morbidity during intensive care and over the long term. At the time of ECMO referral, baseline oxygen dependence is the most important predictor of death, but no combination of the factors considered was associated with a mortality that would preclude ECMO support.

Impact of junctional ectopic tachycardia on postoperative morbidity following repair of congenital heart defects.

OBJECTIVE: To determine the incidence of postoperative junctional ectopic tachycardia (JET), we reviewed 343 consecutive patients undergoing surgery between 1997 and 1999. The impact of this arrhythmia on in-hospital morbidity and our protocol for treatment were assessed. METHODS: We reviewed the postoperative course of patients undergoing surgery for ventricular septal defect (VSD; n=161), tetralogy of Fallot (TOF; n=114), atrioventricular septal defect (AVSD; n=58) and common arterial trunk (n=10). All patients with JET received treatment, in a stepwise manner, beginning with surface cooling, continuous intravenous amiodarone, and/or atrial pacing if the haemodynamics proved unstable. A linear regression model assessed the effect of these treatments upon hours of mechanical ventilation, and stay on the cardiac intensive care unit (CICU). RESULTS: Overall mortality was 2.9% (n=10), with three of these patients having JET and TOF. JET occurred in 37 patients (10.8%), most frequently after TOF repair (21.9%), followed by AVSD (10.3%), VSD (3.7%), and with no occurrence after repair of common arterial trunk. Mean ventilation time increased from 83 to 187 h amongst patients without and with JET patients (P<0.0001). Accordingly, CICU stay increased from 107 to 210 h when JET occurred (P<0.0001). Surface cooling was associated with a prolongation of ventilation and CICU stay, by 74 and 81 h, respectively (P<0.02; P<0.02). Amiodarone prolonged ventilation and CICU stay, respectively, by 274 and 275 h (P<0.05; P<0.06). CONCLUSIONS: Postoperative JET adds considerably to morbidity after congenital cardiac surgery, and is particularly frequent after TOF repair. Aggressive treatment with cooling and/or amiodarone is mandatory, but correlates with increased mechanical ventilation time and CICU stay. Better understanding of the mechanism underlying JET is required to achieve prevention, faster arrhythmic conversion, and reduction of associated in-hospital morbidity.

Near-fatal grape aspiration with complicating acute lung injury successfully treated with extracorporeal membrane oxygenation.

OBJECTIVE: In this report of a near-fatal case of grape aspiration successfully treated with extracorporeal membrane oxygenation (ECMO), we highlight the danger of feeding seedless grapes to young children and demonstrate that ECMO can provide cardiopulmonary support for cases of acquired large-airway disruption and can facilitate therapeutic intervention. DESIGN: Case report. SETTING: A tertiary pediatric intensive care unit and ECMO center. PATIENT: A healthy 14-month-old boy aspirated a seedless grape while playing at home and suffered a cardiopulmonary arrest of 15 mins in duration. He responded to advanced life support with return of cardiac output but developed intractable cardiopulmonary failure secondary to aspirated grape particles and postobstructive pulmonary edema. INTERVENTIONS: The patient was emergently transferred to the regional ECMO center and placed on venoarterial ECMO. Bronchoscopies were performed in the stable environment provided by ECMO, aspirated particles were removed from the large airways, and lung recovery was facilitated. MEASUREMENTS AND MAIN RESULTS: End-organ perfusion was restored via ECMO during a period of severe intractable cardiopulmonary failure. Pulmonary recovery occurred during a 6-day ECMO run and was facilitated by therapeutic bronchoscopy. The patient was reviewed 1 yr later and has made a full neurodevelopmental recovery, despite a 15-min out-of-hospital cardiac arrest. CONCLUSIONS: Aspiration of a seedless grape is a life-threatening event in a small child. This danger is not fully appreciated by parents in the UK. ECMO may be life saving in cases of acquired large-airway disruption resulting in severe cardiopulmonary failure, including foreign body aspiration, as long as end-organ perfusion is maintained.

The echo Doppler spectrum of valvular abnormalities in the hospitalized octogenarian.

Cardiac valves thicken and become more opaque with advancing age. As more individuals live longer and as more treatment modalities such as valvuloplasty evolve, the presence and significance of these valvular abnormalities become important. We retrospectively studied 628 octogenarian patients to try and define further the presence and significance of these abnormalities detected by Doppler echocardiography. A group of 547 patients were suitable for analysis. Age ranged from 80 to 96 years (mean 84.4). The female:male ratio was 1.9:1. Mitral, aortic, and tricuspid regurgitation (MR, AR, and TR) were significant if the jet moved greater than 2 cm from the plane of the valve away or toward the transducer, depending on transducer position. Mitral regurgitation was detected in 331 patients (60.5%) and was significant in 82 patients (15%). Aortic regurgitation was detected in 276 patients (50.5%) and was significant in 70 patients (12.8%). Tricuspid regurgitation was detected in 131 patients (23.9%) and was significant in 30 patients (5.5%). Regurgitant lesions were detected in two valves in 150 patients (27.4%) three valves in 57 patients (10.4%), in all four valves in 17 patients (3.1%). Aortic stenosis was detected in 160 patients (29.3%). The gradient range was 16-156 mmHg (mean 47.8). Significant aortic stenosis was present in 70 patients (12.8%) (gradient greater than 50 mmHg), of whom 54 had isolated pure aortic stenosis and 16 had mixed lesion. In 40% of these patients, significant aortic stenosis was an unexpected finding at two-dimensional echocardiography. Valvular pathology is common in the octogenarian population.(ABSTRACT TRUNCATED AT 250 WORDS)

Geriatric cardiology: managing the most common nonischemic disorders.

Two-dimensional echocardiography is the method of choice for calculation of left ventricular mass, especially in patients with abnormal left ventricular geometry and segmental disease. Predominating diastolic abnormalities may be responsible for signs and symptoms of heart failure in some patients. These patients should not be treated in the conventional manner, but require special treatment with beta blockers or calcium-channel blocking agents.

Postexercise blood pressure as a predictor of hypertension.

A study on 721 healthy male aircrew assessed whether the blood pressure response to exercise could be used to predict the development of hypertension. A positive blood pressure response to exercise, recorded 30 s after the completion of exercise, was defined as a systolic blood pressure of 200 torr or more (systolic test) or a raised diastolic blood pressure (diastolic test). While 236 (32.7%) became hypertensive with a blood pressure greater than 149/90 torr, 17% of these had shown a positive systolic response and 17% a positive diastolic response. The other 485 individuals (67.3%) remained normotensive throughout the mean follow-up period of 68 months (range 12-170 months). Of this group, 88% never manifested a positive systolic or diastolic response to exercise. Although 5% of the normotensive subjects manifested a positive systolic response to exercise, and 12% manifested a positive diastolic response to exercise, a longer period of follow-up may reduce this figure. It is concluded that exercise related blood pressure is a useful test in predicting the development of essential hypertension.