Indomethacin induced and prostaglandin relieved coarctation of the aorta in right aortic arch with left arterial duct: a case report.

We describe the case of an infant with DiGeorge syndrome born with a right aortic arch and left arterial duct. Despite the remote location of the right aortic arch from the left arterial duct, he developed coarctation of the aorta during treatment with indomethacin. This was relieved by prostaglandin treatment. This case highlights the fact that, even in the absence of an arterial duct, ductal tissue can still be present in the aorta, and cause coarctation when exposed to indomethacin. We also demonstrate the utility of prostaglandin for relief of this type of obstruction.

Ethics of pharmacological research involving adolescents.

Pharmacological research in the adolescent population is not meeting adolescents' needs. Medication is still frequently prescribed off label, and studies especially in sensitive areas of adolescent health care are underrepresented. Adolescents did not benefit from the new knowledge gained in cancer research, and their outcome has essentially not improved during the last two decades in comparison to younger children and adults. There are many obstacles that make it challenging to enroll adolescents in pharmacological research. Access can be difficult. Confidentiality plays an essential role for minors and may be a hindrance, notably to studying sexual and mental health matters. Pharmaceutical companies may exclude the adolescent patient because of a lack of profit and in fear of a complex study design. Research concepts should be explained to the adolescent in a comprehensive manner, and assent and consent forms should be clear and understandable. New laws and incentives have been developed to encourage pharmaceutical companies to engage adolescents in their research projects. Centralization and collaboration of all parties involved may make the whole approach to adolescent research more efficient and uniform. The mature minor doctrine has facilitated the enrollment process. Parental consent may be waived for low-risk medical trials to promote recruitment. Ethics committees therefore play a major role in protecting the adolescent from harm from participating in research. In conclusion, pharmacological research in adolescents has to be encouraged. This will increase the safety of current medical treatment regimens and will allow this population to benefit from therapeutic advancements.

Left ventricular distensibility does not explain impaired exercise capacity in pediatric heart transplant recipients.

BACKGROUND: Despite improved ventricular function after heart transplantation, the aerobic capacity, as measured by peak oxygen consumption (VO(2 peak)) of pediatric heart transplant recipients (HTRs), remains 30% to 50% lower than age-matched healthy individuals. Research in adult HTRs suggests that diastolic dysfunction is a major determinant of exercise intolerance; however, it is unknown whether the impaired VO(2 peak) in younger HTRs is due to reduced left ventricular (LV) distensibility. METHODS: Eight HTRs (mean age, 15 years; mean time post-transplant, 7 years) and 8 matched healthy controls were studied. To evaluate LV distensibility, echocardiographic measurements of ventricular volumes were obtained in 3 positions: supine, head-up tilt, and head-down tilt. Subsequently, participants underwent exercise stress testing to evaluate VO(2 peak). RESULTS: As expected, VO(2 peak) was 26% lower in HTRs (p<0.05). Ventricular volumes in each position were small in HTRs (p = 0.01); however, the percentage change in LV end-diastolic volume indexed (EDVi) to body surface area after the transition from supine to head-up tilt and from head-up tilt to head-down tilt were similar between HTRs (p = 0.956) and controls (p = 0.801). The change in EDVi during the transition from head-up tilt to head-down tilt (LV distensibility) strongly predicted VO(2 peak) in patients (R(2) = 0.614, p = 0.021) and controls (R(2) = 0.510, p = 0.047). Importantly, the slope of this relationship did not differ between HTRs (1.01) and controls (0.977; p = 0.951). CONCLUSIONS: LV distensibility does not appear to be a major determinant of exercise intolerance in young HTR.

Aging blunts hyperventilation-induced hypocapnia and reduction in cerebral blood flow velocity during maximal exercise.

Cerebral blood flow (CBF) increases from rest to ∼60% of peak oxygen uptake (VO(2peak)) and thereafter decreases towards baseline due to hyperventilation-induced hypocapnia and subsequent cerebral vasoconstriction. It is unknown what happens to CBF in older adults (OA), who experience a decline in CBF at rest coupled with a blunted ventilatory response during VO(2peak). In 14 OA (71 ± 10 year) and 21 young controls (YA; 23 ± 4 years), we hypothesized that OA would experience less hyperventilation-induced cerebral vasoconstriction and therefore an attenuated reduction in CBF at VO(2peak). Incremental exercise was performed on a cycle ergometer, whilst bilateral middle cerebral artery blood flow velocity (MCA V (mean); transcranial Doppler ultrasound), heart rate (HR; ECG) and end-tidal PCO(2) (P(ET)CO(2)) were monitored continuously. Blood pressure (BP) was monitored intermittently. From rest to 50% of VO(2peak), despite greater elevations in BP in OA, the change in MCA V(mean) was greater in YA compared to OA (28% vs. 15%, respectively; P < 0.0005). In the YA, at intensities >70% of VO(2peak), the hyperventilation-induced declines in both P(ET)CO(2) (14 mmHg (YA) vs. 4 mmHg (OA); P < 0.05) and MCA V(mean) (-21% (YA) vs. -7% (OA); P < 0.0005) were greater in YA compared to OA. Our findings show (1), from rest-to-mild intensity exercise (50% VO(2peak)), elevations in CBF are reduced in OA and (2) age-related declines in hyperventilation during maximal exercise result in less hypocapnic-induced cerebral vasoconstriction.

Reductions in cerebral blood flow during passive heat stress in humans: partitioning the mechanisms.

Cerebral blood flow (CBF) is reduced during passive heat stress, with 50% of this reduction associated with hyperventilatory-induced hypocapnia and subsequent cerebral vasoconstriction. It remains unknown, however, what other factors may contribute to the remaining 50%. We tested the hypothesis that the distribution of cardiac output plays an important role in maintaining cerebral perfusion during mild and severe heat stress. Middle cerebral artery and posterior cerebral artery blood flow velocity (MCAv and PCAv; transcranial Doppler) and left ventricular end-diastolic and end-systolic volumes (2-D echocardiography) were measured under conditions of normothermia and mild and severe passive heat stress (core temperature +0.8 ± 0.1°C (Protocol I; n = 10) and 1.8 ± 0.1°C (Protocol II; n = 8) above baseline). Venous return was manipulated by passive tilt table positioning (30 deg head-down tilt (HDT) and 30 deg head-up tilt (HUT)). Measurements were made under poikilocapnic and isocapnic conditions. Protocol I consisted of mild heat stress which resulted in small reductions in end-tidal CO2 (−5.6 ± 3.5%), MCAv/PCAv (−7.3 ± 2.3% and −10.3 ± 2.9%, respectively) and stroke volume (−8.5 ± 4.2%); while end-diastolic volume was significantly reduced (−16.9 ± 4.0%) and cardiac output augmented (17.2 ± 7.4%). During mild heat stress, CBF was related to left ventricular end-diastolic volume (MCAv, r2 = 0.81; PCAv, r2 = 0.83; P < 0.05) and stroke volume (MCAv, r2 = 0.38; PCAv, r2 = 0.43), but not with cardiac output. Protocol II consisted of severe heat stress which resulted in much greater reductions in end-tidal CO2 (−87.5 ± 31.5%) and CBF (MCAv, −36.4 ± 6.1%; PCAv, −30.1 ± 4.8%; P < 0.01 for all variables), while end-diastolic volume and stroke volume decreased to a similar extent as for mild heat stress. Importantly, isocapnia restored MCAv and PCAv back to normothermic baseline. This investigation therefore produced two novel findings: first, that venous return and stroke volume are related to CBF during mild heat stress; and second, that hyperventilatory hypocapnia has a major influence on CBF during severe passive heat stress.

Left ventricular systolic and diastolic function during tilt-table positioning and passive heat stress in humans.

The ventricular response to passive heat stress has predominantly been studied in the supine position. It is presently unclear how acute changes in venous return influence ventricular function during heat stress. To address this question, left ventricular (LV) systolic and diastolic function were studied in 17 healthy men (24.3 ± 4.0 yr; mean ± SD), using two-dimensional transthoracic echocardiography with Doppler ultrasound, during tilt-table positioning (supine, 30° head-up tilt, and 30° head-down tilt), under normothermic and passive heat stress (core temperature 0.8 ± 0.1°C above baseline) conditions. The supine heat stress LV volumetric and functional response was consistent with previous reports. Combining head-up tilt with heat stress reduced end-diastolic (25.2 ± 4.1%) and end-systolic (65.4 ± 10.5%) volume from baseline, whereas heart rate (37.7 ± 2.0%), ejection fraction (9.4 ± 2.4%), and LV elastance (37.7 ± 3.6%) increased, and stroke volume (-28.6 ± 9.4%) and early diastolic inflow (-17.5 ± 6.5%) and annular tissue (-35.6 ± 7.0%) velocities were reduced. Combining head-down tilt with heat stress restored end-diastolic volume, whereas LV elastance (16.8 ± 3.2%), ejection fraction (7.2 ± 2.1%), and systolic annular tissue velocities (22.4 ± 5.0%) remained elevated above baseline, and end-systolic volume was reduced (-15.3 ± 3.9%). Stroke volume and the early and late diastolic inflow and annular tissue velocities were unchanged from baseline. This investigation extends previous work by demonstrating increased LV systolic function with heat stress, under varied levels of venous return, and highlights the preload dependency of early diastolic function during passive heat stress.

Immunosuppression armamentarium in 2010: mechanistic and clinical considerations.

Effective immunosuppression is the key to successful organ transplantation, with success being defined as minimal rejection risk with concomitant minimal drug toxicities. Despite the general recognition of this fact, a paucity of appropriate clinical trials in children has contributed to lack of standardization of clinical management regimens, resulting in an extensive diversity of favored approaches. Nonetheless, although consensus has not been reached on the ideal approach to immunosuppression in pediatric transplantation, new drug therapies have contributed to a continuing improvement in graft and patient survival. Future clinical research must focus on diminishing the extensive burden of toxicities of these therapeutic agents in children.