Luis A. Altamirano-Diaz

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

Non‐technical summary  Heat stress reduces brain blood flow and impairs orthostatic tolerance. Brain blood flow is largely controlled by the partial pressure of arterial . Indeed, hyperthermia‐induced over‐breathing and related reductions in arterial account for ∼50% of the reduction in brain blood flow. This investigation tested the unique hypothesis that the distribution of cardiac output during heat stress (challenged by thermoregulatory increases in skin blood flow and sweat loss) contributes to the remaining 50%. We show that cardiac output is not related to brain blood flow, but rather arterial plays a much larger role than previously suggested. These findings help us understand the mechanisms relating heat stress with an increased likelihood of fainting, and are also relevant to pathological conditions that are accompanied by elevations in body temperature.

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.

Early post‐transplant vaccination with pandemic influenza A/H1N1 vaccine in pediatric heart transplant recipients

Altamirano‐Diaz L, West L, Humar A, Ely L, Urschel S, Gubbay J, Crowcroft N, Kumar D. Early post‐transplant vaccination with pandemic influenza A/H1N1 vaccine in pediatric heart transplant recipients.
Pediatr Transplantation 2011: 15:172–175.

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.

Pharmacological therapy for the prevention and management of cardiomyopathy in Duchenne muscular dystrophy: A systematic review

Cardiomyopathy is a major source of morbidity and mortality in Duchenne muscular dystrophy (DMD) patients now that respiratory care has improved. There is currently no definitive evidence guiding the management of DMD-associated cardiomyopathy (DMD-CM). The objective of this systematic review was to evaluate the effectiveness of pharmacotherapies for the prevention and/or management of DMD-CM and to determine the optimal timing to commence these interventions. A systematic search was conducted in January 2016 using MEDLINE, EMBASE and CINAHL databases and grey literature sources for studies evaluating the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers or aldosterone antagonists. Study quality assessment was conducted using the Downs and Black quality assessment checklist. PRISMA reporting guidelines were used. Of the 15 studies included in this review, most were of low methodological quality. Meta-analysis was not possible due to heterogeneity of studies. ACE inhibitors, angiotensin receptor blockers, beta-blockers and/or aldosterone antagonists tended to improve or preserve left ventricular systolic function and delay the progression of DMD-CM. While there is evidence supporting the use of heart failure medication in patients with DMD, data regarding these interventions for delaying the onset of DMD-CM and when to initiate therapy are lacking. PROSPERO registration: CRD42015029555.

Resting and exercise cerebral blood flow in long-term heart transplant recipients

Of 3 patients undergoing drive-line ID he developed a pseudoaneurysm that was emergently surgically treated. The 26 patients with drive-line infection who were treated medically required multiple re-admissions due to worsening drainage. Two of these were admitted in septic shock and were considered not surgical candidates. Ultimately, they succumbed to their infections. Eight of them underwent heart transplantation; 5 had positive intra-operative pump-pocket cultures. Twenty medically treated patients are still alive. Thus, despite improved survival associated with LVAD therapy, infection continues to be a major limiting factor. We believe that surgery should typically be reserved for stable medically intractable infections or patients who present with septic emboli. Pump or pump-pocket infection can be treated with pump exchange or intra-abdominal relocation. Drive-lines should be unroofed to prevent component seeding. Infected pump and pockets should be widely debrided and pumps relocated to prevent them from re-infection. Despite these results, the best alternative to avoid recurrence of LVAD-associated infection appears to be removal of the pump. Therefore, it is imperative that, when device exchange or relocation is contemplated, a thorough work-up be undertaken to prove the patient has not recovered. We currently use a work-up similar to that described by Birks and colleagues. If the patient has recovered, then the decision is made to attempt to explant the device.

Does obesity affect the non-invasive measurement of cardiac output performed by electrical cardiometry in children and adolescents?

Electrical cardiometry (EC) is a non-invasive and inexpensive method for hemodynamic assessment and monitoring. However, its feasibility for widespread clinical use, especially for the obese population, has yet to be determined. In this study, we evaluated the agreement and reliability of EC compared to transthoracic Doppler echocardiography (TTE) in normal, overweight, and obese children and adolescents. We measured stroke volume (SV) and cardiac output (CO) of 131 participants using EC and TTE simultaneously. We further divided these participants according to BMI percentiles for subanalyses: <85% normal weight (n = 41), between 85 and 95% overweight (n = 7), and >95% obese (n = 83). Due to small sample size of the overweight group, we combined overweight and obese groups (OW+OB) with no significant change in results (SV and CO) before and after combining groups. There were strong correlations between EC and TTE measurements of SV (r = 0.869 and r = 0.846; p < 0.0001) and CO (r = 0.831 and r = 0.815; p < 0.0001) in normal and OW+OB groups, respectively. Bias and percentage error for CO measurements were 0.240 and 29.7%, and 0.042 and 29.5% in the normal and OW+OB groups, respectively. Indexed values for SV were lower in the OW+OB group than in the normal weight group when measured by EC (p < 0.0001) but no differences were seen when measured by TTE (p = 0.096). In all weight groups, there were strong correlations and good agreement between EC and TTE. However, EC may underestimate hemodynamic measurements in obese participants due to fat tissue.

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.

Implementation of clinical research trials using web-based and mobile devices: challenges and solutions

BackgroundWith the increasing implementation of web-based, mobile health interventions in clinical trials, it is crucial for researchers to address the security and privacy concerns of patient information according to high ethical standards. The full process of meeting these standards is often made more complicated due to the use of internet-based technology and smartphones for treatment, telecommunication, and data collection; however, this process is not well-documented in the literature.ResultsThe Smart Heart Trial is a single-arm feasibility study that is currently assessing the effects of a web-based, mobile lifestyle intervention for overweight and obese children and youth with congenital heart disease in Southwestern Ontario. Participants receive telephone counseling regarding nutrition and fitness; and complete goal-setting activities on a web-based application. This paper provides a detailed overview of the challenges the study faced in meeting the high standards of our Research Ethics Board, specifically regarding patient privacy.ConclusionWe outline our solutions, successes, limitations, and lessons learned to inform future similar studies; and model much needed transparency in ensuring high quality security and protection of patient privacy when using web-based and mobile devices for telecommunication and data collection in clinical research.