Prospective Studies In Children Research Articles

NFS-07. RESPONSE OF A CENTRAL NERVOUS SYSTEM (CNS) HEMANGIOBLASTOMA TO BELZUTIFAN IN A PEDIATRIC PATIENT WITH VON HIPPEL-LINDAU DISEASE (VHL)

Abstract BACKGROUND VHL is a rare cancer predisposition syndrome which affects many organ systems, leading to renal clear cell carcinoma (RCC), pheochromocytoma, retinal angiomas and CNS hemangioblastomas. Surgical resection has traditionally been the mainstay of treatment of VHL-associated tumors. In 2021, belzutifan, a Hypoxia Inducible Factor 2-alpha inhibitor was approved by the Food and Drug Administration for the treatment of VHL-associated RCC based on efficacy in adults. There is a paucity of data in pediatric VHL patients with hemangioblastoma treated with this novel agent. Herein we present such a case. CASE A 15-year-old male, diagnosed with VHL caused by a de novo germline mutation at the age of 12, was found to have a left craniocervical junction lesion consistent with a hemangioblastoma on surveillance MRI. The lesion demonstrated growth upon serial imaging but remained asymptomatic. Due to location, the patient was started on medical treatment using once daily oral belzutifan (120mg) continuously, sperm banking was performed prior to initiation of therapy. Hematologic and metabolic laboratory values were monitored, in addition to regular physical examinations including blood oxygen saturation recordings. The first MRI on therapy (3 months after treatment started) demonstrated a major radiologic response using RANO criteria. Treatment has been overall very well tolerated with few treatment-related toxicities limited to CTCAE v5 grade 1 fatigue and grade 2 anemia. No dose reductions or interruptions were required. The patient remains on therapy and has completed 11 months of treatment with further reduction in the size of this target lesion. CONCLUSION Hemangioblastomas are preponderantly characterized by their highly vascular nature making surgical resection in some cases arduous depending on location. This unique pediatric case adds to the growing evidence that therapy with belzutifan may be a safe and efficacious option for VHL-associated CNS Hemangioblastomas. Prospective studies in children are needed.

Ustekinumab trough levels in children with Crohn's disease refractory to anti-tumor necrosis factor agents: a prospective case series of off-label use.

Background: Ustekinumab is used off-label in pediatric Crohn's disease refractory to anti-tumor necrosis factor. Data on optimal dosing, target trough levels, and potential benefit of therapeutic drug monitoring in children treated with ustekinumab are limited. Materials and Methods: We describe a series of six adolescents who consented to be treated with ustekinumab. We measured their trough levels, C-reactive protein, and fecal calprotectin before every administration. Results: Standard adult dosing was effective to achieve biochemical remission (fecal calprotectin < 250mg/kg) in one patient and clinical remission (resolution of symptoms) in another. The other four patients failed to respond on standard dosing and underwent intravenous re-induction and interval shortening to increase ustekinumab trough levels. This resulted in biochemical remission in one patient and clinical remission in another, suggesting an exposure-response relationship. The remaining two patients had no therapeutic benefit, and ustekinumab was discontinued. Conclusion: In this report, we show that ustekinumab can induce remission in pediatric patients with anti-tumor necrosis factor refractory Crohn's disease. It is worth escalating the dose before abandoning the drug as ineffective. Prospective studies in children are needed to determine long-term efficacy of ustekinumab, usefulness of therapeutic drug monitoring strategies, and, if applicable, optimal target trough levels.

Investigation of the efficacy and adverse effects of lacosamide over 36 months

ObjectiveTo evaluate the efficacy and retention rate of lacosamide (LCM) over 36 months as a treatment for children and adolescents with focal and generalized epilepsy based on a retrospective study. MethodsAll patients prescribed LCM as monotherapy and add-on therapy between October 2016 and September 2019 at Jichi Children’s Medical Center Tochigi were included in the study. The response rate, retention rate, and adverse effects were calculated. ResultsA total of 126 (female, n = 73) patients of 1.3 to 34.9 years old (median age: 12.8 years; mean ± SD 13.2 ± 6.6 years) received LCM as monotherapy or add-on treatment for focal, generalized, and combined focal and generalized epilepsy. The response rate was 40.5% at 3 months, 40.5% at 6 months, 38.1% at 9 months, 35.7% at 12 months, 25.9% at 24 months, and 29.4% at 36 months. For 34 patients who were observable for 36 months, the retention rate was 70.6% at 3 months, but then gradually declined to 34.8% at 36 months. According to the number of concomitant anti-seizure medications (ASMs), the retention rate was higher in patients receiving <3 ASMs than in those receiving ≥3 ASMs at all observation points. The most common adverse effects were somnolence in 21 patients (16.7%) and dizziness in 5 patients (39.7%). ConclusionOur response rate was lower and our retention rate was higher in comparison to a previous study that observed patients over 36 months. Further prospective studies in children are required to confirm the response rate and retention rate in patients treated with LCM over 36 months.

Insulin Resistance in Children and the role of Endocrine-Disrupting Chemicals: Taking Stock of the Situation

The prevalence of non-communicable diseases, of which insulin resistance is a major constituent, among the pediatric population is exponentially increasing worldwide; this is causing a significant health burden, making understanding the basis of this phenomenon an issue of primary importance. During the last decades, we also observed that exposure to endocrine-disrupting chemicals is becoming more and more common; this has led researchers to investigate the mechanism of action and define the role of those substances in interfering with human metabolism and hormonal balance, especially at a young age. We reviewed the literature on prospective, epidemiological, and cross-sectional studies that have shown a link between exposure to pesticides, polychlorinated biphenyls, bisphenol A, phthalates, aromatic polycyclic hydrocarbons, or dioxins and insulin resistance; the strength of the associations varies between the substances and human biomonitoring studies have helped in defining the role of these chemicals. The number of prospective studies in children and even in adults is still low and heterogenous, still, evidence that Endocrine disruptors might be involved in the development of insulin resistance and related diseases is accumulating. This review aims to analyze the latest findings linking exposure to endocrine-disrupting chemicals with insulin resistance in children with the perspective of taking a cue for conducting new studies and identifying the most concerning Endocrine disruptors exposures, in order to guide future risk assessment and policy action aimed to limit the negative consequences of endocrine disrupting chemical exposure.

Vedolizumab Is Safe and Efficacious for the Treatment of Pediatric-Onset Inflammatory Bowel Disease Patients Who Fail a Primary Biologic Agent.

BackgroundVedolizumab (VDZ) is currently licensed for use in adults for the treatment of inflammatory bowel disease (IBD). We aimed to investigate the clinical course of pediatric-onset IBD following treatment with VDZ as more than a secondary biologic agent. We also evaluated factors associated with secondary loss of response (LOR) and durability of VDZ treatment.MethodsPediatric-onset IBD patients diagnosed at an age younger than 18 years who had received VDZ as more than a secondary biologic agent were included in this retrospective observational study conducted at the Department of Pediatrics of two centers in Korea. Comparative analysis was conducted between groups divided according to the development of secondary LOR during VDZ treatment.ResultsA total of 24 patients comprising 10 patients with Crohn’s disease and 14 with ulcerative colitis were included. Of these, 19 were male and 5 were female. The mean age at diagnosis was 14.6 ± 2.5 years. The mean age at initiation of VDZ was 20.5 ± 2.8 years. Nine patients (37.5%) had received two or more biologic agents before starting VDZ. During a median of 0.9 years follow-up from VDZ initiation, 9 patients (37.5%) experienced LOR requiring interval shortening and 4 patients (16.7%) were changed to a different biologic agent. According to multivariate Cox proportional hazard regression analysis, administration of two or more biologic agents before VDZ treatment was the only factor positively associated with LOR (hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.026–30.56; P = 0.047), while LOR was the only factor negatively associated with VDZ durability (HR, 0.003; 95% CI, 0.00–0.08; P = 0.010). No adverse events were observed during treatment with VDZ.ConclusionVDZ is safe and efficacious for the treatment of pediatric-onset IBD patients failing a primary biologic agent. The durability of VDZ may be enhanced by introducing VDZ earlier in the disease course. Further prospective studies in children are required in the future to validate these findings.

Total dairy consumption in relation to overweight and obesity in children and adolescents: A systematic review and meta-analysis.

A systematic review and meta-analysis of cross-sectional and prospective cohort studies was conducted to assess the associations between total dairy consumption and its different subtypes with the prevalence and incidence of overweight, obesity, and overweight/obesity in children and adolescents. A literature search was conducted in Medline through PUBMED and Cochrane Library databases until October 18, 2021. Articles reporting the risk estimates as odd ratios (OR), risk ratios (RR), or hazard ratios and their corresponding 95% confidence interval (CI) for the association between dairy product consumption and the risk of overweight and/or obesity were included. In the meta-analysis from cross-sectional studies, results showed an inverse association between total dairy consumption and obesity prevalence (OR (95% CI): 0.66 (0.48-0.91). No significant associations were found between milk or yogurt and obesity prevalence risk. Regarding prospective studies, total milk consumption was positively associated with overweight prevalence (OR (95% CI): 1.13 (1.01-1.26)) and incidence (RR (95%CI): 1.17 (1.01-1.35)) risk. Evidence from pooled analysis of cross-sectional studies suggested an inverse association between total dairy consumption and obesity. However, there is limited and no conclusive evidence to confirm an inverse relationship from pooled analysis of prospective studies in children and adolescents.

Hemostatic Balance in Severe Trauma.

Acute coagulopathy is prevalent in adult and pediatric trauma patients and is associated with increased morbidity and mortality. While reasonable hypotheses have been created to explain the underlying perturbations of adult trauma coagulopathy (i.e., tissue factor-related increase in thrombin generation, protein C activation, hypoperfusion, and hyperfibrinolysis), only a small number of studies have been performed to prove whether these mechanisms can likewise be detected in pediatric trauma patients. In addition, severe hypofibrinogenemia (<100 mg/dL) is a frequent finding in pediatric trauma patients (>20%). Although the probability of life-threatening coagulopathy is low with minor to moderate injury, it is present in almost all patients with an injury severity score >25, hypotension, hypothermia, and acidosis. As these multifactorial changes in hemostasis cannot be adequately and rapidly measured using standard laboratory testing, the use of viscoelastic measurements has been established in adult trauma management, but prospective studies in children are urgently needed. Apart from diagnostic challenges, several studies have focused on the impact of blood product ratios on the treatment of massively bleeding pediatric trauma patients. The majority of these studies were unable to show improved survival by using higher plasma to red blood cell ratios or higher platelet to red blood cells ratios, but there are no published randomized trials to definitively answer this question. A goal-directed transfusion protocol using viscoelastic tests together with early substitution with an antifibrinolytic and fibrinogen replacement is a promising alternative to traditional ratio-based interventions. Another crucial factor in treating trauma-induced coagulopathy is the early detection of hypofibrinogenemia, a common condition in massively transfused patients. Early treatment of hypofibrinogenemia is associated with improved morbidity and mortality in adults, but needs to be further studied in future pediatric trials. Pediatric trauma patients are not only threatened by coagulopathy-related bleeding but are also at higher risk for venous thromboembolism. Pediatric trauma patients with brain injury, central venous catheters, immobilization, or surgical procedures are at highest risk for developing a deep venous thrombosis. There are no specific pediatric guidelines established to prevent venous thromboembolism in children suffering from traumatic injury.

Vitamin D and sleep in children.

The impact of vitamin D on human health including sleep has been well described in adults. Its deficiency has been associated with multiple sleep disorders such as decrease in sleep duration, worsening of sleep quality, and even OSA. Such correlation is less evident in the pediatric population. In the current study, we examined the relationship between sleep architecture and vitamin D status in children referred to a sleep clinic. This was a retrospective-cohort study in a tertiary care children's hospital over a 1-year period. Children who underwent an in-laboratory overnight-polysomnogram and had a 25-hydroxy vitamin D level obtained within 120 days of the sleep study were included. Patients with OSA or central sleep apnea were excluded. Data from polysomnograms and Pediatric Sleep Questionnaires were collected and analyzed. A total of 39 patients (mean age, 6.6 years; 46% female) were included in the study. Twenty (51%) patients had vitamin D deficiency (25-hydroxy vitamin D level < 30 ng/mL). Children with vitamin D deficiency had less total sleep time (470.3 minutes ± 35.6 vs 420.3 minutes ± 61.7; P = .004) and poorer sleep efficiency (91.9% ± 5.6% vs 84.5% ± 9.5%; P = .015) compared with children with sufficient vitamin D. In addition, children with vitamin D deficiency had later weekday bedtimes (21:02 Pm ± 1:01 vs 20:19 Pm ± 0:55; P = .037) and later weekend bedtimes (21:42 Pm ± 0:59 vs 20:47 Pm ± 1:08; P = .016) than children with sufficient vitamin D, with a tendency for later wake time that did not reach statistical significance. The remainder of the polysomnogram findings and Pediatric Sleep Questionnaire data were not different between the 2 groups. Vitamin D deficiency in children was associated with objectively measured decreased sleep duration and poorer sleep efficiency. Furthermore, vitamin D deficiency was associated with delayed bedtimes, suggesting that vitamin D and circadian rhythm could be related. Future prospective studies in children would be helpful to learn if vitamin D deficiency leads to sleep disturbance or vice versa.

0956 Vitamin D and Sleep in Children

Abstract Introduction The impact of vitamin D on human health including sleep has been well described in adults. Its deficiency has been associated with multiple sleep disorders such as decrease in sleep duration, worsening of sleep quality and even obstructive sleep apnea. Such correlation is less evident in pediatric population. In the current study, we examined the relationship between sleep architecture and vitamin D status in children referred to a sleep clinic. Methods Retrospective-cohort study in a tertiary care children’s hospital over a one-year period. Children who underwent an in-laboratory-overnight-polysomnogram and had a 25-hydroxy vitamin D level (25-OH-vitD) obtained within 120 days of the sleep study were included. Patients with obstructive or central sleep apnea were excluded. Data from polysomnograms (PSG) and Pediatric Sleep Questionnaires (PSQ) were collected and analyzed. Results A total of 39 patients were included in the study with mean age of 6.6 years and 46% females. Twenty (51%) patients had vitamin D deficiency (25-OH-vitD less than 30 ng/ml). Children with vitamin D deficiency had less total sleep time (470.3 minutes +/-35.6 vs 420.3 minutes +/-61.7, p=0.004) and poorer sleep efficiency (91.9 % +/-5.6 vs 84.5 % +/-9.5, p=0.015) compared to vitamin D sufficient children. In addition, vitamin D deficient children had later weekday bedtimes (21:02 +/- 1:01 vs 20:19 +/- 0:55, p=0.037) and later weekend bedtimes (21:42 +/- 0:59 vs 20:47 +/- 1:08, p=0.016) with tendency for later wake up time that did not reach statistical significance. The remainder of polysomnographic findings and PSQ data were not different between the two groups. Conclusion Vitamin D deficiency in children is associated with objectively measured decreased sleep duration and poorer sleep efficiency. Furthermore, vitamin D deficiency was associated with delayed bedtimes, suggesting that vitamin D may influence circadian rhythm. Future prospective studies in children would be helpful in validating the effect of vitamin D on sleep. Support None

Prognostic Significance of IL-6 in Hodgkin Lymphoma

Elevated serum interleukin-6 (IL-6) in Hodgkin lymphoma (HL) is reported to correlate with B symptoms, response rate and survival in adult patients. The authors studied prognostic significance of IL-6 expression by immunohistochemistry on Hodgkin-Reed Sternberg cells and background reactive cells in a retrospective cohort of pediatric HL patients treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) from January 2009 through December 2013. Of 142 patients, tissue blocks were retrieved in 110 patients. On logistic regression analysis, IL-6 expression on background cells alone was among the factors associated with inferior response rate (OR-9.9, 95%CI-1.2, 78.3; p = 0.03). On multivariate analysis, IL-6 expression on background cells alone had significant impact on 5 y freedom from treatment failure (FFTF) (HR-7.7, 95% CI-1.2, 48.6; p = 0.03). IL-6 expression by immunohistochemistry in the background cells is an independent poor predictor of response and FFTF in pediatric HL. Further prospective studies in children are needed to confirm the current findings and whether IL-6 expression can be used to stratify treatment.

Pediatric neuroanesthesia

Pediatric neuroanesthesia is a fascinating, yet challenging branch of anesthesia. This review highlights some of the recent insights into pediatric neuroanesthesia from the past 18 months. Although there are incontrovertible evidences in animals suggesting that prolonged exposure to general anesthesia causes long-term neurological impairment, the translational relevance of these findings in humans is debatable. Early surgery for pediatric drug-refractory epilepsy is supported by emerging literature, but poses unique perioperative problems for the treating neuroanesthesiologist. Similarly, minimizing intraoperative blood loss and blood transfusion concerns every anesthesiologist managing small children. The usefulness of tranexamic acid in children is further enhanced by some studies in spine surgeries. Some pertinent issues related to intraoperative neuromonitoring are also discussed in the text. There are several logistical and ethical problems of carrying out high-quality prospective studies in children but important findings on prevention of anesthetic neurotoxicity; minimizing intraoperative blood loss, intraoperative neurophysiological monitoring, examining optimal doses and choices of anesthetic agents in epilepsy surgery have been published recently.

Hydronephrosis and risk of later development of hypertension.

Congenital ureteral obstruction is a fairly common condition in infants, and its clinical management has been long debated during the last decade. The long-term physiological consequences of today's conservative non-surgical management in many asymptomatic hydronephrotic children are unclear. Experimental studies in rats and mice, retrospective studies in children and adults, as well as prospective studies in children are included in this mini review. Experimental models of hydronephrosis in rats and mice have demonstrated that partial ureteropelvic junction obstruction (UPJO) is casually linked with development of hypertension and renal injuries in later life. The mechanisms are multifactorial and involve increased activity of the renin-angiotensin-aldosterone system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the affected kidney appear to play important roles in the development and maintenance of hypertension. Clinical case reports in adults and recent prospective studies in children have associated hydronephrosis with elevated blood pressure, which could be reduced by surgical management of the obstruction. Based on current experimental and clinical knowledge regarding the link between partial UPJO and changes in blood pressure, it is proposed that today's non-operative management of hydronephrosis should be reconsidered to reduce the risk of developing elevated blood pressure or hypertension in later life.

Peritoneal dialysis for the management of pediatric patients with acute kidney injury.

Renal replacement therapy (RRT) is the most important supportive measure used in the management of acute kidney injury (AKI). Peritoneal dialysis (PD) is a safe, simple and inexpensive procedure and has been used in pediatric AKI patients, ranging from neonates to adolescents. It is the modality of choice for RRT in developing countries with cost constraints and limited resources. However, its use has declined with the availability of newer types of extracorporeal modalities for RRT in the developed world. Much controversy exists regarding the dosing and adequacy of PD in the management of AKI. Data in infants and children have shown that PD can provide adequate clearance, ultrafiltration and correction of metabolic abnormalities even in those who are critically ill. Although there are no prospective studies in children, data from retrospective studies reveal no differences in mortality rates between different modalities of RRT. In this review, we discuss the advantages and limitations of PD, indications for acute PD, strategies to improve the efficiency of acute PD and outcomes of PD in children with AKI.

Microalbuminuria in pediatric patients with hypertension

Microalbuminuria in adults has been found to be an early indicator of both renal and systemic vascular disease, as well as significant cardiovascular risk predictor and therapeutic marker. Its role in essential hypertension in adults has also been well established. As diseases like hypertension and obesity have their roots in childhood and are already present in children, influencing the morbidity in adulthood, the role of microalbuminuria has been extensively investigated in children as well. Most investigations have been performed in diabetic children, confirming its clinical significance. There is also enough evidence to suggest that microalbuminuria in obese children should be taken as seriously as in children with diabetes. In children with hypertension rare studies also indicate that its presence identifies hypertensive children with higher risk, although the exact role has to be confirmed in prospective and larger studies. The mechanisms of microalbuminuria onset could be the result of renal damage secondary to hypertension or underlying renal and systemic endothelial dysfunction. Evidence from small intervention studies in children with microalbuminuria also suggests that early intervention with antihypertensive drugs is likely to be beneficial, pointing out the role of microalbuminuria as a therapeutic marker in children too. In addition, we have to stress the importance of follow-up of children with microalbuminuria, confirmation of its persistence and identification of progression. However, longitudinal prospective studies in children, investigating its future cardiovascular risk, are still lacking.

Invasive fungal diseases in children with hematological malignancies and stem cell transplant recipients

Invasive Fungal Disease (IFD) remains a major cause of morbidity and mortality in patients with hematological malignancies or undergoing stem cell transplantation. New surrogate markers of IFD - galactomannan antigen, β -D-glucan, fungal polymerase chain reaction… - and the availability of modern antifungal drugs have changed the management of this serious complication, but both have limitations in children. There are still some unclear issues, particularly in pediatric patients, regardless of the medical and economic possibilities of hospitals: IFD remains difficult to diagnose in a timely way, stem cell transplant recipients have different risk of IFD, antifungal drugs are not free from adverse effects and prospective studies in children are scarce. In this sense, diagnosis criteria have to be assessed , risk stratification should be redefined and the different types of prophylaxis/treatment -prophylaxis, preemptive, empiric and targeted treatment- must be used correctly. We consider low risk for IFD children undergoing autologous stem cell transplantation and children with acute lymphoblastic leukemia, both should receive fluconazole as primary prophylaxis and empiric therapy with an agent with activity against mold. In those undergoing allogeneic stem cell transplantation or chemotherapy for acute myeloid leukemia, prophylaxis should be performed with a mold active agent -triazoles priority-. We rarely use preemptive therapy because of a high false positive rate of galactomannan. In proven and probable IFD we use targeted therapy, selecting a drug based on the type of infection, sensitivity to the drug in our hospital and prior antifungal prophylaxis/treatment. In selected patients, antifungal combination therapy should be a valid option. Despite great advances, there are still thought provoking questions on the diagnosis and management of IFD in children with hematological diseases.

Laparoscopic Pediatric Surgery

Although laparoscopic surgery in children was once considered controversial, it has since been recognized for producing safe, feasible, adequate, and good cosmetic outcomes, compared to open surgery. In addition, like laparoscopic surgery in adults, some pediatric laparoscopic surgery has developed into standard operations for treatment of some diseases. In performance of pediatric laparoscopic surgery, some difficulties in securing sufficient space in a narrow visual field and surmounting the learning curve have been encountered due to a lack of pediatric diseases, resulting in insufficient laparoscopic surgical experience. However, development of pediatric laparoscopic instruments and improved laparoscopic surgical techniques have enabled pediatric surgeons to overcome such difficulties and to perform single port laparoscopic surgery and robot surgery. However, conduct of randomized prospective studies in children is difficult, and few meta analyses have been conducted; therefore, it is still too early for pediatric surgeons to reach a consensus. In particular, in Korea, only a small number of pediatric surgeons have attempted performance of advanced high-tech pediatric laparoscopic surgery and built up such experience. The purpose of this review is to explore current trends in laparoscopic surgery performed in domestic and foreign pediatric surgical patients on the basis of recent literature and my personal experience.

Tribute: The American Society of Pediatric Hematology/Oncology (ASPHO) 2012 distinguished career award goes to Dr. Victor Blanchette

Tribute: The American Society of Pediatric Hematology/Oncology (ASPHO) 2012 distinguished career award goes to Dr. Victor Blanchette

Anaesthesia and postoperative analgesia in surgical neonates with or without Down's syndrome: is it really different?

Reports conflict on optimal postoperative analgesic treatment in children with intellectual disability. We retrospectively compared postoperative analgesics consumption between neonates with and without Down's syndrome in relation to anaesthesia requirements and pain scores. We analysed hypnotic and analgesic drug administration, pain scores [COMFORT-Behaviour (COMFORT-B) scale], and duration of mechanical ventilation during the first 48 h after surgical repair of congenital duodenal obstruction in neonates, between 1999 and 2011. Data of 15 children with Down's syndrome were compared with data of 30 children without Down's syndrome. General anaesthesia requirements did not differ. The median (inter-quartile range) maintenance dose of morphine during the first 24 h after operation was 9.5 (7.8-10.1) µg kg(-1) h(-1) in the Down's syndrome group vs 7.7 (5.0-10.0) µg kg(-1) h(-1) in the control group (P=0.46). Morphine doses at postoperative day 2 and COMFORT-B scores at day 1 did not significantly differ between the two groups. COMFORT-B scores at day two were lower in children with Down's syndrome (P=0.04). The duration of postoperative mechanical ventilation did not statistically differ between the two groups (P=0.89). In this study, neonates with and without Down's syndrome received adequate postoperative analgesia, as judged from comparable analgesic consumption and pain scores. We recommend prospective studies in children of different age groups with Down's syndrome and in other groups of intellectually disabled children to provide further investigation of the hypothesis that intellectual disability predisposes to different analgesic requirements.

Ethical Issues in Prospective Studies in Children: The many Shades of Gray

ABSTRACT Children being a vulnerable, unique, yet heterogenous population, pose varied ethical questions in clinical research. These need to be actively recognized and addressed in order to strike the right balance between ‘individual’ good and 'societal’ good. Certain general principles which can be streamlined into guidelines specific for each population and study is the need of the hour. How to cite this article Singh M, Madhusudan. Ethical Issues in Prospective Studies in Children: The many Shades of Gray. J Postgrad Med Edu Res 2012;46(3):126-128.

Quantification of left-to-right shunt through patent ductus arteriosus by colour Doppler in children admitted for a device closure

Our animal model suggests that quantification of ductal flow from colour Doppler pixels is possible. We aimed to clarify whether this method can be used to determine a clinically significant ductal shunt in children. We retrospectively quantified ductal flow from saved images from 20 children who had been admitted for device occlusion of patent ductus arteriosus. Colour Doppler images over the main stem of the pulmonary artery were obtained in longitudinal cross-sections. The colour pixel percentages during diastole, representing ductal flow, were correlated with the documented shunt, measured invasively according to Fick's principle. The ratio of pulmonary to systemic flow correlated best with the sum of the percentages of green colour pixels (r = 0.73, r2 = 0.54, p < 0.001). When the shunt was 1.5:1 or more, 12 out of 13 infants had 50% or more of the region of interest covered with green pixels--sensitivity 92%, specificity 71%. The correlation between ductal diameter and pulmonary-to-systemic flow ratio was less significant (r = 0.6, r2 = 0.37, p < 0.03). We conclude that clinically significant shunts with pulmonary-to-systemic flow ratio over 1.5 can be diagnosed with this method where neither the size of the patient nor echocardiographic settings seem to be critical. The method could be used to provide an objective indication for ductal closure, but further prospective studies in children are needed to verify the power of the method.