Therapeutic Approaches to Dysautonomia in Childhood, with a Special Focus on Long COVID.

BACKGROUND: Dysautonomia seems to be important for the pathophysiology of psychosomatic diseases and, more recently, for long COVID. This concept may explain the clinical symptoms and could help open new therapeutic approaches. METHODS: We compared our data from an analysis of heart rate variability (HRV) in an active standing test in 28 adolescents who had developed an inappropriate sinus tachycardia (IST, n = 13) or postural orthostatic tachycardia syndrome (POTS, n = 15) after contracting COVID-19 disease and/or vaccination with 64 adolescents from our database who developed dysautonomia due to psychosomatic diseases prior to the COVID-19 pandemic. We prove the effects of our treatment: omega-3 fatty acid supplementation (O3-FA, n = 18) in addition to propranolol (low dose, up to 20-20-0 mg, n = 32) or ivabradine 5-5-0 mg (n = 17) on heart rate regulation and heart rate variability (HRV). RESULTS: The HRV data were not different between the adolescents with SARS-CoV-2-related disorders and the adolescents with dysautonomia prior to the pandemic. The heart rate increases in children with POTS while standing were significantly lower after low-dose propranolol (27.2 ± 17.4 bpm***), ivabradine (23.6 ± 8.12 bpm*), and O-3-FA (25.6 ± 8.4 bpm*). The heart rate in children with IST while lying/standing was significantly lower after propranolol (81.6 ± 10.1 bpm**/101.8 ± 18.8***), ivabradine (84.2 ± 8.4 bpm***/105.4 ± 14.6**), and O-3-FA (88.6 ± 7.9 bpm*/112.1/14.9*). CONCLUSIONS: The HRV data of adolescents with dysautonomia after COVID-19 disease/vaccination are not significantly different from a historical control of adolescents with dysautonomia due to psychosomatic diseases prior to the pandemic. Low-dose propranolol > ivabradine > omega-3 fatty acids significantly decrease elevated heart rates in patients with IST and the heart rate increases in patients with POTS and may be beneficial in these children with dysautonomia.

Dysautonomia in Children with Post-Acute Sequelae of Coronavirus 2019 Disease and/or Vaccination.

Long-term health problems such as fatigue, palpitations, syncope, and dizziness are well-known in patients after COVID-19 (post-acute sequelae of coronavirus (PASC)). More recently, comparable problems have been noticed after the SARS-CoV-2 vaccination (post-VAC). The pathophysiology of these problems is not well-understood. METHODS: In 38 children and young adults, we tested if these health problems were related to dysautonomia in an active standing test (Group 1: 19 patients after COVID-19; Group 2: 12 patients with a breakthrough infection despite a vaccination; and Group 3: 7 patients after a vaccination without COVID-19). The data were compared with a control group of 47 healthy age-matched patients, as recently published. RESULTS: All patients had a normal left ventricular function as measured by echocardiography. Significantly elevated diastolic blood pressure in all patient groups indicated a regulatory cardiovascular problem. Compared with the healthy control group, the patient groups showed significantly elevated heart rates whilst lying and standing, with significantly higher heart rate increases. The stress index was significantly enhanced in all patient groups whilst lying and standing. Significantly decreased pNN20 values, mostly whilst standing, indicated a lower vagus activity in all patient groups. The respiratory rates were significantly elevated in Groups 1 and 2. CONCLUSION: The uniform increase in the heart rates and stress indices, together with low pNN20 values, indicated dysautonomia in children with health problems after COVID-19 disease and/or vaccination. A total of 8 patients fulfilled the criteria of postural orthostatic tachycardia syndrome and 9 patients of an inappropriate sinus tachycardia, who were successfully treated with omega-3 fatty acid supplementation and pharmacotherapy.

Autoantibody Release in Children after Corona Virus mRNA Vaccination: A Risk Factor of Multisystem Inflammatory Syndrome?

Multisystem inflammatory syndrome (MIS) is a new systemic inflammatory acute onset disease that mainly affects children (MIS-C) and, at a lesser frequency, adults (MIS-A); it typically occurs 3-6 weeks after acute SARS-CoV infection. It has been postulated and shown in adults that MIS may occur after SARS-CoV-2 vaccination (MIS-V). Our current case is one of the first published cases with a multisystem inflammatory syndrome in an 18-year-old adolescent after the SARS-CoV-2 vaccine from Pfizer/BionTech (BNT162b2), who fulfills the published level 1 criteria for a definitive disease: age < 21 years, fever > 3 consecutive days, pericardial effusion, elevated CRP/NT-BNP/Troponin T/D-dimeres, cardiac involvement, and positive SARS-CoV-2 antibodies. The disease starts 10 weeks after the second vaccination, with a fever (up to 40 °C) and was treated with amoxicillin for suspected pneumonia. The SARS CoV-2-PCR and several antigen tests were negative. With an ongoing fever, he was hospitalized 14 days later. A pericardial effusion (10 mm) was diagnosed by echocardiography. The C-reactive protein (174 mg/L), NT-BNP (280 pg/mL), and Troponin T (28 pg/mL) values were elevated. Due to highly elevated D-dimeres (>35,000 µg/L), a pulmonary embolism was excluded by thoracal computer tomography. If the boy did not improve with intravenous antibiotics, he was treated with intravenous immunoglobulins; however, the therapy was discontinued after 230 mg/kg if he developed high fever and hypotension. A further specialized clinic treated him with colchicine and ibuprofen. The MIS-V was discovered late, 4 months after the onset of the disease. As recently shown in four children with MIS-C after SARS-CoV-2 infection and a girl with Hashimoto thyroiditis after BNT162b2 vaccination, we found elevated functional autoantibodies against G-protein-coupled receptors that may be important for pathophysiology but are not conclusive for the diagnosis of MIS-C. Conclusion: We are aware that a misattribution of MIS-V as a severe complication of coronavirus vaccination can lead to increased vaccine hesitancy and blunt the global COVID-19 vaccination drive. However, the pediatric population is at a higher risk for MIS-C and a very low risk for COVID-19 mortality. The publication of such cases is very important to make doctors aware of this complication of the vaccination, so that therapy with intravenous immunoglobulins can be initiated at an early stage.

Pathophysiological mechanisms of bradycardia in patients with anorexia nervosa.

BACKGROUND: The purpose of this investigation was to examine heart rate variability (HRV), interbeat interval (IBI), and their interrelationship in healthy controls, bradycardic hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) mutation carriers, and patients with anorexia nervosa (AN). We tested the hypothesis that neural mechanisms cause bradycardia in patients with AN. Therefore, we assumed that saturation of the HRV/IBI relationship as a consequence of sustained parasympathetic control of the sinus node is exclusively detectable in patients with AN. METHODS: Patients with AN between the ages of 12 and 16 years admitted to our hospital due to malnutrition were grouped and included in the present investigation (N = 20). A matched-pair group with healthy children and adolescents was created. Groups were matched for age and sex. A 24-hour Holter electrocardiography (ECG) was performed in controls and patients. More specifically, all patients underwent two 24-hour Holter ECG examinations (admission; refeeding treatment). Additionally, the IBI was recorded during the night in HCN4 mutation carriers (N = 4). HRV parameters were analyzed in 5-minute sequences during the night and plotted against mean corresponding IBI length. HRV, IBI, and their interrelationship were examined using Spearman's rank correlation analyses, Mann-Whitney U tests, and Wilcoxon signed-rank tests. RESULTS: The relationship between IBI and HRV showed signs of saturation in patients with AN. Furthermore, signs of HRV saturation were present in two HCN4 mutation carriers. In contrast, signs of HRV saturation were not present in controls. CONCLUSIONS: The existence of HRV saturation does not support the existence of parasympathetically mediated bradycardia. Nonneural mechanisms, such as HCN4 downregulation, may be responsible for bradycardia and HRV saturation in patients with AN.

Diagnosis and management of an inappropriate sinus tachycardia in adolescence based upon a Holter ECG: A retrospective analysis of 479 patients.

Inappropriate sinus tachycardia (IST) is a common disease of the autonomic nervous system in children and adults. Diagnosis and treatment of IST in adolescents is not well defined. In this retrospective study, we tested our hypothesis regarding autonomic dysfunction in childhood by analyzing 24-h heart rate variability (HRV) in 479 children, with a mean age of 13.7 ± 2.1 years, who were referred to the outpatient clinic in the Pediatrics Department within the last 15 years. Seventy-four adolescents with a mean 24-h heart rate ≥ 95 bpm (our cut-off for an IST based upon 66 healthy controls) were deemed to have IST. We found the risk of IST to be high in adolescents with attention deficit disorder (OR = 3.5,p<0.001), pre-hypertension (OR = 2.5, p = 0.043) and hypertension (OR = 2.1,p = 0.02); insignificantly enhanced in children with short stature (OR = 1.9,p = 0.19), surgically-treated congenital heart disease (OR = 1.4,p = 0.51) and obesity without hypertension (OR = 1.4;p = 0.25); and negligible in adolescents with anorexia nervosa (OR = 0.3, p = 0.26) and constitutional thinness (OR = 0.9,p = 0.89). IST was associated with a significant decrease in global HRV and elevated blood pressures, indicating an enhanced cardiovascular risk. Methylphenidate did not increase 24-h heart rates, whereas omega-3 fatty acid supplementation significantly decreased elevated heart rates and increased HRV in adolescents with IST. In this retrospective analysis, 15.4% of adolescents suffered from IST with a 24-h heart rate ≥ 95 bpm, predominately due to attention deficit disorder and hypertension.

Resolution of a therapy-resistant focal atrial tachycardia after omega-3 fatty acid supplementation.

We report on a 14-year-old boy with focal atrial tachycardia. After failure of catheter ablation and medical therapy he received 2 g omega-3 fatty acid supplementation while waiting on repeat ablation. Focal atrial tachycardia disappeared 4 weeks later and antiarrhythmic therapy was terminated. We discuss the antiarrhythmic effect of omega 3-fatty acids on the autonomous nervous system based upon six 24-hour Holter electrocardiographs.

Omega-3 Fatty Acid Supplementation Improves Heart Rate Variability in Obese Children.

Obese children and adolescents are at high risk of developing cardiovascular diseases later in life. We hypothesized that cardiovascular prophylaxis with omega-3 fatty acids could benefit them. In our study, 20 children and adolescents (mean body mass index percentile: 99.1; mean age: 11.0 years) underwent two ambulatory 24 h Holter electrocardiography (ECG) recordings (before and after at least 3 months of omega-3 fatty acid supplementation). Time domain heart rate variability (HRV) and heart rate (HR) were examined for these patients. As a control, we used 24 h Holter ECG recordings of 94 nonobese children and adolescents. Time domain HRV parameters, which are indicators of vagal stimulation, were significantly lower in obese patients than in healthy controls, but HR was higher (standard deviation of the normal-to-normal [SDNN] interbeat intervals: -34.02%; root mean square of successive differences [RMSSD] between normal heartbeats: -40.66%; percentage of consecutive RR intervals [pNN50]: -60.24%; HR: +13.37%). After omega-3 fatty acid supplementation, time domain HRV parameters and HR of obese patients were similar to the values of healthy controls (SDNN interbeat intervals: -21.73%; RMSSD: -19.56%; pNN50: -25.59%; HR: +3.94%). Therefore, omega-3 fatty acid supplementation may be used for cardiovascular prophylaxis in obese children and adolescents.

A case series on the potential effect of omega-3-fatty acid supplementation on 24-h heart rate variability and its circadian variation in children with attention deficit (hyperactivity) disorder.

Attention deficit disorder with and without hyperactivity (ADHD) in children is associated with decreased 24-h heart rate variability (HRV). Previous research has shown that supplementation of omega-3-fatty acid increases HRV. Here, we aimed to investigate whether the supplementation of omega-3-fatty acids would increase 24-h HRV in an uncontrolled case series of children with ADHD. HRV was recorded in 18 children and adolescents (age 13.35 ± 2.8 years) before and after omega-3 supplementation. Preliminary results indicate that omega-3 supplementation in children with AD(H)D may reduce mean heart rate and increase its variability. Future studies would do well to implement randomized, placebo-controlled designs with greater methodological rigor.

Resting state vagal tone in attention deficit (hyperactivity) disorder: A meta-analysis.

OBJECTIVES: To quantify evidence on resting-state vagal activity in patients with attention deficit hyperactivity disorder (ADHD) relative to controls using meta-analysis. METHODS: Three electronic databases (PubMed, PsycINFO, CINAHL Plus) were reviewed to identify studies. Studies reporting on any measure of short-term, vagally mediated heart rate variability during resting state in clinically diagnosed ADHD patients as well as non-ADHD healthy controls were eligible for inclusion. RESULTS: Eight studies reporting on 587 participants met inclusion criteria. Random-effect meta-analysis revealed no significant main effect comparing individuals with ADHD (n = 317) and healthy controls (n = 270) (Hedges' g = 0.06, 95% CI: 0.18-0.29, Z = 0.48, P = 0.63; k = 8). Sub-group analysis showed consistent results among studies in adults (k = 2) and children (k = 6) with ADHD. CONCLUSIONS: Unlike a variety of internalising psychiatric disorders, ADHD is not associated with altered short-term measures of resting-state vagal tone.

The Impact of Early Life Stress on Growth and Cardiovascular Risk: A Possible Example for Autonomic Imprinting?

INTRODUCTION: Early life stress is imprinting regulatory properties with life-long consequences. We investigated heart rate variability in a group of small children with height below the third percentile, who experienced an episode of early life stress due to heart failure or intra uterine growth retardation. These children appear to develop autonomic dysfunction in later life. RESULTS: Compared to the healthy control group heart rate variability (HRV) is reduced on average in a group of 101 children with short stature. Low HRV correlates to groups of children born small for gestational age (SGA), children with cardiac growth failure and children with congenital syndromes, but not to those with constitutional growth delay (CGD), who had normal HRV. Reduced HRV indicated by lower RMSSD and High Frequency (HF)-Power is indicating reduced vagal activity as a sign of autonomic imbalance. CONCLUSION: It is not short stature itself, but rather the underlying diseases that are the cause for reduced HRV in children with height below the third percentile. These high risk children-allocated in the groups with an adverse autonomic imprinting in utero or infancy (SGA, congenital heart disease and congenital syndromes)-have the highest risk for 'stress diseases' such as cardiovascular disease in later life. The incidence of attention deficit disorder is remarkably high in our group of short children.

Modified Clonidine Testing for Growth Hormone Stimulation Reveals α2-Adrenoreceptor Sub Sensitivity in Children with Idiopathic Growth Hormone Deficiency.

INTRODUCTION: The association between short stature and increased risk of ischemic heart disease has been subject to studies for decades. The recent discussion of cardiovascular risk during growth hormone therapy has given new importance to this question. We have hypothesized that the autonomic system is a crucial element relating to this subject. METHODS: Heart rate variability calculated from 24-hour electrocardiogram data is providing insight into the regulatory state of the autonomous nervous system and is an approved surrogate parameter for estimating cardiovascular risk. We have calculated heart rate variability during clonidine testing for growth hormone stimulation of 56 children. As clonidine is a well-known effector of the autonomous system, stimulating vagal tone and decreasing sympathetic activity, we compared the autonomous reactions of children with constitutional growth delay (CGD), growth hormone deficiency (GHD) and former small for gestational age (SGA). RESULTS: During clonidine testing children with CGD showed the expected α2-adrenoreceptor mediated autonomous response of vagal stimulation for several hours. This vagal reaction was significantly reduced in the SGA group and nearly non- existent in the GHD group. DISCUSSION: Children with GHD show a reduced autonomous response to clonidine indicating α2-adrenoreceptor sub sensitivity. This can be found prior to the start of growth hormone treatment. Since reduction of HRV is an approved surrogate parameter, increased cardiovascular risk has to be assumed for patients with GHD. In the SGA group a similar but less severe reduction of the autonomous response to clonidine was found. These findings may enrich the interpretation of the data on growth hormone therapy, which are being collected by the SAGhE study group.

Ultrasonographic imaging of inflammatory bowel disease in pediatric patients.

Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases in pediatric patients. Choosing the optimal imaging modality for the assessment of gastrointestinal disease in pediatric patients can be challenging. The invasiveness and patient acceptance, the radiation exposure and the quality performance of the diagnostic test need to be considered. By reviewing the literature regarding imaging in inflammatory bowel disease the value of ultrasound in the clinical management of pediatric patients is highlighted. Transabdominal ultrasound is a useful, noninvasive method for the initial diagnosis of IBD in children; it also provides guidance for therapeutic decisions and helps to characterize and predict the course of the disease in individual patients. Ultrasound techniques including color Doppler imaging and contrast-enhanced ultrasound are promising imaging tools to determine disease activity and complications. Comparative studies between different imaging methods are needed.

Beta-Blockers (Carvedilol) in Children with Systemic Ventricle Systolic Dysfunction - Systematic Review and Meta-Analysis.

BACKGROUND: Numerous prospective randomized clinical trials demonstrated favorable effect of beta-blockers in adults with chronic heart failure. However, effectiveness of beta blockers in pediatric patients with systemic ventricle systolic dysfunction was not recognized sufficiently. Limited number of pediatric patients might be the course of unrecognized carvediolol treatment benefit. Currently, no meta-analysis has examined the impact of carvedilol and conventional therapy on the clinical outcome in children with chronic heart failure due to impaired systemic ventricle systolic function. MATERIALS AND METHODS: We have systematically searched the Medline/PubMed and Cochrane Library for the controlled clinical trials that examine carvedilol and standard treatment efficacy in pediatric patients with systemic ventricle systolic dysfunction. Mean differences for continuous variables, odds ratios for dichotomous outcomes, heterogeneity between studies and publication bias were calculated using Cochrane Review Manager (Rev Man 5.2). RESULTS: Total of 8 prospective/observational studies met established criteria. Odds ratio for chronic heart failure related mortality/heart transplantation secondary to carvedilol was 0.52 (95% CI: 0.28-0.97, I(2) = 0%). Our analysis showed that carvedilol could prevent 1 death/ heart transplantation by treating 14 pediatric patients with impaired systemic ventricle systolic function. CONCLUSION: Meta-analysis demonstrated clinical outcome benefit of carvedilol in children with chronic heart failure.

Mechanisms of Beta-Blockers Action in Patients with Heart Failure.

Patients with chronic heart failure have prolonged sympathetic stimulation and subsequent worsening of the failing heart function. Beta-blockers (non-selective, cardio-selective, and non-selective with ancillary properties) counteract the effects of prolonged sympathetic stimulation. Beta-blocker therapy results in the improvement of the left ventricular systolic and diastolic function, reversal remodeling, heart rate control, effective prevention of the malignant arrhythmias, and lowering of the both cardiac afterload and preload in patients with chronic heart failure.

Beta-Blockers in Children with Congenital Heart Disease Before a Corrective Procedure.

The prevalence of heart failure in patients with congenital heart disease, mainly due to large left to right shunts, is as high as 20%. Heart failure has a high impact on prognosis, growth and neurodevelopment. Prior to surgery or after palliative procedures children need a medical heart failure therapy. The traditional therapy with digoxin, diuretics and ACE-inhibitors is not supported by prospective randomized trials. Propranolol had a significant beneficial effect on the clinical heart failure score, neurohormonal activation, heart rate variability and cardiac remodeling in the prospective randomized trial CHF-Pro-Infant. Beta-blocker dosages depend on heart rate with a target between 100 and 110 bpm in infants and an average dose of 2mg/kg/day after a titration period of 2 to 3 weeks. Within the last 18 years after the first case the author treated only infants with severe heart failure and highly elevated Pro-BNP-levels (8879 pg/ml on average). However we never observed serious side effects due to worsening heart failure, severe bradycardia or pulmonary obstruction. Diuretics are given as low as necessary to prevent the activation of the renin-angiotensin-aldosterone system with its detrimental effect on cardiac remodeling.

The Long Way to a Successful Medical Therapy of Heart Failure with Beta-blockers in Children with Heart Disease.

Heart failure remains the main cause of death in children with heart disease. In USA and Europe hospital mortality of children with heart failure is about 7% of children, nearly twice as high as in adults. In this review a group of authors report about their experience with beta-blockers in childhood heart failure. Most of them start to treat children with severe heart failure at a time - 20 years ago - when beta blockers seem to be contraindicated in this situation. The physicians and their patients and/or parents all are aware of the risk of this decision. However, unproven medical therapies for heart failure are the most important therapeutical dilemma in pediatric cardiology. The authors carefully observed a highly selected group of patients with the highest risk to die and had the patience to wait for the longtime follow up. Today - based upon this experience -we know that beta blockers are safe and may save the lives of many children with heart disease all over the world. Together with young colleagues who enthusiastically support this idea the authors now intend to break down the "wall of ignorance" for this promising therapy in pediatric cardiology.

Ventricular arrhythmias in children with attention deficit disorder--a symptom of autonomic imbalance?

OBJECTIVES: Potential side effects of stimulants for attention deficit disorder are in the focus of scientific discussions, intensified by the higher number of prescriptions. Children with known arrhythmias or other severe cardiac problems should not receive stimulants because of their sympathomimetic effects. METHODS: This is a retrospective analysis of 24-hour Holter electrocardiograms from 100 consecutive children with attention deficit disorder from January, 2006 to April, 2012. RESULTS: In all, nine children had significant ventricular arrhythmia (mean age 11.4 ± 3.1 years, 77% male, 77% received methylphenidate). All these children had ventricular parasystole - four of them with an accelerated idioventricular rhythm. A significant circadian rhythm of premature ventricular contractions in seven children and the effect of standing and exercise clearly indicate the influence of the autonomic nervous system. In these children, hourly analysis of circadian rhythm within a 24-hour period showed a highly significant correlation between premature ventricular contractions and the vagal tone indicated by the heart rate variability parameter RMSSD (r = -0.83; p < 0.001). Ventricular arrhythmia was unaffected in seven children who received methylphenidate before diagnosis and decreased during metoprolol treatment in two children. CONCLUSION: By Holter electrocardiogram analysis, we observed a remarkably high incidence of ventricular parasystole and accelerated idioventricular rhythm in nine of 100 children with attention deficit disorder, which depends on autonomic imbalance and not on stimulant treatment.

Why are psychiatric disorders in children becoming more and more common?

UNLABELLED: In the last decades, an increase of new paediatric problems requiring medical care like eating disorders, behavioural and attention problems has been observed. Based on the hypothesis that mental illness is accompanied by autonomic dysfunction, we compared measurements of heart rate variability (HRV) in Holter ECG's from children with attention deficit/hyperactivity disorder (ADHD) with those of healthy children and a historical control from 1997. METHOD: We analysed the HRV parameters SDNN, rMSSD and pNN50 from 24 hours Holter ECG from children (mean age 10.8 years) with ADHD before or during medical therapy with methylphenidate (MPH). These values were compared with aged matched healthy children. RESULTS: Compared to healthy controls ADHD children with and without MPH treatment showed significantly higher mean heart rates, lower pNN50 and lower RMSSD. pNN50 and RMSSD values of healthy children are lower compared to the historical control group from 1997. CONCLUSION: Compared to healthy children the peak of parasympathic activity measured by the HRV values pNN50 and RMSSD in early adolescence was reduced in children with ADHD. Compared to a historical control these values are also reduced in healthy children. A reduced vagal activity will--within the meaning of W. Porges polyvagal theory--have consequences on the social and emotional development of children. Moreover this observation may have consequences for an enhanced cardiovascular risk.