Pulse rate variability and health-related quality of life assessment with the Short Form-8 Japanese version in the general Japanese population.

We aimed to investigate the association between pulse rate variability (PRV) and health-related quality of life (HRQOL) in the general population. A cross-sectional study was conducted with 5908 Japanese men and women aged 30-79 years. PRV was assessed at rest using 5-min recordings of pulse waves with a photoplethysmographic signal from a fingertip sensor, and the time and frequency domains of PRV were determined. HRQOL was assessed with the Short Form-8 (SF-8) Japanese version, and poor HRQOL was defined as an SF-8 sub-scale score < 50. A test for nonlinear trends was performed with the generalized additive model with a smoothing spline adjusted for confounders. The lowest multivariable-adjusted odds ratios for poor physical component score were found in those who had second or third quartile levels of standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive difference (RMSSD), and high-frequency (HF) power and trended slightly upward in the higher levels. PRV-derived parameters were nonlinearly associated with poor physical component scores. In conclusion, reduced PRV-derived SDNN, RMSSD and HF power were associated with poor HRQOL in the domain of physical function. Higher levels of these parameters did not necessarily translate into better HRQOL.

A cost-effectiveness analysis of remote monitoring after pacemaker implantation for bradycardia in Japan.

BACKGROUND: Although remote monitoring (RM) after pacemaker implantation is common, its cost-effectiveness has not been fully investigated. Therefore, we assessed the cost-effectiveness of RM compared with conventional follow-up (CFU) in Japanese patients with pacemakers. METHODS: A Markov model was constructed to analyze costs and quality-adjusted life years after pacemaker implantation. The target population was Japanese patients implanted with a dual-chamber pacemaker for bradycardia. Transition probabilities (e.g. atrial fibrillation, stroke, and device trouble) were obtained from literature and expert sources. Additionally, stroke risk was determined according to anticoagulation and CHADS2 scores. We used a 10-year horizon with sensitivity analyses for significant variables. RESULTS: Compared to CFU, RM was more effective; however, it was also more expensive. When the range of the Japanese willingness-to-pay threshold was considered to be ¥5,000,000, RM was at least cost-neutral relative to the CFU in all elderly patients with pacemakers for bradycardia. The cost-effectiveness of RM relative to CFU could be higher for patients with high CHADS2 scores, especially in patients with a CHADS2 score ≥ 3. Scenario analyses changing the interval between visits to an in-office evaluation in the CFU also demonstrated the same conclusions. In particular, when the interval between office visits was 1 year for the CFU, the RM could be more cost-effective. CONCLUSIONS: This study demonstrated that RM can be a cost-effective option for Japanese patients, especially those with high CHADS2 scores and long-term intervals between office visits.

Cost-effectiveness analysis of cardiac implantable electronic devices with reactive atrial-based antitachycardia pacing.

AIMS: Reactive atrial-based anti-tachycardia pacing (rATP) in pacemakers (PMs) and cardiac resynchronization therapy defibrillators (CRT-Ds) has been reported to prevent progression of atrial fibrillation, and this reduced progression is expected to decrease the risk of complications such as stroke and heart failure (HF). This study aimed to assess the cost-effectiveness of rATP in PMs and CRT-Ds in the Japanese public health insurance system. METHODS AND RESULTS: We developed a Markov model comprising five states: bradycardia, post-stroke, mild HF, severe HF, and death. For devices with rATP and control devices without rATP, we compared the incremental cost-effectiveness ratio (ICER) from the payer's perspective. Costs were estimated from healthcare resource utilisation data in a Japanese claims database. We evaluated model uncertainty by analysing two scenarios for each device. The ICER was 763 729 JPY/QALY (5616 EUR/QALY) for PMs and 1,393 280 JPY/QALY (10 245 EUR/QALY) for CRT-Ds. In all scenarios, ICERs were below 5 million JPY/QALY (36 765 EUR/QALY), supporting robustness of the results. CONCLUSION: According to a willingness to pay threshold of 5 million JPY/QALY, the devices with rATP were cost-effective compared with control devices without rATP, showing that the higher reimbursement price of the functional categories with rATP is justified from a healthcare economic perspective.

Pharmacokinetics of a 503B outsourcing facility-produced theophylline in dogs.

Theophylline is an important drug for treatment of canine chronic bronchitis and bradyarrhythmias, but new products require validation since pharmacokinetics in dogs can vary by formulation. A new, 503B outsourcing facility-produced theophylline product (OFT) is available for veterinary use. Outsourcing facilities have many advantages over traditional compounding sources including current good manufacturing practice compliance. The purpose of this study was to establish the pharmacokinetics of OFT in dogs. Eight healthy dogs received 11 mg/kg intravenous aminophylline and 10 mg/kg oral OFT followed by serial blood sampling in a two-way, randomized, crossover design with 7-day washout. Plasma theophylline concentrations were quantified by liquid chromatography-mass spectrometry. Bioavailability, maximum concentration, time to maximum concentration, half-life and area under the curve were: 97 ± 10%, 7.13 ± 0.71 µg/mL, 10.50 ± 2.07 h, 9.20 ± 2.87 h, and 141 ± 37.6 µg*h/mL, respectively. Steady-state predictions supported twice daily dosing of the OFT, but specific dosage recommendations are hindered by lack of a canine-specific therapeutic range for plasma theophylline concentration. These findings suggest that the OFT is well absorbed and can likely be dosed twice daily in dogs, but future pharmacodynamic and clinical studies are needed to establish a definitive therapeutic range for theophylline in this species.

Heart rate: control mechanisms, pathophysiology and assessment of the neurocardiac system in health and disease.

The monitoring of physiological function and dysfunction is an important principle in modern medicine. Heart rate is a basic example of this type of observation, particularly assessing the neurocardiac system, which entails the autonomic nervous system and intracardiac processes. The neurocardiac axis is an underappreciated and often overlooked system which, if measured appropriately in the clinical setting, may allow identification of patients at risk of disease progression and even mortality. While heart rate itself is a simplistic tool, more information may be gathered through assessing heart rate variability and heart rate recovery time. Studies have demonstrated an association of slow heart rate recovery and lower heart rate variability as markers of elevated sympathetic and lower parasympathetic tone. These parameters have additionally been shown to relate to development of arrhythmia, heart failure, systemic inflammatory processes, ischaemic heart disease and an increased rate of mortality. The aim of this review is to detail how heart rate is homeostatically controlled by the autonomic nervous system, how heart rate can impact on pathophysiological processes, and how heart rate variability and heart rate recovery time may be used in the clinical setting to allow the neurocardiac system to be assessed.

Assessment of adverse events associated with remdesivir use for coronavirus disease 2019 using real-world data.

Background: Remdesivir has been used for treating patients with moderate to severe coronavirus disease 2019 (COVID-19) although there is conflicting evidence regarding its usefulness. Data regarding its safety largely come from the clinical trials conducted to support its emergency use authorization (EUA). This study aimed to identify the adverse events of remdesivir with disproportionately high reporting using real-world data.Research design and methods: The adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) by health-care professionals for drugs that have received EUA or approved for the treatment of COVID-19 in the US were studied. Adisproportionality analysis was performed to determine adverse events more frequently reported with remdesivir compared with other COVID-19 drugs in the database.Results: Elevated liver enzymes, acute kidney injury, raised blood creatinine levels, bradycardia, cardiac arrest, and death had disproportionately higher reporting with remdesivir as asuspect drug compared with other drugs. There is no significant difference in the reporting of these events based on patient sex or age.Conclusions: Our study confirms the drug label information regarding liver enzyme elevation. The renal and cardiac safety signals identified necessitate reevaluation for potential drug-labeling changes.

Assessment of cardiac arrhythmias using long-term continuous monitoring in patients with pulmonary hypertension.

BACKGROUND: Cardiac arrhythmias are considered a prominent phenomenon in patients with pulmonary hypertension (PH). Older studies reported that 8% to 35% of patients with PH had supraventricular tachycardia (SVT), associated with adverse outcomes. Still, these arrhythmias have only been investigated via short-term monitoring or limited electrocardiogram recordings. METHODS: Patients without previous arrhythmias diagnosed with PH at a tertiary facility received an insertable cardiac monitor as part of a prospective cohort study. Baseline assessments included World Health Organization functional class, six-minute walk test, echocardiography, and cardiac magnetic resonance imaging. RESULTS: Thirty-four patients with PH were included. Twenty-four patients had pulmonary arterial hypertension (PAH) and 10 had chronic thromboembolic PH (CTEPH). During 46 patient-years of continuous monitoring (median: 594 (range: 334-654) days per patient), 70 arrhythmia episodes were recorded in 13 patients (38%), with a median of two (range: 1-3) episodes and an arrhythmic burden median of 1.6 (range: 0.1-228) minutes per patient. SVTs were the most common arrhythmias, with 16% of episodes being atrial fibrillation and 84% being other types of SVTs. Additionally, three patients experienced bradycardias, including one resulting in syncope and subsequent pacemaker implantation. None of the patients had sustained ventricular arrhythmias. CONCLUSIONS: Arrhythmias were seen in 38% of contemporary patients with PH during long-term continuous monitoring; however, the vast majority of episodes were short and self-limiting. Modern therapy may alleviate the development of arrhythmias in stable patients with PH. This study is the first study to deploy long-term continuous monitoring in patients with PH.

Detection of Apnea Bradycardia from ECG Signals of Preterm Infants Using Layered Hidden Markov Model.

Apnea-bradycardia (AB) is a common complication in prematurely born infants, which is associated with reduced survival and neurodevelopmental outcomes. Thus, early detection or predication of AB episodes is critical for initiating preventive interventions. To develop automatic real-time operating systems for early detection of AB, recent advances in signal processing can be employed. Hidden Markov Models (HMM) are probabilistic models with the ability of learning different dynamics of the real time-series such as clinical recordings. In this study, a hierarchy of HMMs named as layered HMM was presented to detect AB episodes from pre-processed single-channel Electrocardiography (ECG). For training the hierarchical structure, RR interval, and width of QRS complex were extracted from ECG as observations. The recordings of 32 premature infants with median 31.2 (29.7, 31.9) weeks of gestation were used for this study. The performance of the proposed layered HMM was evaluated in detecting AB. The best average accuracy of 97.14 ± 0.31% with detection delay of - 5.05 ± 0.41 s was achieved. The results show that layered structure can improve the performance of the detection system in early detecting of AB episodes. Such system can be incorporated for more robust long-term monitoring of preterm infants.

Use and Outcomes of Dual Chamber or Cardiac Resynchronization Therapy Defibrillators Among Older Patients Requiring Ventricular Pacing in the National Cardiovascular Data Registry Implantable Cardioverter Defibrillator Registry.

Importance: Frequent right ventricular (RV) pacing can cause and exacerbate heart failure. Cardiac resynchronization therapy (CRT) has been shown to be associated with improved outcomes among patients with reduced left ventricular ejection fraction who need frequent RV pacing, but the patterns of use of CRT vs dual chamber (DC) devices and the associated outcomes among these patients in clinical practice is not known. Objective: To assess outcomes, variability in use of device type, and trends in use of device type over time among patients undergoing implantable cardioverter defibrillator (ICD) implantation who were likely to require frequent RV pacing but who did not have a class I indication for CRT. Design, Setting, and Participants: This retrospective cohort study used the National Cardiovascular Data Registry (NCDR) ICD Registry. A total of 3100 Medicare beneficiaries undergoing first-time implantation of CRT defibrillator (CRT-D) or DC-ICD from 2010 to 2016 who had a class I or II guideline ventricular bradycardia pacing indication but not a class I indication for CRT were included. Data were analyzed from August 2018 to October 2019. Exposures: Implantation of a CRT-D or DC-ICD. Main Outcomes and Measures: All-cause mortality, heart failure hospitalization, and complications were ascertained from Medicare claims data. Multivariable Cox proportional hazards models and Fine-Gray models were used to evaluate 1-year mortality and heart failure hospitalization, respectively. Multivariable logistic regression was used to evaluate 30-day and 90-day complications. All models accounted for clustering. The median odds ratio (MOR) was used to assess variability and represents the odds that a randomly selected patient receiving CRT-D at a hospital with high implant rates would receive CRT-D if they had been treated at a hospital with low CRT-D implant rates. Results: A total of 3100 individuals were included. The mean (SD) age was 76.3 (6.4) years, and 2500 (80.6%) were men. The 1698 patients (54.7%) receiving CRT-D were more likely than those receiving DC-ICD to have third-degree atrioventricular block (828 [48.8%] vs 432 [30.8%]; P < .001), nonischemic cardiomyopathy (508 [29.9%] vs 255 [18.2%]; P < .001), and prior heart failure hospitalizations (703 [41.4%] vs 421 [30.0%]; P < .001). Following adjustment, CRT-D was associated with lower 1-year mortality (hazard ratio [HR], 0.70; 95% CI, 0.57-0.87; P = .001) and heart failure hospitalization (subdistribution HR, 0.77; 95% CI, 0.61-0.97; P = .02) and no difference in complications compared with DC-ICD. Hospital variation in use of CRT was present (MOR, 2.00), and the use of CRT in this cohort was higher over time (654 of 1351 [48.4%] in 2010 vs 362 of 594 [60.9%] in 2016; P < .001). Conclusions and Relevance: In this cohort study of older patients in contemporary practice undergoing ICD implantation with a bradycardia pacing indication but without a class I indication for CRT, CRT-D was associated with better outcomes compared with DC devices. Variability in use of device type was observed, and the rate of CRT implantation increased over time.

Assessment of injury current during leadless pacemaker implantation.

BACKGROUND: Leadless pacemakers are an established treatment option for bradyarrhythmias. Similar to conventional transvenous pacemakers, satisfying pacing values during implantation are targeted for optimal long-term device function. The objective is to investigate the role of a local injury current (IC) in leadless pacemaker implantations. METHOD: The IC, sensing value, capture threshold and impedance were collected in 30 consecutive patients receiving a leadless pacemaker. RESULTS: 39 EGMs were recorded from 30 patients (including 9 device repositions). An IC was detected in 15 cases (38%). At implantation, the presence of an IC was associated with a significantly lower sensing (7.1 ± 3.7 mV vs 12.0 ± 4.0 mV; P = 0.004) and a higher capture threshold (median threshold 1.13 V at 0.24 ms [0.50-2.00] vs 0.50 V at 0.24 ms [0.25-0.75]; P = 0.002) and with a 26 fold higher likelihood of device repositioning compared to the absence of an IC (OR 26.3 [2.79-248], P < 0.001). Patients with an IC in their final implant position had a lower sensing (9.3 ± 4.4 mV vs 13.6 ± 4.7 mV at implantation, P = 0.04), while the initially similar capture threshold was lower after 24 h in the IC group. After 2 weeks, all parameters were similar between the two groups. CONCLUSIONS: Our study shows that an IC can readily be observed during leadless pacemaker implantation associated with a lower sensing and a higher capture threshold at implantation but with similar to even better values during follow-up.

Apnea bradycardia detection based on new coupled hidden semi Markov model.

In this paper, a method for apnea bradycardia detection in preterm infants is presented based on coupled hidden semi Markov model (CHSMM). CHSMM is a generalization of hidden Markov models (HMM) used for modeling mutual interactions among different observations of a stochastic process through using finite number of hidden states with corresponding resting time. We introduce a new set of equations for CHSMM to be integrated in a detection algorithm. The detection algorithm was evaluated on a simulated data to detect a specific dynamic and on a clinical dataset of electrocardiogram signals collected from preterm infants for early detection of apnea bradycardia episodes. For simulated data, the proposed algorithm was able to detect the desired dynamic with sensitivity of 96.67% and specificity of 98.98%. Furthermore, the method detected the apnea bradycardia episodes with 94.87% sensitivity and 96.52% specificity with mean time delay of 0.73 s. The results show that the algorithm based on CHSMM is a robust tool for monitoring of preterm infants in detecting apnea bradycardia episodes. Graphical Abstract Apnea Bradycardia detection using Coupled hidden semi Markov Model from electrocardiography. In this model, a sequence of hidden states is assigned to each observation based on the effects of previous states of all observations.

Development: Epidemiology and management of postoperative apnoea in premature and term newborns.

Postoperative apnoea (PA) is defined as a respiratory pause of more than 15seconds or as a respiratory pause associated with bradycardia < 120/min, desaturation (Sat02<90%), cyanosis or hypotonia. This is a relatively frequent phenomenon that affects 10% of infants under 60 weeks of post-conceptual age, born prematurely or not, and occurs during the first 12-48h postoperatively. The population exposed to PA is heterogeneous and it is necessary to standardise the management both during the intra- and postoperative period, and to adapt this management according to the risk factors for PA and the status as prematurely born infants or not, based on recent data from the literature.

Cardiac Pacing Training in Africa: Endorsed by the Africa Heart Rhythm Association (AFHRA): JACC International.

The field of pacing in Africa has evolved in an uncoordinated way across the continent with significant variation in local expertise, cost, and utilization. There are many countries where pacemaker services do not meet one-hundredth of the national demand. Regional, national, and institutional standards for pacemaker qualification and credentials are lacking. This paper reviews the current needs for bradycardia pacing and evaluates what standards should be set to develop pacemaker services in a resource-constrained continent, including the challenges and opportunities of capacity building and training as well as standards for training programs (training prerequisites, case volumes, program content, and evaluation).

Permanent pacemaker implantation in pediatric heart transplant recipients: A systematic review and evidence quality assessment.

Bradyarrhythmias are a common complication following pediatric OHT and may require permanent pacemaker implantation (PPM). The purpose of this study was to investigate the incidence, predictors, and outcomes of children undergoing PPM implantation following OHT. A PRISMA-compliant systematic literature review was performed using the PubMed database and the Cochrane Library (end-of-search date: January 27, 2019). The Newcastle-Ottawa scale and the Joanna Briggs Institute tool were used to assess the quality of cohort studies and case reports, respectively. We analyzed data from a total of 11 studies recruiting 7198 pediatric patients who underwent heart transplant. PPM implantation was performed in 1.9% (n = 137/7,198; 95% CI: 1.6-2.2) of the patients. Most patients underwent dual-chamber pacing (46%, 95% CI: 32.6-59.7). Male-to-female ratio was 1.3:1. Mean patient age at the time of OHT was 10.1 ± 6.3. Overall, biatrial anastomosis was used in 62.2% (95% CI: 52.8-70.6) of the patients. The bicaval technique was performed in the remaining 37.8% (95% CI: 29.4-47.1). Sinus node dysfunction was the most frequent indication for PPM implantation (54.4%; 95% CI: 42.6-65.7) followed by AV block (45.6%; 95% CI: 34.3-57.3). The median time interval between OHT and PPM implantation ranged from 17 days to 12.5 years. All-cause mortality was 27.9% (95% CI: 18.6-39.6) during a median follow-up of 5 years. PPM implantation is rarely required after pediatric OHT. The most common indication for pacing is sinus node dysfunction, and patients undergoing biatrial anastomosis may be more likely to require PPM.

Protocols for early discharging of premature infants: an empirical assessment on safety and savings.

Background Preterm newborns may be discharged when clinical conditions are stable. Several criteria for early discharge have been proposed in the literature. This study carried out the first quantitative comparison of their impact in terms of hospitalization savings, safety and costs. Methods This study was based on the clinical histories of 213 premature infants born in the Neonatal Intensive Care Unit of Padova University Hospital between 2013 and 2014. Seventeen early discharge criteria were drawn from the literature and retrospectively applied to these data, and computation of hospitalization savings, safety and costs implied by each criterion was carried out. Results Among the criteria considered, average gains ranged from 1.1 to 10.3 hospital days and between 0.3 and 1.1 fewer infections per discharged infant. Criteria that led to saving more hospital days had higher cost-effectiveness in terms of crisis and infection, and they spared infants from more infections. However, episodes of apnea and bradycardia were detected after the potential early discharge date for all criteria, with a mean number of episodes numbering between 0.3 and 1.4. Conclusion The results highlight a clear trade-off between days saved and health risks for infants, with potential consequences for health care costs.

Novel technologies for heart rate assessment during neonatal resuscitation at birth - A systematic review.

BACKGROUND: 6.5-9 million newborns worldwide require resuscitation at birth annually. During neonatal resuscitation, inaccurate or slow heart rate (HR) assessments may significantly increase risk of infant mortality or morbidity. Therefore fast, accurate, and effective HR assessment tools are critical for neonatal resuscitation. OBJECTIVE: To systematically review the literature about accuracy, latency, and efficacy of technologies for HR assessment during neonatal resuscitation. METHODS: Adhering to PRISMA guidelines, PubMed, EMBASE, and Google Scholar databases were systematically searched to identify studies related to technologies for HR assessment, which could be used to guide neonatal resuscitation. RESULTS: Forty-six studies evaluating HR assessment technologies for neonatal resuscitation were identified. In total, 16 studies (3/16 randomized trials and 13/16 observational studies) compared two or more HR assessment technologies to measure accuracy, latency, and efficacy. Of the trials, 1/3 had a low risk of bias while 2/3 had high risks. All observational studies had high risks of bias. Most studies considered infants not requiring resuscitation, constituting indirect evidence and lower certainty in the context of neonatal resuscitation. Two trials reported faster times to HR assessment using electrocardiogram with a mean(SD) 66(20) versus 114(39) s and a median(IQR) 24(19-39) versus 48(36-69) s (both p < 0.001), compared to pulse oximetry. CONCLUSION: While electrocardiography is faster to assess HR at birth and more reliable to detect HR changes compared to other recommended technologies, practice should not exclusively rely on ECG. While novel technologies could support HR assessment, no studies validate their clinical efficacy during neonatal resuscitation.

Complications and associated healthcare costs of transvenous cardiac pacemakers in Germany.

Aim: This study evaluated the occurrence and associated costs of pacemaker complications in Germany from 2010 to 2013. Patients & methods: Patients with a de novo or replacement implantation of a single or dual chamber pacemaker between 2010 and 2013 were followed for 12 months post-implant using German health insurance claims data. A case-control analysis was performed using propensity score matching to estimate the costs of complications. Results: Out of 12,922 implanted patients, 12.0% had a complication in the year following the implant. Complications related to lead and pocket were found in 10.2% of all implanted patients; infections occurred in 1.7% patients. Healthcare costs up to 36 months post complication were on average €4627 higher than for pacemaker patients without a complication. Conclusion: Pacemaker complications are common and represent a burden for patients and healthcare systems generating substantial costs. Most of the pacemaker complications involved the pacing lead or pacemaker pocket.