Ventricular arrhythmia in dialysis patients: A link with higher hemoglobin levels?

We investigated the frequencies and associated risk factors of cardiac arrhythmias and heart rate variability (HRV) in hemodialysis (HD) patients. One hundred fifty prevalent HD patients underwent 48-hour Holter monitoring. Holter monitoring was analyzed in 4 phases: early post-HD phase (12 hours), late post-HD phase (20 hours), pre-HD phase (12 hours), and HD phase (4 hours). Echocardiography was applied to measure the left ventricular mass index in a subgroup of patients (n: 52). Patients with ventricular premature contraction (VPC) were significantly older, had a longer HD duration, and higher hemoglobin (Hb) levels. Left ventricular mass index was significantly correlated with the frequency of VPC, during the HD and pre HD phases (r: 0.435, 0.312, respectively). In logistic regression analysis, patients with Hb level >11.9 g/dL (high tertile) had a 4.5-fold increased risk of VPC compared with those with Hb levels <10.8 g/dL (P: 0.04). In HRV analysis, age (P<0.001), and diabetes (P: 0.03) were found to be independent predictors of low standard deviation of all mean normal-to-normal RR intervals. Increased left ventricular mass index is associated with a high frequency of VPC in the pre-HD and HD periods. The occurrence of VPC is predicted by older age, longer dialysis duration, and higher Hb levels, while older age and diabetes are the determinants of HRV. The relation between higher Hb levels and the frequency of VPC might provide a clue for the explanation of the detrimental effect of higher Hb levels on HD patients.     

Doppler echocardiograph evaluation of pulmonary hypertension in patients undergoing hemodialysis

Pulmonary hypertension (PH) has been reported in hemodialysis (HD) patients, but data regarding its incidence and mechanisms are scarce. The aims of this study was to evaluate the prevalence of unexplained PH in long-term HD patients, and to examine some possible etiologic factors for its occurrence. The prevalence of PH was estimated by Doppler echocardiography in a cohort of 86 stable patients on HD via arteriovenous access for more than 12 months. All the patients underwent full clinical evaluation, chest radiography, and a standard 12-lead echocardiograph. Laboratory investigation included a mean of 12 months (serum calcium, phosphorus, parathormone (PTH), alkaline phosphatase, lipids, and hemoglobin). Pulmonary hypertension was defined as pulmonary artery systolic pressure >35 mmHg as determined by Doppler echocardiography using the modified Bernoulli equation. Pulmonary hypertension was detected in 23 patients (26.74%). Of those with PH, left ventricular hypertrophy was seen in 13 patients (56.52%), and valvular calcifications in 6 patients (26.08%). There were no significant differences between both groups with regard to age, sex, duration of dialysis, shunt location, and all the biological parameters of the study. The presence of PH was not related to the level of PTH, or the severity of other metabolic abnormalities. This study demonstrates a high prevalence of PH among patients with ESRD receiving long-term HD via surgical arteriovenous access. The role of the vascular access, anemia, or secondary hyperparathyroidism as the etiology of PH in HD patients did not hold in this study.     

Clinical epidemiology of parathyroidectomy in hemodialysis patients: the USRDS waves 1, 3, and 4 study

Despite advances in the medical management of secondary hyperparathyroidism, parathyroidectomy remains necessary in some end-stage renal disease patients. Observational studies may help with the design of intervention trials. We linked the retrospective Waves 1, 3, and 4 Dialysis Morbidity and Mortality Study datasets to Medicare claims data to identify incident parathyroidectomy in 10,588 Medicare patients receiving hemodialysis in the United States on December 31, 1993. The mean age was 60.0 years, and the mean follow-up 3.6 years. De novo parathyroidectomy incidence was 14.2/1000 patient-years. Considered as quintiles (Q), higher levels of standard bone metabolism variables were associated (p<0.0001) with parathyroidectomy stepwise, such that adjusted hazards ratios (AHR) for Q5 (vs. Q1) were, for calcium (>10.3 mg/dL), 5.09 (3.64-7.10); for phosphorus (>7.5 mg/dL), 2.92 (2.06-4.15); for calcium-phosphorus product (>71 mg2/dL2), 3.32 (2.27-4.85); and for parathyroid hormone (PTH; >480 pg/mL), 13.81 (7.47-25.55). Other antecedent associations included younger age, lower hemoglobin, and longer dialysis vintage, while transplantation, as a time-dependent covariate, was associated with lower hazards ratios. Using interval Poisson analysis, parathyroidectomy was associated with higher mortality risk ratios in the first year, and progressively lower risk ratios subsequently. Demographic variables may modify the risk of parathyroidectomy. Younger patients on long-term hemodialysis may be at a special risk. Parathyroidectomy risk increases stepwise with alterations in bone metabolism variables, suggesting that a single-threshold management approach may not be ideal.     

Hemodialysis in a patient with severe hemophilia A and factor VIII inhibitor

Hemophilia A is a hereditary X‐linked recessive disease caused by mutations in the gene encoding factor VIII (FVIII), occurring in 1 out of 10,000 persons. Life expectancy and quality of life have dramatically improved recently in patients with hemophilia. Chronic kidney disease and need for renal replacement therapy in these patients are rare. The development of inhibitors to FVIII is the most serious complication of hemophilia and makes treatment of bleeds very challenging. We describe here a 28‐year‐old male patient with severe hemophilia A with presence of factor VIII inhibitor, who had end stage renal disease. Central venous access device was inserted along with infusion of factor eight inhibitor bypass activity before and after the procedure. He is currently on thrice weekly hemodialysis and doing well for 6 months without bleeding episodes. To our knowledge, hemophilia A with factor VIII inhibitor managed with hemodialysis has not been reported so far.     

End-stage renal disease patients on hemodialysis: a study from a tertiary care center in a developing country

The exact number of patients with chronic renal failure requiring renal replacement therapy in developing world is not known. Unlike the developed world, most developing countries lack renal registries. This study was initiated to know demographic and clinical data of end-stage renal disease (ESRD) patients presenting to maintenance hemodialysis (MHD) at a government funded tertiary care centre in a developing country. A prospective analysis of all new ESRD patients attending to hemodialysis at our centre from 2004 to 2007 had been done. There were 237 new hemodialysis patients during a three-year period. Males were 153 and females were 84, with the mean age 44.92 years. Diabetes mellitus (31.22%) was the most common cause of ESRD. Only 29.95% of patients had education on renal replacement therapy. 65.40% patients had emergency hemodialysis. Internal jugular catheter was the most common form of vascular access at initiation of hemodialysis. Arteriovenous fistula was secured in 29.95% of patients at presentation. Catheter-related infection appeared in 13.55% of patients on catheter. The most common infection in dialysis patients was urinary tract infection (37.14%). Renal transplantation was opted by 9.7% patients and continuous ambulatory peritoneal dialysis in 20.25% and 103 (43.45%) were lost to follow up. The rest (8.86%) continued on MHD. There were 42 (17.72%) deaths over a three-year period. The present study provided the information of the practice of hemodialysis, its population characteristics and outcomes from a developing country.     

Comparison of ultrasound echo‐tracking technology and pulse wave velocity for measuring carotid elasticity among hemodialysis patients

This study aims to investigate the correlation between carotid elasticity in hemodialysis patients as evaluated by ultrasound echo‐tracking technology and aortic pulse wave velocity. A total of 103 patients with end‐stage renal disease who underwent stable hemodialysis were enrolled. An ultrasonic echo‐tracking method was used to evaluate the elastic modulus and the stiffness index (β), which were compared with pulse wave velocity (PWV). Blood glucose, blood lipids, and serum creatinine were also tested. These indices were analyzed to determine the independent factor for arterial elasticity. The carotid elastic modulus and β were in good correlation with PWV among hemodialysis patients (P = 0.000). Diabetes and age are independent risk factors for arterial elasticity among hemodialysis patients. Ultrasound echo‐tracking technology is a sensitive and accurate method for evaluating arterial elasticity and is a good alternative to traditional PWV.     

Outcomes of patients with end‐stage renal disease (ESRD) under chronic hemodialysis requiring continuous renal replacement therapy (CRRT) and patients without ESRD in acute kidney injury requiring CRRT: A single‐center study

In most continuous renal replacement therapy (CRRT) studies, end‐stage renal disease (ESRD) patients were excluded and the outcomes of patients with ESRD treated with chronic hemodialysis (HD) were unknown. The purposes of this study were to (1) evaluate short‐term patient survival and (2) compare the survival of conventional HD patients needing CRRT with the survival of non‐ ESRD patients in acute kidney injury (AKI) requiring CRRT. We evaluated adults (>18 years) requiring CRRT who were treated in the intensive care unit (ICU) at Kosin University Gospel Hospital from January 1, 2009 to December 31, 2010. A total of 100 (24 ESRD, 76 non‐ESRD) patients underwent CRRT during the study period. Patients were divided into two major groups: patients with ESRD requiring chronic dialysis and patients without ESRD (non‐ESRD) with AKI. We compared the survival of conventional HD patients requiring CRRT with the survival of non‐ ESRD patients in AKI requiring CRRT. For non‐ESRD patients, the 90‐day survival rate was 41.6%. For ESRD patients, the 90‐day survival rate was 55.3%. Multivariate Cox proportional hazards analyses demonstrated that conventional HD was not a significant predictor of mortality (hazard ratio [HR]: 0.334, 95% confidence interval [CI]: 0.063–1.763, P = 0.196), after adjustment for age, gender, presence of sepsis, APACHE score, use of vasoactive drugs, number of organ failures, ultrafiltration rate, and arterial pH. The survival rates of non‐ESRD and ESRD patients requiring CRRT did not differ; ESRD with conventional HD patients may be not a significant predictor of mortality.     

Left ventricular geometric patterns in end‐stage kidney disease: Determinants and course over time

Introduction : While concentric left ventricular hypertrophy (cLVH) predominates in non–dialysis‐dependent chronic kidney disease (CKD), eccentric left ventricular hypertrophy (eLVH) is most prevalent in dialysis‐dependent CKD stage 5 (CKD5D). In these patients, the risk of sudden death is 5× higher than in individuals with cLVH. Currently, it is unknown which factors determine left ventricular (LV) geometry and how it changes over time in CKD5D. Methods : Data from participants of the CONvective TRAnsport Study who underwent serial transthoracic echocardiography were used. Based on left ventricular mass (LVM) and relative wall thickness (RWT), 4 types of left ventricular geometry were distinguished: normal, concentric remodeling, eLVH, and cLVH. Determinants of eLVH were assessed with logistic regression. Left ventricular geometry of patients who died and survived were compared. Long‐term changes in RWT and LVM were evaluated with a linear mixed model. Findings : Three hundred twenty‐two patients (63.1 ± 13.3 years) were included. At baseline, LVH was present in 71% (cLVH: 27%; eLVH: 44%). Prior cardiovascular disease (CVD) was positively associated with eLVH and ß‐blocker use inversely. None of the putative volume parameters showed any relationship with eLVH. Although eLVH was most prevalent in non‐survivors, the distribution of left ventricular geometry did not vary over time. Discussion : The finding that previous CVD was positively associated with eLVH may result from the permanent high cardiac output and the strong tendency for aortic valve calcification in this group of long‐term hemodialysis patients, who suffer generally also from chronic anemia and various other metabolic derangements. No association was found between eLVH and parameters of fluid balance. The distribution of left ventricular geometry did not alter over time. The assumption that LV geometry worsens over time in susceptible individuals, who then suffer from a high risk of dying, may explain these findings.     

Relationship between erythropoietin resistance index and left ventricular mass and function and cardiovascular events in patients on chronic hemodialysis

The response to erythropoietin (EPO) treatment varies considerably in individual patients on chronic hemodialysis. The EPO resistance index (ERI) has been considered useful to assess the EPO resistance and can be easily calculated in the clinic. The aim of this study was to investigate the association between ERI and left ventricular mass (LVM) and function and to determine whether ERI was associated with cardiovascular events in patients on hemodialysis. This study was designed prospectively. Clinical, laboratory, and echocardiographic variables were assessed in 72 patients on hemodialysis. The ERI was determined as the weekly weight-adjusted dose of EPO (U/kg/week) divided by hemoglobin concentration (g/dL). Patients were divided into three groups by tertiles of ERI. Patients with higher tertiles of ERI had a higher LVM index and lower LV ejection fraction compared with those with lower tertiles of ERI (P = 0.019 and P = 0.030, respectively). The median follow-up period was 53 months. The Kaplan-Meier plot showed increased frequency of cardiovascular events in patients with higher tertiles of ERI, compared with those with lower tertiles of ERI (P = 0.011, log-rank test). The multivariate Cox proportional hazard models showed that the ERI was the significant independent predictor of cardiovascular events (HR 3.00, 95% CI, 1.04-8.62, P = 0.042). Our data show that ERI was related with LVM index, LV systolic function and cardiovascular events in patients with hemodialysis. By monitoring of ERI, early identification of the EPO resistance may be helpful to predict the cardiovascular risk in hemodialysis patients.     

Intensive dialysis and pregnancy

Pregnancy in women with end stage renal disease on renal replacement therapy is uncommon due to the physiologic changes associated with renal failure as well as the complexities and risk involved in managing these patients. As most of these women had long periods of illness with chronic kidney disease, the effects of their chronic illness together with the current societal trends to delay child bearing to a more advanced maternal age can hamper fertility. For those able to conceive, intensified hemodialysis (HD), through longer and/or more frequent dialysis sessions, offers improved maternal and neonatal outcomes. Intensified HD is most conveniently offered in the patient's home, where possible. This review expands the scope of the Implementing Hemodialysis in the Home website and associated supplement published previously in Hemodialysis International and includes information tailored to women of reproductive age. We describe the necessary counseling that women should receive before conception and before intensification of HD, and provide a detailed management strategy that includes nephrologic and obstetric care, should pregnancy occur.     

Coenzyme Q10 supplementation and diastolic heart functions in hemodialysis patients: A randomized double‐blind placebo‐controlled trial

Coenzyme Q10 (CoQ10) supplementation has been shown to improve diastolic heart function in various patient cohorts. Systolic and diastolic dysfunctions are common in patients with end‐stage renal disease. Favorable effects of CoQ10 on cardiac functions are yet to be seen in hemodialysis patients. We aimed to evaluate effect of CoQ10 supplementation on diastolic function in a cohort of maintenance hemodialysis patients. This was a prospective, double‐blind, placebo‐controlled, crossover study in which all patients received placebo and oral CoQ10 200 mg/d during the 8 weeks in each phase, with a 4‐week washout period. Participants underwent conventional and tissue Doppler echocardiography before and after each study phase. Parameters characterizing left ventricle diastolic function and other standard echocardiographic measurements were recorded. Twenty‐eight patients were randomized, but 22 patients completed study protocol. Intraventricular septum (IVS) thickness and left ventricle mass were significantly decreased in CoQ10 group (P = 0.03 and P = 0.01, respectively). Myocardial peak systolic and early diastolic velocities derived from IVS were significantly increased (P = 0.048 and P = 0.04, respectively). Isovolumetric relaxation time and E/Em ratio calculated for IVS also significantly reduced in CoQ10 group (p = 0.02 and p = 0.04, respectively). There was no significant difference in any of the studied echocardiographic parameters in placebo group. The results of this study showed that CoQ10 supplementation did not significantly improved diastolic heart functions compared with placebo in maintenance hemodialysis patients.     

超声心动图在早期高血压性心脏病患者中的诊断价值分析

目的:研究超声心动图诊断早期高血压性心脏病的临床价值。方法:回顾性收集我院2020年1月-2020年12月收诊的早期高血压性心脏病患者80例的临床资料,并选取同期健康体检的志愿者80名,分别设为实验组、对照组。收集两组的超声心动图资料,对比两组的LVEF、LVEDD、ISV等超声心动图资料,并收集整理超声心动图对实验组患者的诊断准确率以及不同血压分级患者的超声心动图资料。结果:超声心动图诊断早期HHD的准确率为95.0%。实验组患者的LVEDD与对照组健康志愿者比较差异不明显,P>0.05;实验组的ISV、LVPW、LAD值均高于对照组健康志愿者,P<0.05;且实验组的LVEF和E/A比值明显低于对照组,P<0.05;在实验组患者中,随着血压分级的增加,ISV、LVPW、LAD值也随之提高,二者呈正相关关系,P<0.05;随着血压分级增加,LVEF水平和E/A比值随之下降,二者呈负相关关系,P<0.05;血压分级与LVEDD无明显关系,P>0.05。结论:超声心动图在早期高血压性心脏病患者的诊断中应用价值高,能早期检测出左室舒张功能受损、左房扩大等,利于临床医师早期诊断高血压性心脏病,同时指导临床治疗,值得推广。     

Intermittent pneumatic compression in patients with ESRD. A systematic review

Introduction: Patients with end‐stage renal disease (ESRD) experience frequent hemodialysis (HD) complications. Intradialytic hypotension (IDH) is a common complication presenting in approximately between 20 and 50% of HD sessions. Available interventions such as volume replacement or vasoactive medications are associated with significant side effects. Intermittent pneumatic compression (IPC) has been proposed as a feasible intervention for the prevention of IDH, treatment of peripheral arterial disease and venous ulcers. These devices apply intermittent pressure to the legs improving arterial blood flow, mobilization of pooled blood with an increase in venous return increasing the effective circulatory volume. Our goal was to identify the published clinical evidence on whether IPC has a circulatory benefit and is it well‐tolerated among patients receiving HD. Methods: We conducted a systematic review to identify studies assessing the efficacy and safety of IPC in patients with ESRD. Our primary outcome was IDH. Secondary outcomes such as HD comfort, ultrafiltration volume, and physical activity were collected. No restrictions where used and we included all observational and interventional studies. Two reviewers performed screening and study quality assessment. Findings: We included seven studies. Out of the seven studies, five addressed IDH, and the rest were included for secondary outcomes such as physical capacity and HD comfort. In one randomized crossover trial comparing exercise against IPC, 21 patients were randomized to 3 different arms (no intervention, cycling, IPC) a decrease in the rates of IDH with IPC was described (43%, 38%, and 24% respectively P = 0.014). The smaller studies corroborated these results. All studies where at high risk of bias. Discussion: IPC might offer significant benefits for patients undergoing HD not limited to prevention of IDH but also improvement of hemodialysis comfort and physical capacity. However, our results should be interpreted in the context of its limitations.     

A rare case of Actinomyces skin and soft tissue infection in an end‐stage kidney disease patient with a review of the literature

End‐stage kidney disease (ESKD) patients are a commonly overlooked immunocompromised population that places them at risk for rare infections. We describe the case of a 78‐year‐old man with a history of ESKD managed with thrice weekly in‐center hemodialysis who had a prolonged episode of left elbow pain and drainage and was eventually found to have a skin and soft tissue infection from Actinomyces radingae. We review the bacteriology of Actinomyces spp. and the experiences of other providers who have treated actinomycosis in individuals with ESKD. The anatomic sites and demographics of these individuals are heterogeneous, but they all generally require a long antibiotic course with a beta‐lactam and portend to a good prognosis. High index of suspicion is needed to identify rare and atypical infections in the ESKD population.     

The permanent catheter

An elderly woman receiving hemodialysis via a right brachiocephalic arteriovenous fistula presented to the clinic for elective removal of a tunneled hemodialysis catheter inserted 5 years ago. The catheter had not been removed earlier at the patient's request. Removal was now unsuccessful in the clinic. Exploration in the operating room revealed the innominate vein had fibrosed around the length of the catheter. The procedure was abandoned, catheter cut short and the remnant left in situ. This case serves as a reminder to exercise caution if there is difficulty in removing the catheter even after the cuff is dissected free, and to remove them once a working fistula or graft is available. Failing which, the patient bears an unnecessary risk of line infection, or as in this case, the catheter may unintentionally end up what its common misnomer “perm‐cath” alludes to – becoming truly “permanent.”     

Tuberculosis in end-stage renal disease patients on hemodialysis

Recent studies have shown that there is an increase in the incidence of mycobacterium tuberculosis (MBT). This is more prevalent among immune compromised patients (those on dialysis) and recipients of organ transplants. Furthermore, extra-pulmonary presentation appears to be more common and difficult to diagnose. We aimed in this study to assess and evaluate the presentation of MBT in a retrospective study conducted among 256 hemodialysis (HD) patients where 18 of them were diagnosed and managed for tuberculosis over a 10-year period between 1990 and 2000. The mean age of the patients was 38 years (21-75 years). The mean interval between the onset of HD and the time of diagnosis was about 24 months (1-120 months). The diagnosis of tuberculosis was made either by isolation of acid-fast bacilli (AFB), the typical caseating granuloma on biopsy, or by recovery of tubercle bacilli from the culture of the biopsy material. Extra-pulmonary tuberculosis was more common (77.8%) than pulmonary tuberculosis (22.2%). The various extra-pulmonary tuberculosis sites noted were cervical lymphadenitis (16.7%), gastrointestinal (16.7%), genitourinary (11.1%), peritonitis (11.1%), pleural effusion (5.6%), pericardial effusion (5.6%), miliary tuberculosis (5.6%), and pyrexia of unknown origin (5.6%). None of the patients with extra-pulmonary tuberculosis had evidence of pulmonary tuberculosis. The atypical presentation with insidious onset was quite common. Anergy to tuberculin skin test was noticed in 56% of cases. All of our patients received modified antituberculosis treatment for 1 year with adequate response, and without undue side effects. We conclude that a high index of suspicion is required especially in the diagnosis of extra-pulmonary tuberculosis, and when there is a high percentage of anergy to tuberculin skin test. Tissue biopsy both for characteristic histology and demonstration of MTB, either by staining or culture, remains the main criteria for the diagnosis of extra-pulmonary tuberculosis.     

Predialysis volume overload and patient‐reported sleep duration and quality in patients receiving hemodialysis

Introduction: Previous studies of patients with end‐stage renal disease have examined the role of fluid shifts on apnea‐hypopnea episodes, but the association between volume overload and patient‐reported sleep quality or duration has not been well‐established. Methods: We studied the association between predialysis bioimpedance spectroscopy‐derived volume estimates and self‐reported sleep quality and duration in 638 patients in the United States Renal Data System ACTIVE/ADIPOSE study receiving hemodialysis from 2009 to 2011. We used questionnaires to assess self‐reported sleep duration and quality. We used relative hydration status (fluid overload/extracellular water; FO/ECW) as the primary predictor and examined associations with hours of sleep duration using linear regression. We used multivariable ordinal logistic regression to determine the association between categories of relative hydration status (normal hydration [FO/ECW < 6.8%], mild overhydration [FO/ECW 6.8%–15%], and hyperhydration [FO/ECW > 15%]) and four levels of difficulty with falling asleep, waking, and returning to sleep. Findings: Higher relative hydration status was associated with fewer hours of sleep (?0.31 hours per 10%, 95% confidence interval (CI) ?0.49 to ?0.13). Compared to the normal hydration group, there was a statistically significant association between higher relative hydration status category and more frequent nighttime waking (OR: mild overhydration 1.92 [95% CI 1.23–2.99], hyperhydration 1.87 [95% CI 1.16–2.99]), a trend toward more difficulty returning to sleep (OR: mild overhydration 1.46 [95% CI 0.94–2.27], hyperhydration 1.52 [95% CI 0.95–2.43]), and no association between relative hydration category and difficulty falling asleep. Discussion: Hydration status was associated with self‐reported sleep duration in patients on dialysis. Future studies should prospectively examine the effects of optimizing fluid status on sleep duration and quality.     

Modification of cardiovascular risk in hemodialysis patients: an evidence-based review

Cardiovascular disease accounts for 40% to 50% of deaths in dialysis populations. Overall, the risk of cardiac mortality is 10-fold to 20-fold greater in dialysis patients than in age and sex-matched controls without chronic kidney disease. The aim of this paper is to review critically the evidence that cardiac outcomes in dialysis patients are modified by cardiovascular risk factor interventions. There is limited, but as yet inconclusive controlled trial evidence that cardiovascular outcomes in dialysis populations may be improved by antioxidants (vitamin E or acetylcysteine), ensuring that hemoglobin levels do not exceed 120 g/L (especially in the setting of known cardiovascular disease), prescribing carvedilol in the setting of dilated cardiomyopathy, and by using cinacalcet in uncontrolled secondary hyperparathyroidism. Similarly, there are a number of negative controlled trials, which have demonstrated that statins, high-dose folic acid, angiotensin-converting enzyme inhibitors, multiple risk factor intervention via multidisciplinary clinics, and high-dose or high-flux dialysis are ineffective in preventing cardiovascular disease. Although none of these studies could be considered conclusive, the negative trials to date should raise significant concerns about the heavy reliance of current clinical practice guidelines on extrapolation of findings from cardiovascular intervention trials in the general population. It may be that cardiovascular disease in dialysis populations is less amenable to intervention, either because of the advanced stage of chronic kidney disease or because the pathogenesis of cardiovascular disease in dialysis patients is different from that in the general population. Large, well-conducted, multicenter randomized-controlled trials in this area are urgently required.