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Author contributions | Dr. CM-K had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: KEW, KP, CM-K, LT, AD, KB. Acquisition, analysis, or interpretation of data: CM-K, LT, JA, MDC, KP, KW, AD, KEW. Drafting of the manuscript: CM-K, KP, AD. Critical revision of the manuscript for important intellectual content: KP, KEW, MK, CM-K, LSM, AD. Statistical analysis: CM-K, MDC, JA. Obtained funding: KEW, MK. Administrative, technical, or material support: LT, KB, MDC, JA, AD, KW. Supervision: KEW, KP, CM-K, KB, KW. All authors read and approved the final manuscript. | PMC9881516 |
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Funding | This research was supported by the National Institute of Mental Health/NIMH (U01MH121954). | PMC9881516 |
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Availability of data and materials | The datasets generated and analyzed during this study are not publicly available due to the sensitive nature of the data. They can be made available from the corresponding author on reasonable request and with execution of appropriate Data Use Agreements. | PMC9881516 |
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Declarations | PMC9881516 |
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Ethics approval and consent to participate | Ethical approval for the study was obtained from the RAND Corporation Human Subjects Protection Committee and the University of New Mexico Health Sciences Institutional Review Board. Written informed consent was waived as no patient identifiers were collected and survey responses were anonymous. | PMC9881516 |
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Consent for publication | Not applicable. | PMC9881516 |
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Competing interests | The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | PMC9881516 |
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References | PMC9881516 |
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Aims/hypothesis | Gestational diabetes | GESTATIONAL DIABETES | Pregnant women are advised to consume a minimum of 175 g per day of carbohydrate to meet maternal and fetal brain glucose requirements. This recommendation comes from a theoretical calculation of carbohydrate requirements in pregnancy, rather than from clinical data. This study aimed to determine whether fasting maternal ketone levels are associated with habitual carbohydrate intake in a subset of participants of the Study of PRobiotics IN Gestational diabetes (SPRING) randomised controlled trial. | PMC10789657 |
Methods | overweight or obesity | EARLY PREGNANCY | Food frequency questionnaires on dietary intake during pregnancy were completed by pregnant women with overweight or obesity at 28 weeks’ gestation (considering their intake from the beginning of pregnancy). Dietary intake from early pregnancy through to 28 weeks was analysed for macronutrient intake. At the same time, overnight fasting serum samples were obtained and analysed for metabolic parameters including serum β-hydroxybutyrate, OGTTs, insulin and C-peptide. | PMC10789657 |
Results | Fasting serum β-hydroxybutyrate levels amongst 108 women (mean BMI 34.7 ± 6.3 kg/m | PMC10789657 |
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Conclusions/interpretation | Fasting serum β-hydroxybutyrate levels are not associated with habitual carbohydrate intake at 28 weeks’ gestation in pregnant women with overweight and obesity. | PMC10789657 |
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Graphical Abstract | PMC10789657 |
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Supplementary Information | The online version of this article (10.1007/s00125-023-06044-w) contains peer-reviewed but unedited supplementary material. | PMC10789657 |
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Keywords | Open Access funding enabled and organized by CAUL and its Member Institutions
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Introduction | low habitual carbohydrate, ketonaemia | KETONAEMIA, EARLY PREGNANCY | Current dietary advice for pregnant women is to avoid diets that lead to increased ketonaemia [Ketones are produced from the breakdown of lipids when glucose availability is low. Ketogenesis is increased in pregnancy, particularly in the third trimester [Outside pregnancy, a diet with less than 50 g of carbohydrate per day is generally considered to be ketogenic [In order for clinicians to be able to provide women with accurate advice about carbohydrate intake in pregnancy, we need to better understand the relationship between maternal dietary carbohydrate intake and serum B-OHB levels. To our knowledge there are no studies that analyse fasting B-OHB levels in pregnant women and correlate these levels with carbohydrate intake. Our hypothesis was that low habitual carbohydrate intake is associated with higher circulating B-OHB concentrations. The aim of this study was to determine the association between daily habitual carbohydrate intake from early pregnancy through to 28 weeks’ gestation and serum B-OHB levels at 28 weeks’ gestation in pregnant women with overweight and obesity. | PMC10789657 |
Methods | GDM | GDM, DIABETES AND PREGNANCY, COMPLICATED PREGNANCIES, GESTATIONAL DIABETES | Food frequency questionnaires were completed in a subset of 108 women with uncomplicated pregnancies enrolled in the Study of Probiotics IN Gestational Diabetes (SPRING), an RCT of probiotics to prevent GDM in pregnant women with overweight and obesity (ACTRN12611001208998) [Demographic data were collected for each woman including ethnicity, maternal age at delivery, maternal BMI at the 28 week-gestation antenatal visit, and intervention group in the study (probiotic or placebo). The study population by design has a higher BMI than the general obstetric population in Australia; it has a higher proportion of women with white ethnicity and who have completed tertiary education (as a proxy for socioeconomic status) [Mass spectrometry was used to analyse serum B-OHB levels. Analytical reagents DL-β-hydroxybutyric acid sodium salt (β-HBA, catalogue no. H6501), 3-nitrophenyl hydrazine (3NPH, catalogue no. N21804), Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis was performed using a Shimadzu Nexera ultraperformance LC system (Kyoto, Japan) attached to a SCIEX 5500 QTRAP mass spectrometer (Framingham, MA, USA). Chromatographic separations were carried out using a Kinetex 2.6 μm 150×2.1 mm C18 column (Phenomenex, Lane Cove, NSW, Australia), with a total flow of 0.3500 ml/min at 40°C. The pressure range was 0–12,000 psi for Pump A/B and 0–900 psi for Pump C. Buffers for mobile phase for gradient elution consisted of Buffer A, made up of (vol./vol.) 1% ACN, 0.1% formic acid and Buffer B composed of 90% ACN, 0.1% formic acid. The mass spectrometer, coupled with an electron spray ionisation source, was operated in the negative multiple reaction monitoring (MRM) mode and included source parameters of ion spray voltage (ISV) at −4200 V; temperature 450°C; GS1 (nebuliser gas) 35; curtain gas 20. Each standard and sample was injected at a volume of 10 μl and subsequently 50 μl. Optimised parameters through manual infusion for maximum sensitivity for each compound transition included the collision energy, declustering potential and collision cell exit potential. Individual fragment ions were detected using the Q3 mass analyser to identify the Q1/Q3 pairs for each analyte. The two most sensitive pairs of Q1/Q3 per analyte were used for the subsequent analyses. The retention time for propionic acid was ~5.94, butyric acid was ~7.71, acetic acid was ∼4.17, β-HBA was ~4.10 and 2EBA was ∼10.14 min. UPLC/MRM-MS data was processed using Multiquant 3.0 (SCIEX) software to optimise Gaussian smoothing to peaks and retrieve area measurements.Obstetric outcomes were obtained for each woman including GDM status defined according to the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) guidelines [ | PMC10789657 |
Statistics | HC | Women were divided into two groups; high carbohydrate intake (HC) as defined by carbohydrate intake greater than the median amount in g/day, and low carbohydrate intake (LC) defined as less than the median amount in g/day (155 g/day). Participant clinical, dietary and biochemical parameters are presented as mean ± SD (continuous data) or % (categorical data) and compared using two-sided | PMC10789657 |
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Results | PMC10789657 |
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Circulating B-OHB levels | weight gain | The limit of detection for B-OHB for our measurement was 20 μmol/l and the range in the overall cohort was from 22.2 to 296.5 μmol/l. In the LC group, nine participants (17.0%) did not show detectable levels of B-OHB in their fasting blood. In the HC group, four participants (7.3%) had no detectable B-OHB levels (B-OHB concentrations and carbohydrate intake. (Given that the B-OHB concentrations at 28 weeks’ gestation were quite variable, we therefore investigated whether dietary intakes of other macronutrients were different between participants with B-OHB concentrations above and below the median of 65 μmol/l. There were no significant differences between the low (LB) and high (HB) B-OHB groups in routine dietary macronutrient intake, maternal BMI, age, blood pressure, gestational weight gain, infant birthweight or length, or in circulating maternal cholesterol or triglycerides (ESM Tables Differences in glucose and insulin between participants in the LB and HB groups. ( | PMC10789657 |
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Discussion | obesity, LGA, weight gain, GDM, hormone-sensitive lipase | GDM, OBESITY, EARLY PREGNANCY | In this cohort of women with overweight and obesity at 28 weeks’ gestation of pregnancy, with a median habitual dietary carbohydrate intake of 155 g/day, maternal fasting serum B-OHB levels ranged from 22.2 to 296.5 μmol/l (0.0222–0.297 mmol/l). While this is below 500 μmol/l or 0.5 mmol/l, which is the level considered to be normal, it is within the range of levels that has previously been associated with reduced childhood IQ (70–250 μmol/l or 0.07–0.25 mmol/l) [We found that in pregnant women with overweight and obesity, routine daily carbohydrate consumption from early pregnancy through to 28 weeks’ gestation was not correlated with fasting serum B-OHB levels. This finding remained after exclusion of women with GDM, suggesting the lack of correlation is not related to women’s carbohydrate tolerance. In addition, women with habitual low carbohydrate intake did not have higher serum B-OHB levels than those with high carbohydrate intake. This is despite the mean carbohydrate intake in the LC group being 119 g/day and hence 30% below the recommendation of ≥175 g/day, and the mean carbohydrate intake in the HC group being 207 g/day and 18% above the recommended minimum intake. The variability in fasting serum B-OHB levels cannot therefore be explained by habitual carbohydrate intake.Amongst women with normoglycaemic pregnancies, those with higher serum B-OHB levels had lower fasting insulin and C-peptide levels. One explanation for this could be the inhibitory effect that insulin has on ketone production. The production of ketones involves two processes: first lipolysis, where lipids (mostly from adipose tissue stores) are broken down into fatty acids and glycerol, and second ketogenesis, where fatty acids are converted to ketones in the liver. Lipolysis is inhibited by insulin through inhibition of intracellular hormone-sensitive lipase [This is the first study to evaluate the relationship between maternal ketone levels and habitual daily carbohydrate intake. Most previous studies looking at the effects of low-carbohydrate diets in pregnancy have been trials evaluating the effectiveness of carbohydrate restriction for glucose management in women with GDM. In one study, women on a low-carbohydrate diet (carbohydrate intake comprising less than 42% of total daily energy) had lower need for pharmacological treatment of their GDM and a lower incidence of large for gestational age (LGA) infants than women on a high-carbohydrate diet (carbohydrate intake greater than 45% of total daily energy) [Limitations of this study include the fact that dietary data was self-reported in a questionnaire, meaning there is a risk of recall bias. Given that the median weight gain in our cohort was 8 kg (4.7–12 kg) but the reported median energy intake is only 6136 kJ/day (4918–7489), it is very likely that the participants were underreporting their energy intake, as this is common in pregnant women with obesity [While women were advised to fast for 9.5–12 h, the exact length of each woman’s fast prior to serum blood collection was not recorded. Serum B-OHB levels rise in pregnancy during fasting, with significant differences in serum B-OHB between pregnant and non-pregnant women first seen at 16 h into an overnight fast [Our finding that habitual daily carbohydrate intake is not correlated with fasting serum B-OHB levels in pregnancy is important. Current guidelines which recommend that women should consume a minimum of 175 g/day of carbohydrate are based on calculations rather than on clinical evidence. This is the first study to assess whether daily carbohydrate intake affects serum B-OHB levels. Our findings challenge the current dietary recommendations that women should consume a minimum amount of carbohydrate every day, since only a single participant of the 34 who consumed the recommended amount of carbohydrate had undetectable B-OHB levels whereas the other 33 had detectable levels (Fig. Representation of the B-OHB levels according to carbohydrate intake in the study cohort. The recommended daily carbohydrate intake of ≥175 g/day, covering 97.5% of the estimated daily needs of the maternal and fetal brain consumption, and the estimated mean requirements of 135 g/day, covering the maternal and fetal brain needs of 50% of the population, are indicated by the vertical bars. The shaded area represents the desired carbohydrate intake and B-OHB levels | PMC10789657 |
Conclusion | Fasting serum B-OHB levels are not correlated with habitual daily carbohydrate intake at 28 weeks’ gestation in pregnant women with overweight and obesity. Further research is needed to further evaluate the relationship between carbohydrate intake and maternal ketone levels, as well as the main determinants of elevated ketone levels in pregnancy. | PMC10789657 |
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Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (PDF 123 KB) | PMC10789657 |
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Data availability | The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data is located in controlled access data storage at The University of Queensland. | PMC10789657 |
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Funding | HANSEN | Open Access funding enabled and organized by CAUL and its Member Institutions The SPRING study was supported by the National Health and Medical Research Council (APP1028575). Probiotics and placebo capsules for the SPRING study were donated by Chr. Hansen A/S. The sponsor was not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report. | PMC10789657 |
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Authors’ relationships and activities | The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. | PMC10789657 |
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Contribution statement | HTN | HTN | This study was conceived of and designed by HLT, HLB, LKC, HDM and MDN. The data was acquired and analysed by HLT, HTN, GM and MDN. All authors contributed to the interpretation of the data. The manuscript was co-written by HLT and MDN and edited and approved by all authors. MDN is responsible for the integrity of the work as a whole. | PMC10789657 |
References | PMC10789657 |
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1. Introduction and Background | insufficiency of the venous valves, ischemia, ulcers, atherosclerotic, numbness, pain, gangrene, infection, atherosclerotic ischemia, chronic arterial ulcers, atherosclerosis, ulcer, Atherosclerotic | HEALING ULCERS, LEG ULCERS, ISCHEMIA, DISEASE, ARTERIAL LEG ULCERS, ULCERS, GANGRENE, DISORDERS, VENOUS ULCERS, CHRONIC LEG ULCERS, INFECTION, SECONDARY, ARTERIAL ULCER, WOUND INFECTIONS, ATHEROSCLEROSIS, ULCER, COMPLICATIONS | Leg ulcers are a very serious worldwide medical problem. When the ulcer is extensive and deep the prognosis is usually unfavorable. The treatment requires comprehensive solutions that take into account modern specialized medical dressings, and more and more often, selected methods in the field of physical medicine. The study included 30 patients (13 women—43.4% and 17 men—56.6%) with chronic arterial ulcers of the lower limbs. The mean age of the treated patients was 65.63 ± 8.77 years. Patients were randomly assigned to two study groups. In group 1 (16 patients), specialist ATRAUMAN Ag medical dressings and local hyperbaric oxygen therapy treatments were used. In group 2 (14 patients), only specialized ATRAUMAN Ag dressings were used. The treatment was carried out for 4 weeks. The progress of healing ulcers was assessed by using the planimetric method, while the intensity of pain ailments was assessed by the visual analog VAS scale. In both study groups, a statistically significant reduction in the mean surface area of the treated ulcers was obtained, respectively, from 8.53 ± 1.71 cmLeg ulcers, regardless of their etiology, require urgent and multidirectional therapeutic treatment in each case. Patients with lower limb ulcers are at a very high risk of complications from the vascular system and the consequent need to amputate the limbs [The most common type of chronic leg ulcers is venous ulcers caused by excessive pressure in the venous system and an insufficiency of the venous valves. Arterial ulcers are next in frequency, with atherosclerosis being the most common cause. The disease is diagnosed annually in about 40.000 patients. The incidence of atherosclerosis is four times higher in men than in women and the clinical symptoms of atherosclerotic changes are most often visible between 50 and 60 years of age. Despite the intensive development of medicine, the etiopathogenesis of this disease is still not fully understood [The Incidence of arterial ulcers of the lower limbs is estimated in Europe and the United States at 500–1000 new cases per million inhabitants per year, and their incidence is 1.3–2.3% of the population [Atherosclerotic changes cause difficult blood flow in blood vessels and hemodynamic disorders. One of the three main clinical manifestations is atherosclerotic ischemia of the lower limbs, which, in the advanced stage of the disease, may take the form of critical ischemia of the lower limbs. The basic cause is usually the occlusion of large arteries, which gradually reduces the blood supply to the peripheral structures of the limbs at rest, as a result of which, their supply of nutrients is significantly reduced, causing very severe pain, a numbness of the limbs, and difficulty in moving. A reduced blood perfusion leads to changes in the microcirculation and is manifested by foot pain, trophic changes in the skin, non-healing ulcers, or tissue gangrene [The basic methods of the atherosclerosis treatment of the lower limbs are in fact vascular revascularization and endovascular procedures [In the last twenty years, there have been reports in the literature on the use of innovative non-pharmacological methods on the treatment chronic wounds, also used in the treatment of leg ulcers. In addition to the outer cover of wounds, these methods stimulate the natural processes of tissue regeneration, provide the right environment for the healing process, and protect the inside of the wound against the development of infection. Other (alternative) methods of therapy include negative pressure wound therapy (NPWT)—which is also increasingly used—platelet-rich plasma and cellular growth factors, selected methods of physical medicine (low-energy lasers, high-voltage electrostimulation, magnetotherapy, magnetostimulation, ultrasound, deep oscillation treatments, vibroacoustic therapy, ozone therapy), and dressings containing silver with antibacterial and antifungal properties. As a result of the content of active ingredients, such as absorption gels or sodium hyaluronate, modern dressings also create optimal conditions around wounds, favoring the intensification of the healing process. They also play an important role in wound cleaning. Wound cleaning is a very important element of the therapy that affects the course of the healing process. This requires carrying out specific procedures or treatments related to their cleaning, exudating removal. Modern dressings used in the treatment of ulcers are classified as so-called active dressings, i.e., those that support the healing process of ulcers. Firstly, modern dressings maintain a moist wound environment, optimize the level of exudate typical of chronic wounds (balance the enzyme/inhibitor ratio, reduce the concentration of pro-inflammatory cytokines, increase the availability of growth factors and nutrients in the wound), protect the wound from bacterial access, and ensure proper exchange of gaseous and optimal constant temperature without increasing the risk of infection. Such conditions are conducive to biological processes and facilitate cell division, migration, and differentiation, regulate enzymatic activity, and accelerate the reconstruction of protective layers of the epithelium, stimulating granulation. It is also important to isolate and protect the wound against the harmful effects of external factors. The dressing may adhere to the wound surface, but it should be easy to remove from the wound (without damaging the newly formed granulation tissue). It should also have sorption properties and prevent secondary wound infections. Currently, the raw material used in specialist dressings is very often ionic silver with a documented strong bactericidal effect [Among the physical methods used in the treatment of wounds of various etiologies there are also hyperbaric oxygen therapy procedures (in addition to those mentioned above) [A few years ago, hyperbaric chambers for the local application of oxygen therapy appeared on the medical market, which, while retaining all the advantages of systemic hyperbaric oxygen therapy, ensure comparable therapeutic effectiveness, and at the same time, guarantee a greater safety of therapy as they are devoid of typical side effects occurring in the case of systemic hyperbaric oxygen application. Local hyperbaric oxygen therapy also allows the treatment of those patients in whom systemic hyperbaric oxygen therapy is contraindicated for many reasons [The aim of the study was to compare the therapeutic efficacy of combined treatment, including medical active dressings and topical hyperbaric oxygen therapy versus medical active dressings applied alone in the treatment of arterial leg ulcers. | PMC10300718 |
2. Material and Methods | swelling, allergy, painless, gangrene, necrotic, pain, purulent, infection, necrosis, ulcerations, ulcer | ACUTE ISCHEMIA, GENERALIZED INFECTION, ALLERGY, ULCERS, POLAND, NECROSIS, VASCULARIZATION, DEEP VEIN THROMBOSIS, GANGRENE, NECROTIC, INFECTION; LOCAL, INFECTION, ULCERATION, ULCER, ATROPHIC, COMPLICATIONS, INFILTRATION, ARTERIAL LEG ULCERS, ULCERATIONS | The study included 30 patients (13 women and 17 men) aged 47–80, hospitalized in the Department of Internal Medicine, Angiology and Physical Medicine in Bytom with a diagnosis of arterial ulceration of the lower limbs, who had no indications for vascular revascularization.After collecting their medical history and performing a physical examination, the patients were randomly (one-to-one) assigned to two study groups. Group 1 (16 patients) was treated with specialist ATRAUMAN Ag dressings and local hyperbaric oxygen therapy procedures. In group 2 (14 patients), only specialized ATRAUMAN Ag medical dressings were used. The treatment was carried out for a total of 4 weeks.The use of ATRAUMAN Ag dressings was dictated by the current recommendations for their use. It is a specialist dressing that does not stick to the wound, and thus allows for its painless removal, which is not without significance in the case of coexisting pain. In addition, these dressings provide good ventilation and oxygenation of the wound, which accelerate healing and minimizes the risk of complications. In addition, the constant release of silver ions into the wound bed stabilizes bacterial activity at a low level, and the creation and maintenance of an optimal moist wound environment stimulates the autolysis of necrosis and the formation of new granulation tissue.The mean age of patients in group 1 (66.31 ± 7.7 years) did not differ statistically significantly as compared to group 2 (64.85 ± 10.09 years) (The ulceration conditions in both groups were comparable. The ulcerations were located above the lateral or medial malleolus. The surface of the wounds was usually covered with pale yellow fibrin with single necrotic hyphae. The wounds were characterized by atrophic changes. The skin around the ulcerations was parchment-like, shiny, with an unpleasant odor, a slight exudation, and an admixture of purulent secretion. In both groups, the ulceration area and depth (small shallow ulcer on distal leg, no exposed bone, no gangrene), incidence of infection (mild clinical manifestation of infection; local swelling and opaque to white secretion) and ABI index values (0.6–0.79) were all, in both groups, in grade 1, according to the WIfl Classification System [The inclusion criteria for the study were as follows: arterial leg ulcers of the lower limbs, age ≥47 and ≤80 years, lack of qualification for vascular revascularization, and voluntary patient consent to participate in the study. Exclusion criteria from the study were as follows: etiology of ulcers other than arterial, deep vein thrombosis, acute ischemia of the lower limbs, qualification for vascular vascularization, age <47 and >80 years, generalized infection, contraindications to hyperbaric oxygen therapy treatments, allergy to silver, and a lack of patient consent to participate in the study.Prior to the treatment implementation, each patient from both study groups underwent a Doppler ultrasound examination (in order to determine the etiology of the ulceration). A surgical consultation was also performed in each patient. In the case of necrotic tissue or purulent infiltration within the ulceration, surgical wound debridement was performed before inclusion to the study.Specialized dressings were changed every three days in both study groups. The dressings used in the study had the properties to ensure a moist environment conducive to accelerating the healing of ulcers. They did not require daily replacement and at the time of their change, they did not damage the newly formed granulation tissue. The only contraindication to their use during the studies was the previously diagnosed allergy of patients to the active substance contained in them (silver ions).The OXYBARIA-S device (manufacturer Firma FASER S.A., Świętochłowice, Poland) was used for local hyperbaric oxygen therapy [During the treatment, various forms of standard pharmacotherapy were used (pentoxifylline, sulodexide, and local antiseptic therapy). No antibiotics were administered before or during the evaluation period.The study protocol was approved by the local bioethics committee of the Medical University of Silesia in Katowice (approval number: KNW/0022/KB1/102/II/16/19). Each patient signed a written informed consent to participate in the study. | PMC10300718 |
2.1. Planimetric Assessment of Ulcer Surface Area | ULCERS | In clinical practice, modern measurement methods are used to assess the effects of wound treatment using computer programs for the digital processing of images used for image processing. They are advanced techniques of non-contact planimetry characterized by high reliability and an accuracy of measurements. They do not require direct contact with the wound, which reduces the risk of its contamination and damage to the treated tissues.Author’s computer software was used to assess the surface of the treated ulcers by a planimetric measurement of the surface area in manual mode [ | PMC10300718 |
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2.2. Measurement of Pain Intensity | pain | Before and after the end of the treatment, the intensity of pain ailments was assessed with the use of the ten-point visual analog scale (VAS) for a subjective assessment of pain intensity. In this method, the patient marks a section of a straight line, usually 10 cm long, with opposite ends marked, and a 1 cm scale, a point that corresponds to the intensity of pain experienced by him—from 0, which means no pain at all, to 10, which, in simple terms, indicates unbearable pain (the strongest pain the patient has ever felt in their life) [ | PMC10300718 |
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2.3. Statistical Analysis | POLAND | Statistica 13 software (Statsoft, Poland) was used for statistical analysis. The Shapiro–Wilk test was used to test the normality of data. The statistics is presented as mean, standard deviation (SD), and 95% confidence intervals (CI). The Mann–Whitney U test was used to compare two unmatched groups. The Wilcoxon test was used to compare two matched groups of data. Statistical significance level was | PMC10300718 |
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3. Results | ulcer, ulcers, pain | ULCER, ULCERS, ULCERATION | Before treatment, the mean ulceration area in group 1 (8.53 ± 1.71 cmBefore the treatment, the average value of the pain intensity in group 1 (7.93 ± 0.68 points) did not differ statistically significantly from the mean value of the ulcer surface area in group 2 (8.00 ± 0.67 points) (The percentage improvement after the applied treatment was also analyzed in terms of reducing the surface area of ulcers and pain. In group 1, the area of treated ulcers decreased on average by 34.6 ± 8.47%, and in group 2 by 25.23 ± 6.01%. The observed difference was statistically significant (All examined patients completed a full therapeutic cycle and did not report any side effects related to the treatment during and after the therapeutic cycle. | PMC10300718 |
4. Discussion | obesity, diabetic angiopathy, venous diseases, arterial insufficiency, hyperlipidemia, ulcers, necrotic, venous leg ulcers, pain, lower limb amputations, ulcer, arterial occlusive disease, diabetes | OBESITY, RECURRENCE, HEALED ULCER, ULCERS, ADVERSE EFFECTS, PERIPHERAL ARTERIAL DISEASE, VENOUS LEG ULCER, HYPERLIPIDEMIA, PROLIFERATION, INFLAMMATION, NECROTIC, HAND SWELLING, DIABETES, ARTERIAL INSUFFICIENCY, VENOUS DISEASE, ULCER, ARTERIAL OCCLUSIVE DISEASE, COMPLICATIONS, INFECTED WOUNDS, DIABETIC ANGIOPATHY, LEG ULCERS, ARTERIAL LEG ULCERS, DISEASE, CHRONIC LEG ULCERS, MALNUTRITION | The knowledge of the use of various treatment methods in the case of hard-to-heal wounds, including leg ulcers, is systematically and continuously expanded and updated. The modern concept of wound treatment involves a comprehension of the underlying disease and is aimed at creating conditions conducive to healing, e.g., by eliminating risk factors responsible for the abnormal course of healing such as obesity, diabetes, malnutrition, hyperlipidemia or nicotinism [It should be emphasized that in patients with complications of peripheral arterial disease—also in the form of arterial leg ulcers—the most important treatment is vascular revascularization, which enables the restoration of a possibly physiological blood supply. In patients who are not eligible for vascular revascularization for various reasons, recommended and effective methods should be implemented, among which, dressings are considered the standard of local treatment; however, there is a rise in innovative methods in the field of physical medicine (physiotherapy), which could also be effective. This comprehensive, coordinated approach, while taking into account various methods of action, is intended to accelerate the healing process, facilitate the cleansing of necrotic tissue from ulcers, reduce exudation and swelling, and support granulation processes. However, the effects of the treatment of hard-to-heal wounds are still not fully satisfactory, as they often do not ensure complete wound healing [Currently, the greatest hopes are associated with dressings that contain active substances. The developed concept of an “ideal” dressing assumes that it should not only have a defensive function and provide a sufficiently moist environment, but also directly stimulate cell regeneration [Eleven specialists in the management of various types of wounds discussed best practices, recommendations, and guidelines for the management of the main types of chronic wounds. An analysis of the collected literature showed that significant progress has been made in the understanding of wound healing processes over the past decade. There have also been many publications emphasizing the importance of medical dressings and various forms of therapy. Experts also point out that more emphasis should be placed on making the right diagnosis and choosing the right dressing and appropriate therapy. Such a holistic approach to the treatment of the patient and the wound bed is aimed at achieving the best therapeutic result while preventing the recurrence of wounds [Bowers and Franco, however, disagree. These authors believe that patients with arterial ulcers should be immediately referred to a vascular surgeon who should consider appropriate intervention [In our study, we used specialized active dressings containing silver ions, the effect of which resulted in a statistically significant reduction in the surface area of the treated ulcers, thus accelerating the healing process in both assessed groups of patients. The therapeutic effect obtained was greater in the group of patients who additionally received local HBOT treatments. It was most likely related to the synergistic therapeutic effect of simultaneously used therapies. HBOT treatments improve tissue metabolism and their increased oxygenation, which translate into higher results. In hyperbaric treatment, hemoglobin is more saturated with oxygen; the oxygen concentration dissolves physically and is not bound to hemoglobin increase in the serum, thereby resulting in significantly accelerated healing processes. The proper course of the wound healing process involving leg ulcers requires the right amount of oxygen supply to the tissues. At the stage of inflammation, oxygen affects the intensity of migration and proliferation of fibroblasts. If the supply of the appropriate amount of oxygen and nutrients involved in the tissue regeneration process is limited, the healing process is disturbed and thus significantly prolonged [In the analysis conducted by Bouza et al., the authors analyzed the scientific evidence confirming the effectiveness of modern dressings used in the treatment of leg ulcers by searching the available databases. As in our case, the authors did not find any studies that focused solely on arterial ulcers. The results of the analysis showed no statistically significant differences in the percentage of healed ulcers or reduction in wound size for both modern and conventional dressings. As in the case of hyperbaric oxygen therapy treatments, it can be inferred that the current medical literature is poor in terms of research regarding this topic. There is insufficient scientific evidence to determine whether the choice of a specific type of dressing has the most beneficial effect on the course of ulcer healing [In one of the older articles, the authors evaluated randomized clinical trials to determine whether applied topical agents and dressings affect the rate of healing of arterial ulcers of the lower extremities. Only one study met the inclusion criteria and was analyzed. The authors emphasize that the study included a group that was too small in number of participants to be analyzed, and the observation period was too short. On this basis, it cannot be concluded whether there was any difference in cure rates [Mosti et al. compared the treatment efficacy of a microbiological binding (MB) dressing with a silver-containing hydrofiber (SCH) dressing. The study group consisted of 20 patients (15 patients with venous leg ulcers and 5 with arterial leg ulcers). An assessment was made on the bacterial load of heavily colonized or locally infected wounds. The analysis of the obtained results showed that both types of dressings are effective in reducing the bacterial load in critically colonized or locally infected chronic leg ulcers. However, MB dressings showed a higher efficiency. No adverse effects were found [Unfortunately, the available literature also lacks current papers that would explicitly discuss the therapeutic benefits of HBOT in the treatment of arterial ulcers. Therefore, we could not compare our preliminary results or assess the safety of the therapy used in relation to other scientific reports.In one of the few articles by Kranke et al. in 2015, they reviewed the available results of randomized trials, in which they tried to answer the following questions: (1) does hyperbaric oxygen therapy (HBOT) increase the percentage of patients with healed chronic wounds and (2) does the need to perform lower limb amputations subsequently decrease? Most of the studies were concerned with ulcers related to diabetes and venous diseases, which confirm the effectiveness of HBOT therapy in terms of wound healing. The authors did not find any data confirming or disproving the effect of HBOT on the healing of arterial ulcers [In turn, Heyboer et al. conducted a retrospective analysis on a group of patients who received hyperbaric oxygen therapy treatments for ulcers caused by arterial insufficiency that did not heal despite standard treatment. Eighty-two patients were analyzed. The overall cure rate was 43.9% and the amputation rate was 17.1%. According to the authors, hyperbaric oxygenation may constitute a positive role in the treatment of leg ulcers of arterial etiology, which failed standard treatment [Beric et al. conducted a prospective clinical trial with 80 patients. The patients were divided into two groups: (group 1) 40 patients with arterial occlusive disease and lower limb wounds, with a subgroup (n = 20) treated with HBO therapy, and (group 2) 40 patients with diabetic angiopathy and lower limb wounds, with a subgroup (n = 20) treated with HBO therapy in addition to standard therapy. In both groups, statistically significantly higher results were found in patients who underwent HBO treatments as an addition to the standard therapy [The analysis of the obtained results also showed beneficial therapeutic effects related to the reduction in pain in both study groups. The mechanisms of the analgesic effect of HBOT include, among others: stimulating the secretion of endogenous endorphins and inhibiting the activity of the local inflammatory process.John et al. summarized in their article the available scientific reports on the non-surgical treatment of arterial leg ulcers, topical therapies, pharmacological agents, apparatus and available devices. Only randomized clinical trials and meta-analyses were included. The results showed that, despite some limitations of these methods and side effects, their use should be considered in each case because these procedures are characterized as having good tolerance, accessibility, and impact on the reduction in pain ailments [Taking into account the good tolerance of the treatments and the small number of contraindications to the use of local hyperbaric oxygen therapy, when used together with active specialized dressings, these treatments can be a valuable supplement to pharmacological treatment. Moreover, it should be emphasized that local HBOT can be conducted at home and is preferred for people with limited mobility who, for various reasons, cannot be treated in specialist stationary centers. Furthermore, this method reduces pain and also improves tissue oxygen perfusion.These positive preliminary therapeutic effects should allow for the optimization of future therapeutic procedures and the refinement of the treatment of chronic arterial ulcers of the lower limbs. | PMC10300718 |
Limitations of the Study | This study had some limitations. First, this was a pilot study performed in a single institution with the risk of potential bias with respect to data collection. The study also did not include the analysis of previous standards of care used in the analyzed group of patients. | PMC10300718 |
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Author Contributions | J.P.: Study design, data collection, data interpretation, manuscript preparation, the literature search; S.S.: data collection, statistical analysis; G.C.: data interpretation. All authors have read and agreed to the published version of the manuscript. | PMC10300718 |
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Institutional Review Board Statement | POLAND | The study was conducted in accordance with the Declaration of Helsinki (1964) and its protocol has been accepted by the local bioethical committee at Medical University of Silesia in Katowice, Poland (approval reference number: KNW/0022/KB1/102/II/16/19). Every patient has signed forms of written informed consent approval for all procedures conducted in the study. | PMC10300718 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10300718 |
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Data Availability Statement | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10300718 |
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Conflicts of Interest | The authors declare no conflict of interest regarding the material discussed in the manuscript. | PMC10300718 |
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References | pain | ULCERS, ULCERATION | The procedure of local hyperbaric oxygen therapy with the use of OXYBARIA-S device (manufacturer Firma FASER S.A., Świętochłowice, Poland).Comparison of the average values of the surface area of treated arterial ulcers of the lower limbs between the study groups before and after treatment, together with statistical analysis.* Mann–Whitney U test; ** Wilcoxon test.Comparison of mean pain intensity values assessed on the VAS scale between the study groups before and after treatment with statistical analysis.* Mann–Whitney U test; ** Wilcoxon test.Comparison of the percentage improvement after the applied treatment between the study groups in terms of reducing the size of the ulceration area and pain with statistical analysis.* Mann–Whitney U test. | PMC10300718 |
1. Introduction | rheumatoid arthritis, low back pain, seizures, osteoarthritis, hypoactive, painless, chronic musculoskeletal pain, pain, shoulder pain, chronic neck pain, hyperactive | RHEUMATOID ARTHRITIS, AUTONOMIC IMBALANCE, OSTEOARTHRITIS, MUSCULOSKELETAL DISORDERS, SYNDROMES, HEART, DISEASES, AUTONOMIC DYSREGULATION | Heart rate variability (HRV) analysis has emerged as a simple and non-invasive technique to indirectly evaluate the autonomic nervous system (ANS), and it is considered a sensible and advanced index of health status. Pulsed electromagnetic fields (PEMFs) are widely used in clinical settings for improving the health status of individuals with chronic musculoskeletal pain. The aim of the present single-blind, randomized, placebo-controlled parallel pilot study was to investigate the acute effect of a single session of PEMFs stimulation by a PAP ion magnetic induction (PAPIMI) device on ANS activity, as measured by HRV, in patients with chronic musculoskeletal pain, and compare such effect with that induced by a sham (control) PAPIMI inductor. Thirty-two patients were randomized into two groups: PAPIMI intervention (PAP) (n = 17) and sham PAPIMI intervention (SHAM-PAP) (n = 15). HRV was assessed before and following the interventions. The PAP group showed a significant increase in all values of the time-domain parameters (SDNN, RMSSD, NN50, and pNN50) and the HF component of HRV, suggesting a parasympathetic effect. In contrast, the SHAM-PAP group showed no significant differences in all HRV indices following the intervention. Preliminary findings suggested that PAPIMI inductor could influence ANS activity and provided initial evidence of the potential physiological response induced by the PAPIMI device.The autonomic nervous system (ANS) plays a critical role in the regulation and coordination of the physiological processes in human biological organisms, and individual differences in autonomic balance have long been associated with health and pathological conditions [The ANS is assumed to be composed of two major antagonistic subsystems that commonly act in dynamic balance: the sympathetic branch, involved in regulating energy mobilization, and the parasympathetic branch, implicated in vegetative and restorative functions [The dynamic balance between distinct components of the ANS can be threatened and altered by metabolic (inner) and environmental (external) stimuli, which may cause a condition of autonomic imbalance. Specifically, the loss of autonomic balance, in which one branch of the ANS prevails over the other, is characterized by a lack of dynamic adaptability and of the health of the organism. A substantial amount of empirical evidence indicates that a host of pathological conditions and diseases are associated with autonomic dysregulation, in which, typically, the sympathetic system is hyperactive and the parasympathetic system is hypoactive [Among the methods adopted to assess ANS function, heart rate variability (HRV) analysis has emerged as a simple and noninvasive technique to indirectly evaluate the autonomic activity, representing one of the most important quantitative markers of ANS balance/imbalance [As regards the link to pathological conditions, it was reported that ANS imbalance is associated with chronic musculoskeletal pain. This common physiological disfunction is defined as a pain that affects bones, muscles, ligaments, tendons, and even nerves; it comprises a number of different pain syndromes such as chronic neck pain, shoulder pain, low back pain, and also pain associated with osteoarthritis and rheumatoid arthritis [Different non-pharmacologic approaches are available for relieving the pain associated with musculoskeletal disorders [The PAP ion magnetic induction (PAPIMI) device is a certified and approved medical instrument that belongs to the large family of PEMFs. This device provides a non-invasive, painless, contact-free ion-induction therapy that was shown to be effective for the treatment of refractory seizures [Therefore, the aim of the present single-blind, randomized, placebo-controlled parallel pilot study was to investigate the acute effect of a single-session treatment of PEMFs stimulation by PAPIMI inductor on ANS balance, as measured by HRV, in patients suffering from chronic musculoskeletal pain, and compare such effect with that induced by a sham (control) PAPIMI inductor. We hypothesized that PAPIMI intervention, as compared to the sham one, could induce a more effective parasympathetic response, which would result in an increased HRV. | PMC10001461 |
2. Materials and Methods | PMC10001461 |
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2.1. Participants | painful symptoms, chronic musculoskeletal pain, musculoskeletal pain | MAY, SYNDROME, BLIND | From a population of 95 patients, 32 subjects (17 men and 15 women) with painful symptoms in the musculoskeletal system, aged between 28 and 68 years old (50.06 ± 10.85), were enrolled in the study. Patients were recruited from April to May 2022 from the physiotherapy center “Centro FisioterapicoApuano” in Lucca (Italy) where the study was also conducted.All patients who were considered eligible for the study had chronic musculoskeletal pain (of more than 3 months’ duration) [Participants were recruited after being evaluated by a physiotherapist from the center, who confirmed a diagnosis of musculoskeletal pain syndrome and collected participants’ pharmacological information through an in-person interview. Prior to the start of the study, informed consent was read and signed by each patient. The study was approved by the local institutional review committee (Prot. N. 12774E_spe). Each subject was blind to study design, outcome, and group allocation. | PMC10001461 |
2.2. Experimental Procedure | Patients were randomized into two different groups: PAPIMI intervention (PAP) (n = 17) and sham (control) PAPIMI intervention (SHAM-PAP) (n = 15) ( | PMC10001461 |
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2.3. Interventions | PAP and SHAM-PAP interventions were administered to all patients by a single licensed and registered physiotherapist. | PMC10001461 |
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2.3.1. PAPIMI Intervention | pain | Patients allocated to the PAP intervention group were treated with a PAP ion magnetic inductor (PAPIMIThe PAPIMI is an approved medical device that belongs to the large family of PEMFs, and it is based on the principle of ion induction. The device is composed of a capacitor that stores electrical energy, which is then conducted through a plasma chamber (spark gap). The plasma chamber technology is used to discharge a very high voltage from the capacitor into a spiral coil applicator to create high intensity electromagnetic pulses.Due to very high voltages reaching up to 40kV and peak currents of several 10 kA, an energy output per pulse of about 60 W (joules) with a magnetic induction of 50–150 mT is achieved. Each pulse has a base frequency of about 240 kHz and a duration of about 50 μs. Additionally, the pulse repetition rate can be varied between 1 and 8 Hz. The generated pulses are transmitted without any direct contact with the body, which is penetrated by the induction field. This latter generates weak electric currents having the same intensity and frequency as the originally generated magnetic pulse [The PAPIMI intervention was tailored according to the individual’s needs and administered through the spiral coil applicator. The treatment coil used for the intervention (diameter 18 cm) enhanced ion induction to 100 mT and was centered over the referred pain zone. The applicator was held at a distance of approximately 4 cm from the relevant part of the body ( | PMC10001461 |
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2.3.2. Sham (Control) Papimi Intervention | Patients allocated to the sham intervention group received an inactive PEMF treatment and underwent the same procedure as that of the experimental group. The PAPIMI sham device was externally identical to the active one, except that it was deactivated prior to the exposure so that no pulsed electromagnetic fields were generated. | PMC10001461 |
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2.4. Data Collection Measurements | Before and immediately after each intervention, HRV was evaluated. Patients were recorded for a short period of 5 min in a resting state using a Polar H7 heart belt (Polar Electro, Kempele, Finland) [R-R intervals were subsequently evaluated using Kubios HRV Premium 3.4.1 desktop software (Kubios OY, Kuopio, Finland) to calculate all the HRV parameters considered in this study (see | PMC10001461 |
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2.5. Outcome Measures | Pre- and post-treatment values of HRV were examined. HRV evaluation, based on processing R-R intervals, was divided into time- and frequency-domain linear analysis [The following time-domain parameters of HRV were considered: standard deviation of adjacent NN intervals (SDNN), the root mean square of successive R-R interval differences (RMSSD), the number of adjacent NN intervals differing by more than 50 milliseconds (NN50), and the percentage of successive R-R intervals differing by more than 50 ms (pNN50). RMSSD, NN50, and pNN50 are correlated with parasympathetic activation [The frequency-domain index of HRV analyzed in this study was the high frequency (HF) band, from 0.15 to 0.4 Hz. The HF band is indicative of parasympathetic activity and is called the respiratory band because it corresponds to the HR variations related to the respiratory cycle [ | PMC10001461 |
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2.6. Statistical Analysis | All the subjects’ demographic data as well as their HRV parameters were described using arithmetic means, standard deviations (SDs), and standard errors of the mean (SEM). The chi-squared test was used to test for gender differences between groups, and results were expressed in percentages. In addition, group differences were evaluated for age, body mass index (BMI) and HR using the two-sample In the present study, HRV analysis was executed using the restricted weak stationarity (RWS) test proposed by Porta and colleagues (2004), which assesses stationarity (i.e., the steadiness of the mean and variance, respectively) over M patterns [To assess the effect of PAP and SHAM-PAP interventions on the ANS, each time-domain parameter of HRV (SDNN, RMSSD, NN50, and pNN50, respectively) and the frequency-domain index of HRV (HF band) taken into account for this study were entered in a mixed analysis of variance (ANOVA) with INTERVENTION GROUP as the between-subject factor (two levels: PAP and SHAM-PAP) and TIME as a within-subject factor (two levels: pre-intervention and post-intervention). Post hoc pairwise analysis was conducted with Bonferroni adjustment for multiple comparisons. The threshold for statistical significance was set to | PMC10001461 |
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3. Results | PMC10001461 |
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3.1. Sample Characteristics and HRV Pre-Intervention Scores | ADVERSE EVENTS, ADVERSE EFFECT | Out of 95 patients, 32 were included in this study and randomized into two groups (PAP and SHAM-PAP). Patients who experienced any adverse effect from treatment would have been excluded from the study. Since no adverse events were reported, none of the participants was lost for this reason, and all received the treatment (The demographics, characteristics, and baseline values of HRV parameters are presented in | PMC10001461 |
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3.2. HRV Post-Intervention Scores | The analyzed parameters of time- and frequency-domain of HRV after PAP and SHAM-PAP interventions are reported in | PMC10001461 |
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3.2.1. SDNN | For the SDNN index, the results of the mixed ANOVA showed a significant main effect for TIME [ | PMC10001461 |
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3.2.2. RMSSD | For the RMSSD index, a significant main effect for TIME [ | PMC10001461 |
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3.2.3. NN50 | For the NN50 index, no significant main effect for TIME [ | PMC10001461 |
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3.2.4. pNN50 | For the pNN50 index, a significant main effect for TIME [ | PMC10001461 |
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3.2.5. HF | For the HF band, mixed ANOVA showed a significant main effect of TIME [ | PMC10001461 |
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4. Discussion | musculoskeletal pain, chronic musculoskeletal pain, pain | MUSCULOSKELETAL DISORDERS | In the current study, we investigated the influence of a single session of PEMFs stimulation using PAPIMI device on modulating ANS activity in patients with chronic musculoskeletal pain. An HRV analysis was employed in order to detect changes in vagal tone after the intervention.Our results showed that all values of time-domain parameters and HF component of HRV significantly increased following PAP treatment, indicating that PAPIMI device modulated ANS activity by inducing a parasympathetic response. In contrast, no significant differences in all HRV indices were found following the SHAM-PAP intervention.In clinical practice, PEMFs are widely used as a safe and non-pharmacologic intervention for the treatment of musculoskeletal disorders [Among PEMFs, PAPIMI inductor represents a promising ion magnetic field device which has proven to help restore health status in subjects with pathological conditions [Our findings shed light on the effectiveness of PAPIMI device in inducing a health status-related parasympathetic response, as indirectly shown by an increased HRV, in patients with chronic musculoskeletal pain. A possible hypothesis that could explain such effect is related to the influence PEMFs have on the membrane potential of body cells [Finally, this is the first study investigating the influence of PAPIMI device on the ANS activity in patients with chronic musculoskeletal pain. Taking into account the low risk of side effects and the high tolerance of PEMFs intervention, findings from our pilot study indicate that PAPIMI inductor could be considered a potentially promising device in clinical practice for the treatment and management of chronic musculoskeletal pain, thus further contributing to improvements in patient health status. To the best of our knowledge, in the literature, only two studies have explored the effects of PAPIMI inductor in human subjects [Some limitations concerning the present pilot study should be addressed. First, the number of participants remains relatively small. Second, a comparison with a control group of healthy subjects was not planned for this study. Future non-pilot studies should preferably include a larger patient sample and a group of healthy individuals as well. Third, we did not provide an evaluation of subjects’ feeling of well-being or pain perception that could provide information on the responsiveness of patients to PAPIMI intervention. Nevertheless, it is worth mentioning that the analysis of the cardiovascular autonomic control seems to be more sensitive than a self-reported measure of pain for estimating the effectiveness of a non-pharmacological treatment in patients with musculoskeletal pain [Future studies exploring the effect of PAP treatment in subjects with chronic musculoskeletal pain should be carried out with a longer intervention period [ | PMC10001461 |
Author Contributions | Conceptualization, A.V., G.P., S.G. (Sara Guarducci), R.B. and D.M.; methodology, A.V., G.P., S.G. (Sara Guarducci), R.B., S.G. (Susanna Garfagnini), and D.M.; formal analysis, G.P. and M.M.; investigation, A.V. and S.G. (Susanna Garfagnini); data curation, G.P., S.G. (Sara Guarducci), and M.M.; writing—original draft preparation, A.V., G.P., and S.G. (Sara Guarducci); writing—review and editing, A.V., G.P., S.G. (Sara Guarducci), S.G. (Susanna Garfagnini), M.M., R.B. and D.M.; visualization, G.P., M.M. and D.M.; supervision, S.G. (Susanna Garfagnini), R.B. and D.M.; project administration, A.V., S.G. (Susanna Garfagnini) and D.M. All authors have read and agreed to the published version of the manuscript. | PMC10001461 |
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Institutional Review Board Statement | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the local institutional review committee (Prot. N. 12774E_spe, date of approval: 5 June 2018). | PMC10001461 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10001461 |
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Data Availability Statement | The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy issues. | PMC10001461 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10001461 |
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References | Flow-chart of the study.PAPIMI intervention. (Time-domain parameters of HRV at rest, pre- and post-treatment. (Frequency-domain parameter of HRV at rest, pre- and post-treatment. HF band. Data presented are mean ± standard errors of the mean (SEM). Asterisk marks a significant difference (Baseline values of PAPIMI (PAP) and Sham PAPIMI (SHAM-PAP) groups.Numbers in table are mean ± standard deviations (SDs) | PMC10001461 |
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Subject terms | hypertensive, Pain, pain | Ambulatory blood pressure monitoring (ABPM) may be stressful and associated with discomfort, possibly influenced by the number of cuff inflations. We compared a low frequency (LF-ABPM) regimen with one cuff inflation per hour, with a high frequency (HF-ABPM) regimen performed according to current guidelines using three cuff-inflations per hour during daytime and two cuff-inflations during night time. In a crossover study, patients underwent ABPMs with both frequencies, in a randomized order, within an interval of a few days. Patients reported pain (visual analogue scale from 0 to 10) and sleep disturbances after each ABPM. The primary endpoint was the difference in mean 24 h systolic BP (SBP) between HF-ABPM and LF-ABPM. A total of 171 patients were randomized, and data from 131 (age 58 ± 14 years, 47% females, 24% normotensive, 53% mildly hypertensive, and 22% moderately-severely hypertensive) completing both ABPMs were included in the analysis. Mean SBP was 137.5 mmHg (95% CI, 134.8;140.2) for HF-ABPM and 138.2 mmHg (95%CI, 135.2;141.1) for LF-ABPM. The 95% limits of agreement were −15.3 mmHg and +14.0 mmHg. Mean 24 h SBP difference between HF-ABPM and LF-ABPM was −0.7 mmHg (95%CI, −2.0;0.6). Coefficients of variation were similar for LF-ABPM and HF-ABPM. Pain scores (median with interquartile range), for HF-ABPM and LF-ABPM were 1.5 (0.6;3.0) and 1.3 (0.6;2.9) during daytime, and 1.3 (0.4:3.4) and 0.9 (0.4;2.0) during nighttime ( | PMC10844074 |
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Introduction | Hypertension, hypertensive | HYPERTENSION | Ambulatory blood pressure monitoring (ABPM) is recommended as the most accurate non-invasive method for the assessment of blood pressure (BP) and BP-related cardiovascular risk [The current ESH guidelines and the International Society of Hypertension recommend 2–3 cuff inflations every hour during ABPM [Previous investigations suggest that BP transiently rises during cuff inflation, particularly in hypertensive patients [In the present randomized crossover study, we compared ABPM using one measurement per hour for 24 h with current guideline recommendations of three measurements per hour during daytime and two per hour during nighttime. | PMC10844074 |
Methods | PMC10844074 |
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Participants | hypertension, Chronic kidney disease, Hypertension | PERSISTENT ATRIAL FIBRILLATION, TREATMENT RESISTANT HYPERTENSION, HYPERTENSION, HYPERTENSION, CHRONIC KIDNEY DISEASE | Patients (≥ 18 years) were recruited from the Hypertension Clinic at Aarhus University Hospital, Denmark and from two local private cardiology clinics. Suspected treatment resistant hypertension was the main reason for attending these clinics. Exclusion criteria were pregnancy, change in antihypertensive medication within 14 days prior to inclusion, treating physician preference of using an ABPM-device other than the devices described below, arm circumference above or below available cuff sizes (20–42 cm), inability to give informed consent, or not expecting to sleep during the night on either day of ABPM (nightshift work or other reasons). Patients were not invited to participate if permanent- or persistent atrial fibrillation were noted in their electronic patient records three years prior to inclusion. Information about patient characteristics, comorbidities, and medication were obtained from electronic patient records.Included patients were assigned a hypertension category based on their first ABPM. Normotension/controlled hypertension was defined as 24 h SBP/diastolic BP (DBP) < 130/80 mmHg, mild hypertension as 24 h SBP 130–149 mmHg and moderate/severe hypertension as 24 h SBP ≥ 150 mmHg. Chronic kidney disease was defined as estimated glomerular filtration rate below 60 ml/min/1.73 m | PMC10844074 |
Materials | Prior to the first ABPM, a Microlife watchBP Office BP device (Microlife, AG Widnau, Switzerland) was used for bilateral BP measurements. If the inter-arm difference was larger than 10/5 mmHg (SBP/DBP) the ABPM device was fitted to the arm with the highest BP. If not, patients were given the option to choose which arm the cuff was fitted on. The same arm was used for both ABPMs.Spacelabs Ontrak and Spacelabs 90217A (Spacelabs Healthcare, Snoqualmie, Washington, USA) were used for the ABPMs. Both devices are validated according to internationally recognized standards [During high frequency ABPM (HF-ABPM), daytime was predefined as 07:00–23:00 and BP was measured every 20 min in this time interval and every 30 min for the remaining eight hours. Low frequency ABPM (LF-ABPM) measured BP once every hour during all 24 h. Patients reported individual bed- and rising times after each ABPM, and these were used to define awake and sleep measurements post hoc. If a planned measurement failed, the device was programmed to perform one extra measurement within two minutes. Initially, four measurements were made during fitting to ensure that the device worked correctly. These initial measurements and measurements performed after 24 h of recording, were removed from our analysis. | PMC10844074 |
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Study protocol | Pain, pain | All patients scheduled for a planned ABPM were screened and eligible patients were asked to participate. Patients who accepted to enter the study were randomized 1:1, using an online random number generator [Patients were prepared for the ABPM in accordance with current guidelines [Immediately after each ABPM, the patients filled in a questionnaire concerning antihypertensive medication taken for the last 24 h, self-perceived sleep interruptions attributed to the measurements, symptoms from the arm after removal of the cuff, and pain perceived during day and night measurements. Pain associated with cuff inflations was reported on a visual analogue scale (VAS) from 0 to 10. Only patients who completed both questionnaires were included in the questionnaire analysis. | PMC10844074 |
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Statistical evaluation | SD | REGRESSION | The primary outcome was the difference in 24 h mean SBP between HF-ABPM and LF-ABPM. Secondary outcomes were mean differences in SBP for day- and nighttime, DBP values (24 h, daytime, and nighttime means), 95% limits of agreement (95% LoA) interval, coefficient of variation (CV) for both SBP and DBP values calculated as standard deviation (SD) / mean × 100, and questionnaire data as reported above. The mean difference and the LOA between HF- and LF-ABPM were calculated using Bland-Alman plots and the relationships between differences and means were tested with simple linear regression and plotted appropriately, 24 h means are also presented in scatter plots with a line of equality as reference [Data were analyzed using STATA (Version 17, StataCorp, College Station, TX, USA). Continuous variables were evaluated for normal distribution using QQ-plots and histograms. BP results are presented as means with 95% confidence intervals (CI). All other continuous, normally distributed variables are presented as means ± SD, and data with a skewed distribution are presented as median with interquartile range (IQR). Dichotomous variables are presented as number of patients with % of total population. For independent data unpaired t-test, Mann-Whitney-U test and chi-squared-test were used for normally distributed, skewed, and dichotomous data, respectively. For paired data a paired t-test, Wilcoxon matched-pairs signed-rank test, and McNemar’s test were used for normally distributed, skewed, and dichotomous, data respectively. A | PMC10844074 |
Results | PMC10844074 |
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General characteristics | A total of 171 patients were randomized. However, 40 (23.4%) did not complete the study or were excluded because of reasons outlined in Fig. | PMC10844074 |
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Flowchart of inclusion. | SD | HF-ABPM High frequency ambulatory blood pressure monitoring, LF-ABPM Low frequency ambulatory blood pressure monitoring.Baseline characteristics of the 131 patients finalizing both ABPMs are shown as total study population and according to measurement order (HF-ABPM first and LF-APBM first) in Table Basic characteristics of the included patients.Data are presented as mean ± SD or median (interquartile range) for continuous variables and Ambulatory blood pressure monitoring characteristics of the included patients.Data are presented as mean ± SD or median (interquartile range) for continuous variables and number (%) for categorical variables. Percentage correct measurements are the total number of correct measurements divided by the maximal number of possible correct measurements (24 for LF-ABPM and 64 for HF-ABPM). | PMC10844074 |
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24 h blood pressure differences and agreement | BLOOD | There were no significant differences in 24 h BP means between HF-ABPM and LF-ABPM and a high level of agreement between the two measurement protocols. As shown in Table Blood pressure values and coefficients of variance during 24-hour ambulatory blood pressure monitoring.Data are mean with 95% confidence intervals. The difference is calculated as HF-ABPM – LF-ABPM. | PMC10844074 |
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24 h blood pressures. | Bland-Altman plots ( | PMC10844074 |
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Daytime and nighttime blood pressure differences and agreement | Daytime and nighttime averages were similar for the two measurement frequencies. Table | PMC10844074 |
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Day and nighttime blood pressures. | Bland-Altman plots for daytime SBP (We found that 49.6% of patients had a concordant dipping status between LF-ABPM and HF-ABPM (Supplementary Table | PMC10844074 |
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First time ABPM, hypertension categories, and order of measurement | hypertension | HYPERTENSION | Patients who underwent ABPM for the first time in the present study (For patients with moderate/severe hypertension LF-ABPM measured all but daytime SBP and nighttime DBP slightly higher compared to HF-ABPM (Supplementary Table There were no differences in neither 24 h, daytime, and nighttime BP values between those randomized to HF-ABPM first and those randomized to LF-ABPM first. | PMC10844074 |
Questionnaire on pain and sleep | ABPM-related pain, SD | Most patients rated ABPM-related pain low on a VAS. However, patients reported HF-ABPM to be slightly more painful compared to LF-ABPM (Table Questionnaire data.Data are presented as mean ± SD or median (interquartile range) for continuous variables and number (%) for categorical variables. | PMC10844074 |
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Discussion | We here present the first randomized study comparing 24 h ABPM with hourly measurements to 24 h ABPM using the currently recommended frequencies of 2–3 measurements per hour in a patient-population covering a broad range of BP levels. We found a good agreement between HF-ABPM and LF-ABPM for both SBP and DBP values. In addition, LF-ABPM was rated slightly less painful during cuff inflation. Our data support that one measurement every hour is sufficient to achieve correct values for BP as well as for BP variability. | PMC10844074 |
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Low vs. high measurement frequency | The present findings are in accordance with two smaller studies, which compared hourly measurements with 4 measurements per hour without detecting any difference in BP values [The most utilized method for investigating the influence of measurement frequencies is post-hoc random removal of individual measurements after performing a single ABPM, to simulate a lower measurement frequency [A possible concern using LF-ABPM could be that failed measurements might influence BP estimation to a larger degree than for HF-ABPM. Our study was not designed to answer this concern, but we found no indication of this as SBP difference between HF-ABPM and LF-ABPM did not seem to change with fewer successful measurements during LF-ABPM. However, since only 12 patients had less than 20 successful measurements, this finding is uncertain. Yang et al. found as few as 8 valid daytime readings and 4 valid nighttime readings were enough for results to be comparable to what was attained using current guideline recommended frequencies [ | PMC10844074 |
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Agreement between HF-ABPM and LF-ABPM | Only a few of the studies investigating measurement frequency reported 95% LoA or SD of difference, from which 95% LoA can be calculated [ | PMC10844074 |
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Blood pressure variability | It has been argued that an ABPM measurement frequency of once every hour could limit correct assessment of BP variability [ | PMC10844074 |
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Sleep quality and pain | pain | Some patients report pain from cuff inflations as a major complaint in relation to ABPM [Earlier studies have emphasized that interrupted sleep and a subsequent possible increase in nighttime BP as limitations of ABPM [ | PMC10844074 |
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Limitations and strengths | end-organ damage, hypertension, pain | HYPERTENSION | A possible limitation of all hospital-based hypertension studies is external validity and whether findings can be extrapolated to other settings. Patients referred to a specialized hypertension clinic more frequently have treatment-resistant hypertension or more advanced end-organ damage compared to patients treated in primary care clinics.LF-ABPM is the standard practice in our clinic and several patients from our cohort had undergone one or more ABPMs before inclusion. Patients who previously underwent LF-ABPM, and found it painful or stressful, may decline participation in a study involving several ABPMs. However, when comparing patients who underwent ABPM for the first time with the total study population, we found no difference in 24 h BP or their rating of pain and sleep disturbances. We consider the risk of selection bias to be minimal based on the similarity between first-time ABPM patients and patients with prior ABPM experience. The low number of patients who reported “too uncomfortable/painful” as the reason to decline participation in the study further supports this. | PMC10844074 |
Conclusion | pain | This is the first randomized study to investigate whether ABPM using hourly measurements may be an alternative to current guideline-recommended measurement frequencies. We found good agreement and no clinically significant BP differences between the two measurement frequencies. In addition, there was a modest reduction in reported pain during LF-ABPM compared to HF-ABPM. ABPM using hourly measurements might increase patient acceptance of repeated ABPMs without reducing data quality and thereby potentially increase BP control. Future research should focus on investigating the usefulness of LF-ABPM in predicting cardiovascular risk compared to HF-ABPM. | PMC10844074 |
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Summary | PMC10844074 |
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What is known about the topic |
Current guidelines recommend 2–3 measurements per hour during ambulatory blood pressure monitoring (ABPM) but provide no clear evidence for this.Previous studies have tried to mimic a lower measurement frequency by random removal of data from ABPM using 2–3 recordings per hour.A direct comparison of a high | PMC10844074 |
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What this study adds | pain |
First randomized trial to actually compare hourly measurements with current guideline recommendations.There are no clinically relevant differences in neither blood pressure nor blood pressure variation between the two measurement frequencies.ABPM related pain was significantly less both during daytime and nighttime when using hourly measurements.Our data suggest that ABPM using hourly measurements is an alternative to current guideline recommendations. | PMC10844074 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41371-023-00868-0. | PMC10844074 |
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Acknowledgements | Cardiologists Inger Sihm, MD, PhD, and Niels Henrik Vinther Krarup, MD, PhD deserve our thankfulness for their active participation and patient referral. We are grateful for the skilled assistance of technician Lene Schlamovitz and for her persistent helpfulness during this study. | PMC10844074 |
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Author contributions | MBT designed the study, collected, and analyzed data, and wrote the manuscript. JN, KLC, MR, and NHB all helped design the study, collect, and analyze data, and providing feedback on the manuscript. | PMC10844074 |
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Funding | Aarhus University and the Central Denmark Research Foundation. Open access funding provided by Aarhus University Hospital. | PMC10844074 |
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Data availability | The raw data that support the findings of this study are currently safely stored at our research facility. It contains patient specific data and is therefore not publicly available. This is in agreement with the General Data Protection Regulation of the European Union. Data can be made available upon reasonable request. | PMC10844074 |
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Competing interests | The authors declare no competing interests. | PMC10844074 |
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Ethical approval | The Committees on Health Research Ethics and to the Danish Data Protection Agency were notified of the study and both parties approved its conduction. All participants gave informed written consent before entering the study. | PMC10844074 |
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