Several studies on the nutritional status of chronic kidney disease patients living on haemodialysis revealed high prevalence of malnutrition (18–94%). A hospital-based study in Nepal revealed 66.7% mild to moderately malnourished and National Kidney Center reported common protein-energy malnutrition problem among haemodialysis patients. As almost all patients undergoing maintenance haemodialysis looked malnourished, this study was carried out to explore prevailing dietary knowledge and practice of the patients.A descriptive cross-sectional survey of 471 patients undergoing haemodialysis from June 2015 to July in 2015 was carried out. After stratification through a systematic random sampling method, 40 (67%) patients from National Kidney Center and 20 (33%) from Bir Hospital were selected, interviewed face to face by using structured questionnaire. Ethical and institutional approval and patients' consent were obtained.The level of knowledge score found to be medium and practice score was even low. Seventy percent knew about renal diet but only 36 (60%) believed in it. After having kidney disease 42 (70%) had changed their dietary practice. Surprisingly, 38 (63.3%) said they ate the food what the other member in their family ate.Considerable limited knowledge (medium) and practices (low) scores were found. Had they have taken adequate dietician's support, they might have taken right kind and right amounts of foods and benefitted in controlling potassium, phosphate and protein at the recommended level. Plant-based diet could assist in end stage renal disease in a number of ways: an edge of protection against diet cost, reduce inter-related co-morbidities or complications (hypertension and diabetes). Ethical approval was obtained from concerned Research Committee of National Kidney Center of Health Care Foundation-Nepal and National Academy of Medical Sciences (NAMS)- Bir Hospital authority.18During the study- a total of 60 patients at Bir Hospital and 411 patients at National Kidney Center were undergoing haemodialysis treatment. With a margin of error of 0.10, a confidence level of 90% and a population proportion of 0.5 -we calculated a sample size of 60. The systematic sampling method was adopted after stratification , in which individual patient was selected for interview and then the subsequent patient was chosen applying a systematic interval until the desired sample size was reached.Where z: Value of z at confidence interval of 90%, z = 1.645p = 50% prevalenceq = 1-pe = margin of error- 10%Since it was a new study in the context of Nepal- the questionnaires were generated by reviewing similar studies conducted in other countries and also reviewing various relevant articles on ESRD and diet. Then the content experts in the field of nutrition science reviewed the questions and objectives before using it. The study was undertaken after doing a pilot test of questionnaires in 20 patients undergoing haemodialysis treatment at National Kidney Center. The reliability test of the tool was done, where Cronbach Alpha Coefficient was (r = 0.75). It showed that repeatability was good indicating that these tools would produce stable and consistent results on knowledge on ESRD- renal diet-attitude towards it and dietary practice. Face validity appeared to measure what it intended to measure.Subsequently- the purpose of the research was explained to each participant individually prior to the interview. All were assured of privacy and confidentiality. Those who could read and write gave written consent and verbal consent was obtained from those who could not read and write.Since high-quality cross-sectional studies are susceptible to bias- we considered controlling selection bias by considering eligibility . Then- applied simple random sampling after stratification so that every patient, at both the strata - had an equal chance of being included. In order to control information bias- we did not take minor (<108 years)-those unwilling to participate in this study- did not speak and understand the Nepali language- who were getting psychiatric treatment additionally and known case of depression in medical record file.At first, obtained data was entered in to the Microsoft Excel 2007 and analysed by using Statistical Package for the Social Sciences- version 18.0. An association between knowledge and practice with their selected demographic variables are presented in frequency distribution and percentages.The demographic characteristics of ESRD patients undergoing haemodialysis treatment at National Kidney Center and Bir Hospital studied were age- sex- ethnicity-education level and marital status- where 34 (56.7%) revealed aged 50 years and above- 40 (66.67%) were male and only 20 (33.33%) were female.About 45 (75%) of the respondents said they knew about renal diet. Among the respondents- 24 (40%) said they did not believe in renal diet. About 41 (69.3%) said meat was not good for the ESRD patient and 44 (73.3%) said “red meat is harmful for ESRD” case. Forty-seven (78.3%) said drinking excess milk was not good for chronic kidney disease. Among the respondents, only 30 (50%) of them said that they knew which particular fruits could be consumed daily. Similarly, about 28 (47.7%) said they did not know spinach was harmful for ESRD patients living on haemodialysis. More than a quarter of subjects 16 (26.7%) did not know the need of salt intake reduction. Only 31 (51.7%) of them knew that they could enjoy food during haemodialysis. Thirty-six (60%) of the ESRD patients knew and visited the dietician for a dietary counselling .This study resulted that 36 (60%) of the patients had no knowledge about the potassium containing food items and 47 (78.3%) did not have idea about controlling the level of potassium in blood . SimilarAmong the respondents, 42 (70%) said they changed dietary practice after having kidney disease . NotablyIt is evident that about 11 (68%) respondents considered that the meat was not good for kidney disease, whereas 12 (20%) told they consumed meat every day, 23 (38.3%) said they knew about the source of potassium food item, but 34 (56.7%) consumed potatoes and yam in excess amount. Only 13 (21.7%) knew about controlling the potassium level in blood and 42 (70%) of them did not apply potassium leaching process in their daily life . Forty-fThe government of Nepal has nutritional program running under the umbrella of Ministry of Health and Population. But disease-specific guidelines for non-communicable diseases like diabetes, hypertension and CKD are not available as yet. Balancing the nutritional status among CKD patients is very vital to those undergoing haemodialysis treatment. Generally, as haemodialysis patients have reduced appetite, their attending physician or nephrologists are the first point to get nutritional advice.19 Generally, in early stage of chronic kidney disease, there may not be any signs or symptoms. As chronic kidney disease progresses to end-stage renal disease, signs and symptoms might appear.20 Then, the one and only immediate solution is to put the patients on dialysis.When kidneys can't do their function themselves, human body can't remove extra fluids and waste products from bloodstream, restore electrolyte levels, and help in controlling blood pressure. Dialysis does some of the work of the kidneys by filtering harmful wastes, salts and fluid from the blood.20The chronic diseases - heart disease, diabetes, some kinds of cancer, dental disease, and adult bone loss, all have a connection to poor diet. These diseases cannot be prevented by a good diet alone; they are to some extent determined by a person's genetic constitution, activities, and lifestyle. Within the range set by individual's genetic inheritance, however, the likelihood of developing these diseases is strongly influenced by persons' daily choices.21 this study aimed at determining the dietary knowledge and practice among those patients living on haemodialysis treatment at National Kidney Center and National Academy of Medical Sciences- Bir Hospital - Kathmandu- Nepal.The ESRD patients' energy requirement vary greatly, depending on the underlying cause of the renal failure and any other comorbidity. As nutritional status is an important predictor of outcome in ESRD patients living on maintenance HD-Though the nutritional status of individuals depends on multi-factors e.g. food accessibility- affordability-nutrition knowledge- the nutritional education-adherence of education and practice can make a huge difference.22 A study done on at Nepal Medical College and Teaching Hospital-Kathmandu revealed that 57% were male. Ghimire M et al. studied 50 ESRD patients- in which they found the age ranging from 18–79 years and males 64%.23 The majority of the respondents were male (66.67%) in our study- which indicates that male are still ahead of female in seeking treatment. Both the male and female patients can live on maintenance haemodialysis and contribute immensely in the nation-building activities given that they are well and balanced-nourished.In this study about 43% respondents aged 18 to 50 years were living on HD-which is a highly productive age group. Aged 50 and above revealed 57% with the ESRD. But in an earlier study conducted in Nepal reported that aged 41–60 constituted 45.8%- where the majority respondents were male (64.6%).24 This trend seem to be quite relevant to our study- where higher age group male are found compared to women. According to Centers for Disease Control and Prevention- the risk of CKD also increases with an increasing age and men with CKD are 50% more likely than women to have kidney failure.25Another largest retrospective cohort conducted in Nepal (1991–2000) found that the mean age of patients were 46.7±16.7 years with age ranging from 8 to 89 years. Of which- 905 (65%) patients were male. Similar to other studies in India -Saudi Arabia  and Japan .26 Ghimirey A et al. found that stage V CKD (ESRD) patients having co-morbid conditions of hypertension in 79.6% and diabetes mellitus in 15.6% and in 4.7% both hypertension with diabetes mellitus. But none of the patients were on medications for the management of their disease states.27The patients said they knew and also felt about the pre-symptoms before their ESRD was diagnosed. About 46% said that swelling was seen on legs-eyelids, face flowed by nausea, vomiting 13.3%, loss of appetite- headache and Insomnia 10%- back pain 3.3% and weight loss 1.7%. In fact- a person can lose a lot of kidney function before symptoms of kidney disease occur.32 The scenario of our context might not be exception to it. In addition to the above- it could be due to lack of awareness of patients on renal diet and the involvement of the clinical dietician in managing ESRD care. Since this study was the cross-sectional pattern- it does not allow for the establishment of cause and effect relationships. Therefore- future studies aiming at exploring casual relation would be of helpful.It is reported that diet-related decisions are influenced by multiple factors, including taste, financial constraints, individual preferences- social status- education level-societal norms- health- and relationships- trust in food sources- and convenience. Dietary preferences and behaviours are highly individual.33In this study- majority of patients 91.7% said that less water intake would help in managing kidney disease. Patients should limit fluid 1 to 1.5 litres a day and water intake to avoid fluid overload in the body. Personalized fluid consumption goals and education can improve the patient compliance with dietary restrictions.26Although studies are small- several support the idea that plant-based diets can delay the progression of CKD- provide endothelial protection- control high blood pressure- and decrease proteinuria. These days-our dialysis patients seldom die secondary to high potassium or uremia.34Researchers recommended to promote plant-based diet for ESRD as well as all types CKD patients- which can provide nutrients that not only assists in ESRD but also can provide an edge of protection against diet cost-reduce inter-related co-morbidities or complications (diabetes and hypertension).35A consulting clinical dietician at Gig HarbourWashington- USA reported although the studies are small in size- several evidence support the idea that plant-based diets can delay even the progression of CKD- provide endothelial protection- control high blood pressure- and decrease proteinuria. These days- dialysis patients seldom die secondary to high potassium or uremia.36 It is still a “Thorny” issue since the influence of most dietary interventions has been examined in small studies in patients with CKD. A careful renal diet management could be considered until a plant-based diet will be examined through large randomized controlled trials in patients with CKD.Michael Greger reported that the researcher at Harvard University followed thousands of women- their diet and their kidney for more than a decade that concluded animal protein was the culprit in declining kidney function. Studies reported that kidney appeared to handle plant protein very differently from animal protein and plant protein was found to help preserve function in ailing kidneys. Animal protein tends to have a higher level of sulfur-containing amino (methionine)- which produces sulfuric acid when metabolized in the body. Worst offenders: fish (including tuna), pork, poultry, cheese. An equivalent amount of plant protein causes no noticeable stress on kidneys. In contrary- fruit and vegetables are generally base forming- which helps neutralise acids in our kidneys and eating normal whole foods can return dopamine sensitivity to normal levels.An effective strategy to enhance the dietary management is inevitable by adhering to dietary restriction but through a proper diet therapy without causing malnutrition means assuring the daily calorie-vitamin- minerals and protein in-take- adequate energy.Thus- it is vitally important for the ESRD patients to know about the importance of dietician's role since they could benefit tremendously by visiting dietician for a proper dietary counselling and nutritional management.


Children with diabetic ketoacidosis often have elevated lactate. In this study, we investigated the clinical variables associated with hyperlactatemia in children with diabetic ketoacidosis.We designed a single-center retrospective descriptive study of children with diabetic ketoacidosis in a pediatric intensive care unit.p = 0.003),diastolic blood pressure (p = 0.001) and stage of severity (p = 0.042) were independently associated with the development of hyperlactatemia in diabetic ketoacidosis. We found that lactate level was not significantly associated with length of hospital stay (p = 0.115) or the length of time to diabetic ketoacidosis resolution (p = 0.143).Of the 107 patients with diabetic ketoacidosis included in the analysis, 61 developed hyperlactatemia. Multivariate logistic regression analysis showed that heart rate (Children with diabetic ketoacidosis presenting with severer stage, elevated heart rate and higher diastolic blood pressure may be prone to hyperlactatemia. Hyperlactatemia was not associated with length of time to DKA resolution and length of hospital stay. Diabetic ketoacidosis (DKA) is an acute complication of diabetes mellitus typically characterized by hyperglycemia, ketonemia, and acidemia . DKA typLactic acidosis is a common complication in children with DKA in the emergency department . LactateWe performed a retrospective study of patients with DKA who were admitted to the pediatric ICU in the First Hospital of Jilin University. Our department with more than 20 beds is the earliest and largest pediatric ICU in Jilin Province China and nearly 1000 patients are admitted every year. Almost all the emergency patients with DKA were admitted to our department. The protocol for the study project has been approved by the ethics committee of The First Hospital of Jilin University (2020 − 396) conforms to the provisions of the Declaration of Helsinki. The requirement for informed consent was abandoned in accordance with the rules of the ethics committee.Patients were identified by electronic queries from the pediatric ICU medical records. Children with DKA admitted to pediatric ICU of the First Hospital of Jilin University between January 2017 and June 2020 were collected for analysis. The exclusion criteria were death or discharge within 24 h. Two trained researchers extracted the data from complete medical records. Age, sex, family history, clinical history, length of hospital stay, the length of time to resolution of DKA, laboratory examination results, and vital signs upon admission to pediatric ICU were recorded. The laboratory examination results included pH, leukocyte count, C reactive protein, procalcitonin, creatinine, blood urea nitrogen, alanine transaminase, triglyceride, ferritin, blood glucose, C peptide, glycosylated hemoglobin, and lactic dehydrogenase. All the blood samples were collected within 24 h after admission. The diagnosis of hyperlactatemia was based on the highest lactate level before the correction of ketoacidosis during hospitalization. All the patients with DKA received intravenous fluids and insulin to correct dehydration, electrolyte imbalances,reduce glucose levels and suppress ketogenesis after admission. After ketoacidosis was corrected, patients were transferred to pediatric endocrinology department for better monitoring blood glucose and adjusting insulin dose. Resolution of DKA was defined as pH > 7.3, bicarbonate > 18 mmol/L and urine ketones (1 + or 0).Data were recorded in a standardized electronic data collection table. Patients were excluded if they had DKA combined with other genetic metabolic diseases which are prone to develop hyperlactatemia, such as methylmalonic acidemia. Hyperlactatemia was defined as lactate levels > 2 mmol/L, which is consistent with a previous study . All elip < 0.05.The data were described according to their distribution and type. Normally distributed data were represented as mean (SD), non-normally distributed data as median , and categorical data as proportions. Chi-square tests were used to compare categorical variables between the hyperlactatemia and non-hyperlactatemia low lactate level groups. Group comparisons for normally distributed variables were performed using a t-test, and the rank sum test was used for non-normally distributed variables. Multivariate logistic regression performed for independent variables were shown to be significant through univariate analysis. Spearman correlation coefficients were used to evaluate the univariate relationship between non-normally distributed continuous variables. Data analysis was performed using SPSS software version 23, with the level of significance set at p = 0.016). The severity of the two groups was different (p = 0.044). They also had higher leukocyte counts, procalcitonin, blood glucose, creatinine, and blood urea nitrogen than that of the non-hyperlactatemia group (Table p = 0.003),diastolic blood pressure (p = 0.001) and stage of severity (p = 0.042)were independently associated with the development of hyperlactatemia in DKA . The r value between length of stay and lactate levels indicated a very low correlation of r = 0.154 with an insignificant p-value of 0.115 . Our results showed a very low correlation of r = 0.143 between length of time to DKA resolution and lactate levels, with an insignificant p-value of 0.143 days in the non-hyperlactatemia group and 108, 12.75) days in the hyperlactatemia group (1days in .75 days This study was a large single-center retrospective study of hyperlactatemia in patients with DKA. We assessed the incidence, characteristics, and clinical outcomes of patients with hyperlactatemia induced by DKA and identified independent risk factors for the development of hyperlactatemia.The clinical manifestations of DKA include dehydration, Kussmaul respiration, nausea, vomiting, abdominal pain, loss of consciousness, leukocytosis, and increased serum amylase .A study The mechanism by which patients with DKA develop hyperlactatemia has not been clearly described yet. There were more patients with new-onset diabetes mellitus in our hyperlactatemia group than in the non-hyperlactatemia group. Children whose parents were unaware of the symptoms of diabetes mellitus may be more prone to DKA during their initial diagnosis of diabetes mellitus . AnotherOur results found that patients with hyperlactatemia had higher creatinine and blood urea nitrogen. The levels of creatinine and blood urea nitrogen could not meet the criteria for diagnosis of acute kidney injury. A previous study showed that acute kidney injury occurred in nearly 30 % of patients with diabetes . The renA previous study indicated that the maximal lactate level 24 h after ICU admission was strongly associated with in-hospital mortality and 90-day survival in patients . AnotherOur multivariate logistic regression analysis showed that heart rate ,diastolic blood pressure and stage of severity were independently associated with a higher risk of hyperlactatemia in DKA. DKA is often accompanied by dehydration . PatientThere are several limitations to our investigation. The data were obtained retrospectively from medical records, whose accuracy depends on appropriate diagnostic record-keeping. Of the patients included in this study, only one had died. This low incidence of mortality limits the power to detect the difference in the outcome of variables between the two groups in our study. Additionally, this study was only representative of single-center pediatric ICU and the sample size was relatively small. In the future, it is necessary to further study the prevalence, pathogenesis, and clinical significance of hyperlactatemia in DKA patients.Hyperlactatemia is common in patients with DKA. Overall, our results suggest that diastolic blood pressure, heart rate might and stage of severity may be predictors for hyperlactatemia in DKA. We further found that hyperlactatemia was not a prognostic marker of DKA and hyperlactatemia was not associated with length of time to DKA resolution and length of hospital stay.


It has been suggested that there is a significant progress in coronary artery disease (CAD) by many pathophysiological mechanisms. Nondipper hypertension (NDH) has been shown to have higher target organ damage and have a higher rate of cardiovascular mortality and morbidity. In this study, we investigated the effect of nondipper hypertension on the progression of coronary atherosclerosis.A total of 186 patients who underwent coronary angiography twice between 6 months and 3 years were included in the study. Coronary angiography was repeated on the admission day due to angina or positive exercise test and the patients were divided into groups.Progression of coronary artery disease was detected in 58 of 186 patients. Seventy-one of the total patients were found to be nondipper hypertensive. Nondipper hypertension, hypertension, diabetes mellitus, low-density lipoprotein, and total cholesterol were found to be effective in the progression of CAD. Among these parameters, it was seen that nondipper hypertension and hyperlipidemia were the most important independent risk factors. Coronary artery disease is a progressive disease, and this progression depends on many reasons. In our study, we showed that nondipper hypertension is a new parameter that is effective in CAD progression. Although coronary artery disease (CAD) occurs in the early first stages of life, the onset and severity of the atherosclerotic process cannot be predicted. It is not known whether this process is associated to morphological progress [1]. The progression of atherosclerosis occurs by two mechanisms. The first is localized inflammation and thrombosis-related plaque rupture, with the artery filling partially or completely, and the other is progressive lipid accumulation that causes stenosis in the coronary artery . Progress due to gradual lipid accumulation is characterized by the fact that the existing stenosis becomes more severe . Both types may occur at different rates in the same or different coronary arteries of any individual. Although there are many causes of CAD progressions, some causes and results are still not fully explained.Cardiovascular parameters such as blood pressure, heart rate, coronary tone change with circadian rhythm throughout the day [3]. This circadian rhythm in blood pressure led to the creation of a new classification. In this classification made with ambulatory blood pressure monitoring, 10% or more decrease in blood pressure value measured at night compared to daytime value is defined as dipper hypertension, and less than 10% decrease as nondipper hypertension [4]. Patients with nondipper hypertension have been shown to have higher target organ damage and have a higher rate of cardiovascular mortality and morbidity . Blood pressure variability (BPV) has been associated with measures of arterial stiffness and endothelial dysfunction, but whether BPV is directly associated with coronary atheroma progression-regression remains less well explored. However, its effect on coronary artery disease progression is unknown.Lifestyle factors and the presence of existing diseases have been associated with the incidence of CAD. The importance of these factors in the progression of angiographic CAD has not been well studied. Our study aims to compare serial coronary angiograms of patients and to associate nondipper hypertension with CAD progression.Patients who underwent angiography twice due to angina or positive exercise test between April 2020 and October 2020 were included in the study. Local ethics committee approval was obtained for the study (2020/219). For the patients included in the study to be included in the study, the condition that the second angiography should be at least 6 months and a maximum of 3 years from the first angiography was sought. A new lesion in the second coronary angiography or 20% increase or ≥0.4 mm in MLD at the follow-up angiogram on QCA was accepted as possible coronary artery disease progression [7]. The groups were divided into two according to whether there was progression or not. Patients under 18 and over 75 years of age, those with kidney failure , liver failure , a history of malignancy, and those who underwent coronary artery bypass surgery during these two coronary angiographies were not included in the study. Hypertension was defined as repeated arterial blood pressure measurements exceeding 140/90 mm Hg or treatment with antihypertensive medications for a known diagnosis of hypertension. Diabetes mellitus was diagnosed by fasting blood glucose ≥ 126 mg/dL, blood glucose > 200 mg/dL at any time, or a history of diabetes mellitus, including those treated with diet, oral medications, or insulin. Hyperlipidemia was defined as a baseline cholesterol level > 200 mg/dL and/or a low-density lipoprotein cholesterol level > 130 mg/dL or previously diagnosed and treated hyperlipidemia. While patients with chronic coronary syndrome who did not develop stent restenosis were included in the study, patients with stent thrombosis or restenosis were not included in the study [8]. Patients who had previously undergone angiography (6 months to 3 years) and who needed angiography according to the evaluation of the positive effort test or ischemia detected in myocardial perfusion scintigraphy were taken to angiography procedure for the second time were included in the study.Blood pressure measurements in the clinic were performed using a sphygmomanometer according to the European Society of Hypertension. Ambulatory blood pressure measurement (ABPM) was performed using the Microlife WatchBP device in the 24 h after the patient was included based on inclusion criteria using a cuff proper for the patient’s arm diameter. BP measurements were performed every 30 min during the daytime (between 07:00 and 22:00) and every 60 min during the night (22:00–07:00). Night, daytime, and 24-h BP measurements obtained from the measurements made for 24 h were analyzed. The percentage of drop in BP at night was calculated using “Night BP decrease (%) = (Daytime BP – Night KB) × 100 / Night BP” formula. If the mean BP measured during the night is less than 10% lower than the mean daytime measurement, these individuals were considered to be “nondipper”, and if the difference is 10% or more, to be “dipper”. According to these reduction rates, patients were grouped as divided as nondipper and dipper hypertension.Selective coronary angiography was performed on all patients using the standard Judkins technique from the femoral or radial approach, according to the operator’s request. Nitrate was given to all patients to minimize their effects on coronary vasoconstriction and coronary lumen diameter. Sublingual glyceryl trinitrate (0.5 mg) or isosorbide dinitrate (5 mg) was given to patients presenting with stable angina (2–10 min before contrast injection). Coronary angiography analyses were performed by specialist cardiologists. Patients were followed angiographically in all epicardial coronary arteries (including subbranches) one individually. The first angiographies and last angiographies of the patients were recorded individually and quantitatively assessed with the use of Coronary Angiography Analysis System (CAAS).Each patient’s coronary arteriogram pair was evaluated by two experienced cardiologists who did not know the patient information and the timing of coronary angiography. Coronary artery segments were selected according to defined localizations. For each segment, measurements were made in the end-diastolic frames. Coronary strictures were measured where their severity appeared maximum. Coronary diameters were measured using the CAAS  developed by Reiber and validated by different authors [9–11]. The body of the Judkins coronary catheter was used for calibration to determine absolute measurements in millimeters. Since the CAAS is less reliable for coronary arteries smaller than 1 mm in diameter, the stenosis assessment of these vessels was performed visually. Since the measurements of the images showing the most severe stenosis were considered to be sufficient, orthogonal images were not measured and averaged. For this evaluation, Toshiba Infx brand angiography device was used. In this evaluation, 20% shot of the old lesion in two cardiologist measurements was accepted as progression.At the time of admittance, tripotassium-ethylenediaminetetraacetic acid (EDTA)-based complete blood count, and from the blood samples taken into Isotherm-Gel Clot Activator-based biochemistry tubes, biochemistry parameters , sedimentation, and complete blood count were studied for all patients. To assess the inflammatory status of the participants, the C-reactive protein (CRP) level was measured using a BN2 nephelometer . Utests and the independent samples t-test were applied for continuous variables. Nonnormally distributed variables were expressed as median (range) and normally distributed variables were as mean ± standard deviation (SD), as appropriate. A p-value of <0.05 was considered to be statistically significant. Moreover, we used logistic regression analyses to observe the association between coronary progressions and the impact of the primary variable and of other variables that probably acted as confounders . All factors with a significance of p < 0.05 were entered a stepwise multivariate logistic regression analysis.Statistical analyses were performed using SPSS Statistical Package version 22.0 for Windows . Histogram, q-q values were examined. The Kolmogorov–Smirnov test was performed to assess data normality. The Levene test was used to assess variance homogeneity. Differences between groups with and without CAD were compared. Pearson’s χ2 analysis was applied for categorical variables. The Mann–WhitneyA total of 186 patients who met the study criteria were included in the study. Coronary artery disease progression was detected in 58 (31.2%) of 186 patients. Seventy-one of the total patients were found to be nondipper hypertensive. Although the majority of the study population (74.7%) was male, no significant difference was found between the two groups according to sex. In the study, the average age was found to be 63 ± 7 and there was no significant difference between the two groups (p = 0.057). There was no significant difference between patients with coronary noreflow and normal coronary flow groups in terms of hemodynamic parameters, heart rate, systolic, and diastolic blood pressure.In the history evaluation of the patients, a significant difference was found between the two groups in hypertension, diabetes mellitus, and hyperlipidemia, which are effective in the progression of CAD . There was no statistical difference between the two groups in terms of smoking and body mass index (Table 1). The main focus of this study is nondipper hypertension that is an independent risk factor in coronary artery progression regardless of the existing hypertension (Table 1). Nondipper hypertension was detected in 58.1% of patients with coronary progression and 28.9% of patients without progression (p < 0.001) . Another important finding of the study in terms of nondipper hypertension is the progression development independent of the nocturnal blood pressure reduction rate. Coronary progression developed in 18 patients with a 0% reduction in blood pressure at night, 23 patients with a drop between 0%–5%, and 17 patients with a decrease of 5%–10%. There was no statistically significant difference .When the laboratory analyses were evaluated, some parameters in terms of biochemical parameters revealed that there was no significant difference between the groupssuch as creatinine, total protein, sodium, potassium, high-density lipoprotein (HDL-C), triglyceride levels, and glomerular filtration rate levels (p > 0.05) (Table 1). However, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and CRP values were found to be significantly higher in the coronary artery progression group than in the nonprogressions group (Table 1). When the hematological parameters were examined between the two groups, no significant difference was found between the hemoglobin, platelet, and lymphocyte counts (p > 0.05).It was determined that there was no statistically significant difference in all the above parameters examined between nondipper hypertensive patients and the dipper group except for hypertension, and hypertension was found to be statistically significant between the two groups (p: 0.020) (Table 2). In our study, we determined that several parameters are effective in CAD progression in addition to nondipper hypertension. Since the variables were found to affect the CAD progression between the groups, the effects of multiple variables on CAD progression were analyzed by univariate and multivariate logistic regression analyses. At univariate analysis, hyperlipidemia (odds ratio (OR) 4.620, 95% confidence interval (CI) 2.441–8.855; p = 0.001), hypertension , diabetes mellitus , CRP , low density lipoprotein , and nondipper hypertensions  were independent risk factors of progression in patients with CAD progressions (Table 3). Multivariate analysis showed that hyperlipidemia , diabetes mellitus , low density lipoprotein , CRP , and nondipper hypertensions  were effective and that the age had some effect if not statistically significant. Based on these results, the two most effective parameters in the progression of CAD were hyperlipidemia and nondipper hypertension in the history. This is the first study conducted with nondipper hypertension in the development of CAD progression. In this study, it has been shown that nondipper hypertension is an independent risk factor for the progression of coronary artery disease. Moreover, it is effective in hyperlipidemia, diabetes mellitus, and LDL on the progression of CAD.Atherosclerosis is a process characterized by intimal thickening in the arterial vasculature, accompanied by inflammatory cell infiltration, smooth muscle cell proliferation, excessive accumulation of oxidized low-density lipoproteins, and plaque development [12]. These parameters are known to play an important role in the formation and growth of atherosclerotic plaque, including high cholesterol, diabetes, and high blood pressure [13]. In coronary artery disease progression, smoking affects factors other than hypertension and diabetes. In the study conducted by Sahin et al., it was shown that the copper level was high in the blood in the group with CAD progression, and the chromium level was low compared to the group without progression [14].The relationship of high pressure change with the measurements of arterial stiffness and endothelial dysfunction suggests a contribution to vascular function changes . In addition, hypertension was shown as a risk factor in the development of coronary calcium progression [17]. In these studies, the effectiveness of variable high pressure on endothelial dysfunction was mentioned and it was said that it would lead to pathophysiology. In nondipper hypertension, it can be thought to act with this mechanism, as there is variable high pressure. In addition, while analyzing the relationship between antihypertensive therapy and cardiovascular risk, they also examined whether blood pressure was effectively reduced by antihypertensive therapy [17]. It was found that the risk of stroke and coronary events increased in participants with blood pressure falling to normal levels compared to participants who achieved normal blood pressure levels without treatment, but the rapid CAD progression was not accelerated. Of course, in this study, arterial blood pressure was investigated, not nondipper hypertension. In other words, arterial hypertension was shown to be a persistent risk in this study [18]. In our study, similar to this study, the presence of nondipper phenomena in patients with or without arterial hypertension increases coronary progression. Vascular endothelial damage is one of the first and most important steps in the coronary progression process. After endothelial damage, lipid accumulation starts to increase in the same area, and tissue proliferation increases. Endothelial growth factors are released by the cells that accumulate in this region and cause the proliferation of smooth muscle cells [19]. In our study, we believe that this is due to occasional attacks of hypertension and does not indicate the expected decrease. A strong link between atherogenic risk factors and endothelial dysfunction has been identified. By down-regulation of endothelial nitric oxide synthase (NOS) expression, oxidized LDL-C reduces receptor-mediated NO release, increases superoxide anion production, and NO inactivation causes a strong impairment of endothelial function. Disruption of NO production or activity predisposes individuals to many diseases targeting the cardiovascular system such as CAD, HT, heart failure, kidney failure, diabetes mellitus, metabolic syndrome, and obesity, and accelerates atherosclerosis [20]. Particularly in hypertensive patients, impairment of nitric oxide bioavailability causes impairment of endothelium-mediated vasodilatation, and this may be an indicator of atherosclerosis and progression in atherosclerosis [21]. “Nondipper” blood pressure is seen in approximately 25% of the hypertensive cases, and when subgroups such as diabetics are included, the prevalence increases even more [22]. It is known that there is a direct proportion between blood pressure level, and the grade of endothelial dysfunction, vascular damage, and end-organ damage [5]. Individuals with nondipper blood pressure have been found to have more frequent end-organ damage , and cardiovascular morbidity and mortality . Nondipper hypertension, as in our study, plays an important role in atherosclerosis because it is a branch of hypertension [5]. In their studies comparing nondipper and dipper patient groups for endothelial dysfunction, Higashi et al. evaluated the 24-h urinary excretion of nitric oxide end-product nitrite/nitrate and cyclic guanosine monophosphate as an indicator of endothelial dysfunction, and as a result, 24-h urinary nitrite/nitrate and cyclic guanosine monophosphate levels were found to be significantly lower in the nondipper patient group [23]. This data strengthens our hypothesis and should be regarded as evidence that nondipper hypertension causes endothelial dysfunction. We think that exposure of the endothelium to higher pressure for a longer period due to insufficient blood pressure drop at night may increase the progression of CAD more by causing more endothelial damage and vascular inflammation in the nondipper group.In the studies performed by Smith et al. and Wild et al., the patients who underwent percutaneous coronary intervention had approximately 25%–30% DM . In our study, this rate was similar to other studies, and 26.8% of patients with a history of percutaneous coronary intervention had DM. Those with diabetes mellitus have a higher rate of thrombotic events than those who do not and require a more frequent reintervention procedure [26]. In our study, there was a statistically significant difference in CAD progression compared to those without diabetes mellitus. It is important that we were unable to access data on medical treatments received before and after discharge from patients without diabetes mellitus and from those with diabetes mellitus. In addition, the duration of diabetes mellitus and whether they were under glycemic control could not be evaluated. As a result, these factors may be considered to increase or decrease CAD progression.Coronary artery disease is a progressive disease and this progression depends on many reasons. In our study, we showed that it has an effect on nondipper hypertension as a new parameter that affects this progression. Our results show that treatment of nondipper hypertension may reduce the additional contribution to progress.The most important limitation of study is the number of patients and being a single-center study. In addition, the use of intracoronary ultrasound, which gives better results in CAD progression, will be more qualitative.


Adrenocorticotropic hormone (ACTH) is widely used in adrenal vein sampling (AVS) and can be administered as a bolus injection or continuous infusion. The optimal administration method has not been determined. We aimed to compare the effects of ACTH bolus with infusion on cannulation success, lateralization assessment and adverse events (AEs).Retrospectively collected data from patients with primary aldosteronism who underwent AVS with ACTH at a tertiary hospital in China. Rate of successful cannulation, lateralization index (LI), complete biochemical remission and AEs related to AVS were analyzed.The study included 80 patients receiving ACTH bolus and 94 receiving infusions. The rate of successful cannulation was comparable between bolus and infusion groups . In those with successful cannulation, the bolus group had a higher selectivity index than the infusion group, while LI  and rate of complete biochemical remission  did not significantly differ between the two groups. One in the bolus and one patient in the infusion group had adrenal vein rupture but they recovered with conservative treatment. The bolus group reported more transient AEs such as palpitation (52.9% vs 2.2%) and abdominal discomfort (40.0% vs 2.2%) than the infusion group.Due to their similar effects on cannulation success and lateralization, but a lower rate of transient AEs in the infusion group, the continuous infusion method should be recommended for ACTH stimulation in AVS. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension . DiagnosTo introduce an additional variation in the AVS protocol, the method of ACTH administration varies in different centers, including bolus injection, continuous infusion and bolus plus continuous infusion . Some reThis study therefore aims to compare the effect of bolus ACTH injection and continuous infusion on the rates of cannulation success, assessment of lateralization together with post-operative cure, as well as AEs associated with AVS.This study was retrospectively conducted at the First Affiliated Hospital of Chongqing Medical University in China using the database of the Chongqing Primary Aldosteronism Study (CONPASS) . The inclusion criteria were: 1) hypertensive patients underwent the screening and confirmatory test of PA and confirmed with PA diagnosis by at least one positive confirmatory test (described as follows); 2) completed AVS with ACTH stimulation. PA patients had missing data of AVS or complicated with autonomous cortisol secretion based on abnormal dexamethasone suppression tests were excluded from the analysis. When analyze the effects of different methods of ACTH administration on lateralization and surgical outcomes, those with unsuccessful cannulation (right and/or left selectivity index<3) were excluded. When analyze the blood pressure, heart rate and AEs during ACTH administration, the patients had missing data were excluded.The ethics committee of the First Affiliated Hospital of Chongqing Medical University approved the protocol. Informed written consent was obtained from each participant.The methods of screening and confirmatory tests have been reported before –21. For Patients who tested positive proceeded to the confirmatory tests. For patients who tested negative, if PA was strongly suspected based on young age, hypokalemia, or resistant hypertension, they also proceeded to the confirmatory test. The diagnosis of PA was confirmed if at least one confirmatory test was positive: plasma aldosterone concentration (PAC) is not suppressed to less than 8 ng/dl 220 pmol/l) in the saline infusion test or PAC is not suppressed to less than 11 ng/dl (300 pmol/L) in the captopril challenge test or PAC is not suppressed to less than 6 ng/dl (166 pmol/L) in the fludrocortisone suppression test 20 pmol/l. PatientAVS was performed in the morning between 08:00 and 12:00 with ACTH stimulation , 18. DurFrom November 2016 to September 2019, ACTH was administered as a bolus injection. With local anesthesia, a 5F sheath was inserted into the right femoral vein followed by catheter insertion in the right and left adrenal veins. At this time, 25IU ACTH  was injected, and 15 minutes later, blood samples were collected simultaneously from bilateral adrenal veins. Three tubes of blood in each adrenal vein were collected consecutively, and one tube of blood in the inferior vena cava (IVC) was collected immediately after the collection of each side of the adrenal vein blood. The adrenal vein blood samples with the highest level of cortisol were usually used for index calculation. As the AEs were often reported by patients following bolus injections of ACTH, from Oct 2019, ACTH was administered as continuous infusion which was started 30 minutes before sampling and continued throughout the procedure at 5 IU/hr (50μg/hr).The selectivity index (SI), namely plasma cortisol concentration (PCC) in adrenal vein/PCC in IVC>3, was considered to be successful cannulation. The ratio of PAC : PCC on the side with the higher ratio over the contralateral PAC: PCC ratio is defined as the lateralization index (LI). The cutoff for diagnosing lateralization was defined as LI>4 or LI between 3-4 together with a contralateral suppression (PAC/PCC of nondominant side < PAC/PCC of IVC) , 18. ThePRC and PAC were measured with automated chemiluminescence immunoassays . The intra-and inter-assay coefficients of variation for PRC were from 1.2% to 3.7% and from 2.9% to 12.8%, respectively. The analytical sensitivity was 0.53 mIU/l, and the functional sensitivity was 1.6 mIU/l. The lower limit of detection was 0.5 mIU/l. The PAC assay has a measuring range from 2.2 ng/dl  to 100 ng/dl, with a functional sensitivity of 3 ng/dl. The intra-assay coefficient of variation for PAC was from 2.4% to 4.8% and the inter-assay coefficient of variation was from 4.4% to 6.7%. Quality control was performed every day in the laboratory.P-values <0.05 (two-tailed) were considered statistically significant.Data distributions were analyzed with the Kolmogorov-Smirnov test. Normally distributed variables were expressed as the mean ± standard deviation (SD); variables with skewed distributions were expressed as the median (interquartile range); categorical variables were described as a percentage. Variables with skewed distributions were analyzed after natural logarithm transformation. Categorical variables were analyzed by the χ2 test, and quantitative variables were analyzed by Student’s t-test. Comparisons at different time points were made using repeated measures of analysis of variance. SPSS 21 was used for statistical analysis. From Nov 2016 to Jan 2021, a total of 85 patients with PA received an ACTH bolus and 99 received an ACTH infusion. One patient with missing data of AVS and nine PA patients complicated with autonomous cortisol secretion  were excluded from the study. Details of the ten patients were provided in the Using SI>3 in both adrenal veins as the criteria for bilateral successful cannulation, five and six patients had unsuccessful cannulation in the bolus and infusion groups respectively, resulting in comparable successful cannulation rates . In those with successful cannulation, the bolus group had a higher SI in the right adrenal vein and tendency of higher SI in the left adrenal vein when compared with the infusion group  vs. 37.8(27.9-53.1), P<0.001; left adrenal vein SI: 26.9(16.7-42.3) vs. 22.1(15.1-35.0), P=0.075; In those with successful cannulation, PAC, PCC and PAC/PCC ratio in bilateral adrenal veins did not significantly differ between the infusion group and the bolus group Table 2.For those with successful cannulation, 44 and 53 patients in the bolus and infusion group respectively underwent laparoscopic adrenalectomy. Among them, 43 and 53 showed complete biochemical remission. The rate of complete biochemical remission was not significantly different between the bolus and infusion groups .Twenty-two patients had missing data on blood pressure and/or AEs after ACTH administration , therefore, they were excluded from the analysis concerning the vital sign and AEs.The changes in blood pressure and heart rate during ACTH administration were shown in ACTH bolus led to a significantly higher heart rate at 2 minutes when compared to ACTH infusion (85(77-93) vs 69(65-75) beats per min, P<0.001). The heart rate decreased to a level lower than the baseline at 30 min after ACTH bolus, resulting a significantly lower heart rate when compared to patients who had ACTH infusion (62(59-71) vs 68(63-74) per min, P=0.002) Table 3.One patient in the bolus and one in the infusion group had adrenal vein rupture but they recovered with conservative treatment. Palpitation (52.9%), abdominal discomfort (40.0%), chest tightness (24.3%) and hot flushes (22.9%) were common in the bolus group, while only 2% of subjects in the infusion group reported ACTH-related AEs during AVS Table 4.In patients who seek surgical cure of PA, current guidelines recommend the use of AVS for accurate subtyping , 3. ACTHThe history of ACTH use in AVS dates back to 1979, when Weinberger et al. introduced continuous infusion of ACTH (5 IU/h) in AVS to reduce errors induced by the episodic production of aldosterone as well as dilution by nonadrenal venous sources . ThereafNone of the prior studies evaluated the effect of different methods of ACTH administration on cannulation success, which is the main purpose of using ACTH. Our study reassuringly demonstrated comparable cannulation success between the bolus and infusion groups. While there was a significantly higher SI in the right adrenal vein in patients who received bolus ACTH, the SI in all groups were well above the threshold of 3 for determining successful cannulation and therefore no impact on cannulation success was observed.Previous studies have reported the effects of ACTH on blood pressure and heart rate –28. In thttps://www.fda.gov/) as well as Synacthen (http://www.tga.gov.au) mention that tachycardia and bradycardia are the most common AEs of these drugs, in accordance with our findings. The faster changes in blood pressure and heart rate induced by ACTH bolus injection than infusion most likely contribute to the higher rate of AEs reported in the bolus group. In order of frequency, palpitations, abdominal discomfort, chest tightness, dizziness, hot flushes, acroanaesthesia, dyspnea and nausea were reported in up to half of the patients who received ACTH as a bolus injection compared to less than 2% in the group who received ACTH infusion. Although the serious AEs of AVS were not different between the two methods, the transient symptoms caused by bolus would contribute to patient discomfort and are almost entirely preventable using the infusion protocol.Up till now, no reported studies have specifically compared the two methods of ACTH stimulation in terms of AEs. As ACTH is mostly used in diagnostic procedures rather than treatment, and tend to be used only for a short period of time, the AEs related to ACTH are rarely investigated in published studies. However, the drug information documents for Cosyntropin ; the Science and Technology Research Program of Chongqing Municipal Education Commission (KJZD-K202000401).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Results: 61 MV ICU adult patients  were enrolled in this study. No significant differences in HR, SBP, and DBP were observed both for two techniques measured separately and between them. Statistically significant differences were noticed analysing SpO2 in the rhythmic initiation technique (RIT) group . Conclusions: Short-term PNF interventions did not influence clinically relevant vital parameters among MV patients and seem to be feasible in this group of ICU patients.Physical therapy is part of the treatment for patients admitted to ICU. Proprioceptive neuromuscular facilitation (PNF) is one of the physiotherapy concepts including manual techniques and verbal stimulation. The purpose of this paper is to examine the feasibility of PNF techniques in mechanically ventilated (MV) ICU patients. Another aim is to verify whether the technique using resistance during the patient’s inhalation will have a different effect than the technique used to teaching the correct breathing patterns. Methods: Patients admitted to tertiary ICU were enrolled in this study, randomly divided into two groups, and received four 90-second manual breathing stimulations each. The following vital signs were assessed: HR, SBP, DBP, and SpO Physical therapy is an inherent part of medical procedures applied in intensive care units (ICU) . Several2) and thoraco–abdominal motion (TAM) in myotonic dystrophy [Proprioceptive neuromuscular facilitation (PNF) is a widely used physical therapy approach , which iystrophy , and didystrophy ,20,21. HThis study was a randomized clinical trial. Initially, 69 subjects were enrolled. The patients considered suitable for this study were randomly assigned to either rhythmic initiation technique (RIT) or initial stretch technique (IST) group. The flow chart of the study is shown in The inclusion criteria were as follows: (1) adults of both sexes, (2) conscious and cooperative, (3) mechanically ventilated in assisted ventilation mode, (4) haemodynamically stable.The exclusion criteria were as follows: (1) fever above 38.3 °C , (2) haeThe RIT and IST groups received one session by a physiotherapist specialized in PNF techniques  and the treatment consisted of four 90-second manual stimulations each . Vital signs were assessed before and after the session.The RIT was performed to teach coordination of motion and to establish the correct breathing pattern ,24. The During the treatment the ventilator operating mode (pressure support ventilation) did not change. Moreover, from the beginning of the rehabilitation until the last measurement, the patient’s body position was unchanged. After data collecting, general physiotherapy session was allowed in both groups, adjusted to the health condition of the patient.The research was carried out from 5th November 2016 until 29th October 2018 and was conducted in the Anaesthesiology and Intensive Therapy Unit of the University Clinic Centre in Gdansk, Poland. A consent NKBBN/444-179/2016 for conducting this research was given by the Independent Bioethics Committee for Scientific Research at the Medical University of Gdansk, Poland.PNF techniques included one session of physiotherapy including four 90-second manual stimulations each . After every stimulation the patient rested for one minute. Conscious and cooperative patients were instructed by the physiotherapist (PT) to follow commands.The first group was treated with the RIT derived from the PNF concept . This teAt the beginning of the session, the PT kept his/her hands on the upper part of the chest wall, just below the clavicles, supporting the patient’s exhalation phase by guiding the movement. Subsequently, a slight posterior caudal pressure was applied to the chest wall using a verbal cue “exhale”. While inhaling, the physiotherapist’s hands exerted a slight direct resistance against the expanding upper ribs, giving the patient a perception of the movement and helping to perform it. At the same time, the patient was verbally encouraged to take a deep breath. a. The seThe second group was treated with the IST, a technique also originating from the PNF concept  . This teThe IST technique involved the PT placing his hands in the same areas as for the RIT as presented in As in the case of providing the RIT, after every stimulation using the IST, the patient was resting for 1 minute without any support from the PT.2) in order to assess changes in the patients’ vital functions when applying the RIT and the IST from the PNF concept.The following vital signs were assessed: heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and percutaneous oxygen saturation  before, and 5 and 60 min after, the physiotherapy session.t-test, Wilcoxon–Mann–Whitney test). The Kruskal–Wallis, Friedman, and ANOVA tests were used to compare more than two groups of data. The appropriate post-hoc tests, in the cases of statistically significant results for the above-mentioned tests, were also performed. For qualitative variables, the frequency of the analysed categories consisted the basic statistics. The assumed significance level was α = 0.05.The results were generated using the R statistics language . Basic s2)) regardless of the technique used (RIT or IST) or the time after the technique was applied.Characteristics of the 61 patients are presented in p values were also included.The medians, minimal, and maximal values of all measured vital signs, respectively, are shown in Most of patient appreciated the treatment and could fulfil it without any disturbance. Eight of them  for patients undergoing the RIT technique were tested as shown in the p-value = 0.013 allows to state that there are statistically significant differences between these values.There were no statistically significant differences between the RIT and the IST for all analysed vital signs in all measurement times. SpO2 using the Friedman test a statistically significant difference was observed . The Friedman post hoc analysis showed a statistically significant difference in the value of SpO2 between the measurements taken 60 and 5 min after the end of the therapy . Statistically significant differences were neither found when comparing the measurements taken 60 min after physiotherapy to the measurement before therapy  nor the measurements taken 5 min after physiotherapy to the measurement before therapy .Having analysed the influence of RIT on SpO2 values at the analysed time points. The obtained p-value = 0.227 does not allow for the adoption of an alternative hypothesis stating the existence of differences between the analysed groups of SpO2 values .The collected HR values for the studied group of patients before the therapy, 5 and 60 min after the therapy performed with the RIT technique do not differ in terms of the Friedman test  test. The obtained p-value = 0.485 indicates no statistically significant differences between the SBP values due to the techniques (IST/RIT) and time (0/5/60).Subsequently, the ANOVA (Two-way) test was performed to analyse SBP values. The obtained p-value = 0.717 indicates no statistically significant difference.Also, when assessing DBP changes due to the techniques (IST/RIT) and time (0/5/60), the obtained 2 when applying both techniques are shown in The observed the differences among median values of HR, SBP, DBP, and SpO2 more efficiently than the SBE technique. The authors concluded that the initial stretch, occurring in the IST, may affect the intercostal muscles in patients with muscular dystrophy by providing sensory stimulation to the physiological afferentation of facilitated muscles.Rhythmic initiation technique (RIT) and initial stretch technique (IST) applied in conscious mechanically ventilated patients elicited no statistically significant differences in heart rate, blood pressure, and oxygen saturation. The obtained results indicate that both techniques (IST and RIT) led to similar results and did not destabilise the clinical condition of mechanically ventilated ICU patients in relation to the analysed parameters. This indicates that interventions used in the present study can be feasible and safe when manual chest and diaphragm stimulations are applied in ICU subjects. Nitz and Burke  studied 2 value either because the initial stretch at the end of the exhalation was too intense stimulation for them or the influence of received medications might have compromised the inspiratory muscle response to quick stretch applied at the end of the exhalation.We suppose that patients participating in our study did not respond to the IST by increasing SpOStable HR, SBP, and DBP during both PNF stimulations indicate that the techniques used were optimally adjusted to the patients’ condition. Aggressive stimulation could lead to tachycardia or induce pain and exhaustion. Nitz and Burke  noticed Both stimulation from the PNF concept, the IST and the RIT, improve coordination and awareness of motion ,23—regreWe had difficulties recruiting patients who met the inclusion criteria. Many patients in the Anaesthesiology and Intensive Therapy Unit of the University Clinic Centre in Gdańsk, Poland, are hospitalized for severe trauma and after major surgical operations. These excluded the application of the IST stimulation when the additional manual quick tap at the end of exhalation is applied. It is in this context important to emphasize that, according to Weigl et al. , the morIn the present study, no statistically significant differences were found in cardiovascular parameters. It is possible, if the amount of physical therapy had been more intense than one per day, we might have observed statistically significant changes with clinical importance. A survey of 146 ICU patients published by Castro et al.  showed tMajor limitations of the present study were the enrolment of 69 patients and performing the physiotherapy stimulations only once. Moreover, using arterial blood gases as well as ventilatory parameters  could help obtain more precise data on the ventilatory responses.Short-term physical therapy interventions using the stimulations derived from the PNF concept did not have a clinically relevant effect on observed vital signs. Taking this into consideration, we can conclude that both stimulations are feasible and safe as a physiotherapy tool in mechanically ventilated ICU patients. Further clinical studies are needed to estimate how physical therapy interventions using PNF techniques correlate with respiratory parameters and health conditions of ICU patients.The exerted manual mobilisation of the chest and diaphragm using the RIT and IST originating from the PNF concept could be utilized during early physical therapy of ICU subjects. Since the applied techniques normalize breathing patterns improving respiratory muscles function  they mig


Introduction: Exercise pulmonary hypertension (exPH) has been defined as total pulmonary resistance (TPR) >3 mm Hg/L/min and mean pulmonary artery pressure (mPAP) >30 mm Hg, albeit with a considerable risk of false positives in elderly patients with lower cardiac output during exercise.Methods: We retrospectively analysed patients with unclear dyspnea receiving right heart catheterisation at rest and exercise (n=244) between January 2015 and January 2020. Lung function testing, blood gas analysis, and echocardiography were performed. We elaborated a combinatorial score to advance the current definition of exPH in an elderly population (mean age 67.0 years±11.9). A stepwise regression model was calculated to non-invasively predict exPH.Results: Analysis of variables across the achieved peak power allowed the creation of a model for defining exPH, where three out of four criteria needed to be fulfilled: Peak power ≤100 Watt, pulmonary capillary wedge pressure ≥18 mm Hg, pulmonary vascular resistance >3 Wood Units, and mPAP ≥35 mm Hg. The new scoring model resulted in a lower number of exPH diagnoses than the current suggestion (63.1% vs. 78.3%). We present a combinatorial model with vital capacity (VCmax) and valvular dysfunction to predict exPH  based on our suggested criteria. The odds of the presence of exPH were 2.1 for a 1 l loss in VCmax and 3.6 for having valvular dysfunction.Conclusion: We advance a revised definition of exPH in elderly patients in order to overcome current limitations. We establish a new non-invasive approach to predict exPH by assessing VCmax and valvular dysfunction for early risk stratification in elderly patients. A low diffusion capacity of carbon monoxide (DLCO) was suggested to identify exPH patients with parenchymatous lung disease,18 This definition, however, was abandoned due to its dependence on age and exercise capacity, with a high number of false positive results.20 A French group established a new definition for exPH using a combination of mPAP>30 mm Hg and total pulmonary resistance .19 TPR represents the steepness of PAP-increase during exercise. A TPR>3 mm Hg/L/min and an mPAP>30 mm Hg during exercise may currently be the best way to define exPH.21 These cut-off values have been shown to be independently associated with cardiovascular event-free survival (hazard ratio 2.03) in a population of patients with preserved ejection fraction during a mean follow-up of 3.7 years,22 which confirms the clinical relevance of further investigating patients with unclear dyspnea and ambiguous resting right heart catheterisation (RHC). This definition can be seen as the current gold standard to define exPH. Concerns have been raised about its applicability in elderly (>60 years), multi-morbid, and frail patients with lower cardiac output and muscular limitations during exercise.23 We aimed to fill this gap by investigating elderly patients reporting to our medical unit for unclear dyspnea who received RHC at rest (rRHC) and exercise (exRHC).Until 2009 exPH was defined as an invasively measured mPAP>30 mm Hg.A criterion of exercise capacity in cardiopulmonary exercise testing (CPET) is maximal power of performance [W]. This, however, has not found its way into exPH definitions so far. Thus, we aimed to develop a new combinatorial definition of exPH taking into account hemodynamic parameters of RHC as well as maximal power of performance. Our diagnostic score should be compared to the current standard (TPR>3 mm Hg/L/min and an mPAP>30 mm Hg). We hypothesise that our new score will reduce the number of exPH diagnoses in the elderly population compared to the currently suggested definition. Finally, we analysed non-invasive parameters in terms of their potential to predict exPH based on this new model and aiming to avoid invasive RHC testing in elderly patients without missing the correct diagnosis (high sensitivity is necessary).We performed a retrospective, exploratory study screening a total of 244 patients who had reported to our clinic between January 2015 and January 2020 for diagnostics of unclear dyspnea and who had received rRHC and exRHC following inconclusive non-invasive pneumological and cardiological investigation (dyspnea out-of-proportion of the underlying disorder). The medical decision for the necessity of invasive RHC evaluation was made by an experienced cardiologist after informed consent was signed by the patient or legal guardian. Patients had to be at least 50 years of age; clinically stable medical comorbidities were no exclusion criteria for participation as we wanted to access real-life data to elaborate a definition for exPH. As exPH can occur in the presence or absence of resting PH, patients were included regardless of their resting mPAP (and thus the presence of resting PH). Patients who did not fulfil the inclusion criteria and/or were unable or unwilling to provide informed consent for RHC investigation were excluded from the study.17 As we wanted to include the parameter maximal performance as a single factor, a maximal workload of 100W or less was deemed as a relevant limitation of cardiorespiratory fitness and was awarded one point. Furthermore, we chose 100W analogous to the suggested workload to define and assess non-invasive exercise hypertension (or exaggerated blood pressure response) during bicycle ergometry.24 ExRHC was performed on a bicycle ergometer directy after the resting measurements, either in patients without (<25 mm Hg) or moderately elevated mPAP (25-35 mm Hg) at rest. PH at rest was defined according to the suggestions of the Task Force of the 6th World Symposium on Pulmonary Hypertension, during which the mPAP threshold was lowered to 20 mm Hg.25 We performed exPH in the presence of moderate PH at rest to analyse the slope of mPAP increase during low-dose exercise (25-50W) in order to assess the effect of pulmonary vasodilatation at an intensity which represents everyday activities. There was no predetermined workload to achieve and patients in both groups were asked to exercise until maximal exertion, or the occurrence of medical reasons to prematurely terminate the stress test . In both groups, starting at a workload of 25W, an increase of 25W every two minutes was performed until maximal exertion.From 244 patients undergoing exRHC the development of pulmonary capillary wedge pressure (exPAWP), mean pulmonary artery pressure (exmPAP), pulmonary vascular resistance (exPVR), and the maximal performance  were analysed during exercise . For eacmax, and echocardiographic systolic pulmonary artery pressure, sPAP, are influenced by fluid status).Progression of coronary artery disease and acute infection had to be excluded invasively or non-invasively prior to RHC. Acute heart failure had to be clinically excluded. In case of fluid retention pharmacological (mainly using intravenous diuretics) or invasive  measures had to be taken to ensure recompensation prior to RHC. We only included patients who had received lung function testing, transthoracic echocardiography, and arterial blood gas analysis within 24 hours of RHC to avoid a bias created by a different fluid status 26 ventilation deficits or emphysematous aspects  at lung function testing (LFT), while cardiac disease was defined as the presence of coronary artery disease, cardiomyopathy, relevant valvular heart disease (≥ grade II stenosis or insufficiency of transthoracic echocardiography), or chronic heart failure (≥ NYHA II).Pulmonary disease was defined as relevant restrictive This study was conducted in accordance with the amended Declaration of Helsinki, and ethical approval was obtained . Written RHC consent had to be given separately.aO2) of resting blood gas analysis was calculated according to the formula: SaO2 (%) x Hb (g/dL) x 1.34 (mL/g) + paO2 (mm Hg) x 0.0031 (1/ mm Hg *mL/dL). Capillary partial pressure of oxygen (paO2) and carbon dioxide (paCO2) were also measured. LFT was done following established guidelines.26 Transthoracic echocardiography was performed by experienced cardiologists. Left ventricular ejection fraction (LVEF) was determined using the eyeballing method and separated into >50%, 40-50% and <40%. Right ventricular function (RVEF) was assessed by eyeballing and measuring tricuspid annular plane systolic excursion (TAPSE) 27 and systolic pulmonary artery pressure (sPAP) was determined by estimating RA pressure and calculating the pressure gradient from tricuspid regurgitation velocity according to established guidelines.28 Categorisation of valve dysfunction was done according to current guidelines.30Oxygen content  applying Fick’s law  in advanced tricuspid valve insufficiencies , since thermodilution may produce lower results in relevant (at least grade two) tricuspid regurgitation.32 At least two measurements within 10% range had to be documented.RHC was performed in a supine position with a fluid-filled 7 French Swan-Ganz catheter. Right brachial or internal jugular veins were used for access under sonographic guidance. Systemic blood pressure was taken using a cuff sphygmomanometer. Midchest position was used as zero reference. Right atrial (RA), right ventricular (RV), pulmonary artery (PA) and wedge  pressures were registered consecutively at the end of expiration during stable heart rate and mPAP-values. Appropriate wedge position had to be confirmed by deflating the balloon and immediate demonstration of a PA-curve profile. Mixed venous blood was taken and systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were calculated (PVR=mPAP-PAWP/CO) and SVR=MAP-CVP/CO; CVP being central venous pressure and CO being cardiac output. We used an exercise protocol starting with a 2min warm-up phase at 0W followed by a 25W increment every 2min until exhaustion or contraindication for continuation  occurred. Patients were instructed to cycle at 60 revolutions/min. Cardiac output was measured with thermodilution in case of minor valve dysfunction 34 Missing data were replaced by regression imputation. Alpha was set at .05. We opted to use an in/exclusion algorithm (using the Akaike information criterion (AIC)) to elucidate the most relevant variables for the prediction model.Descriptive and exploratory analyses of data were performed with SPSS  The Kolmogorov-Smirnov test (including Lilliefors significance correction) and Shapiro-Wilk test were used for normality testing. Differences between subgroups were analysed using the Mann-Whitney U test and chi-squared test (with Yates’ continuity correction where appropriate) to investigate explanatory variables. Analysis of associations was performed using Spearman’s Rho correlation coefficients and multivariable logistic regression modelling was done with functions from the R-Program.max alone was done with minimal ROC distance. Odds Ratios (OR) were transformed from the regression coefficients and estimated probabilities of exPH were illustrated. Predictive capabilities of the model were visualised in a nomogram. Cut-offs to determine exPH were chosen based on clinical relevance and visual inspection of diagrams. The study variables were analysed and cut-off values were set at the respective deflection points across the achieved peak performance.Area under curve (AUC) was measured to discriminate the capability of the final model from a receiver operating characteristics (ROC) analysis. In order to obtain an estimate of sensitivity and specificity from logistic regression modelling the cut-off value was set as 0.5, and searching for an optimal cut-off in VC17 Baseline data of rRHC and exRHC are shown in A total of 244 patients were initially evaluated. 36.9% of the entire population (mean age 67.0 years±11.9) had PH at rest, 12.3% had precapillary, 12.7% postcapillary and 11.9% combined pre- and postcapillary PH according to current guidelines.19 in our population  and the currently suggested ‘gold standard’ exTPR>3 mm Hg/L/min and exmPAP>30 mm Hg pulation .We analysed the hemodynamic variables exmPAP, exTPR, exPVR, and exPAWP and their relationships to the achieved power [W] see .24 Furthermore, peak performance of 100W was deemed to represent sufficient cardiorespiratory fitness for our elderly population. With higher workload, the probability of exPH may further decrease, represented by decreasing exmPAP, exPAWP and exPVR. Mean exPAWP at 100W was 18.3 mm Hg, which made us set the threshold to 18 mm Hg . At 100W PVR fell to 3WU, the current threshold to define pre-capillary PH with an mPAP>20 mm Hg at rest. Accounting for these workload haemodynamics and our multimorbid population, we chose the threshold of PVR>3WU as a cut-off, which is higher than the suggested PVR>2.10WU in patients>50 years in upright (as opposed to our supine) ergometry.35The currently recommended cut-off for exPH in terms of mPAP is 30 mm Hg (82.8% of our patients demonstrated an exmPAP>30 mm Hg). Since we found a rather large difference between resting and exmPAP  we increAccording to our data and reflections we suggest a new score to define exPH incorporating the following four variables: (1) ExPAWP ≥18 mm Hg , (2) exmPAP≥35 mm Hg , (3) exPVR>3WU and (4) a maximal performance of ≤100Watt. For each criterion one point was awarded; exPH was diagnosed if three or four points were present. 7.4% received no points, 12.7% one, 16.8% two, 30.7% three, and 32.4% four points. Thus, 63.1% of patients were diagnosed with exPH.As standardised echocardiography, 6 MWD, and LFT with calculation of all variables was not available in all 244 exRHC patients within 24 hours of RHC investigation, the absolute numbers used for further analysis differed across the variables  and 4. SP = .273) or coronary artery disease (P = .776) did not differentiate patients with or without exPH. 42.7% of our patients suffered from pulmonary disease, 100% from heart disease according to our definitions. The presence of pulmonary disease (P < .001) between males  and females (71.7W±37.2).Significant valvular dysfunction was mainly driven by tricuspid regurgitation (54.1%) and aortic stenosis (24.6%), followed by mitral (18.0%) and aortic regurgitation (3.3%). Maximal power differed significantly (2 14.5%).sPAP proved to be dominant in a logistic regression model suppressing the other variables. The Odds Ratio (OR) for the presence of exPH and an increase of 20 mm Hg in sPAP was 3.1 and the AUC was 0.70  and age , while age itself was significantly associated with valvular dysfunction (P < .001). Thus, an alternative model without sPAP was calculated based on the significant variables from bivariate analysis  and stepwise forward/backward selection modelling was performed, leaving only VCmax, age, and valvular dysfunction . This model increased specificity to 44.2% with little loss of sensitivity (94.3%).The problem of multicollinearity demonstrates that simultaneous integration of certain variables from bivariate analysis is not valid: sPAP showed significant associations with valvular dysfunction . Bivariate analysis of variables in the 131 patients did not change the selection of factors for the prediction model  were yielded. The OR was 3.6 (CI: 1.4-10.8) for valvular dysfunction and 2.1 (CI: 1.4-3.3) for 1l loss in VCmax , while VCSub-analysis of the group without resting PH (n=80) demonstrated a sensitivity of 90.5% (CI: 77.9-96.2%) and a specificity of 50.0% (CI: 34.8-65.2%), while a calculation in the group with resting PH (n=51) showed a sensitivity of 95.7% (CI: 85.5-98.8%); specificity could not be reasonably calculated due to the low case number.max, higher sPAP, more valvular dysfunctions, diuretics, atrial fibrillation, and hypertension. We suggest our new scoring system for defining exPH in elderly patients with low output during exercise (CO<10 L/min).In our alternative model a lower number of patients qualified for exPH than in the current suggestion of TPR>3 mm Hg/L/min and mPAP>30 mm Hg (63.1% vs. 78.3%), which is likely to reduce the number of false positives in our elderly population (mean age 67.0 years±11.9). Patients with exPH were significantly older, had lower VC19  and American22  study. In contrast, our population consisted of more elderly (69.9 years±11.0 in exPH patients and 62.2 years±11.7 in those without exPH) multi-morbid patients (100% suffering from heart and 42.7% from pulmonary disease). We did not find evidence that resting left or right ventricular function had an influence on the presence of exPH. More subtle methods to detect differences, such as strain analysis, may be needed. Furthermore, a higher number (40.3% vs. 20.0%) of our exPH patients had significant valvular disease  compared to a previous study.19Our study investigated a significantly different population of patients compared to a French36Additionally, we used a different algorithm for study inclusion than previous works: All patients who received exRHC were included in the analysis to define alternative thresholds independent of the presence of resting PH (most of our patients had borderline PH at rest). In clinical practice we perform exRHC in patients with moderate PH at rest to analyse the hemodynamic response to low-intensity exercise. This is highly relevant to understand patients’ workload and the stress on pulmonary vasculature during daily (low-intensity) activities, such as walking, shopping, or doing the household. This approach can be seen analogous to established exercise testing with bicycle ergometry, which is also performed in patients with overt arterial hypertension at rest to analyse  blood pressure response during exercise. Due to the low exercise time of our exRHC exams it is unlikely that patients will suffer harm, even in the case of (moderate) resting PH (no adverse events were observed during exPH). However, as the increase of PH (and thus hypoxemia) during exercise may amplify anaerobic peripheral muscle work and lactate accumulation, further studies might integrate exRHC with capillary (or even muscle) lactate measurements to better understand the metabolic, on top of the cardio-circulatory, burden. Different testing protocols (ramp vs. continuous testing) might be needed in a multimorbid population.23 Muscular limitations leading to exCO<10 L/min may lead to high exTPR-values but lower exmPAP. This was exactly the case in our population, with 90.7% showing an exTPR >3 mm Hg/L/min and a mean exCO of 7.3 L/min. Thus, exTPR may increase the number of false positives in the elderly who fail to generate an exCO>10 L/min. Especially in our elderly population with lower exCO, we believe exTPR to be a poor discriminator for exPH and therefore excluded it in our model. We found the deflection points of exmPAP and exPAWP at a performance of 100W, which supports the decision to take a cut-off of 100W workload for the diagnostic score. The drop of exmPAP and PAWP with higher performance may reflect better vascular compliance in patients with higher cardiorespiratory fitness .39 A PVR threshold >3WU has been suggested at rest17 and exercise19 and was reached at 100W (3.8WU±1.5). Across all variables CRF turned out to play a major role in the definition of exPH. Similarly to CPET, CRF should also be implemented in scores used to define exPH, because higher CRF is associated with the improvement of haemodynamics in PH.41 We did not find body mass index (BMI) to have a significant impact on the presence of exPH, which has already been shown in the literature19 This does not contradict the claim for the integration of CRF into exPH definitions, since BMI only reflects a body mass-to-body surface ratio and does not consider actual muscle mass or body composition.It has been postulated that the suggested algorithm of exmPAP>30 mm Hg and exTPR>3 mm Hg/L/min (may be seen as current gold standard) might be problematic in elderly patients.22We aimed to suggest a clinically reasonable cut-off by using deflection points (as a marker for better pulmonary compliance with higher peak workload) as thresholds : The wor42 However, from a pathophysiological and clinical perspective there is a great difference in an SBP of 200 mm Hg at 100W , or 200 mm Hg at a workload of 300W in a trained athlete at peak performance with adequate  vascular compliance and immediate decline of pressure after exercise termination. In our point of view the same mechanism should be applied to the definition of exPH, independent of resting PH. Our study provides a first impulse. Clearly, there need to be further studies to refine this.We believe that it is reasonable that the workload achieved should, or even must, be included in guidelines on exPH. In conventional bicycle ergometry , exercise hypertension is often defined as a systolic blood pressure (SBP)>200 mm Hg at a workload of 100W and has been associated with increased cardiovascular mortality. This is a practical approach, although data is lacking on this account. max and valvular dysfunction to predict exPH , with associated OR of 2.1 for a 1l loss in VCmax and 3.6 for valvular dysfunction. A sub-analysis of the group with and without resting PH did not yield a clinically relevant difference in test strength. Valvular dysfunction by itself (mainly driven by tricuspid regurgitation and aortic stenosis) proved to be very specific  would have less than 50% probability of exPH . On the other hand if the same patient suffered from valvular disease, probability would rise to 75% . Non-invasive evaluation of lung function and echocardiography for exPH estimation is appealing, since data can easily be acquired.Since RHC in elderly patients may not always be feasible, we calculated a prediction model of exPH with non-invasive variables from echocardiography and lung function testing. sPAP was the most sensitive marker for exPH (sensitivity 97.6%), but at the price of very low specificity (22.2%). The OR for an increase of 20 mm Hg sPAP was 3.1. By considering the multicollinearity of variables , we used a combinatorial model with VCt 2.52 l . A nomogt 2.52 l . From a 43 but has to be verified in different patient populations with mild and severe disease. In the future, the relatively moderate specificity of our prediction model could be improved by changing the cut-off values to higher levels, for instance to an exmPAP of 40 mm Hg and an exPAWP of 20 mm Hg together with a higher peak performance . Further data is needed on this as well as on the issue of treatment initiation in isolated exPH. 44We are aware that the test strength is not sufficient to suggest our prediction model as a gold standard to replace invasive diagnostics. However, its high sensitivity may prove useful as a screening test to exclude exPH,ExRHC is a challenging procedure and needs training and routine to acquire solid data. Technical obstacles of RHC have to be discussed as well. For instance, it may be difficult to immediately reach the wedge position at peak performance and high pulmonary artery pressures, leading to dislodgement of the catheter to more proximal areas. Failure of immediate ‘wedging’ may lead to false low values. The inter-study comparison of data may also be hampered by the sequence of data collection: we have established the following sequence of data acquisition at peak performance: (1) PA-values, (2) PAWP, and (3) PA position to obtain CO. This procedure may be done differently in other institutions with a certain degree of variation in values.19 Similar to existing literature, our heart failure group mainly consisted of patients with preserved ejection fraction.19 We have little data on patients with highly reduced ejection fraction. Categorisation of our heart failure group (as well as the group with pulmonary disease) was arbitrary and may include entities with different pathophysiologies. Additionally, (stress) echocardiography and gas exchange were not applicable during RHC, this could have provided more information on the etiology of disease. Our cut-off values for the score were oriented on the dynamics across performance  and may not apply to a younger population. Due to the retrospective nature of our study, our data is subject to bias and needs to be validated in a prospective cohort of elderly patients. Unfortunately, we do not have a follow-up of our patients over time to see whether our model translates into higher mortality rates in exPH patients.We are aware of some limitations of this study, which mainly concern the rather low number of data sets for the prediction model (n=131), although seminal papers on exRHC have similar case counts and study design.max and valvular dysfunction as significant factors for a non-invasive prediction model to estimate and screen for exPH in elderly patients. This may allow clinicians to circumvent invasive procedures in this high-risk group and will help to stratify patients who may qualify for early treatment initiation in isolated exPH.We provide an alternative score than the currently proposed definition of exPH (exTPR>3 mm Hg/L/min +exmPAP>30 mm Hg) for elderly patients with concomitant cardiopulmonary diseases; this reduces the number of exPH diagnoses in this population. Our score integrates peak performance as an essential variable of exercise testing. Only a combinatorial approach, such as ours, can pay tribute to changing vascular compliance during exercise to differentiate physiological alterations from actual disease. Additionally, we identify VCWe thank Mr Kelly for native proofreading of the manuscript. We are also grateful to Mr Marcus Möllenberg, who conducted a number of right heart catheterisations and echocardiographies. Special thanks go to Prof. Tienush Rassaf for proofreading the manuscript.The authors declare that they have no competing interests. The results have not been presented elsewhere.Patient or their legal guardians signed consent for the right heart catheter procedures. This study was conducted in accordance with the amended Declaration of Helsinki, and ethical approval was obtained .No funding was obtained for this study.