Hypertension remains a public health challenge worldwide however, the prevention, detection, treatment and management of this condition are not highly prioritized. Health knowledge has an important impact on individual’s health. The ability to actively participate in screening, diagnosis and management of hypertension are influenced by patient’s knowledge of hypertension. To understand why hypertension is so difficult to control, it may be of benefit to gain an understanding of the patient’s perspective. Hence, the aim of the study is to explore the perceptions of patients on prevention and diagnosis of hypertension in Fiji.The study used a qualitative method approach. The study was conducted at the four purposively selected health centers in the Lautoka/ Yasawa medical subdivision. A purposive sampling was used which included all the patients who attended the SOPD, age more than 18 years and above, diagnosed with hypertension for 6 months or more and attended clinic at one of the 4 selected health centers. Semi-structured open-ended interview guide were used to collect data among patients through in-depth interviews. Thematic analysis was used manually to analyze the data using four steps that is immersion in the data, coding the data, creating categories and identifying themes / subthemes.Twenty-five SOPD patients took part in the in-depth interview and the responses were grouped into two themes. The themes emerged included hypertension knowledge and diagnosis of hypertension in a closed family and self. Subthemes derived from the hypertension knowledge were measures of awareness, hypertension aetiology, risk perception, origin of information and concept of prevention. Sub themes derived from the diagnosis of hypertension in a closed family were perception when first diagnosed, hypertension in relation and hypertension impact. Patients’ knowledge on etiologies and risk factors of hypertension were generally poor. Majority of the participants learnt about hypertension in hospitals and few over radios and television. Diagnosis in a closed family triggered worrisome, fear and fright on some patients.Majority of the patients have less knowledge about various risk factors of hypertension. Worrisome, fearful, frightful, frustration and sadness were some of the reactions and emotions highlighted by the patients. It is important to design culturally tailored interventions that address the psychological and behavioral needs of the patients. Recommendation to conduct further studies to understand the perception of hypertension among the general public. Hypertension is a worldwide epidemic affecting nearly one billion people and is the commonest risk factor for premature death and manageable chronic condition throughout the world. It is a serious medical condition that significantly increase the risk on target organs resulting in stroke, heart attack, blindness or renal failure , 2. GlobBiological, social, and psychological factors are often considered as significant risks of hypertension. Psychological state of an individual greatly affects the physical condition of human body. The Health Belief Model (HBM) and the Protection Motivation Theory (PMT) are some of the examples that explain the association between perceptions of risk with health behavior. These theories emphasize that perception of risk is important in educating patients on their health-seeking behavior including preventive measures , 6.Developed countries and neighbors to Fiji, such as Australia and New Zealand also report high cases of hypertension. In Australia, based on measured data from the 2017–2018 Australian Bureau of Statistics National Health Survey, about 1 in 3 people aged 18 years and above have high blood pressure. In New Zealand, high blood pressure affects 1 in 5 people. Steps 2013 study conducted in Samoa found 38% of the adults above 18 years are living with hypertension. In Fiji, hypertension is the second most common cause of heart disease. According to the latest World Health Organization (WHO) data published in 2018, hypertension deaths in Fiji reached 381 or 6.5% of total deaths. The age adjusted death rate is 59.07 per 100,000 of population that rank Fiji number 2 in the world [Individuals from different family background, cultural backgrounds, socioeconomic status, education background and age group have different perceptions of hypertension. Health knowledge has an important impact on individual’s health . The abith to 19th, 2022. A qualitative study focuses on understanding people’s beliefs, experiences, attitudes, behavior and interactions towards health-related issues. It is also helpful in collecting genuine information from different socioeconomic demographics and provide valuable insights into public experiences [The study had applied a qualitative approach exploring the perceptions of hypertensive patients on hypertension knowledge and diagnosis of hypertension in a closed family and self in the Lautoka medical area from May 9eriences .The study was conducted at the four health centres in Lautoka Subdivision namely Lautoka, Punjas, Kamikamica Park and Viseisei Health centre. There are 8 health centres in Lautoka Subdivision however these four health centres were purposively selected because they usually run busy special outpatient department (SOPD) services. These health centres were noted to be the busiest centres in the Lautoka Medical area which cater for approximately 2000–3000 patients per week. These health centres run general outpatient services as well as SOPD for diabetes, hypertension, cardiac / dyslipidaemia. The function of these health centres is to promote wellness at primary health care level. The SOPD clinics in the 4 health centres are carried out twice a week (Tuesdays and Wednesdays). Approximately 250–300 patients attend SOPD clinic each week.The study included all the hypertensive patients within the medical area and focused on essential hypertensive patients that attended SOPD clinics at the 4 primary health centres in Lautoka medical area in May, 2022.The study sample (Hypertension patients) had fulfilled the following criteria: SOPD patients that attend SOPD clinics at the 4 selected health centres in Lautoka Subdivision during the period of data collection, diagnosed with hypertension for more than six months, age more than 18 years and above, of male or female gender, citizen of Fiji and lived in Lautoka and agreed to participate in the study.The exclusion criteria included patients not willing to participate, those patients who attend SOPD clinics in other health facilities apart from the selected 4 health centres, patients with mental / psychiatric conditions .Purposive sampling was conducted among the patients who met the study criteria. Twenty-five SOPD patients were included in total, 6 participants from each health centre, who were approached using face to face in-depth interview until theoretical data saturation was achieved .th of May, 2022 which helped define research questions and was feasible reflected in the data collection. Two (2) interviews were conducted among patients and HCWs to see what their views were on the questions as well as the quality of interviews. The English version was used for both the patient and HCW.A semi structed interview guide was used to collect data. The questions were developed based on the literature review and in line with the study research questions. It had 2 sections with a total of 20 questions, the first section on demography had 7 questions followed by 13 open-ended questions for the second section. The instrument was piloted first at Punjas Health centre on the 9After getting ethics approval, the Chief Medical Officer West (CMOW) and the Sub Divisional Medical Officer (SDMO) Lautoka were approached and formally informed about the study, Approval was granted by CMOW for the 4 health centres. The SOPD nurses at the 4 health centres were approached and informed about the study and their help was requested in locating SOPD patients by confirming their attendance for their SOPD clinic however they were not involved in the data collection process. Flyers that contain information about the research was placed at each SOPD clinics in the four health centres few days prior to the data collection.A short introduction of the study was provided verbally (in English and Itaukei language) by the principal researcher (Avock Johnny Jonathan) and one research assistant (in Hindi language) to the patients while they waited for their turn for SOPD clinic consultation. The verbal introduction was carried out during the done for the 2 weeks of data collection. Together with the verbal introduction, information sheet was provided to all the SOPD patients in their preferred language. The patients who agreed to participate in the study at their own free time were given consent forms in their preferred language.The patients who agreed to take part in the research were interviewed by the researcher in a quiet room at each health facility at the preferred time by both the participant and the researcher. Patients were interviewed in the SOPD room. Each interview lasted approximately 30–40 minutes. All interviews were recorded. The research assistant in the Hindustani language helped the researcher to translate during the interviews with 1 participant. In depth interviews were carried out until data saturation was achieved during the 2 weeks period of data collection.All interviews / discussions were transcribed verbatim by the principal researcher. Transcription was done on the same day of the interview. A review of transcriptions was done to correct errors and removed references of names and places ensuring anonymity for the participants. Data analysis was carried out after the transcriptions were clarified.Thematic analysis was used manually to analyze the data in this study. Thematic analysis was carried out using four steps that is immersion in the data, coding the data, creating categories and identifying themes / subthemes –14. The Study rigor refers to quality, authenticity, and truthfulness of findings of qualitative research relating to the degree of trust, or confidence, readers have in the results , 16. TheTwenty-five SOPD patients had participated in the face-to-face interview. There were more female participants (68%) compared to male participants (32%). Majority of the participants were from 50 years to 60 years age group (68%). In terms of ethnicity, the participants were Itaukei (36%), Fijian of Indian Descent 60% and others (n = 1). Education level background, majority of the participants had studies up to secondary school level (68%). Each participant was assigned a number from Participant 1 to participant 25 .From the thematic analysis, two major themes emerged which include knowledge on hypertension and diagnosis of hypertension in a close family/self. Each themes includes different sub-themes and categories . Each paThe first few questions asked to SOPD patients were about their knowledge on hypertension. The patients have highlighted various aspects of hypertension information that they are aware of such as hypertension etiology, risk perceptions, origin of information and concept of prevention. These various aspects are highlighted in the sub themes below.Hypertension awareness. A few patients had mentioned that they had no knowledge at all while most stated that they had a little bit of information about hypertension.I don’t know anything about high blood pressure. They only tell me I have high blood pressure. I think it’s too much pressure on the blood’ .‘Most of the participants had minimal information about hypertension.‘I know high blood pressure can cause stroke and heart attack if we don’t watch our diet’ .Only two of the participants had most of the information’s about hypertension.I know hypertension arise due to our unhealthy lifestyle choice, from the unhealthy food we eat, salt intake, lack of rest and stress, smoking, alcohol, kava and lack of exercise. Also, it can cause stroke, heart attack and other heart problem’ ‘Hypertension etiology. Majority of the participants were able to identify at least two factors that can cause hypertension.Majority have highlighted that stress is causing high blood pressure. Some of the reasons given by patients were stress from work place, stress looking after grandchildren, worried about financial support, worried about their children and their school welfare, worried about no job, worried about upcoming family function such as wedding, or even deaths in the family and pressure from the husband / partner.‘I think stressing too much and worrying a lot causes high blood pressure. For me, I used to work six days in a week, going to work in the morning and coming back in the afternoon as late as 5pm, to cook, clean and do the washing. This routine has caused high blood pressure’ .Another participant stated:‘It’s through unhealthy choices and not getting enough exercise, causing obesity and high blood pressure’ Some participants stated smoking, alcohol, and kava can cause hypertension.‘High blood pressure can also be caused by smoking, it contains bad fats that can damage the heart and also alcohol and kava’ .Few participants believed that a person could get hypertension if its genetically linked.‘My dad had high blood pressure, and now I have high blood pressure. I think it runs in the family’ Some of the participants also stated that unhealthy choice of diet is causing high blood pressure.‘Eating high amount of salt, oily food and meat every day can cause high blood pressure’ Few of the participants had mentioned that they don’t know the causes of hypertension.‘I don’t know anything about hypertension. I was only told when I came to the hospital that I had high blood pressure and I don’t know what’s causing it although I feel well and healthy’ .Risk perception. Majority of the participants stated that the middle aged and older generation are at more risk of developing hypertension.‘I believe the middle age and the older generation risking their life more because these are the age group where you actively working to feed your family, stress with finance, work, family and on the hand, we are the ones smoking, drinking alcohol, kava’ Some of the participants had mentioned that men are more prone to hypertension because they tend to smoke, drink excessive alcohol and kava.‘In my opinion, men are at more risk than women because they drink kava nearly every night and smoke as well. After kava, something called washdown. They start drinking few bottles of beer and we have noticed that more men are dying in the village from the complication of hypertension’ A few of the participants had mentioned that the older generation are at more risk because they do not exercise a lot and a few believe that it’s the age group whereby people easily develop high blood pressure.‘The older generation are at risk because they worry more, they also look after the whole family giving them more stress and they hardly do exercise’ Another participant stated:‘My dad had hypertension when he was old, around 50s and I also had hypertension in early 50s’ .A few participants have stated that the middle age group are at more risk of developing hypertension.‘I think the middle age group are at more risk because we now seeing them more in numbers attending SOPD clinic’ .A participant stated:‘The middle age group because they are smoking a lot, drinking kava and alcohol more nowadays’ Origin of information. Most of the SOPD patients have stated that they get information about hypertension from medical professionals when they visit the health centre.‘I was sick one time, I had continuous headache and came to the health centre. that’s when the doctor told me I had high blood pressure’ .Some of the patients have stated that get information about hypertension from radios and TV.‘I was listening to a Hindi program and they were discussing about high blood pressure’ A participant had stated that she gets information about hypertension from community outreach clinic.‘The nurses will come around during village visit to check all our blood pressure and they always advise us when they see our blood pressure is high’ Another participant stated that she gets information about hypertension from church health screening.‘We have a health department in the church and they check our height, weight, BP and sugar every 6 months. From there I started to know about my high blood pressure’ Some participants stated that they get information about hypertension from the mass media and internet.‘I was watching a video about high blood pressure on Facebook and it was showing how high blood pressure can cause heart attack’ A few participants stated that they get information about hypertension from their families and relatives.‘My family and relatives. Whenever someone die from hypertension in the family, we start talking about it and advising each other’ Concept of prevention. A participant stated that hypertension cannot be prevented.‘Once hypertension is in the family, it cannot be prevented. Will live and die with it’ While the rest of the participants agreed that blood pressure can be prevented.‘It’s a choice to live healthy or unhealthy, so yes, we can prevent blood pressure’ .A few participants stated by practicing a healthy proper diet.‘If we eat healthy, we will not be getting high blood pressure. We should eat more vegetables and fruits and cut down on meat, cholesterol and fast foods’ A participant stated:‘We should not be eating a lot of salt in our food, especially raw salt’ Some participants stated that avoiding stress can also prevent hypertension.‘We should not worry; we need a lot of rest. The more then tension and stress, the more our pressure will go up’ Few patients stated that exercise can help prevent hypertension.‘By exercising a lot, we will burn more fats and cholesterol’ Some participants also stated that smoking, drinking kava and alcohol should be stopped.‘More education and awareness to this young generation not to smoke and drink. Many are not aware of the consequences of drinking and smoking’ A few participants stated that hypertension can be prevented by the use of herbal medicine.‘I think taking herbal medicine first can help prevent. If it doesn’t work, then can take start taking the medication given by the doctors’ Further questions were asked about the impact of hypertension on self and on other family members. Under this theme, it explored patients’ perception on themselves when they were first diagnosed and highlighted the impact it had on their family.Perceptions when first diagnosed. Majority of the participants have stated that they have felt worried and unhappy about the news.‘When I first heard about it, I felt sad then I was worried about it. I didn’t want my children to know about it’ Some of the participants stated it made them feel bad and angry.‘I was in denial the first time I was told I had high blood pressure. That feeling of frustration kept coming on me and I wasn’t feeling good about the news’ A participant stated:The first time I was told I had high blood pressure, I had fear of dying from heart attack and stroke’ ‘Another participant stated:It gave me more stress and more high blood pressure’ ‘Impact of hypertension in a relative. Many of the participants stated that they knew people in the family, community, friends or relatives living with hypertension.My late father had died of high blood pressure and stroke. He wasn’t taking his medication every day. From the time he died, we usually visit the hospital regularly to get our blood pressure check’ ‘Another participant stated:‘I know a lot of people from the village that have high blood pressure too. We are all somehow related. Every time, the doctor and nurse come to the village, we always go together to get our blood pressure checked and get our medicine too’ A few of the participants stated that no one else in the family has high blood pressure.My husband and parents don’t have high blood pressure. I’m the only one at home living with high blood pressure but I also know my some of my uncles and aunties have high blood pressure too’ ‘Hypertension impact. Some of the participants have stated that hypertension in the family did not have any impact on them.‘My husband has high blood pressure too and he is still working while I carry out my normal routine at home. It didn’t really affect us because we taking good care of ourselves’ Most of the patients have stated that it had affected them emotionally.‘I feel worried about it sometimes. What if one of us die soon. What will happen if my husband gets stroke or heart attack. I don’t want my children to have high blood pressure too’ Another participant stated:‘Cost of living is high and we live in town. Only my husband is working. The doctor has said for us to eat healthy food only. Buying vegetables and fruits every three, four days is expensive. Preparing healthy meals too is something I can’t afford every day’ This study showed that the patients had low knowledge towards various risk factors of hypertension. They reflected negative emotional reactions to response their psychological needs. To answer the research questions, knowledge on hypertension, origin of information, etc were highlighted in the discussion.The growing number of hypertension cases in this current world is a worry for the nation and its health sector. While hypertension is prevalent in both high income and low- and middle-income countries (LMICs), although 80% of deaths due to cardiovascular diseases occur in LMICs . This caMost of the participants had different views on the risk perceptions. Majority had stated that the middle age and older generation are at more risk of developing hypertension. Based on gender, men are more likely to be affected than women. The association with gender based was more likely for men than women. Family history as stated by some participants as their reason why middle age and older generation are at more risk. Findings from the study conducted by Goldstein, et al., (2006) mentioned that men with one or two hypertensive parents had higher ambulatory BP than women with hypertensive parents, whereas offspring of normotensive parents exhibited no sex difference in BP .Patients usually get information about hypertension through mass media and family discussions. A study conducted by Lin, et al., (2008) mentioned that traditional mass media  were still the most popular sources of information for hypertension knowledge . In thisPrevention of high blood pressure has been recognized as the controlling key to hypertension risk factors and mortality rate especially in LMICs. Identification of the level of knowledge and attitude of the population is an optimum step to prevention . HyperteCurrently, approximately 75%–80% of the world’s population, including hypertensive patients, use herbal medicines due to the receptive nature of the body toward herbs, and the low incidence reported side effects . A few oHypertension in a close family member or friend also affects individual’s hypertension perceptions. It was noteworthy that majority of the patients in this study at least know someone in the family, relatives or a friend living with hypertension. However, a very few patients had stated that they did not know anyone else living with hypertension. For those patients living with another member of the family with hypertension; financial burden had been stated as an impact. To live healthy, requires a healthy choice of food which can be quite expensive and local home-grown food which is a disadvantage for urban dwellers patients hence not affordable. Furthermore, emotional stress has been reported by a few patients where they feel worried that their family members might end up with a sudden heart attack or stroke as they are non-compliant to medication . HoweverThe impact on individuals’ feelings when newly diagnosed with hypertension has been described by the patients in this study as worrisome, fearful, frightful, frustrating and sadness. Many of these patients did not express their reasons. A few of the patients had mentioned anger and frustration as they were not ready to receive the bad news, and as they had felt fit and healthy all along. A study by Ian, et al., in 2019, concluded that despite the availability of new therapies, patients are still diagnosed late and experiencing both emotional and financial impacts from the disease . PatientThe study was limited to SOPD patients and primary HCWs in Lautoka and findings may not be generalized to Fijis populations. Due to the setting of the study and the nature of the study participants, timing of data collection was limited to two weeks. Data was collected based on time available for the participants on their SOPD clinic days.Hypertension knowledge was low on patients. Patients with tertiary education had more knowledge than those who have primary and secondary education including those that never attended school. Risk perceptions differ among patients while majority had stated that the middle age and older generation are at most risk of developing hypertension. Genetics, obesity, smoking were some risk factors identified by some participants. Majority of the patients obtained their information about hypertension from hospitals and clinic. Many of the participants believed that hypertension can be prevented from living a healthy choice lifestyle and majority of the participants have highlighted salt reduction and avoidance of stress as the most common preventive measures. However, some participants still believe that herbal medicine can prevent and treat hypertension.Emotional stress has affected majority of the participants in this study when they have learnt that another member of the family is living with hypertension. The fear of morbidity and mortality was high among patients. Worrisome, fearful, frightful, frustration and sadness were some of the reactions and emotions highlighted by the patients when they had first received the news from HCWs that they were newly or undiagnosed with hypertension. Future researchers are recommended to conduct studies to understand the perception of hypertension among the general public.


Respiratory muscle weakness results in substantial discomfort, disability, and ultimately death in many neuromuscular diseases. Respiratory system impairment manifests as shallow breathing, poor cough and associated difficulty clearing mucus, respiratory tract infections, hypoventilation, sleep-disordered breathing, and chronic ventilatory failure. Ventilatory support  is an established and key treatment for the latter. As survival outcomes improve for people living with many neuromuscular diseases, there is a shift towards more proactive and preventative chronic disease multidisciplinary care models that aim to manage symptoms, improve morbidity, and reduce mortality. Clinical care guidelines typically recommend therapies to improve cough effectiveness and mobilise mucus, with the aim of averting acute respiratory compromise or respiratory tract infections. Moreover, preventing recurrent infective episodes may prevent secondary parenchymal pathology and further lung function decline. Regular use of techniques that augment lung volume has similarly been recommended (volume recruitment). It has been speculated that enhancing lung inflation in people with respiratory muscle weakness when well may improve respiratory system “flexibility”, mitigate restrictive chest wall disease, and slow lung volume decline. Unfortunately, clinical care guidelines are based largely on clinical rationale and consensus opinion rather than level A evidence. This narrative review outlines the physiological changes that occur in people with neuromuscular disease and how these changes impact on breathing, cough, and respiratory tract infections. The biological rationale for lung volume recruitment is provided, and the clinical trials that examine the immediate, short-term, and longer-term outcomes of lung volume recruitment in paediatric and adult neuromuscular diseases are presented and the results synthesised. Respiratory muscle weakness, shallow or laboured breathing, weak cough, inability to clear oral secretions or mucus, chest infections, and/or sleep-disordered breathing are common consequences and complications that many people living with a neuromuscular disease (NMD) experience –5. RespiThe cornerstone of management for respiratory failure in NMD is home mechanical ventilation, most commonly non-invasive ventilation (NIV). This effective therapy can slow the progression of respiratory muscle weakness and lung volume decline, improve symptoms of breathlessness and nocturnal hypoventilation, and prolong survival in ALS/MND , 5, 7–10A growing number of consensus statements and disease-specific treatment guidelines include other respiratory therapies as adjuncts to care –22. AcknMuch of the rationale for using LVR in NMD has been based on clinical reasoning and extrapolation from other patient populations. For example, in the intensive care unit, hyperinflation manoeuvres similar to LVR are performed in intubated patients to inflate areas of under-expanded or collapsed lung and aid sputum clearance –27. WhilThis narrative review summarises our current understanding of the structural  and functional  consequences of NMDs, in both paediatric and adult disease. The evidence of impact with LVR therapy in NMD is presented, research gaps are identified, and potential future developments in the areas are proposed.Clinically, the inability to take a deep breath, as measured by a fall in vital capacity (VC), is a distinctive feature of many NMDs . HoweverIn older children and adults with NMD, restrictive ventilatory impairment is the hallmark of respiratory system involvement, with slow VC, forced vital capacity (FVC), and total lung capacity (TLC) declining as diseases progress , 32–34. In children with Duchenne muscular dystrophy (DMD), the FVC peak is reached much earlier, at around age 15 . As growCrs)] has long been postulated as a factor contributing to lung volume restriction  and expiratory reserve volume (ERV) related to inspiratory and expiratory muscle weakness . Howevertriction , 51. Sixwith NMD  23, 29,, 29,Crs]with NMD , 51–53, VT) during early childhood and frequent challenges with hypoventilation  sleep results in inhibition of the intercostal and accessory muscles, thereby leaving the diaphragm as the sole muscle of inspiration , 55–57. Infants are particularly vulnerable during sleep due to reduced ventilatory drive, lower baseline resting muscle tone, and increased work of breathing . In chilIn a person with respiratory muscle weakness, these normal physiological disturbances often have clinical impact. With increasing diaphragm weakness, the fall in supine VC becomes greater , and REMAlveolar collapse, mucus plugging, and recurrent RTIs are prevalent respiratory complications , and cheInvolvement of the bulbar muscles can also compromise the respiratory function. Approximately 20%–30% of people with ALS/MND have the bulbar-onset phenotype, and the vast majority of all those with ALS/MND develop bulbar symptoms as the disease progresses . Bulbar Whilst difficulty clearing sputum secondary to changes in airway cilia or mucus rheology is uncommon in NMD, mucus consistency can be affected secondary to aspiration of oral secretions or dehydration. The accumulation and drooling of saliva  is reported in almost 50% of people living with ALS/MND and generally attributed to poor saliva control or pooling secondary to weakness and spasticity in the tongue, facial, and pharyngeal muscles .Surprisingly given these potential respiratory complications, the prevalence of respiratory issues in people living with NMD is poorly quantified. A large population-based cohort study conducted in Ontario, Canada, suggested that a third of all people with an NMD may have respiratory system involvement. Thirty-five percent of the 185,586-person cohort were known to a respiratory specialist, 33% had performed respiratory function tests at least once, and 5% were prescribed domiciliary home mechanical ventilation or continuous positive airway pressure (CPAP) for the treatment of sleep-disordered breathing. Including the two-thirds of the population who did not require specialised respiratory care, the individuals with NMD presented to an emergency department 1.6 times every 3 years for respiratory causes, with most of these requiring hospital inpatient admission (1.4 times per 3 years) .Cough is the primary defence mechanism of the respiratory system. It has roles in airway clearance, airway protection, and lung protection by (i) removing sputum, mucus, or foreign particles within the airway, (ii) preventing or minimising aspiration of foreign material into the airway, and (iii) protecting the lungs during a sudden external application of high distending pressure .Two neurophysiologically distinct cough pathways exist: a reflex or laryngeal cough and a tracheobronchial cough. The former is a vagally mediated reflex, activated when the receptors situated in the larynx or proximal trachea are stimulated. These receptors respond primarily to mechanical stimuli, such as aspiration of foreign matter or excessive distension, and hence have a predominantly airway protection role. In contrast, tracheobronchial cough is generally associated with airway clearance. It can be reflex-initiated by mucus or inhaled particles stimulating chemosensitive receptors distal to the larynx in the tracheobronchial mucosa and submucosa (a “spontaneous cough”), or voluntary  . LaryngeVT to 50% of VC  and hence intrathoracic pressure (time points 3 to 4 in 2O) have been described  falls abruptly to atmospheric, creating a pressure gradient between this central point and the higher Ppl and alveolar pressure (PA) developed during the compressive phase. A 30–50 ms burst of supramaximal expiratory flow results, generating a transient “cough spike” with flow rates reaching 10–12 L/s (600–720 L/min)  . Expiratin) Ppl  73, 79), 79PAW) , 79PAW) The appreciation of cough neurophysiology and mechanics is growing; however, the assessment of cough is not as well developed. The peak expiratory flow rate achieved during a cough  is the most widely used measure and has been adopted as a surrogate marker of “cough effectiveness”; however, other metrics such as cough volume may be more important in NMD. Although PCF evolved from the measurement of peak expiratory flow (PEF) , 81, PCFPeak flow metres, primarily used for PEF measurement in asthma management, are inexpensive, readily available devices that have been repurposed by some clinicians and researchers to measure PCF. However, considerable PEF measurement error has been demonstrated –99, depeIn infants, technical challenges and lack of normative data mean that the value of respiratory function tests in general remains debatable in clinical management. Spirometry testing can be accurate in pre-school children with appropriate environment, equipment, and training , though Clinical interpretation of any test requires knowledge of “normal” values, within-subject repeatability and reproducibility, but these have not been satisfactorily established for PCF. Reported mean values in healthy adult participants vary widely , 112–124Despite these issues, PCF is likely to be the most common cough measure in clinical practice. The latest European Respiratory Society statement on respiratory muscle testing includes PCF and states it “estimates the effectiveness of mucus clearance and expiratory muscle function” . TestingThe clinical significance of PCF is unclear; although PCF is commonly interpreted as a marker of cough effectiveness, few studies have related this to difficulty clearing secretions or expectorating sputum. To our knowledge, no studies have directly examined the relationship between PCF and airway clearance in people with NMD. In people with obstructive airways disease, no correlation is observed between radioaerosol clearance of mucus and the PCF achieved , 127. UsNonetheless, in the NMD field, a threshold of 160 L/min has been reported as the PCF required for effective airway clearance , 62, basr2 = 0.58). Stepwise regression identified that the IC component contributed 44% of the variance  in people with NMD; however, based on first principles, it is possible that variables such as lung volume are linked to Ppl and hence an “effective cough” in this population. However, the reverse is also true, in that high Ppl can also be generated in the absence of high lung volumes. A study conducted in people with tetraplegia demonstrated that whilst abdominal muscle stimulation and glottic closure during a cough manoeuvre produced the highest oesophageal (Poes), gastric pressure (Pga) and PCF with concomitant airflow limitation in all participants, an un-stimulated cough  against a closed glottis still achieved flow limitation in half the group  can achieve an adequate Ppl due to the effect of higher chest wall and/or lung recoil pressures , possibly due to lower lung volumes, as VC was the only respiratory marker found to be associated with RTI . This inGiven that respiratory complications are the primary cause of discomfort and death in people with NMD, authors have sought to predict those at risk of developing an RTI. In the paediatric cohort, a VC <1.1 L or PCF <160 L/min were able to distinguish those who had a severe RTI in the past or not . In DMD,However, these thresholds have been derived from retrospective data and not validated prospectively. The respiratory function has been measured post RTI ; hence, In a recent adult cohort, these threshold values were unable to discriminate the participants who had an RTI history or not, with thresholds of VC <1.1 L or PCF <270 L/min correctly classifying only 61% and 50% of the group, respectively . These fGiven the relationship between poor lung function, morbidity, and mortality, multidisciplinary respiratory care is considered vital for people with respiratory dysfunction secondary to NMD. Monitoring function, initiating therapies at the appropriate time, ongoing assessment and titration of treatments, responding to acute illness, and providing suitable end-of-life care are all important clinical care objectives.Ventilatory support is an established and key treatment for hypoventilation and chronic ventilatory failure; NIV has a significant impact on survival when nocturnal hypoventilation is present and is recommended in clinical care guidelines –21, 141.Adjunctive respiratory management of people with NMD is less clearly defined. Summarising the evidence of efficacy is challenging as the research is of a lesser quality, and various techniques and dosages are employed . Whilst Airway clearance techniques are therapies that aim to improve cough effectiveness, mobilise mucus, and increase lung volume . A conseAirway clearance techniques have traditionally been employed to augment cough or to reinflate areas of collapsed lung, improve alveolar ventilation, and mobilise mucus from the peripheral and central airways during sputum encumbrance or acute respiratory illness . More reCrs in intubated and ventilated patients , and comes ready-assembled. Alternatively, a standard manual resuscitation bag found in any hospital can be employed. Single-breath methods of inflation require a machine to deliver the driving pressure; if patients are not using NIV at home, then machine provision incurs an additional cost. If the person is an existing NIV user, their ventilator could be utilised, but not all machines are capable of performing volume-limited ventilation. Pressure-limited bilevel devices are the most commonly prescribed domiciliary NIV machines and can deliver LVR; however, this requires the users to frequently change ventilator settings back and forth from the nocturnally prescribed pressures to the assisted inflation settings. Inspiratory positive pressure breathing (IPPB) devices or MI-E machines avoid this risk, as they are used for the single purpose of hyperinflating and are fully programmable; however, they are expensive , heavier, and less portable. Whilst these machines may be available or funded in some jurisdictions, their cost is prohibitive in many other environments. Furthermore, they arguably require more specialised skills to set up and titrate , 169, anafter an active breath to spontaneous IC , or the PCF obtained when coughing from the inflated volume   . No diff = 0.33) . Similar = 0.33)  or with  = 0.33) .In contrast, one case series of 282 consecutive patients attending a single centre reported that LVR using a bag and one-way valve resulted in a larger assisted inflation than LVR via volume-limited NIV or a bag without a valve, although both methods achieved assisted ICs above spontaneous VC  . This reassisted–PCF difference)  , 194. Onis point . The cliduring the manoeuvre (CL), or Crs after a therapy session  demonstrates increased chest wall displacement attributable to expansion of the pulmonary-apposed (upper) and abdomen-apposed (lower) ribcage with LVR , 195. Hoanoeuvre , 196, thanoeuvre . The vas session , 197–200 session , 30, 201Crs was not assessed, this change may also have reflected PCF measurement variability. The same authors recently showed a benefit of LVR on the expiratory flow rates measured using a peak flow metre during volitional airway clearance and airway protection behaviours in the same patient cohort  with a control period in 29 participants with ALS/MND who used LVR at home. The forced vital capacity, PCF, and sniff nasal inspiratory pressure (SNIP) were measured at baseline, 15 and 30 min post therapy. A significant interaction effect was found; however, this represented a statistically significant difference in FVC between groups at 15 min and not a difference in the change over time. Unassisted PCF increased post-LVR at 15 min and 30 min after the single session compared with baseline, with significant between-group differences. The authors postulated that the mean increase of 54 L/min may represent an improvement in compliance ; howevert cohort . WhetherLVR in the participants with NMD during the manoeuvre. Between-group differences were observed at all time points, with PCF and all lung volumes except that RV was significantly lower in the NMD cohort. However, in contrast to the Cleary study in people with ALS/MND (Crs), measured using the pulse inflation method (Crs (37 ± 5 to 50 ± 7 ml/cmH2O) representing a change of 40 ± 10%; however, the levels returned to baseline within an hour. The individual data suggest that there may be responders and non-responders; 8 out of 12 participants obtained an improvement greater than 20% of baseline, whereas the other third had smaller or a negative response. Another interpretation may be that the findings represent test/re-test variability. The authors concluded that resolution of atelectasis was not the mechanism by which Crs increased, as the static lung volume did not change  increase of 90 (45–135 ml)], with values returning to baseline within an hour. A similar increase in FVC was shown with MI-E [mean = 59 (10–109 ml)], representing a <10% change from mean baseline values in the SMA subgroup, which persisted at 1 h but had diminished within 2 h . In the e cohort . This ste cohort , and simagnitude .CL and/or lung volume following a single session of therapy, others found no change in these parameters. Given the small number of the participants involved (ranging from 6 to 20), this lack of consensus is not surprising; it is plausible that there are responders and non-responders, perhaps related to individual baseline characteristics such as degree of lung volume restriction or disease duration. Alternatively, this variation may be random and reflect no true effect. The studies by De Troyer   . The int < 0.01) .However, these retrospective cohort studies have a number of additional limitations that cast doubt on the strength of the conclusions made, including poorly defined follow-up periods and incomplete data sets with the potential for retention bias. Furthermore, categorising patients and comparing those who increased vs. decreased MIC over time without considering the underlying disease, in a sample of 43 participants with a mixture of rapidly and slowly progressive NMDs , introduCrs, they did not measure this  or qualitative outcomes , 226 andOverall retrospective MI-E study findings in paediatrics are relatively consistent with a reduction in hospital admissions, days hospitalised or emergency department presentations. All studies are limited by their retrospective nature, limited reporting of MI-E prescription, and, if usage frequency was available, it was patient/caregiver self-report. Despite this, the studies suggest overall that MI-E may impact hospitalisation, either through reduced infections or through greater ability to manage episodes at home.The quality of life data are also reasonably consistent, with the participants in all studies identifying a number of health and lifestyle benefits that led to widespread acceptance of the device by both families and children with NMD. Though multiple positive impacts are identified in these studies, MI-E use was not without its challenges. These included portability, power dependence, and increased pressure on those caregivers trained in MI-E administration amongst the most common.Moran et al. explored these findings further using semi-structured interviews to investigate the experiences of a small cohort (11 participants) of both parents and children regularly using MI-E at home . They idThe role of MI-E to both augment volume and assist with secretion management makes it impossible to partition out the relative benefits of regular lung volume recruitment vs. any benefit of a change in respiratory tract infections and/or hospitalisation. This limitation is particularly apparent in the paediatric literature.Two prospective, uncontrolled studies examined the respiratory function 3–6 months after prescribing LVR in NMD populations naïve to therapy , 178. ThTwenty-four older participants (mean age of 54 years) with a diagnosis of ALS/MND, post-polio syndrome, or myotonic dystrophy were investigated by Kaminska et al. Adherence diaries, questionnaires assessing QoL, and acceptance of LVR were measured 3 months after initiating twice-daily LVR . There wThese themes were also evident in a randomised comparison study comparing a year-long trial of LVR with MI-E in participants with ALS/MND. Of the 21 participants in the LVR arm, 71% reported performing two sessions a day compared with 53% of the MI-E group. Of the 15 participants who did not use a technique as prescribed, 11 had severe bulbar impairment. No change was noted in the carer strain or QoL indices. There was a low event rate of RTI in both groups (the primary outcome), and respiratory function analysis was limited to VC and PCF. No differences were noted between groups in the average rate of decline per month. Two major limitations of this study were the commencement of assisted inflation therapy at the same time as NIV initiation, a substantial confounder given the impact of NIV on the respiratory function, symptoms, and QoL in people with ALS/MND; and the lack of a control or active control group .A comparator intervention was also included in the two RCTs that assessed the effect of LVR in people with cervical SCI. The participants were allocated to LVR or incentive spirometry (with the addition of inspiratory muscle strength training in one study)  for betwRecently, Katz and colleagues published the results of their RCT in children with DMD, a multicentre, single-blinded trial of standard care or standard care plus twice-daily LVR over 2 years. A total of 66 boys with median age of 11.5 (interquartile range 9.5–13.5) years and with normal to very mild respiratory impairment [median FVC 85% (73%–96%)] completed the study. No difference in the change in % predicted FVC was seen between the two arms, or in any of the secondary outcome measures that included the MIC–VC difference, MIP, MEP, or TLC. Adherence to therapy was sub-optimal (41% of participants); however, after adjusting for usage, the results were similar .The prospective studies detailed above are consistent in their findings, with all reporting no demonstrable effect of regular LVR on VC, MIC or LIC, or QoL in the populations studied. Interestingly, Sawnani and colleagues used a MI-E device to deliver regular assisted inflation therapy to 34 children with muscular dystrophy and worse respiratory function (56% predicted FVC) in their randomised controlled trial (RCT) and did find an improvement in FVC at interim time points, but not at the 1-year mark . It is pCrs) would be maintained over time. A study currently underway from our group is comparing 3 months of regular LVR with an active control . Full clinical trial results will be available in late 2023, but preliminary results from Sheers et al. in 76 participants with heterogeneous NMDs (ALS/MND = 34%) and a mean baseline VC 41% predicted demonstrated a significant improvement in LIC of 12%  in the LVR group at 3 months compared with control [mean change 0% ], but no between-group difference in Crs , including resistance (Rrs) and reactance (Xrs) components, and can detect ventilation inhomogeneity and alveoli closure . Mechanisms of action have generally been theorised from “first principles” in the literature, whereas more sophisticated measures would provide better empirical evidence of efficacy. For example, the forced oscillation technique (FOT) measures impedence of the respiratory system  to assess short-term changes with assisted inflation therapies , 206. ThAs with much physical therapy research, accurate and objective recording of LVR “dose” of therapy is challenging. Adherence with LVR is variable across all of the reported, longer-term research, and with the exception of Chatwin et al. , Sawnania priori hypotheses in larger numbers of people living with NMD are required, and should include clinical outcomes such as hospitalisation, time to ventilatory support, and mortality. Models for this approach already exist, for example, the 20-year cohort study by Berlowitz and colleagues examining the effect of NIV on survival in MND , the concomitant change in clinical presentation, shift in care objectives, and growth in international recommendations for LVR use, it is doubtful that an RCT design of adequate duration can be conducted to answer the questions raised above. Prospective longitudinal studies with l in MND , and thel in MND . Reachin


Six amino acids, five vitamins, co-factors and carbohydrates, nine lipids and two xenobiotics were associated with orthostatic blood pressure after adjusting for age, gender and systolic blood pressure. After additional adjustments for BMI, diabetes, smoking and antihypertensive treatment, the association remained significant for six lipids, four amino acids and one xenobiotic. Twenty-two out of 818 plasma metabolites were associated with orthostatic blood pressure responses. Eleven metabolites, including lipids in the dihydrosphingomyelin and sphingosine pathways, were independently associated with orthostatic systolic blood pressure responses after additional adjustment for markers of cardio-metabolic disease.Whereas autonomic dysfunction and the metabolic syndrome are clinically associated, the relationships with the plasma metabolome is unknown. We explored the association between orthostatic blood pressure responses and 818 plasma metabolites in middle-aged subjects from the general population. We included 3803 out of 6251 subjects  from the Malmö sub-cohort of The Swedish CardioPulmonary bioImage Study with information on smoking habits, diabetes, antihypertensive drug treatment, anthropometrics, hemodynamic measurements and 818 plasma metabolites (mass-spectrometry). The associations between each metabolite and orthostatic systolic blood pressure responses were determined using multivariable linear regression analysis and  Whereas there are some specific reversible clinical causes of this condition, such as excessive blood pressure lowering therapy or dehydration, OH in the population often indicates some degree of cardiovascular autonomic dysfunction3. OH is strongly associated with cardiovascular disease (CVD) and often correlates with markers of poor cardio-metabolic health. Previous studies have shown that OH, or even more subtle changes indicating cardiovascular autonomic dysfunction, can be an early sign of cardio-metabolic disease and predict cardiovascular mortality5.Orthostatic hypotension (OH), defined as decrease of systolic and/or diastolic blood pressure of more than 20/10 mmHg upon standing6, is a major health concern that has been affecting a steadily increasing part of the global population. Those affected are known to be at high risk of cardiovascular events such as stroke and myocardial infarction that account today for approximately one third of deaths globally8. Unhealthy diet and a low level of physical activity are two major risk factors that can be modified.The metabolic syndrome, defined by visceral obesity, dyslipidemia, hyperglycemia and hypertension9. The metabolome can be seen as a footprint of our overall health status and its composition may potentially yield valuable information on multiple diseases. It is affected by genetics, diet, physical activity, the microbiome, inflammation/stress, the metabolic condition, hormonal homeostasis and drug treatment10. A special attention has been paid to the composition of metabolome in order to investigate if certain single metabolites, or compositions of metabolome can be linked to cardio-metabolic disease in a way that could make them suitable as markers in risk assessment15.In recent decades the development of methods to identify and measure quantities of metabolites has accelerated15.In recent years, bacterial endotoxins like lipopolysaccharides (LPS), degradants of components of red meat such as trimethylamine oxide (TMAO), several short chain fatty acids (SCFA), branched-chain amino acids (BCAA), aromatic amino acids (AAA) as well as bile acids were found to be associated with different outcomes of cardio-metabolic diseaseBesides changes in lifestyle and diet, fecal microbiota transplantation, probiotic, prebiotic and antibiotic treatment as well as small molecule antimicrobial enzyme therapeutics have been proposed as interventions that target the gut microbiota and thereby imbalances in the metabolome.Whether components of the metabolome are associated with markers of autonomic dysfunction, such as impaired orthostatic blood pressure responses, is unknown.Orthostatic hypotension is closely associated with cardiovascular risk factors and the metabolic syndrome, especially in the elderly population. We therefore hypothesized that metabolites, such as for example sphingolipids, that are associated with hypertension, diabetes and cardiovascular disease, may also be associated with cardiovascular autonomic dysfunction in terms of a maladaptive orthostatic blood pressure response.In this explorative study we examined the association between orthostatic blood pressure responses and untargeted plasma metabolites in a random sample from the middle-aged population.16.The Swedish CardioPulmonary bioImage Study (SCAPIS) is a collaborative study between six Swedish universities and university hospitals . A total of 30,154 subjects from the general population in the age range 50–64 years were invited by letter to participate during the period 2013–2018A total of 6251 men and women were included at the Malmö site, which corresponded to a participation rate of 53%. Comprehensive examinations were carried out at three different days with one week apart. Of the 6251 participants, a total of 4126 individuals had information on plasma metabolites measures, 3979 of these had recorded orthostatic blood pressure responses at the same visit. After excluding subjects with missing values of orthostatic blood pressure reaction (n = 313) and information on covariates , a total of 3803 subjects were included in the fully adjusted analyses . All methods were performed in accordance with the relevant guidelines and regulations.17. The compounds were annotated by matching to a library of more than 3300 purified standard metabolites or recurrent unknown entities. The library is based on authenticated standards that contains the retention time/index (RI), mass to charge ratio (m/z), and chromatographic data17. The missing values for each metabolite was imputed from the minimum value across all batches. In addition, each metabolite was assigned to broad biochemical classes, as well as to its specific biochemical class (metabolite sub-pathway). In our analyses, metabolites which were classified as drugs in the xenobiotics, were converted to present or absent. The metabolite levels were normalized by natural logarithm and the values were given in arbitrary units. Only annotated metabolites with a call rate > 75% and non-drug related xenobiotics were included in the analyses, resulting in 818 metabolites included, 96 of which were non-drug related xenobiotics.During the baseline examinations of SCAPIS, overnight fasting blood samples were drawn in the morning and then were stored at -80 ˚C until time of metabolomics analyses. In the study, non-targeted metabolomics  were performed on plasma samples. Samples were prepared by the automated MicroLab STAR® system from Hamilton Company . For the purposes of quality control, several internal standards were used prior to the extraction process. Proteins were precipitated with methanol and vigorously shaken for 2 min followed by centrifugation (Glen Mills GenoGrinder 2000) to remove proteins, dissociate small molecules bound to or trapped in the precipitated protein matrix, and to recover chemically diverse metabolites. The resulting extract was divided into five fractions: one for analysis by reverse phases (RP)/Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS) methods with negative ion mode electrospray ionization (ESI), one for analysis by HILIC/UPLC-MS/MS with negative ion mode ESI, two for analysis by two separate RP/UPLC-MS/MS methods with positive ion mode ESI, and one sample was reserved for backup. Raw data of metabolites were extracted, peak-identified and quality control-processed by Metabolon’s hardware and software which were described previously16.Orthostatic blood pressure reactions were calculated by subtracting the blood pressure after 3 min of standing up from the blood pressure measured after 5 min resting in the supine position measured in millimeter quicksilver (mmHg)2.Orthostatic hypotension (OH) was defined as decrease in systolic and/or diastolic blood pressure greater than 20/10 mmHg upon standingThe blood pressure was measured twice in supine position in both arms with an automatic device after 5 minutes of rest . The average of the two blood pressure recordings in the arm with the higher mean blood pressure was included in the analysis. For the recordings in the supine position, the arm was supported at heart level.2). Smoking status was obtained from questionnaires and ascertained as smokers and non-smokers. Diabetes was defined as previously known diabetes (self-reported) or by getting diagnosed during the examinations by an elevated fasting plasma glucose sample. Antihypertensive treatment was defined according to the answer of the questionnaire: “Have you been taking medicines for high blood pressure in the last 2 weeks?”. Detailed information on the methods used in the Malmö cohort of SCAPIS are found elsewhere16.Baseline information was collected during examinations. Body weight (kg) and standing height (meter) were measured without shoes. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/mContinuous variables are presented as means ± standard deviations (SDs) and categorical variables are shown as numbers, percentages . The associations between each metabolite  and orthostatic systolic blood pressure responses (dependent variable) were determined using multiple linear regression analysis. The multivariate models were adjusted for the potential confounders as follows: Model 1 was adjusted for age, gender and systolic blood pressure; Model 2 was additionally adjusted for BMI, diabetes, smoking status, and anti-hypertensive drug treatment.18. A Bonferroni corrected p value of maximum 6.11 × 10–5 (0.05/818) was considered as significant in the analyses of metabolites in model 1. Then we selected the metabolites significantly associated with orthostatic systolic blood pressure responses in model 1, to examine their relationships with additional adjustments in model 2. A Bonferroni-corrected p value < 2.273 × 10–3 (0.05/22) was considered as significant in model 2. In addition, we also explored the associations between all metabolites and manifest OH using logistic regression analysis. The same two models were conducted and the results are reported as OR with 95% CI. A p value of < 6.11 × 10–5 was regarded as statistically significant.Beta coefficients with 95% confidence intervals (Cis) are reported. Considering the number of metabolites (n = 818), we decided to use the Bonferroni correction to minimize the chance of false-positive findingswww.spss.com) and R studio (Version 1.3.1093).All the analyses were performed using IBM SPSS Statistics V.27 (2). Diabetes Mellitus was prevalent in 8.3%. Manifest orthostatic hypotension (OH) was present in 56 of 3803 recordings i.e. 1.5%. Systolic blood pressure was normal on average (122 ± 16 mmHg). A total of 14.4% were current smokers and 20.3% reported antihypertensive drug treatment.Characteristics of the study population are presented in Table Subjects that were excluded from the fully adjusted analyses (n = 2448) had a slightly higher prevalence of OH, higher resting blood pressure, and were slightly more likely to have diabetes and to be smokers .Significant results on associations between metabolites and orthostatic systolic blood pressure responses are depicted in Tables p value < 2.273 × 10–3).After additional adjustments for BMI, diabetes, smoking and antihypertensive treatment  whereas vitamins, cofactors and most amino acids showed positive beta coefficients in relation to orthostatic blood pressure responses  as well as a glutamine degradant, respectively , and fatty acid metabolism  pathways. Furthermore, of 3 amino acids that play a role in the creatine, the glutamate and the methionine, cysteine, SAM and taurine metabolism pathways, and a food/plant based component  is a sphingolipid that is found in 5–10% of cells and plays a role in membrane-related biological processes20. Excessive sphingomyelin was previously shown to be associated with insulin resistance20.Sphingomyelin is found mainly in membranous myelin sheaths and is suggested to be an insulator of nerve fibers. It has been discovered that it plays a role in cell signaling pathways, including apoptosisSphingosine and sphingadiene are the backbone of all sphingolipids. They and their derivatives are important second messengers involved in functions such as cell growth, differentiation, and apoptosis.21. In addition, recent studies have shown that the sphingolipid plasma S1P (Sphingosine-1-Phosphate) links to hypertension and biomarkers of inflammation and cardiovascular disease22. S1P has been shown to be released by circulating cells such as leukocytes, erythrocytes and blood platelets facilitated among others by the influence of inflammatory mediators such as TNF-alpha. In our study S1P wasn´t shown to associate with orthostatic blood pressure responses when adjusting for age, gender and supine systolic blood pressure. The role of sphingolipids in cell processes and sphingomyelin’s role as a nerve insulator could on the other hand be regarded as protective features against orthostatic hypotension.The negative association between sphingolipids and systolic orthostatic blood pressure decrease may possibly be explained by their previously shown association with high BMI, nonalcoholic fatty liver disease and insulin resistance23. In rodent studies, beneficial effects of dietary linoleic acid administration were found on insulin resistance and glucose tolerance24. Long-chain acyl fatty acid derivatives accumulate in the cytosol and serum of patients suffering from mitochondrial carnitine palmitoyltransferase II deficiency, the most common inherited disorder of lipid metabolism in adults. Carnitine plays a critical role in energy production. It transports long-chain fatty acids into the mitochondria so they can be oxidized to produce energy. It also transports the toxic compounds generated out of this cellular organelle to prevent their accumulation. Given these key functions, carnitine is concentrated in tissues like skeletal and cardiac muscle that utilize fatty acids as a dietary fuel25.Dihomo-linoleoylcarnitine was another metabolite associated with systolic orthostatic blood pressure response. Previous findings on dihomo-linoleic acid, obesity and metabolic health in humans are mixed26.We found one previous study about metabolic changes preceding cardiac dysfunction that showed an association between linoleoylcarnitine and hypertension and hypertension-induced left ventricular hypertrophy in rodentsIn our study dihomo-linoleoyl carnitine we found a positive association with systolic orthostatic blood pressure decrease.25. Phospholipid synthesis has been shown to be vital for cell survival, normal development and the maintenance of health. Alterations in phospholipid levels have previously been shown to be associated with lipid profiles, obesity and insulin resistance28and with hypertension as well as hypertension-induced left ventricular hypertrophy in rodents26.1-myristoyl-2-arachidonoyl-GPC is a metabolite of the phosphatidylcholine (PC) metabolism. Not much is known about this molecule, whereas three other metabolites of this pathway choline, trimethylamine N-oxide (TMAO), and betaine respectively, previously showed to predict risk for CVDWe found 1-myristol-2-arachidonoyl-GPC to be inversely associated with systolic orthostatic blood pressure decrease.In our study, three amino acids and one derivative showed association with systolic orthostatic blood pressure responses.29.Creatine is an amino acid that is most abundant in muscles, the heart and brain. Its primary role is to bind with inorganic phosphate in the cell to form phosphocreatine, and thereby serve as a high-energy phosphate source of energy to resynthesize adenosine triphosphate (ATP) that has been degraded to adenosine diphosphate (ADP) + Pi as a source of energy to fuel cellular metabolism. It increases cellular energy availability and is among other consumed by bodybuilders for muscle gain. It has also shown to be neuroprotective and is thought to have anti-inflammatory and immunomodulating effectsIn our study creatine had a negative association with systolic orthostatic blood pressure responses.30. We found it to be inversely associated with systolic orthostatic blood pressure decrease.Cysteine-S-sulfate is an abnormal metabolite discovered in the urine and blood of a patient with cysteine oxidase deficiency, a rare disorder of sulfur amino acid metabolism associated with brain damage and mental retardation31. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function. Symptoms of glutamine deficiency include increased susceptibility to infections, bowel changes, diarrhea, ulcers, and weight loss. A side effect of too high levels are vegetative symptoms, skin rash, muscle and joint pain and swelling of hands and feet.Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal musclesWe found glutamine and the glutamine degradant to have a positive association with systolic orthostatic blood pressure decrease.33 in humans. Blood pressure lowering effects were previously reported in animal experiments34.Metabolites of the glucuronidation of piperine pathway are a black pepper constituent which recently have shown to have antioxidant, anti-inflammatory, antidiabetic, anti-mutagenic, tumor-inhibiting, drug metabolism inhibiting and antidiarrheal properties17H21NO3 to have a negative association with systolic orthostatic blood pressure responses.We found glucuronide of piperine metabolite C18. The exploratory nature of our study also means, that the results should be confirmed in independent samples, and that the epidemiological and clinical impact of the results is yet to be determined. Still, we find the results valuable as a base for further studies.This is an exploratory study, meaning that we needed to apply correction for multiple testing. We chose the Bonferroni approach, which may be too conservative, however lowering the risk of type 1 error8. An increased prevalence of orthostatic hypotension is seen after the 6th decade and it is rising exponentially in the last decades of life1.Our findings are from the general population in the age group 50–64 years and may not be generalized to other age groups. Regarding the metabolome and cardio-metabolic health it would be interesting in future studies to compare the metabolome in young and healthy age groups with middle aged and old age groups. Cardio-metabolic disease develops and progresses throughout a lifetime and may become manifest in the age-group of the current study, at least as subclinical diseaseWe analyzed possible associations between orthostatic blood pressure responses as a marker of suggested autonomic dysfunction and 818 metabolites to cover as many pathways as possible. We only examined every metabolite for itself, so we did not test for any patterns of differences in clusters of metabolites.35. Impaired orthostatic blood pressure reactions36 as well as deep breathing tests37 have previously been shown to be associated with coronary artery calcium deposits in SCAPIS.It may be discussed, whether or not the subtle changes in orthostatic blood pressure adaptations, seen in this generally healthy population, reflects overt autonomic dysfunction. However, postural change in blood pressure is one of the five Ewing's tests, which have been used for assessing autonomic function for several decadesThe cross-sectional design limits the interpretation of the results: We cannot comment on the causes and effects of single metabolites on orthostatic blood pressure responses, but solely that an association exists. It is however known, that autonomic dysfunction in most cases is a consequence of cardio-metabolic disease.1. Nevertheless, the low prevalence is a limitation and it is hard to predict the reliability of just a single visit evaluation. Orthostatic hypotension is known to possibly be affected by acute and transient conditions like dehydration, hypoglycemia, fatigue and low blood count3. The reliability of single orthostatic blood pressure recordings should be assessed in future studies. It should also be mentioned, that more precise measurement of orthostatic blood pressure reactions, including the detection of transient orthostatic hypotension, can be achieved by a tilt-test with prolonged continuous blood pressure and heart rate monitoring in up to 20 min after tilting2.A methodological limitation is, that the orthostatic blood pressure responses were only measured once at 3 min after standing up, and there are no additional measurements to record possible delayed abnormal orthostatic blood pressure responses. The low prevalence of manifest orthostatic hypotension is in concordance with the prevalence found in earlier studiesAnother limitation is, that we in this exploratory study didn´t adjust for kidney and liver function and other conditions that could possibly influence the absorption, excretion, accumulation and half-life of the metabolites, and thereby the levels of measured concentrations.On the other hand, we managed to include a vast amount of metabolites in the analyses. The real effects of the metabolites found to associate with orthostatic blood pressure responses should now be addressed more thoroughly in future studies.Finally, since we assessed linear models in this study, we cannot rule out that some metabolites could be non-linearly related to orthostatic blood pressure reactions.In this exploratory study we found 22 metabolites, of which nine lipids, that were associated with orthostatic blood pressure responses. Of interest, eleven of these metabolites, including six lipids, four amino acids and one plant derivative, associated with orthostatic blood pressure responses after additional adjustment for traditional metabolic cardiovascular risk factors.Whereas the clinical importance of our findings is currently limited, we suggest, that these eleven metabolites and their pathways should be further investigated in order to enhance the understanding of the role of the metabolome in the association between cardiovascular disease and autonomic dysfunction.Impaired orthostatic blood pressure response is a very common phenomenon that increases with age. Even though this condition may often be asymptomatic, even a slightly impaired blood pressure response to standing may reflect underlying cardiovascular autonomic dysfunction, and such abnormalities are strongly associated with cardiovascular risk factors and incident cardiovascular disease.The metabolome is believed to harbor an enormous pool of novel valuable information on cardiovascular disease. Few studies have however investigated the human metabolome in relation to autonomic dysfunction. In this study, we identified eleven metabolites, that associated with impaired systolic orthostatic blood pressure reactions in a middle-aged population-based cohort.These eleven metabolites seem to be involved in diverse pathways, including metabolism, neuroprotection, inflammation and/or immunomodulation. Whereas based on an early exploratory study, we think that our current results may still guide future research of the human metabolome in relation to cardiovascular autonomic dysfunction. Ultimately, such studies may reveal new pathways that could be targeted for treatment.This study reveals eleven diverse metabolites that are independently associated with impaired orthostatic blood pressure reaction.What is new:An impaired orthostatic blood pressure reaction is a marker of subtle cardiovascular autonomic dysfunction, that are associated with cardiovascular risk. We here point to eleven specific metabolites that may be involved in this association.What is relevant:Our results may guide future research on the human metabolome in relation to cardiovascular autonomic dysfunction. Ultimately, such studies may reveal new pathways that could be targeted for prevention and treatment of cardiovascular disease.Clinical and pathological implications:Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.


The development of AKI (acute kidney injury) in critically ill patients in pediatric intensive care units (PICUs) is one of the most important factors affecting mortality. There are scoring modalities used to predict mortality in PICUs. We compared the AKIN (Acute Kidney Injury Network) and pRIFLE  AKI classifications and PICU scoring modalities in this study. Methods: A total of 716 children, whose serum creatinine levels were within the normal limits at the time of admission to the PICU between January 2018 and December 2020, were included. Along with the demographic and clinical variables, AKIN and pRIFLE classifications were recorded at the most advanced stage of AKI. Along with the PIM-2, PRISM III, and PELOD-2 scores, the highest value of the pSOFA score was recorded. Results: According to the pRIFLE and AKIN classifications, 62 (8.7%) patients developed kidney injury, which had a statistically significant effect on mortality. The occurrence of renal injury was found to be statistically strongly and significantly correlated with high PRISM III, PELOD-2, and pSOFA scores. When the stages of kidney injury according to the AKIN criteria were compared with the PRISM III, PELOD 2, and pSOFA scores, a significant difference was found between the patients who did not develop AKI and those who developed stage 1, stage 2, and stage 3 kidney injury. For the PRISM III, PELOD 2, and pSOFA scores, there were no significant differences between the stages according to the AKIN criteria. A substantial difference was discovered between the patients who did not develop AKI and those who were in the risk, injury, and failure plus loss stages according to the pRIFLE criteria. According to the PIM-2 ratio and pRIFLE criteria, there was a statistically significant difference between patients in the injury and failure plus loss stages and those who did not develop AKI. Conclusions: Our study is the first pediatric study to show a substantial correlation between the variables associated with the PICU scoring modalities in critically ill children with AKI. Identifying the risk factors for the development of AKI and planning antimicrobial regimens for patients with favorable prognoses at the time of PICU admission could lower mortality rates. Acute kidney injury (AKI) in children is a life-threatening clinical condition in which numerous organs and systems are impacted by a rapid decline in the glomerular filtration rate (GFR), accumulation of uremic toxins such as urea and serum creatinine (sCr), and deterioration of kidney structure and function over the course of hours or days. AKI is typically treatable, but in rare cases, it might progress to chronic kidney disease (CKD) ,2. The iTo diagnose AKI with a single definition, various classifications have been developed. A definition and categorization approach for AKI known as the risk, injury, failure, loss, and end-stage (RIFLE) criteria has been developed, and its application is now widely accepted . In the There are no previous publications about the relationship between mortality scoring systems and scores related to AKI. The purpose of this study was to examine whether or not there is a correlation between scores in the PICU among children diagnosed with AKI based on the AKIN and pRIFLE criteria.This was a single-center, retrospective, cross-sectional study of patients who were admitted to a tertiary PICU. Medical records of the 785 patients, who were aged between 1 month and 18 years and followed up in the PICU between January 2018 and December 2020, were evaluated. The exclusion criteria were high creatinine levels at admission due to any cause. This study was planned in accordance with the Helsinki Declaration decisions, patient rights regulations, and ethical committees, and approval from the ethics committee was obtained. Age, gender, the presence of underlying conditions, all medications, the presence of mechanical ventilation, length of PICU stay, and prognosis were noted from the medical records.All of the patients’ stages of acute kidney injury were determined using the pRIFLE and AKIN criteria. A total of five groups were formed by evaluating the decrease in GFR and changes in urine output within seven-day periods according to the pRIFLE criteria, in addition to the three stages of “risk,” “injury,” and “failure” according to the severity of AKI, and the two stages of “loss” and “end stage” according to the clinical outcome . Three s2, pO2, and total CO2 for acid–base balance, and serum glucose, potassium, creatinine, blood urea nitrogen, white blood cell count, platelet count, prothrombin time, and activated partial thromboplastin time in biochemical tests. It is an intensive care scoring system that is calculated by evaluating the first 24 h of intensive care unit admission. The PIM-2 score is calculated within the first hour of the patient’s admission to the intensive care unit. The PIM-2 score is calculated with the scores given according to the patient’s systolic blood pressure, pupillary response, FiO2 × 100/PaO2, baseline gap, need for mechanical ventilation, and hospitalization diagnosis. PELOD-2 and pSOFA scores are organ failure scores in which the highest value is recorded by evaluating the patient every 24 h during their stay in the intensive care unit. In pSOFA, PaO2/FiO2, SpO2/FiO2, platelets, bilirubin, mean arterial pressure, inotrope requirement, serum creatinine, and Glasgow coma score are evaluated. In PELOD-2, pupil response, serum lactate level, PaCO2, mechanical ventilation need, and white blood cell count are recorded and calculated. The PIM-2 score, which was computed using the data at the time of admission to the PICU, and the PRISM III score, which was derived using the patient’s data in the first 24 h of admission, were noted from the file records. Throughout the course of the PICU stay, the highest PELOD-2 and pSOFA values were determined every 24 h [The PRISM-III score includes systolic blood pressure, heart rate, body temperature, Glasgow coma score, and pupillary reflex, as well as acidosis, pH, pCOery 24 h ,12,13,14p-value of <0.05 was considered statistically significant.Statistical analysis: The statistical analyses were evaluated using the Statistical Package for Social Sciences . None of the continuous variables displayed a normal distribution, which was assessed using histograms, Q–Q plots, and the Shapiro–Wilk test. Continuous variables are presented as median (minimum to maximum) values. Variables that were categorized are displayed as frequency and percentage distributions. Comparisons between two groups and more than two groups were performed using the Mann–Whitney U test, the Kruskal–Wallis test, the chi-square test, or the Fischer’s exact test. The Spearman correlation coefficient test was used for correlations. In the multivariate analysis, the variables that were shown to have a statistically significant impact on mortality and kidney injury outcomes in the univariate analysis were included as covariates using a forward logistic regression model. A In total, 785 PICU admissions between January 2018 and December 2020 were evaluated. Fifty-nine children with high creatinine levels at admission and ten children with incomplete medical records were excluded from the study. Finally, the medical records of 716 children (346 girls and 370 boys) aged between 1 month and 218 months (median: 47 months) were analyzed. The median length of stay in the PICU was 4 days (0–746 days). Of the 716 children, 29.9% (n = 214) needed mechanical ventilation, 76.6% of the patients who needed mechanical ventilation needed invasive mechanical ventilation, and 23.4% needed non-invasive mechanical ventilation. The most common primary diagnoses for hospitalization in the PICU were a lower respiratory tract infection (24.4%), intoxication (13.9%), and seizures (11.7%). The mortality rate was 8.5% (n = 61). A total of 577 (80.6%) patients had only one primary diagnosis, compared to 119 (16.6%), 16 (2.2%), 3 (0.4%), and 1 (0.1%) who had two, three, four, and five primary diagnoses, respectively. More than half of the patients  had no previous or additional comorbidities at admission. One comorbidity was present in 221 (30.9%) individuals, two were present in 79 (11%), three were present in 20 (2.8%), and four were present in 2 (0.3%). The most prevalent comorbidity was neurological disorders , followed by genetic syndromes  and gastrointestinal disorders .p < 0.001). AKI patients were significantly younger (p < 0.01), and boys had significantly higher levels (p < 0.05) (p < 0.001) and the number of comorbidities (p < 0.001) were found to be higher. In patients with kidney injury, mechanical ventilation (p < 0.001) and invasive mechanical ventilation (p < 0.001) requirements were significantly higher (p < 0.001) in patients with kidney injury (p < 0.001), PELOD 2 (p < 0.001), pSOFA (p < 0.001), and PIM 2 (p < 0.001) scores were also higher in patients with kidney injury (p < 0.001), antifungals (p < 0.001), antiepileptics (p < 0.05), steroids (p < 0.001), inotropes (p < 0.001), proton pump inhibitors (p < 0.001), sedative drugs (p < 0.001), paracetamol/acetyl salicylic acid (p < 0.001), ibuprofen (p = 0.001), opioid analgesics (p < 0.001), diuretics (p < 0.001), antihypertensive medications (p < 0.001), antiarrhythmics (p < 0.001), ketoprofen (p < 0.05), and vasopressin (p < 0.001) was found to be significantly higher  of the patients had an acute kidney injury. According to the pRIFLE criteria, 17 (2.4%) patients were at risk for kidney injury, while 28 (3.9%) patients had an injury, 16 (2.2%) patients had a failure, and 1 (0.1%) patient had a loss. According to the AKIN criteria, 19 (2.7%) patients were stage 1, 28 (3.9%) patients were stage 2, and 15 (2.1%) patients were stage 3. A strong correlation was found between the pRIFLE and AKIN criteria  . In patiy higher . The leny injury . The PRIy injury . In patiy higher .p 0.001). In patients with kidney injury, however, the rates of using antifungals with antibiotics (p 0.001) and antivirals and antifungals together with antibiotics (p = 0.015) were significantly higher. In the subgroup analysis of the effect of antibiotics on kidney injury, in patients with kidney injury, carbapenem (p < 0.001), macrolide (p = 0.003), glycopeptide (p < 0.001), beta-lactam (p = 0.009), cephalosporin (p = 0.014), penicillin (p < 0.001), colistin (p < 0.001), aminoglycoside (p < 0.001), glycylcycline (p < 0.001), quinolone (p < 0.001), lincosamide (p < 0.001), and sulfonamide/cotrimaxazole (p < 0.001) usage rates were found to be significantly higher (p < 0.001) and the AKIN stage . In total, 47% of the patients who did not survive had kidney injury, compared to only 5% of the patients who did survive (p < 0.001). According to the pRIFLE (p < 0.001) and AKIN criteria (p < 0.001), a significant proportion of patients with mortality were found to have a more advanced stage of AKI , comorbidities (p < 0.001), a longer length of hospital stay (p < 0.001), and increased PRISM III (p < 0.001), PELOD-2 (p < 0.001), pSOFA (p < 0.001), and PIM-2 (p < 0.001) scores . There was a significant difference between patients with and without kidney injury (p < 0.05) and those in stages 2 and 3 (p < 0.01). While a significant difference was found between stages 1 and 3 (p < 0.05), there was no significant difference between stages 1 and 2 (p > 0.05) and between stages 2 and 3 (p > 0.05). When the subgroup analysis considered the length of hospital stay, there was a significant difference between patients who did not develop kidney injury and those with stage 1 (p < 0.001), stage 2 (p < 0.001), and stage 3 (p < 0.001) kidney injury according to the AKIN criteria.According to the AKIN criteria, there was no significant difference in age between patients with and without kidney injury  in patients who did not develop kidney injury, 5 (0–40) in kidney injury stage 1 patients, 4 (0–35) in stage 2 patients, and 5 (0–41) in stage 3 patients.p = 0.045), stage 2 (p = 0.003), and stage 3 (p = 0.020) kidney injury. There was no significant difference between stages 1 and 2 (p = 0.922), between stages 1 and 3 (p = 0.754), and between stages 2 and 3 (p = 0.817)  A.p = 0.002), stage 2 (p < 0.001), and stage 3 (p < 0.001) kidney injury. However, there was no significant difference between stage 1 and 2 kidney injuries (p = 0.242), between stage 1 and 3 kidney injuries (p = 0.267), and between stage 2 and 3 kidney injuries (p = 0.768). This was seen when the medians of the PELOD-2 score were compared according to the stages of kidney injury ; for stage 1 patients, it was 10 (0–60); for stage 2 patients, it was 11 (0–42); and for stage 3 patients, it was 11 (0–52). When the medians of the PELOD 2 score were compared with the stages of kidney injury according to the AKIN criteria; there was a significant difference between patients who did not develop kidney injury and those who developed stage 1 (y injury B.p < 0.001), stage 2 (p < 0.001), and stage 3 (p < 0.001) kidney injury. While there was a statistically significant difference between stages 1 and 2 (p = 0.231), there was no statistically significant difference between stages 1 and 3 (p = 0.113), and between stages 2 and 3 (p = 0.490) , followed by 6 (0–15), 11 (0–42) for stage 1 patients, 11 (0–42) for stage 2 patients, and 11 (0–52) for stage 3 patients. According to the AKIN criteria, there was a statistically significant difference between patients who did not develop kidney injury and those who developed stage 1 (= 0.490) C.p = 0.117) kidney injury when the stages of kidney injury were compared with the medians of the PIM-2 score. There was a significant difference between patients without kidney injury and patients with stage 2 (p = 0.001) and stage 3 (p = 0.001) kidney injury. There was no significant difference between stage 1 and 2 kidney injuries (p = 0.340), between stage 1 and 3 kidney injuries (p = 0.224), and between stage 2 and 3 kidney injuries (p = 0.610)  in patients who did not develop kidney injury, 1.2 (0.2–63.3) in stage 1 patients, 2.1  in stage 2 patients, and 4.4 (0.2–42.3) in stage 3 patients. According to the AKIN criteria, there was no significant difference between the patients who did not develop renal injury and those who developed stage 1 (= 0.610) D.p > 0.05). There was a statistically significant difference between the individuals with failure plus loss (p = 0.001) and those without kidney injury (p > 0.05). The risk and injury stages and risk and failure plus loss stages did not differ significantly (p > 0.05), but the risk and failure plus loss stages did differ significantly (p > 0.05), in terms of the length of PICU stay. According to the pRIFLE criteria, there was a significant difference in the length of PICU stay between patients with and without kidney injury (p = 0.001), injury (p = 0.001), and failure plus loss (p = 0.001). For the duration of PICU stay, there was no statistically significant difference between the risk and injury (p > 0.05), risk and failure plus loss (p > 0.05), or injury and failure plus loss (p > 0.05) stages.In terms of the age-related subgroup analysis, the pRIFLE criteria revealed no statistically significant difference between patients with and without kidney injury (p = 0.076) and patients without kidney injury when the stages of renal injury were compared with the medians of the PRISM III score. Patients with and without renal injury were significantly different from each other in the injury (p = 0.004) and failure plus loss (p = 0.008) stages. The stages of risk and injury (p = 0.878), risk and failure plus loss (p = 0.616), and injury and failure plus loss (p = 0.620) did not significantly differ from one another , while it was 4 (0–40), 4.5 (0–35), and 5 (0–41) for patients in the risk, injury, and failure plus loss stages, respectively. According to the pRIFLE criteria, there was no significant difference between the risk group ( another A.p = 0.002), injury (p < 0.001), and failure plus loss (p < 0.001) stages of kidney injury. However, the stages of risk and injury (p = 0.357), risk and failure plus loss (p = 0.304), and injury and failure plus loss (p = 0.672) did not significantly differ from one another , while it was 10 (0–60) for the risk stage, 11 (0–42) for the injury stage, and 11 (0–52) for the failure plus loss stage. When the stages of kidney injury according to the pRIFLE criteria were compared with the medians of the PELOD 2 score, there was a significant difference between the patients without kidney injury and the risk ( another B.p < 0.001), injury (p < 0.001), and failure plus loss (p < 0.001) stages when the medians of the kidney injury stages and the pSOFA score were compared. The risk and injury stages (p = 0.274) and injury and failure plus loss stages (p = 0.254) did not significantly differ from one another, whereas the risk and failure plus loss stages (p = 0.049) did , while it was 6 (0–15) in the risk stage, 8 (0–22) in the injury stage, and 9 (1–16) in the failure plus loss stage when taken into account in the subgroup analysis. According to the pRIFLE criteria, there was a significant difference between patients without kidney injury and patients with kidney injury in the risk (049) did C.p = 0.119) stage when the stages of renal injury were compared with the medians of the PIM-2 score. In both the injury (p = 0.003) and failure plus loss (p 0.001) stages, the difference between patients with and without renal injury was statistically significant. The stages of risk and injury (p = 0.598), risk and failure plus loss (p = 0.190), and injury and failure plus loss (p = 0.261) did not significantly differ from one another (The median PIM-2 score was found to be 1 (0.1–79) in patients without kidney injury, 1.2 (0.2–63.3) in the risk stage, 1.5 (0.2–97.7) in the injury stage, and 4.4 (0.2–42.3) in the failure plus loss stage when taken into account in the subgroup analysis. According to the pRIFLE criteria, there was no significant difference between patients without kidney injury and patients with kidney injury in the risk  and increases morbidity and mortality. Patients with AKI who have recently recovered are at risk of long-term renal complications. Identifying patients at risk and taking necessary precautions are important public health goals to prevent long-term complications of AKI ,16. It hIn our study, younger age, the number of comorbidities, the development of kidney injury, and the use of carbapenem, cephalosporin, penicillin, and glycylcycline were found to have a significant effect on mortality, and it was also found that the pSOFA score was significantly associated with mortality. In our study, 47% of the children who died had AKI, while only 5% of the children who survived had AKI. In studies conducted in PICUs, varying mortality rates have been reported in patients who developed AKI. According to the pRIFLE criteria, Gupta et al.  reportedThe occurrence of renal injury was found to be statistically strongly and significantly correlated with high PRISM III, PELOD-2, and pSOFA scores. When the stages of kidney injury according to the AKIN criteria were compared with the PRISM III, PELOD 2, and pSOFA scores, a significant difference was found between the patients who did not develop AKI and those who developed stage 1, stage 2, and stage 3 kidney injury. For the PRISM III, PELOD 2, and pSOFA scores, there were no significant differences between the stages according to the AKIN criteria. According to the AKIN criteria, 60.2% of the patients in a prospective study involving 108 patients in adult intensive care units were found to have AKI, and both the incidence of AKI and ICU mortality were higher among patients with a SOFA score above nine . A substAccording to the PIM-2 ratio and the pRIFLE criteria, there was a statistically significant difference between patients in the injury and failure plus loss stages and those who did not develop AKI. In a study that looked at 126 patients in a pediatric intensive care unit, according to the pRIFLE criteria, patients who had AKI had higher median PIM-2 scores in escalating phases . A substThis study has some limitations. For instance, this was a retrospective, single-center study, and our center is a tertiary care PICU where patients with underlying diseases are more likely to be admitted.Our study is the first pediatric study to demonstrate the relationship between the AKIN and pRIFLE AKI classifications and the PRISM III, PIM-2, PELOD-2, and pSOFA scores, which are commonly used in pediatric intensive care units to assess mortality risk in critically ill children without kidney disease. It is believed that identifying the risk factors for the development of AKI and planning antimicrobial regimens for patients with favorable prognoses at the time of intensive care unit admission could lower mortality rates. Further new studies including new parameters for the evaluation of kidney damage in intensive care units are needed.