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Article Contents

Introduction, search strategy, dehydration, urological disorders, gastrointestinal disorders, circulatory disorders, mitral valve prolapse, neurological disorders, metabolic disorders, respiratory disorders, pregnancy and breastfeeding, other conditions, hydration status and drugs, overhydration and fluid overload, acknowledgments.

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Acute and chronic effects of hydration status on health

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Ahmed M. El-Sharkawy, Opinder Sahota, Dileep N. Lobo, Acute and chronic effects of hydration status on health, Nutrition Reviews , Volume 73, Issue suppl_2, 1 September 2015, Pages 97–109, https://doi.org/10.1093/nutrit/nuv038

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Maintenance of fluid and electrolyte balance is essential to healthy living as dehydration and fluid overload are associated with morbidity and mortality. This review presents the current evidence for the impact of hydration status on health. The Web of Science, MEDLINE, PubMed, and Google Scholar databases were searched using relevant terms. Randomized controlled trials and large cohort studies published during the 20 years preceding February 2014 were selected. Older articles were included if the topic was not covered by more recent work. Studies show an association between hydration status and disease. However, in many cases, there is insufficient or inconsistent evidence to draw firm conclusions. Dehydration has been linked with urological, gastrointestinal, circulatory, and neurological disorders. Fluid overload has been linked with cardiopulmonary disorders, hyponatremia, edema, gastrointestinal dysfunction, and postoperative complications. There is a growing body of evidence that links states of fluid imbalance and disease. However, in some cases, the evidence is largely associative and lacks consistency, and the number of randomized trials is limited.

Maintenance of fluid and electrolyte balance is essential to healthy living and is particularly important in periods of ill health. Dehydration, overhydration, and salt and water overload have been associated with morbidity and mortality, with older adults being at increased risk. 1–3 Warren et al. 1 reported a 17%, 30-day mortality in older patients with a principal diagnosis of dehydration, per the International Classification of Diseases, 9th Revision, with the 1-year mortality rate approaching 50%. Moreover, a heat wave that affected France in 2003 resulted in a 142% increase in mortality in Paris. 4 , 5 Most deaths occurred in vulnerable groups and resulted from heat-related illnesses, including dehydration. 4 Overhydration, particularly in individuals susceptible to water retention, is reported most commonly as a consequence of iatrogenic salt and water overload 2 , 6 but has also been seen in endurance athletes. 7

At the cellular level, minor changes in cellular water content result in significant alterations in cell metabolism and function, mediated by changes in cell volume. 8 , 9 Cell swelling stimulates protein and glycogen synthesis, and cell shrinkage stimulates proteolysis and glycogen breakdown, with both pathways leading to the production of osmotically more active substances. 9 There is also evidence supporting the effects of cell volume on gene and protein expression, such as heat shock protein expression and antidiuretic hormone (ADH) stimulated by cell shrinkage. 8 In view of this and other reports linking fluid imbalance and disease, the European Food Safety Authority recommends a daily fluid intake of 2.5 L for men and 2.0 L for women to maintain urinary osmolarity of 500 mOsmol/L. 10 However, these guidelines 10 are based on limited evidence.

This narrative review of the published scientific literature presents the current evidence base for the impact of hydration status on human health.

The Web of Science, MEDLINE, PubMed, and Google Scholar databases were searched for relevant studies published during the 20 years preceding February 2014 using the following terms along with the Boolean operators “AND” and “OR”: hydration, dehydration, overhydration, fluid overload, fluids, and disease. The titles of the publications that resulted from the search were reviewed initially. If they were deemed suitable, then the abstracts were reviewed and, if suitable, the full manuscripts were reviewed. Human studies and studies with clinically relevant outcomes were preferentially selected; animal studies were also eligible for inclusion when human data ware not available.

Randomized controlled trials and large cohort studies were selected preferentially; other relevant studies were also eligible for inclusion when the preferred study types were not available. The bibliographies of extracted papers were searched for relevant publications. Older articles identified in this manner were included if the topic was not covered by more recent work.

A state of dehydration occurs with excess loss of total body water and is often associated with electrolyte abnormalities, particularly dysnatremias. Hypertonic dehydration occurs when proportionally more water than sodium is lost from the extracellular fluid compartment. This may occur, e.g., as a result of age-related thirst impairment, which is seen in older adults. Hypotonic dehydration, on the other hand, occurs when the proportion of sodium lost is greater than the proportion of water lost. This may occur with the use of diuretics or in burn victims. Isotonic dehydration results from proportionate loss of water and sodium, and results in normal serum sodium concentrations. This may occur as a result of diarrhea, where there is salt and water loss in equivalent proportions. Common causes of isotonic, hypotonic, and hypertonic dehydration are listed in Table 1 . The level of evidence 11 for the effect of hydration status on disease states is summarized in Table 2 .

Common causes of isotonic, hypotonic, and hypertonic dehydration

a Depending on electrolytes lost.

Summary of the evidence linking dehydration and overhydration to health disorders

a Level of evidence (based on the Oxford Centre for Evidence Based Medicine, 2009) 11 : Ia, systematic reviews (SRs) of RCTs with homogeneity; Ib, individual RCT with narrow confidence interval and >80% follow-up; IIa, SR of cohort studies with homogeneity; IIb, low-quality RCTs and large cohort studies; III, SR of case-control studies with homogeneity or individual case-control studies; IV, case series and poor cohort and case-control studies; V, expert opinion.

Abbreviations : CHD, coronary heart disease; DVT, deep vein thrombosis; MVP, mitral valve prolapse; RCT, randomized controlled trial; UTI, urinary tract infection.

Urinary tract infections

Urinary tract infections (UTIs) are considered the most common bacterial infections and can result in permanent renal scarring in up to 60% of affected children. 12 , 13 The evidence linking hydration status to UTIs is far from conclusive. 14 Increased fluid consumption results in increased urine output and reduced serum and urine osmolality. Animal models have demonstrated that in the proximal urinary tract, high urine volume and flow reduces the antimicrobial load; low urine osmolality provides a more favorable environment for immune cell activity and, therefore, may be protective against pyelonephritis. 14 , 15 However, in the distal urinary tract, concentrated urine with high osmolality may be a protective factor and does not favor bacterial growth in the lower urinary tract. 16–18 Roberts et al. 19 demonstrated that diuresis and increased voiding frequency significantly reduced the bacterial count in female patients with proven lower UTI, although other studies have found no significant difference. 14 , 20

Studies investigating the effects of increased fluid consumption on UTI have also reported conflicting results. Nygaard and Linder 21 reported that half of the 791 female teachers studied avoided drinking during work and were at a 2.2-fold increased risk of UTI. Eckford et al. 22 showed that increased fluid consumption may reduce the risk of UTI in women with a recent history of at least 2 idiopathic infections. In this crossover study, half of the participants were encouraged to consume water, aiming for a urine specific gravity of <1.015 for 4 months before crossover. The authors reported a significant reduction in incidence of UTIs in the group who measured their urine-specific gravity. Pitt 23 also demonstrated that the self-reported fluid consumption of patients with a history of UTIs was half that of the control group (2 glasses/day vs 4 glasses/day). Others have failed to report significant differences in self-reported fluid consumption between UTI patients and controls. 24 , 25

Despite the inconsistent evidence, some expert committees recommend increased fluid intake in patients with UTIs as a measure of prophylaxis as well as treatment, particularly in children with recurrent infections. 26

Urolithiasis

Urolithiasis occurs in up to 10% of the population, with a lifetime recurrence rate of up to 80%. 27 Currently, there is good evidence supporting the link between chronic dehydration and urolithiasis. 28 A study of healthy volunteers demonstrated that consumption of an additional 1.3 L of fluid was associated with reduced risk of crystallization. 28 Increased water intake and associated urinary dilution also resulted in a marked reduction in lithogenic salts. 29 Furthermore, epidemiological studies have shown an association between dehydration and urolithiasis, with a higher incidence being reported in hot climates and during summer months. 30 , 31 This association was further supported by a retrospective cohort study of steelworkers. The study compared the incidence of urolithiasis in hot-area workers with the incidence in those working at room temperature. 32 This study demonstrated that there was a greater prevalence of urolithiasis in those working in hot areas, with those working at high temperatures having a 9-fold increased risk of urolithiasis. 32 Other large population studies have reported that increased fluid intake was inversely associated with stone formation. 33 The strongest evidence, however, shows that increased fluid consumption reduces the risk of stone recurrence. 34 Borghi et al. 34 randomized patients following the development of their first stone to receive a higher intake of water, aiming for a urine output of more than 2 L/day (group 1), or to receive no intervention (a control group, group 2). The authors reported a significant reduction in the recurrence rates of urolithiasis (12.1% in group 1 vs 27.0% in group 2) and increased time to recurrence in the intervention group (38.7 ± 13.2 months in group 1 vs 25.1 ± 16.4 months in group 2). 34

Given the evidence, international guidelines currently recommend increased fluid intake to produce 2–3 L of urine per day as a prophylactic measure for recurrent urolithiasis. 27 , 35

Chronic kidney disease

Chronic kidney disease (CKD) is a progressive condition that leads to fibrosis and scarring of the kidney. Dehydration resulting in increased serum osmolality stimulates the release of ADH from the hypothalamus, increasing water reabsorption in the kidney. ADH also results in peripheral vasoconstriction and renal blood flow redistribution, which may lead to progression of existing CKD. 36 It is also proposed that maintaining a state of euhydration reduces plasma ADH and is, therefore, protective against renal damage.

Studies looking into the role of increased fluid intake and CKD are inconsistent. Some researchers have reported a protective role of increased urine output on the rate of decline in estimated glomerular filtration rate. 37 Strippoli et al. 38 also demonstrated an inverse relationship between water intake and the risk of developing CKD, with those consuming 3.2 L of fluid a day being at lower risk than those who consumed 1.8 L/day (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.32–0.77). However, other researchers have reported increased renal function loss with increased urine volume production in individuals with established CKD. 39 , 40

Bladder cancer

Bladder cancer is the seventh most common cancer in the United Kingdom, with an age-standardized 5-year survival rate of 58.2% for men and 50.2% for women. 41 There is conflicting evidence on the effects of increased fluid consumption on bladder cancer, with the body of evidence suggesting that there is no clear relationship. 42–44 The urogenous theory suggests that the development of bladder cancer is influenced by prolonged exposure to carcinogens in the urine. 45 The theory suggests that increased fluid consumption results in increased urine dilution and voiding frequency, leading to reduced carcinogen contact time with the bladder wall. 46 This is supported by experiments in dogs in which known human bladder carcinogens were administered. 47 The authors reported that increased voiding frequency resulted in a significant reduction in urothelial DNA adducts, likely due to reduced contact time with the carcinogen. 47

Several studies have demonstrated an inverse relationship between increased fluid consumption and increased urinary frequency, particularly nocturia and bladder cancer. 48 , 49 However, others have reported an increased risk of bladder cancer in association with increased fluid consumption. 42 , 43 In many of these studies, however, the increased risks of bladder cancer are attributed to other beverages (tea, coffee, alcohol) or tap water with high chloride content, but not bottled water. 42 , 50 , 51

Functional constipation

Constipation is characterized by the passage of infrequent hard stools. Fluid balance is thought to be necessary to maintain stable bowel function, although the evidence is inconsistent. There are reported associations between a chronic state of dehydration and constipation, especially in the elderly. 52 It is postulated that in a state of dehydration, there is increased fluid absorption from the stool, which may lead to hard stool and reduced stool output. Moreover, adequate hydration is considered to be important in stool consistency and maintaining bowel motility. 53

A randomized crossover study in healthy male volunteers demonstrated that low fluid intake may be an etiological factor in chronic constipation. 54 The study participants were prescribed standardized nutritional and physical activity and randomized to 0.5 L or 2.5 L of fluid per day for 1 week followed by a crossover after a 2-week washout period. The authors demonstrated that during the period of fluid restriction, there was a significant reduction in stool weight and frequency as well as an increased tendency toward constipation. Moreover, bowel function returned to normal when the fluid-restricted group returned to normal fluid consumption. However, the authors did not report any differences in bowel transit time. 54 There is also evidence suggesting that increased water consumption enhances the effects of a high-fiber diet on stool frequency and reduces laxative consumption in adult patients with functional constipation. 55 In addition, increased water consumption has also been shown to improve bowel function in children who use osmotic laxatives for functional constipation. 56 Others, however, have shown no effect of increased fluid consumption on constipation. 57

Although many clinicians and clinical guidelines recommend increasing fluid consumption for the treatment of constipation, the evidence is clear only in the case of patients with both constipation and dehydration. 58

Colorectal cancer

Colorectal cancer is the third most common cancer in the United Kingdom, with a 50% 5-year survival rate. 59 There is limited evidence supporting the theory that increased water consumption reduces the risk of colorectal cancers, particularly distal tumors. It is thought that increased fluid consumption may decrease bowel transit time and, therefore, limit the contact time of carcinogens with the bowel mucosa. 60 Animal models have demonstrated that increased bowel transit time and constipation are significant risk factors for colonic neoplasia due to prolonged contact time with carcinogens. 60 Shannon et al., 61 in a retrospective case-control study, observed that increased water ingestion was inversely associated with the risk of colon cancer. The association was strongest among women who drank 5 or more glasses of water per day relative to those who drank 2 glasses of water per day (OR, 0.55; 95% CI, 0.31–0.99). Among men, the association was less marked (OR, 0.68; 95% CI, 0.38–1.22). 61 Other retrospective case-control studies have demonstrated a strong inverse dose–response relationship between increased water intake and rectal cancer among men after adjustment for other risk factors. However, no differences were observed in women in these studies. 62 , 63

Gallstones affect 10%–15% of adults in the Western world and, although often asymptomatic, can cause serious health complications. 64 It is well reported that biliary stasis is a major risk factor for the development of gallstones. 65 , 66 Water consumption has been shown to induce gallbladder contraction and emptying. 67 , 68 Yamamura et al. 68 demonstrated in healthy volunteers that 400 mL of water resulted in a gallbladder ejection fraction of 33.5 ± 4.2% 20 min after ingestion. Therefore, in theory, this may protect against gallstone formation. 69 However, a direct relationship has yet to be demonstrated, and further studies are needed.

Dehydration has been shown to result in increased plasma viscosity, which is a risk factor for thrombogenesis. 70 , 71 Patients with underlying hematological disorders that predispose to hyperviscosity syndrome, such as myeloma and polycythemia, are, therefore, at increased risk. 72 Exercise-induced dehydration and hyperthermia have also been linked to mortality in sickle cell disease, thought to be a consequence of dehydration that triggers erythrocyte adhesion and vascular occlusion. 73 , 74 Other studies have reported that normal erythrocytes, when dehydrated, display adhesive properties similar to those seen in sickle cell disease. 74

Deep vein thrombosis

Deep vein thrombosis (DVT) affects 1 in 1000 annually and can lead to pulmonary embolism, which can be life threatening. 75 There is limited evidence to support a direct link between dehydration and DVT. Markers of dehydration, including serum osmolality of >297 mOsm/kg and urea-to-creatinine ratio (mmol:mmol) >80, were shown to be associated with a significantly increased risk of DVT in hospitalized patients following an acute ischemic stroke. 76 Some studies have demonstrated that prehydration reduces plasma viscosity and may be protective against DVT associated with long airplane flights. 77

There is insufficient evidence to conclude a strong association between dehydration and DVT; however, expert committees and national guidelines recognize dehydration as a risk factor. 75

Cerebral infarct

Stroke is associated with morbidity and mortality, often with significant physical and psychosocial impact on the patient and his or her family. There is limited evidence linking dehydration to the development of stroke or indeed poor outcome after stroke. In theory, the risk of increased plasma viscosity associated with dehydration may predispose to stroke in a way that is similar to other thrombogenic conditions, particularly in patients with underlying atherosclerosis or those prone to hyperviscosity syndrome. 78 , 79 Tohgi et al. 79 reported that postmortem examinations of older adults revealed that high hematocrit values were associated with a higher risk of cerebral infarction in deep subcortical structures of the brain. The incidence in those with hematocrit values >51% was 9.6 times greater than that for patients with hematocrit values <30%. 79 Furthermore, it is important to note that a significant proportion of patients are at risk of ongoing dehydration following stroke, particularly in the presence of dysphagia. 75 Rodriguez et al. 80 also demonstrated in the THIRST (The Hydration Influence on the Risk of Stroke) study that patients admitted to the hospital with ischemic stroke had higher osmolarity than age- and gender-matched patients.

Some studies have also shown a link between markers of dehydration, including raised plasma osmolality and hematocrit, with increased risk of stroke morbidity and mortality. 81–83 Moreover, in patients with ischemic stroke, the best discharge outcome has been shown to be associated with an initial mid-range hematocrit value. 81–83

Coronary heart disease

Coronary heart disease (CHD) is the most common cause of death in the United Kingdom. 84 There is limited evidence that links dehydration to CHD. Whole-blood viscosity and plasma viscosity are recognized risk factors for myocardial infarction and have been shown to increase with dehydration. 85

Chan et al., 85 in the prospective cohort Adventist Health Study, investigated the association between fatal CHD and intake of water and other beverages. Participants without known heart disease (8280 male and 12 017 female) were followed up for 6 years. The authors reported a significant relative risk reduction in fatal CHD events in participants who drank 5 or more glasses of water/day compared with those who drank 2 or fewer glasses. Other studies, however, have reported no association between increased fluid intake and CHD. 86 Jan et al. 87 demonstrated that in patients admitted to the hospital with myocardial infarction, high plasma viscosity on admission was associated with a higher incidence of complications. The authors also reported that 80% of the patients studied had a reduced fluid intake post myocardial infarction, predisposing them to dehydration. 87

Orthostatic hypotension

Orthostatic or postural hypotension is defined as a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg from the sitting or supine position to standing up. It results from an inadequate physiological response to postural changes in blood pressure. Volume depletion and autonomic dysfunction are common causes of orthostatic hypotension, which can result in cerebral hypoperfusion and syncope. 88 Webber et al. 89 reported that dehydration was one of the most common causes of orthostatic hypotension and syncope in US Air Force trainees. Moreover, increased fluid consumption prior to blood donation has been shown to help relieve some of the presyncopal side effects. 90

Adequate hydration is particularly important in older adults, where there is a high prevalence of falls, which often result in serious injury. Although there is limited evidence directly showing reduced risk of falls in response to increased fluid consumption, adequate hydration is recommended by healthcare professionals. 91

Mitral valve prolapse (MVP) is an abnormal bulging of 1 or both of the mitral valve leaflets into the left atrium during ventricular systole. 92 It is associated with decreased left ventricular volume. 93 , 94 Lax et al. 94 induced mild dehydration using 20 mg of furosemide in 10 healthy male volunteers with normal baseline echocardiograms, reporting MVP in 1 of 10 participants, which resolved with hydration. 94 However, in patients with preexisting MVP, the same group demonstrated no impact from ingesting 1 L of fluid. 95

Maintenance of a well-hydrated state is important to maintaining normal brain function. Dehydration has been linked to headache and cognitive impairment, although the evidence is inconclusive. Moreover, there is evidence linking dehydration to changes in brain morphology. Several studies have reported that acute dehydration resulted in increased ventricular size proportional to body weight loss. 96 , 97 Kempton et al. 96 also reported functional brain changes that were associated with acute dehydration in healthy adolescents. These findings are particularly relevant to patients with underlying neurological disorders.

Delirium, a state of acute confusion, has also been linked to dehydration. There is inconsistent evidence from healthy volunteer studies demonstrating a link between dehydration and cognitive impairment. Dehydration of as little as 2% of total body weight is detrimental to physical, visuomotor, psychomotor, and cognitive performance. 98 , 99 Voyer et al. 100 reported an inverse relationship between water consumption and delirium in residents of long-term care facilities and showed that the risk of delirium is reduced by 33% with each additional glass of water consumed. Another study also showed that dehydration is a risk factor for delirium in hospitalized older adults. 101 Moreover, Lawlor et al. 102 investigated reversible causes of delirium in patients with advanced cancer and reported an association between dehydration and delirium reversibility. However, in the presence of other confounders, this failed to reach statistical significance. 101 In keeping with some of the evidence, national guidelines recommend adequate hydration in patients with delirium. 103

Headache, which has many underlying causes, is one of the most common presentations to general practice physicians in the United Kingdom. There is inconsistent evidence linking dehydration as a cause of headache; however, there is stronger evidence indicating that increased fluid consumption may help relieve some forms of headache. Studies of healthy volunteer have demonstrated that water deprivation results in headache that resolves with rehydration. 104 , 105 Dehydration is also thought to cause postdialysis and alcohol consumption headache. 106–108

In a study by Spigt et al. 109 in which 18 patients with headache were assigned either placebo medication or a 1.5-L increase in daily water intake, no significant differences were observed in the number of headache episodes; however, there was a reduction in headache intensity and duration. A more recent randomized controlled trial demonstrated that increased water consumption of 1.5 L/day in patients with a previous history of headache improved migraine-specific quality-of-life scores. 110 However, no significant changes were observed in headache frequency and duration. 110

Despite the limited evidence, the British Association for the Study of Headache recommends that good hydration be maintained in patients with medication overuse headache and that intravenous fluid therapy be used to help treat patients with migraine. 111

Diabetes mellitus

Diabetes mellitus is a recognized risk factor for dehydration in the context of hyperglycemia, given the osmotic effects of glucose. Raised serum osmolality on admission has been shown to correlate with poor outcome in children admitted with diabetic ketoacidosis. 112 There is also some evidence highlighting a potential protective effect of increased water consumption on the development of hyperglycemia. Roussel et al. 113 tested the fasting glucose of 3615 French men and women aged 30–65 years with a normal fasting glucose at baseline and followed up with them for 9 years. The authors reported an inverse association between water consumption and the development of new-onset hyperglycemia, despite accounting for known risk factors. However, it is difficult to isolate the effects of healthy behaviors that may correlate with increased water consumption.

Obesity is associated with many comorbidities and is quickly becoming one of the most common causes of morbidity and mortality in the developed world. 114 It is postulated that increased water consumption before and/or during meals may help obese individuals by reducing their food intake. However, recent studies have highlighted that this regime may only work in selected individuals. 115–117 Vij et al. 118 demonstrated that consumption of 500 mL of water 3 times a day before meals in overweight girls resulted in a significant reduction in body mass index over an 8-week period. The authors attributed these findings to the thermogenic properties of water, reported to increase the basal metabolic rate by up to 30%. 119 Boschmann et al. 120 demonstrated in a randomized controlled crossover trial that water consumption of 500 mL in obese adults resulted in 24% increased energy expenditure. Dubnov-Raz et al. 121 also demonstrated an increase of 25% in energy expenditure in overweight children who drank 10 mL/kg of cold water. However, these effects are likely the result of cold beverage consumption rather than the water consumed.

Fluid homeostasis within the lung parenchyma contributes to normal cell function and effective gas exchange. 122 In asthma, some studies have demonstrated a link between exercise-induced bronchoconstriction and inability to adequately humidify and warm large quantities of inspired air. 123 However, there is no evidence linking overall state of hydration and pulmonary disease directly.

Physiological changes during pregnancy include increased total body water due to increased plasma volume. 124 Pregnancy is also associated with increased risks of UTI, constipation, and gallstone disease. 125 There is limited evidence supporting the benefit of adequate fluid intake on these conditions. Despite this, healthcare professionals generally advise pregnant women to ensure adequate hydration.

Oligohydramnios

There is good evidence to suggest that inadequate fluid balance may result in oligohydramnios, associated with increased fetal complications and poor perinatal outcome. 124 , 126 It is thought that increasing maternal hydration may induce fetal diuresis, leading to increased amniotic fluid volume. 127 , 128

A randomized controlled trial investigating the effects of intravenous isotonic and hypotonic solution and oral water intake on the amniotic fluid index (AFI) in women with oligohydramnios reported that maternal hydration with intravenous hypotonic and oral water was associated with an increase in AFI as measured by ultrasound. 129 Similar findings were also demonstrated in a randomized controlled observer-blinded trial in women with oligohydramnios who drank an additional 2 L of water. 130 In a more recent study in women with normal amniotic fluid, the authors showed an increase in AFI of 16% following ingestion of 2 L of water and an 8% reduction in the fluid-restricted group who received 100 mL of water. 131 There is clearly good evidence showing a direct relationship between maternal hydration and amniotic fluid volume; however, these studies did not report on clinically relevant fetal or maternal outcomes.

There is inconsistent evidence on the benefits of maintaining a well-hydrated state during labor. Garite et al. 132 demonstrated improved outcomes during labor with increased intravenous fluid rates of 250 mL/h (group 1) in nulliparous women compared with the standard maintenance rate of 125 mL/h (group 2). Group 1 received, on average, 479 mL more fluid than group 2, and exhibited a significantly lower frequency of prolonged labor. 132 Eslamian et al. 133 also compared intravenous fluid rates of 250 mL/h and 125 mL/h during labor in a randomized double-blind study and showed shorter duration of labor and lower frequency of prolonged labor and oxytocin use in the group receiving 250 mL/h. The authors also reported trends toward lower frequency of cesarean section in the group receiving 250 mL/h, although this did not reach statistical significance. 133 Another study, however, failed to show any difference in labor outcomes with increased fluid intake. 134 Moreover, other studies investigating the impact of hydration in preterm labor failed to demonstrate any benefits of fluid therapy, except in women with evidence of dehydration. 135

Breastfeeding

There are well-documented benefits of breastfeeding, both for the mother and the baby. Studies investigating the effect of fluid consumption or restriction on the quantity or quality of breast milk produced found no influence. 136 , 137 Nevertheless, the European Food Safety Authority recommends that breastfeeding women consume an additional 600–700 mL of fluid per hour. 10

Dehydration has been linked with other conditions including hypertension, breast cancer, and dental disorders, although the evidence is limited. 138–140 There is, however, an association between low urine output and daytime hypertension in patients with diabetes. 139

It is also thought that a state of chronic dehydration may predispose to dental disorders by reducing the production of saliva, which protects teeth. 138 Similarly, a small retrospective case-control study reported that patients with a diagnosis of breast cancer reported lower water intake compared with controls. 140

Hydration status can have an impact on the pharmacodynamic and pharmacokinetic properties of medication. 141 An altered hydration state, particularly dehydration, has been shown to have an impact on kidney function 142 and can affect the safety and efficacy of some drugs, particularly those with a narrow therapeutic range, such as lithium. Commonly used drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) can be particularly problematic due to lack of awareness of the renal interactions. 142 Gorski et al. 143 investigated the use NSAIDs among iron-man triathlon competitors and found that 60% of those questioned had used NSAIDs for pain relief in the last 3 months; however, less than a third of the cohort were aware of the potential renal complication of NSAIDs. 143

It is also important to consider drugs such as diuretics and antihypertensives, which may alter the hydration status of individuals and increase their vulnerability to adverse events with heat stress and dehydration. Following the heat wave that affected France in 2003, there was a significant increase in the number of adverse drug reactions reported in association with drugs such as diuretics and angiotensin-converting enzyme inhibitors, among others. 144

Overhydration has also been linked with morbidity and mortality. Some psychiatric conditions predispose to excess fluid consumption, as seen in psychogenic polydipsia where individuals consume excess water, irrespective of osmolality. This can lead to significant consequences such as heart failure and urinary tract abnormalities. 145 Moreover, excess water consumption can cause hyponatremia, which is an independent risk factor for bone fractures. 146–148 This may be a result of reduced bone mineral density and increased risk of osteoporosis. 149

Overhydration in athletes

Overhydration has also been reported to be detrimental in endurance athletes, with excess fluid consumption having been linked to exercise-associated hyponatremia (EAH). Severe EAH can cause cerebral edema and mortality. The incidence of EAH varies from 3% to 29% 7 , 150 in marathon runners, with most studies reporting excess fluid consumption as the main underlying risk factor. 7 , 151 This may be further exacerbated by other factors such as the concomitant use of NSAIDs, which are commonly used for pain relief.

Iatrogenic fluid overload

The most common cause of overhydration is iatrogenic fluid overload and overprescribing, most notably in hospitalized surgical patients. Fluid and electrolyte therapy comprise an essential part of perioperative care, and there is a narrow margin for safety. 152 , 153 The 1999 UK National Confidential Enquiry into perioperative deaths found that at the extremes of age, errors in fluid management, usually fluid excess, were the most common cause of avoidable postoperative morbidity and mortality. 6 Numerous studies have shown that inaccurate prescription of fluid results in fluid overload; some patients were reported to receive up to 5 L of excess water and 500 mmol of excess sodium (and chloride) per day. 154 , 155 This can result in heart failure, pulmonary edema, and renal impairment. Furthermore, a meta-analysis of randomized clinical trials of intravenous fluid therapy in major elective open-abdominal surgery reported a reduction in postoperative complications by 41% and length of hospital stay by 3.4 days in patients managed with appropriate (near zero) fluid balance as opposed to states of fluid imbalance. 153

Fluid overload and bowel function in surgical patients

Postoperative complications such as intestinal ileus are a common cause of morbidity following gastrointestinal surgery. More serious complications such as the breakdown of bowel anastomosis can result in significant morbidity and mortality. Intestinal edema has been shown to play a major role in postoperative gastrointestinal dysfunction. 156 Surgical trauma results in salt and water retention; 152 fluid excess in the perioperative period can lead to edema, not only in the peripheries but also in the gastrointestinal tract, lungs, myocardium, and periorbital tissues. Gastrointestinal edema is associated with anastomotic swelling, 156 an increase in abdominal pressure, reduced splanchnic blood flow, and renal perfusion and may, therefore, result in anastomotic dehiscence. 157 Schnuriger et al. 158 reported that the volume of intravenous crystalloids administered in the first 72 hours post primary colonic surgery following trauma significantly predicted anastomotic leak, with those receiving ≥10.5 L during this period at a 5-fold increased risk of anastomotic dehiscence.

Fluid overload and deep vein thrombosis in surgical patients

DVT is common in surgical patients due to immobilization, among other factors. Hydration status, particularly dehydration, is considered a risk factor due to increased plasma viscosity as discussed previously. Impaired coagulation has also been reported in the context of postoperative fluid overload. 159 Ruttman et al. 160 demonstrated that hemodilution was associated with increased coagulation. In a later study, the authors reported that hemodilution results in decreased activity of anticoagulant factors, therefore, predisposing to clot formation. 161 Janvrin et al. 162 randomized 60 patients admitted for elective laparotomy to receive either intravenous fluids during or after the operation or no intravenous fluids. The authors reported that patients receiving fluids were hemodiluted. Moreover, there was a significantly greater incidence of DVT in the group that received fluids compared with the group that did not, 30% vs 7%, respectively. 162

Monitoring of fluid input and output in all patients is of great importance as knowledge of fluid balance can help direct adequate fluid replacement where needed.

Maintaining a normal state of hydration is important, as dehydration has been shown to be a risk factor for many health conditions. There is a growing body of evidence supporting the link between the state of fluid imbalance and disease. However, the evidence is largely associative and lacks consistency with a limited number of randomized trials.

One of the biggest challenges is achieving consistency in the way hydration, dehydration, and, indeed, overhydration are defined and measured. Many studies often rely on self-reported fluid consumption, which at times, has been shown to be inconsistent and inaccurate. This is perpetuated by the current lack of widely accepted screening tools or gold standard tests that allow for easily performable and replicable measurements of fluid balance. Given these challenges, further work is required to address these important issues.

Funding . A.M.E.-S. was contracted and funded by the European Hydration Institute. He received financial reimbursement for travel and accommodation expenses and an honorarium from the European Hydration Institute for his participation in the conference and for writing this manuscript.

Declaration of interest . A.M.E.-S. and D.N.L. have received unrestricted research funding and travel grants from the European Hydration Institute. D.N.L. has received unrestricted research funding, travel grants, and speaker’s honoraria from Baxter Healthcare, Fresenius Kabi, and BBraun for unrelated work.

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• nervous system disorders
• hyponatremia
• dehydration
• postoperative complications
• gastrointestinal dysfunction
• water-electrolyte balance
• excess fluid volume
• overhydration
• non-covered item or service

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A comparison of the analysis of 3 types of body fluids using the XN-350 hematology analyzer versus light microscopy assessment

Editor(s): Haque., Nazmul

Department of Laboratory Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea.

∗Correspondence: Miyoung Kim, Department of Laboratory Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine 22, Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do, 14068, Republic of Korea (e-mail: [email protected] ).

Abbreviations: AF = ascitic fluid, AHA = automated hematology analyzer, BF = body fluid, CI = confidence interval, CLSI = Clinical and Laboratory Standards Institute, CSF = cerebrospinal fluid, CV = coefficient of variation, ICSH = International Council for Standardization in Haematology, LOB = limit of blank, LOD = limit of detection, MN = mononuclear cells, PF = pleural fluid, PMN = polymorphonuclear cells, RBC = red blood cell, WBC = white blood cell.

How to cite this article: Lee J, Cho Y, Kim HS, Kang HJ, Kim M, Lee YK. A comparison of the analysis of 3 types of body fluids using the XN-350 hematology analyzer versus light microscopy assessment. Medicine . 2021;100:11(e24852).

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

The raw data used in this study are available from the corresponding author upon reasonable request.

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website ( www.md-journal.com ).

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We evaluated the capacity of the XN-350 instrument to analyze 3 different types of body fluid samples under “body fluid mode.”

The performance of XN-350 was evaluated in terms of precision, carryover, limit of blank, limit of detection, limit of quantification, and linearity. Cell enumeration and differential data produced by the XN-350 were compared to manual chamber counting results in 63 cerebrospinal fluid (CSF), 51 ascitic fluid, and 51 pleural fluid (PF) samples. Comparisons between XN-350 versus Cytospin data were also performed in PF samples.

The precision, carry-over, limit of blank, and linearity of the XN-350 were acceptable. The limits of detection for white blood cells (WBCs) and red blood cells were 1.0/μL, and 1,000.0/μL, respectively; the corresponding limits of quantitation (LOQs) were 5.0/μL and 2,000.0/μL, respectively. The XN-350's cell enumeration and differential counting correlated well with those of manual chamber counting for all 3 sample types (except for differential counting in CSF samples), particularly parameters involving monocytes (r = 0.33) and mononuclear cells (MO- body fluid [BF]; r = 0.26), as well as total cell (TC-BF) enumeration (r = 0.50) and WBC-BF (r = 0.50) in PF samples. The MO-BF in CSF samples differed significantly from manual chamber counting results, but neither TC-BF nor WBC-BF in PF samples did. The XN-350 also showed good correlations with Cytospin analyses for differential counting of neutrophils, lymphocytes, and monocytes in PF samples. The differential counting of eosinophils via the XN-350 and Cytospin were not significantly correlated, but the difference between them was not significant.

The XN-350 is an acceptable alternative to manual fluid analysis. Samples with low cellularity around the LOQ should be checked manually. Moreover, manual differential counting should be performed on CSF samples, particularity those with low cell numbers.

1 Introduction

Body fluid (BF) analysis, especially total white blood cell (WBC) count (with differential) and malignant cell detection, is considered a cornerstone test in patients with inflammatory, infectious, and neoplastic diseases. [1–3] Different types of BFs have distinct parameters used for identifying underlying clinical conditions. In pleural fluid (PF), approximately 80% of transudates will have cell counts less than 1000/μL, whereas counts above 10,000/μL are usually associated with parapneumonic effusions. [1] Exudative PF with a predominance of neutrophils reflects acute inflammation or parapneumonic effusion, whereas that with a predominance of lymphocytes suggests the presence of a tubercular infection, metastatic disease, lymphoproliferative disorder, or chylous effusion. [1,3] Eosinophilia is observed in certain conditions such as pulmonary emboli, hemothorax, immunoallergic reaction to chest tubes, parasitic diseases, and Churg-Strauss syndrome. [1] In ascitic fluid (AF), an absolute neutrophil value of >250/μL is indicative of spontaneous bacterial peritonitis; [1,3,4] in contrast, tuberculous peritonitis is usually characterized by a total nucleated cell count of >1000/μL with a predominance of lymphocytes. [1,3] In cerebrospinal fluid (CSF), the predominance of polymorphonuclear cells (PMNs) with increased WBCs suggests bacterial meningitis, whereas a predominance of mononuclear cells (MNs) suggests aseptic meningitis [3,5] . Moreover, it is particularly important to measure low-level cell counts in CSF accurately given that the upper limits of the WBC reference ranges in CSF samples are only 5/μL, 7/μL, and 27/μL in adults, children up to 16 years of age, and neonates, respectively. [1]

The gold standard protocol for enumerating and differentiating cells in BFs is the combination of manual chamber counting with improved Neubauer rules and Cytospin analysis; [1,3,6] nevertheless, these methods have some drawbacks. The accuracy of manual chamber counting depends on the sample volume, dilutions, and number of squares and cells counted. [3] Counting samples with low cellularity can be highly imprecise, while accuracy in enumeration requires highly trained laboratory personnel and is time-consuming. [6] The cytocentrifugation process involved in Cytospin analysis may result in the loss of cells during centrifugation, [7,8] aberrant cell morphology, [9] and clustering of macrophages or mesothelial cells in PF and AF. [10] Despite these drawbacks, the accurate and timely analysis of the cellular compositions of BFs is critical for facilitating prompt patient management.

Automated hematology analyzers (AHAs) equipped with a BF mode are a potential alternative to the manual method. [6,11] AHAs are designed to be faster, more precise, and easier to use than manual methods; [3] they also count more cells and are therefore more precise. [12] Among such AHAs, the XN system (Sysmex Corporation, Kobe, Japan) is equipped with a specific module for BF analysis (XN-BF). [13,14] It adopts a flow cytometry system using a semiconductor laser, and its ability to analyze differences in the intensities of scattered and fluorescent light from individual cells enables cell enumeration and identification. [15] The numbers of particles counted in the WBC and red blood cell (RBC) channels in BF mode are approximately 10- and 3-fold higher than those counted in the whole blood mode, respectively. [15] It is also claimed that the XN counts 3–10 times more cells passing through its detector than do previous-generation instruments, and is therefore expected to increase the precision of low WBC counts. [15]

The International Council for Standardization in Haematology (ICSH) [16] emphasized that an AHA's performance should be verified using patient samples, with results compared to the manual method, prior to its use for routine BF analysis. [1] The verification process should include precision, accuracy, sensitivity, specificity, and reportable range. [16] The correlation between AHAs and the manual method should be confirmed for each type of BF separately, as each has a different matrix and cell type composition than whole blood. [16,17] The Clinical and Laboratory Standards Institute (CLSI) guideline recommends that at least 40 samples that cover the analytical range (particularly medical decision-level ranges) should be tested. [16,17] However, according to a survey performed by the ICSH, the extent of verification varies widely among different laboratories that have introduced AHAs for the routine analysis of BFs. [16] Furthermore, only a few investigators have performed correlation analyses for the different types of BF samples in a particular AHA model. [16] Before introducing an AHA into clinical practice, a full-range verification procedure should be performed along with correlation analyses for different types of BFs, considering each type's unique properties, compositions, and values of clinical significance.

In this study, we performed a full-range verification of the XN-350 instrument in BF mode according to the ICSH guidelines and relevant CLSI documents. [1,17–19] We compared XN-350 reference results to those obtained via manual chamber counting and Cytospin analysis using different types of commonly requested BF samples including CSF, AF, and PF.

2 Materials and methods

The study was approved by Institutional Review Board (IRB No.: HALLYM 2020-06-019), and the requirement for written informed consent was waived due to the observational and anonymized nature of the study. The study was performed in accordance with principles of the Declaration of Helsinki.

2.2 Clinical samples

A total of 165 clinical BF samples (63 CSF, 51 AF, and 51 PF samples) submitted for manual chamber counting at Hallym University Sacred Heart Hospital between October 2017 and November 2017 were investigated to compare the limit of detection (LOD), limit of quantification (LOQ), linearity, and methodology. Sample collection was performed according to the CLSI guideline. [1] CSF samples were collected in sterile tubes while AF and PF samples were collected in K 2 EDTA tubes (Becton Dickinson, Franklin Lakes, NJ). Clotted, extremely viscous, and mucoid samples were not tested. The samples were processed within 2 hours of arrival.

2.3 Manual chamber counting

Manual cell enumeration and differential counting followed the standard operating procedures of our own laboratory, which are based on the CLSI documents H56-A, [1] H26-A2, [17] EP05-A3, [18] EP06-A, [19] and EP17-A2 [20] as well as the ICSH guidelines. [16] If fewer than 200 cells were present in the area of the 9 squares of the hemocytometer, cells in all 9 squares were counted; if more than 200 cells were present in the 9 squares, only the cells in the 4 corner squares were counted; and if more than 200 cells were present within a single square, cells inside the 5 smaller squares within the larger center square were counted. The standard Neubauer calculation formula was used to determine the number of cells per cubic millimeter. [1] WBCs were classified as either PMNs, lymphocytes, or monocytes according to the CLSI's morphologic criteria after staining with Turk solution. [1] Neutrophils, eosinophils, and basophils were classified as PMN cells because of the varying shapes of their nuclei. Lymphocytes (normal lymphocytes as well as plasma cells and atypical lymphocytes) and monocytes (including histiocytes) were classified as MN cells.

2.4 Cytospin analysis

Differential counting of 30 samples was performed using a Cytospin; the samples were centrifuged (1,500 rpm for 5 minutes) in a Shandon Cytospin 3 (Thermo Fisher Scientific, Massachusetts) and labeled with Wright-Giemsa staining (RAL diagnostics, Site Montesquieu Martillac, France).

The differential count was performed at ×400 magnification on 100 cells in each sample. Cells were classified into one of the following: neutrophils, lymphocytes, monocytes/histiocytes/macrophages, eosinophils, and basophils. Lining cells (such as mesothelial cells) and malignant cells were classified as “other” and marked separately when detected.

2.5 Automated analysis using the XN-350 instrument

XN series instruments use size (forward scattered light), internal complexity (sideward scattered light), and DNA/RNA content (fluorescence intensity) information to determine the total WBC counts and differentials. [6] The electrical impedance method is used for the measurement of RBCs. [3]

The XN-BF module provides total cell (TC-BF), high-fluorescence cells (HF-BF), and WBC (WBC-BF) data with a 2-part differential count consisting of PMNs (PMN-BF) and MNs (MN-BF) as well as RBCs (RBC-BF). [6] HF-BF included mesothelial cells, which can interfere with the acquisition of WBC-BF counts. [6,21] Additional differential counting research parameters included neutrophils (NE-BF), lymphocytes (LY-BF), monocytes (MO-BF), and eosinophils (EO-BF). [6] TC-BF#, WBC-BF#, PMN-BF%, and MN-BF% were defined as follows: TC-BF# = WBC-BF# + HF-BF#; WBC-BF# = MN# + PMN#; PMN-BF% = NE-BF% + EO-BF%; and MN-BF% = LY-BF% + MO-BF%.

2.6 Performance evaluation of the XN-350

2.6.1 precision.

Low- and high-level control materials (XN check BF levels 1 and 2; Sysmex, Kobe, Japan) were used for precision analysis. The within-run precision was evaluated using 3 patient samples of low, middle, and high levels for each parameter according to the CLSI guideline. [18] Each sample was tested 10 consecutive times within-run, and the coefficient of variation (CV) was calculated.

Short- and long-term precision was evaluated using the low and high levels of the quality control materials “XN check” BF levels 1 and 2, according to the CLSI guideline. [18] Each sample was tested twice per run, 2 runs per day, for 5 days. The short- and long-term CVs were calculated using the equation provided in the CLSI guideline. [1]

2.6.2 Carryover

Samples with high and low counts for each parameter were selected for a carryover study. Each sample was analyzed 3 times consecutively (H1, H2, H3, L1, L2, and L3). The carryover ratio was calculated using the equation introduced in the CLSI guideline. [17] The carryover percentage was calculated as (L1–L3) × 100/(H3–L3).

2.6.3 Limit of blank (LOB), LOD, and LOQ

The LOB, LOD, and LOQ were determined in accordance with the CLSI guideline. [21] For LOB verification, the Cellpack DCL diluent was measured 10 times and the LOB was calculated according to the following equation: LOB = mean (blank) + 1.645 × standard deviation (blank). For LOD verification, patient samples (CSF, AF, and PF) were diluted to the concentrations recommended by the manufacturer, and each diluted sample was analyzed 10 times. The TC, WBC, and RBC were counted, and the LOD was calculated for each parameter according to the following equation: LOD = LOB + 1.645 × standard deviation (low concentration sample).

To measure and verify the LOQ, low level samples (immediately above and below the LOD levels) were obtained and measured 10 times each, and the percentage CV was calculated. The sample with the lowest concentration that met the accuracy specifications suggested by the manufacturer was considered the LOQ. [17]

2.6.4 Linearity (analytical measurement range)

Linearity was evaluated by analyzing diluted clinical samples using a dilution solution with known concentrations (1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64, 128, 256, 512, and 1,024 for WBCs and 1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64, 128, 256, and 512 for RBCs). Diluted samples were tested in duplicate from the lowest to highest concentrations to avoid carryover effects. Each dilution was measured twice. Results were plotted against the expected cell counts, and linearity was then assessed using Pearson's correlation test according to the CLSI guideline. [19]

2.7 Method comparison

Comparisons between the manual method and XN-350 for basic parameters were performed based on the following categorization: TC count using the manual method vs. TC-BF, WBC count using the manual method (i.e., the TC count minus others) vs. WBC-BF using the XN-350, MN using the manual method (the sum of lymphocytes and monocytes/histiocytes) versus MN-BF using the XN-350, and PMN using the manual method (the sum of neutrophils, eosinophils, and basophils) versus PMN-BF using the XN-350.

Research parameters (represented as percentages) obtained using the manual method (lymphocyte, monocyte, neutrophil, and eosinophil counts) via manual chamber counting or Cytospin analysis were compared to their corresponding parameters obtained using the XN-350 (neutrophil [NE-BF], lymphocyte [LY-BF], monocyte [MO-BF], and eosinophil [EO-BF] counts, respectively). Comparing between the eosinophil percentages obtained using the manual method versus EO-BF was performed only for the Cytospin analysis because manual chamber counting does not differentiate eosinophils from neutrophils.

The correlation between XN-BF parameters and the manual method/Cytospin analysis was evaluated using Pearson's correlation test. The strength of correlation between the 2 methods for each parameter was defined based on the value of Pearson correlation coefficient ( r ) as follows: very strong (0.8 ≤ | r |< 1.0), strong (0.6 ≤ | r | < 0.8), moderate (0.4 ≤ | r | < 0.6), weak (0.2 ≤ |r| < 0.4), or very weak (0 ≤ | r | < 0.2). The agreement between XN-BF parameters and the manual method/Cytospin analysis was assessed using Passing-Bablok regression and Bland-Altman plot analyses. [22,23] The slope and intercept of the Passing-Bablok regression were calculated with their respective 95% confidence intervals (CIs) to identify statistically significant proportional or systematic differences between the 2 methods. If 0 was in the CI of the intercept, and 1 was in the CI of the slope, the 2 methods were deemed comparable within the investigated range. If 0 is not in the CI of the intercept, a systematic difference was deduced, and if 1 was not in the CI of slope, then a proportional difference between the 2 methods was deemed to exist. In Bland-Altman plots, the absolute and relative differences were plotted against the results obtained with light microscopy. Significant bias was defined as the 95% CI of the mean of differences not containing a 0 value.

2.8 Statistical analysis

Pearson's coefficient was calculated to determine the correlations between methods; Passing-Bablok regression and Bland-Altman plot analyses were used to compare different methods. P -values <.05 were considered significant. Statistical analysis was performed using the MedCalc Statistical Software version 18.9.1 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org ; 2018) and Microsoft Excel 2007 (Microsoft, Redmond, Washington).

3.1 Performance evaluation of the XN-350

3.1.1 precision.

The within-run imprecision rates for low-, medium-, and high-level samples subjected to TC-BF, WBC-BF, and RBC-BF measurements were within the acceptable limits suggested by manufacturer, as were the short-term and long-term imprecision rates for low- and high-level controls. The acceptable limits and test results are presented in Supplementary Table 1, https://links.lww.com/MD/F835 .

3.1.2 Carry-over

The carry-overs for WBC-BF (0.06%) and RBC-BF (-0.09%) were negligible and within the manufacturer's specification (less than 0.3%).

3.1.3 LOB, LOD, and LOQ

The LOBs were 0.0/μL, 0.0/μL, and 0.0/μL for TC-BF, WBC-BF, and RBC-BF, respectively. The LODs were 1.0/μL, 1.0/μL, and 1,000.0/μL for TC-BF, WBC-BF, and RBC-BF, respectively. The LOQs were 3.0/μL, 5.0/μL, and 2,000.0/μL for TC-BF, WBC-BF, and RBC-BF, respectively.

3.1.4 Linearity

The linearity of the different parameters was competent. The analytical measurement ranges of WBC-BF and RBC-BF were 5–6,815 /μL (equation: y = 1.012x + 0.0126; r 2 = 0.9985) and 2–1,110 × 10 3 /μL (equation: y = 1.0013x + 0.001; r 2 = 1.0000), respectively.

3.2 Method comparison

3.2.1 comparison between manual chamber counting and xn-350 results.

The results of the Pearson's correlation, Passing-Bablok, and Bland-Altman analyses for all samples as well as CSF samples, AF samples, and PF samples alone are summarized in Tables 1–4 Tables 1, 2, 3, and 4, respectively. The Passing-Bablok and Bland-Altman plots for all samples, CSF samples, AF samples, and PF samples are presented in Supplementary Figures 1, https://links.lww.com/MD/F836 , 2, https://links.lww.com/MD/F837 , 3, https://links.lww.com/MD/F838 , and 4, https://links.lww.com/MD/F839 , respectively.

Overall, the XN-350 showed very strong or strong correlations with manual chamber counting in terms of most cell enumeration and differential counting parameters with a few exceptions. Specifically, TC-BF, WBC-BF, and RBC-BF showed very strong or strong correlations with their corresponding manual chamber counting parameters in CSF samples. PMN-BF and MN-BF showed moderate and weak correlations, respectively, with their corresponding manual chamber counting parameters in CSF samples. The research parameters including NE-BF, LY-BF, and MO-BF, which comprise PMN-BF and MN-BF, also showed moderate, weak, and very weak correlations, respectively, with their corresponding manual chamber counting parameters. In particular, MO-BF showed a proportional difference and significant difference in the Passing-Bablok and Bland-Altman analyses. In AF samples, all the cell enumeration and differential counting XN-350 parameters showed very strong correlations with their corresponding manual chamber counting counterparts. In PF samples, RBC-BF and all the differential counting parameters obtained via manual chamber counting and the XN-350 were very strongly correlated. TC-BF and WBC-BF showed moderate correlations with their corresponding manual chamber counting parameters; however, they did not show any statistically significant difference according to either Passing-Bablok or Bland-Altman analysis.

3.2.2 Cytospin analysis vs. XN-350

A comparison between analyses performed by Cytospin (accompanied by light microscopy) and the XN-350 was performed on 30 of the 51 PF samples based on sample availability ( Table 5 ). None of the samples in the Cytospin analysis contained malignant cells. NE-BF, LY-BF, and MO-BF showed very strong or strong correlations with corresponding Cytospin analysis parameters. EO-BF failed to show any statistically significant correlation with Cytospin analysis; however it also did not show any significant difference in either the Passing-Bablok analysis or the Bland-Altman analysis.

4 Discussion

We evaluated the basic performance of the XN-350 and its correlation with manual chamber counting/Cytospin analysis using 3 different types of BF. The XN-350 showed acceptable precision, carry-over, LOB, and linearity. The LOD and LOQ of the WBC and RBC were not suitable for measuring CSF samples with low cell counts (i.e., near the reference limit). The XN-350 showed strong or very strong correlations with manual chamber counting for most cell enumeration parameters, as well as for 2-part and 4-part differential counting except in CSF samples. The correlations in WBC and RBC cell enumeration with manual chamber counting in PF samples were moderate, with no significant differences. The XN-350 also correlated well with Cytospin analysis results of PF samples for the differential counting of neutrophils, lymphocytes, and monocytes. Differential counting of eosinophils did not show any significant correlation between XN-350 and Cytospin analysis, although the difference was also not significant.

The performance of the XN-350 was acceptable in terms of precision, carry-over, LOB, and linearity. Even though manual chamber counting is the gold standard method for cell enumeration, it is hampered by its high imprecision given that CVs can reach 45% [S56]. Additionally, a major concern with respect to the BF mode in AHAs is poor reproducibility and high background counts, which may lead to falsely elevated cell counts among samples with low cellularity. [25] In our study, the XN-350 showed excellent precision and LOB while carry-over was negligible; the latter could be attributable to the technical aspects of the instrument since it performs a rinse cycle after each run followed by a background check. [6] The linearity was also competent.

The LOD and LOQ values were suitable for the analysis of AF and PF, but were not sufficiently sensitive for the analysis of CSF samples with low cellularity. The LOD and LOQ for WBCs were 1/μL and 5/μL, respectively. AF and PF samples are classified into transudates and exudates, with the cut-off value for the WBC count generally being 1000/μL. [25] CSF samples commonly show low cellularity; therefore, the upper limits of TC and WBC are much lower than those of AF and PF samples. The WBC counts and differentials in CSF samples determine the patient's diagnosis and/or type of meningitis. The upper limits of the TC count reference ranges in CSF are 7/μL in children and 5/μL in adults, [26] whereas WBC counts in CSF range from 0 to 5/μL in adults and up to 30/μL in neonates. [25] The LOD and LOQ of RBCs were 1000/μL and 2000/μL, respectively; these were too high when considering that the upper limits of the reference ranges of RBC in CSF are 50/μL in neonates and 5/μL in adults, [26] whereas RBC counts (particularly in the range of 0–1000/μL) are of little significance in PF and AF. [26] Furthermore, the unit of RBC measurement used by the XN-350 is “ × 10 3 /μL,” which is not sufficiently sensitive for estimating small values.

In light of these data, each laboratory needs to evaluate the basic performance of the XN-350, including LOD and LOQ, when using this instrument for BF analysis and to establish a protocol for how to handle samples with low cellularity around the LOQ. Samples with low cell counts around the LOQ could either be evaluated via manual chamber counting, with the results provided accordingly, or could otherwise be labeled “Below LOQ” (such as <5/μL for WBCs) if the value is not critical for clinical decision-making. At the same time, the manufacturer of the XN-350 instrument should improve the LOD and LOQ of RBCs and provide a unit of measurement that is clinically relevant.

The XN-350 showed strong or very strong correlations with manual chamber counting or Cytospin analysis in most cell enumeration parameters and differential counting. One exception was the parameters related to both 2-part and 4-part differential counting in CSF samples using the XN-350, which showed moderate, weak, or even very weak correlations with manual chamber counting. In particular, differential counting for parameters involving monocytes (MN-BF and MO-BF) showed weak correlations with their corresponding manual chamber counting parameters ( r = 0.33 and r = 0.26, respectively), which might also have weakened the correlation with LO-BF ( r = 0.44). The MO-BF also differed significantly from the corresponding manual chamber counting parameters according to both Passing-Bablok and Bland-Altman analyses. This could be partly due to the low cellularity of the CSF samples as well as the low proportion of monocytes, which often results in poor correlations between the manual methods and AHA or between different AHAs in studies of whole blood with much higher WBC counts than BF samples. [14,27,28] This limitation was not observed in AF or PF samples, which had higher cell numbers in our study. This indirectly indicates that our results may be attributed to the low cell numbers in our CSF samples, and implies that each laboratory ought to establish a threshold value for manual differential counting of samples with low cellularity such as CSF. Nevertheless, the strong correlations between differential counting via the XN-350 and manual chamber counting in AF and PF samples as well as Cytospin analysis in PF samples demonstrate that differential counting using the XN-350 is reliable and can replace manual methods.

Another discrepancy was observed in the enumeration of cells in PF samples. TC-BF and WBC-BF showed only moderate correlations with their corresponding manual chamber counting parameters ( r = 0.50 and r = 0.50, respectively). Both parameters also showed a negative absolute bias compared to manual chamber counting (i.e., higher values on XN-350 analysis), even though the difference was not statistically significant. Similar phenomena were consistently observed in previous studies, particularly for WBC counting; [21,29,30] this could be attributed to the presence of cell debris or interfering fragments that may be counted as WBCs, particularly PMNs. [3] Therefore, some investigators established reference values for AHAs that were separate from (and slightly higher than) those used for the manual method. [21,24,31] This phenomenon was only observed in PF samples; it was not present in AF, which had lower median TC and WBC counts in our study. It remains unclear if this was attributable to sample characteristics or to the cell number range; therefore, further verification is required with a greater number of samples that encompass different ranges of TC and WBC counts across different sample types. Simultaneously, this finding suggests that laboratories should consider separate reference intervals for AHAs in BF mode when using these instruments in routine practice.

The strength of our study was that we evaluated the XN-350 using CSF, AF, and PF, which are the 3 most commonly requested BF samples. By evaluating the similarities and differences in 3 types of samples separately, we were able to assess the applicability of the XN-350 in BF mode to each sample type. A limitation of our study was that our samples did not include any malignant cells; therefore, we were unable to establish reliable criteria for Cytospin analysis reflex testing or for second-level testing such as flow cytometry. Further studies that include samples with malignant cells would be helpful for setting XN-350 reflex testing rules.

5 Conclusion

Our data showed that the performance of the XN-350 was excellent, although there were notable exceptions: the LOD and LOQ were not sensitive enough for CSF samples with very low cellularity, and the WBC differential counting results in CSF samples (particularly parameters involving monocytes) obtained using the XN-350 and manual method were weakly correlated. Taken together, the XN-350 may be regarded as a sensitive and reliable alternative to the manual method for routine BF analysis and could contribute to the timely management of patients. A thorough evaluation of the performance of AHAs for each type of BF, as well as devising policies for managing and reporting samples with low cellularity, are required before their deployment in clinical practice. Separate reference intervals for BF samples measured by AHAs that are independent of those obtained by manual methods should be considered when necessary.

Author contributions

J Lee collected the data, performed the statistical analysis, and wrote the manuscript. Y Cho performed the statistical analysis. H-S Kim and HJ Kang collected the data, reviewed the statistical analysis, and provided expert opinions. M Kim and YK Lee designed and supervised the study.

Conceptualization: Miyoung Kim, Young Kyung Lee.

Data curation: Jiwon Lee, Han-Sung Kim, Hee Jung Kang.

Formal analysis: Jiwon Lee, Younggeun Cho, Han-Sung Kim, Hee Jung Kang.

Project administration: Miyoung Kim.

Supervision: Han-Sung Kim, Hee Jung Kang, Miyoung Kim, Young Kyung Lee.

Writing – original draft: Jiwon Lee, Young Kyung Lee.

Writing – review & editing: Miyoung Kim, Young Kyung Lee.

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automated hematology analyzer; body fluid; chamber counting; correlation; cytospin; performance; XN-350

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Biosensors for Body Fluid Analysis

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Special Issue Information

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A special issue of Biosensors (ISSN 2079-6374). This special issue belongs to the section " Biosensor and Bioelectronic Devices ".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 16908

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Special issue editor.

Dear Colleagues,

I am pleased to introduce this Special Issue focused on biosensors for the analysis of different body fluids.

Biosensors are becoming an important avenue of biomedical research. From a simple thermometer, aimed to detect changes in body temperature, to the development of the first glucometer in 1962, these fascinating devices have gradually been incorporated into clinical practice.

Biosensors are generally small, fast, selective, sensitive, and easy-to-use devices. Their use may speed up test results, allowing early clinical decisions to be taken and benefit the patient. A person’s health status can be continuously monitored (e.g., blood oxygen monitors). Other biosensors are so common that they are used at home, such as the pregnancy test or the aforementioned glucometer.

In places where health facilities are not easily accessible, the introduction of rapid tests becomes even more relevant. Simple tests to detect infectious diseases such as HIV or HVC can make a great difference. In addition, coupling new technologies to biosensors would make health tests more affordable and portable.

In this Special Issue, we aim to gather the most recent research in the field of biosensors that may directly be applied to biofluids (saliva, urine, synovial fluid, cerebrospinal fluid, etc.) without sample pretreatment.

Dr. Esther Serrano-Pertierra Guest Editor

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website . Once you are registered, click here to go to the submission form . Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biosensors is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• body fluids
• point of care
• cerebrospinal fluid
• synovial fluid

Published Papers (5 papers)

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Body Fluid Analysis

Body fluid analysis is a diagnostic procedure used to examine fluid samples extracted from a person's body. This type of analysis enables medical professionals to diagnose illnesses, identify changes in the body's chemistry, and evaluate the progress of treatment. It can also be used to detect pregnancy and determine genetic markers for inherited conditions. By analyzing the physical and chemical properties of a body fluid sample, such as blood, urine, or saliva, healthcare practitioners are able to gain insight into the patient's health. Body fluid analysis is an important tool for improving patient care, as it helps physicians diagnose diseases and monitor treatment plans.

Related Topics

Body Fluid Management

Related Article For "Body Fluid Analysis"

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There are many options for what to drink , but water is the best choice for most people who have access to safe drinking water. It is calorie-free and as easy to find as the nearest tap.

Water helps to restore fluids lost through metabolism, breathing, sweating, and the removal of waste. It helps to keep you from overheating, lubricates the joints and tissues, maintains healthy skin, and is necessary for proper digestion. It’s the perfect zero-calorie beverage for quenching thirst and rehydrating your body.

How Much Water Do I Need?

Water is an essential nutrient at every age, so optimal hydration is a key component for good health. Water accounts for about 60% of an adult’s body weight. We drink fluids when we feel thirst, the major signal alerting us when our body runs low on water. We also customarily drink beverages with meals to help with digestion. But sometimes we drink not based on these factors but on how much we think we should be drinking. One of the most familiar sayings is to aim for “8 glasses a day,” but this may not be appropriate for every person.

General recommendations

• The National Academy of Medicine suggests an adequate intake of daily fluids of about 13 cups and 9 cups for healthy men and women, respectively, with 1 cup equaling 8 ounces. [1] Higher amounts may be needed for those who are physically active or exposed to very warm climates. Lower amounts may be needed for those with smaller body sizes. It’s important to note that this amount is not a daily target, but a general guide. In the average person, drinking less will not necessarily compromise one’s health as each person’s exact fluid needs vary, even day-to-day.
• Fever, exercise, exposure to extreme temperature climates (very hot or cold), and excessive loss of body fluids (such as with vomiting or diarrhea) will increase fluid needs.
• The amount and color of urine can provide a rough estimate of adequate hydration. Generally the color of urine darkens the more concentrated it is (meaning that it contains less water). However, foods, medications, and vitamin supplements can also change urine color. [1] Smaller volumes of urine may indicate dehydration, especially if also darker in color.
• Alcohol can suppress anti-diuretic hormone, a fluid-regulating hormone that signals the kidneys to reduce urination and reabsorb water back into the body. Without it, the body flushes out water more easily. Enjoying more than a couple of drinks within a short time can increase the risk of dehydration, especially if taken on an empty stomach. To prevent this, take alcohol with food and sips of water.
• Although caffeine has long been thought to have a diuretic effect, potentially leading to dehydration, research does not fully support this. The data suggest that more than 180 mg of caffeine daily (about two cups of brewed coffee) may increase urination in the short-term in some people, but will not necessarily lead to dehydration. Therefore, caffeinated beverages including coffee and tea can contribute to total daily water intake. [1]

Keep in mind that about 20% of our total water intake comes not from beverages but from water-rich foods like lettuce, leafy greens, cucumbers, bell peppers, summer squash, celery, berries, and melons.

Aside from including water-rich foods, the following chart is a guide for daily water intake based on age group from the National Academy of Medicine:

Preventing Dehydration: Is Thirst Enough?

As we age, however, the body’s regulation of fluid intake and thirst decline. Research has shown that both of these factors are impaired in the elderly. A Cochrane review found that commonly used indicators of dehydration in older adults (e.g., urine color and volume, feeling thirsty) are not effective and should not be solely used. [3] Certain conditions that impair mental ability and cognition, such as a stroke or dementia, can also impair thirst. People may also voluntarily limit drinking due to incontinence or difficulty getting to a bathroom. In addition to these situations, research has found that athletes, people who are ill, and infants may not have an adequate sense of thirst to replete their fluid needs. [2] Even mild dehydration may produce negative symptoms, so people who cannot rely on thirst or other usual measures may wish to use other strategies. For example, aim to fill a 20-ounce water bottle four times daily and sip throughout the day, or drink a large glass of water with each meal and snack.

Symptoms of dehydration that may occur with as little as a 2% water deficit:

• Confusion or short-term memory loss
• Mood changes like increased irritability or depression

Dehydration can increase the risk of certain medical conditions:

• Urinary tract infections
• Kidney stones
• Constipation  

Like most trends of the moment, alkaline water has become popular through celebrity backing with claims ranging from weight loss to curing cancer. The theory behind alkaline water is the same as that touting the benefits of eating alkaline foods, which purportedly counterbalances the health detriments caused by eating acid-producing foods like meat, sugar, and some grains.

From a scale of 0-14, a higher pH number is alkaline; a lower pH is acidic. The body tightly regulates blood pH levels to about 7.4 because veering away from this number to either extreme can cause negative side effects and even be life-threatening. However, diet alone cannot cause these extremes; they most commonly occur with conditions like uncontrolled diabetes, kidney disease, chronic lung disease, or alcohol abuse.

Alkaline water has a higher pH of about 8-9 than tap water of about 7, due to a higher mineral or salt content. Some water sources can be naturally alkaline if the water picks up minerals as it passes over rocks. However, most commercial brands of alkaline water have been manufactured using an ionizer that reportedly separates out the alkaline components and filters out the acid components, raising the pH. Some people add an alkaline substance like baking soda to regular water.

Scientific evidence is not conclusive on the acid-alkaline theory, also called the acid-ash theory, stating that eating a high amount of certain foods can slightly lower the pH of blood especially in the absence of eating foods supporting a higher alkaline blood pH like fruits, vegetables, and legumes. Controlled clinical trials have not shown that diet alone can significantly change the blood pH of healthy people. Moreover, a direct connection of blood pH in the low-normal range and chronic disease in humans has not been established.

BOTTOM LINE: If the idea of alkaline water encourages you to drink more, then go for it! But it’s likely that drinking plain regular water will provide similar health benefits from simply being well-hydrated—improved energy, mood, and digestive health

Is It Possible To Drink Too Much Water?

There is no Tolerable Upper Intake Level for water because the body can usually excrete extra water through urine or sweat. However, a condition called water toxicity is possible in rare cases, in which a large amount of fluids is taken in a short amount of time, which is faster than the kidney’s ability to excrete it. This leads to a dangerous condition called hyponatremia in which blood levels of sodium fall too low as too much water is taken. The excess total body water dilutes blood sodium levels, which can cause symptoms like confusion, nausea, seizures, and muscle spasms. Hyponatremia is usually only seen in ill people whose kidneys are not functioning properly or under conditions of extreme heat stress or prolonged strenuous exercise where the body cannot excrete the extra water. Very physically active people such as triathletes and marathon runners are at risk for this condition as they tend to drink large amounts of water, while simultaneously losing sodium through their sweat. Women and children are also more susceptible to hyponatremia because of their smaller body size.

Fun Flavors For Water  

Infused water

Instead of purchasing expensive flavored waters in the grocery store, you can easily make your own at home. Try adding any of the following to a cold glass or pitcher of water:

• Sliced citrus fruits or zest (lemon, lime, orange, grapefruit)
• Crushed fresh mint
• Peeled, sliced fresh ginger or sliced cucumber
• Crushed berries

Sparkling water with a splash of juice

Sparkling juices may have as many calories as sugary soda. Instead, make your own sparkling juice at home with 12 ounces of sparkling water and just an ounce or two of juice. For additional flavor, add sliced citrus or fresh herbs like mint.

TIP: To reduce waste, reconsider relying on single-use plastic water bottles and purchase a colorful 20-32 ounce refillable water thermos that is easy to wash and tote with you during the day. 

Are seltzers and other fizzy waters safe and healthy to drink?

BOTTOM LINE: Carbonated waters, if unsweetened, are safe to drink and a good beverage choice. They are not associated with health problems that are linked with sweetened, carbonated beverages like soda.

• Harvard T.H. Chan School of Public Health is a member of the Nutrition and Obesity Policy Research and Evaluation Network’s (NOPREN) Drinking Water Working Group. A collaborative network of the Centers for Disease Control and Prevention, the NOPREN Drinking Water Working Group focuses on policies and economic issues regarding free and safe drinking water access in various settings by conducting research and evaluation to help identify, develop and implement drinking-water-related policies, programs, and practices. Visit the network’s website to access recent water research and evidence-based resources.
• The Harvard Prevention Research Center on Nutrition and Physical Activity provides tools and resources for making clean, cold, free water more accessible in environments like schools and afterschool programs, as well as tips for making water more tasty and fun for kids.
• The National Academy of Sciences. Dietary References Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. https://www.nap.edu/read/10925/chapter/6#102 Accessed 8/5/2019.
• Millard-Stafford M, Wendland DM, O’Dea NK, Norman TL. Thirst and hydration status in everyday life. Nutr Rev . 2012 Nov;70 Suppl 2:S147-51.
• Hooper L, Abdelhamid A, Attreed NJ, Campbell WW, Channell AM, et al. Clinical symptoms, signs and tests for identification of impending and current water-loss dehydration in older people. Cochrane Database Syst Rev . 2015 Apr 30;(4):CD009647.

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The contents of this website are for educational purposes and are not intended to offer personal medical advice. You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The Nutrition Source does not recommend or endorse any products.

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Open Access

Peer-reviewed

Research Article

Perceptions on the collection of body fluids for research on persistence of Ebola virus: A qualitative study

Roles Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Unit Medical Anthropology and Global Health, Department of Social and Preventive Medicine, Center for Public Health, Medical University of Vienna, Austria

Roles Conceptualization, Project administration, Supervision, Writing – review & editing

Affiliation WHO country office Sierra Leone, Freetown, Sierra Leone

Roles Investigation, Project administration, Writing – review & editing

Roles Conceptualization, Funding acquisition, Validation, Writing – review & editing

Affiliation UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), World Health Organization, Geneva, Switzerland

• Ruth Kutalek, 
• Florence Baingana, 
• Stephen Sevalie, 
• Nathalie Broutet, 
• Anna Thorson

• Published: May 14, 2020
• https://doi.org/10.1371/journal.pntd.0008327
• Reader Comments

Against the background of the international public health emergency related to the Ebola outbreak in the Democratic Republic of Congo, in addition to other recent large Ebola epidemics, the issue of transmission due to viral persistence from survivors’ body fluids is becoming increasingly urgent. Clinical research in which body fluids play a role is critical and semen testing programs are part of the suggested response to the outbreak. Broad acceptance and understanding of testing programs and research, often in resource poor settings, is essential for the success and sustainability of clinical studies and an accurate epidemic response. Study participants’ perceptions on the collection of body fluids are therefore relevant for the programmatic planning and implementation of clinical studies.

Study aim and methods

In this qualitative study we aimed to explore the perceptions on bio-sampling in the Sierra Leone Ebola Virus Persistence Study (SLEVP study). We were interested to understand how norms on gender and sexuality related to perceptions and experiences of study participants and staff, specifically, in what way perceptions of the body, on intimacy and on body fluids related to the study process. We purposively sampled former study participants for in-depth interviews and focus-group discussions. We conducted 56 in-depth interviews and eight focus group discussions with 93 participants. In a participatory approach we included study participants in the analysis of data.

Overall the SLEVP study was well perceived by study participants and study staff. Study participants conceived the testing of their body fluids positively and saw it as a useful means to know their status. However, some study participants were ambivalent and sometimes reluctant towards sampling of certain body fluids (especially semen, blood and vaginal fluid) due to religious or cultural reasons. Self-sampling was described by study participants as a highly unusual phenomenon. Several narratives were related to the loss of body fluids (especially semen) that would make men weak and powerless, or women dizzy and sick (especially blood). Some rumors indicated mistrust related to study aims that may have been expressions of broader societal challenges and historical circumstances. These reservations could eventually be overcome by guaranteeing confidentiality and privacy and by comprehensive professional counseling.

In the course of the sampling exercise, study participants were often obliged to transgress cultural and intimate boundaries. It is therefore important to understand the potential importance some of these perceptions have on the recruitment of study participants and the acceptability of studies, on a symbolic as well as a structural level. In order to capture any reservations it is necessary to provide plenty of possibilities of information sharing and follow-up of continuous consent.

Author summary

Recent studies have shown that the Ebola Virus might persist in body fluids of survivors of the disease. Clinical research in which body fluids (semen, vaginal fluids, blood, sweat, tears, breast milk and rectal fluids) are sampled play an increasingly important role, specifically in light of growing EVD epidemics. The success of these studies, e.g. how many participants are recruited in a study and how many are staying until the end of a study, is highly dependent on the participants’ cooperation and understanding of testing programs. However, until now there has been only little research on how studies and testing programs in which body fluids are sampled are perceived and understood by study participants. In this study we were therefore interested to understand how study participants perceived the sampling and collection of body fluids and how their cultural or religious background may influence the willingness to participate and stay in a clinical study. We conducted one-to-one interviews and focus-group discussions with 93 former study participants of a viral persistence study. We found that overall study participants conceived the testing of their body fluids positively and saw it as a useful means to know their status. However, some study participants were ambivalent and sometimes reluctant towards sampling of certain body fluids (especially semen, blood and vaginal fluid) due to religious or cultural reasons. Self-sampling was described by study participants as a highly unusual phenomenon. Participants explained that the collection of certain body fluids would make men weak and powerless (especially the sampling of semen), or women dizzy and sick (especially blood). Rumors indicated that some participants mistrusted the study aims. In the course of the sampling exercise, study participants often felt that they had to transgress cultural and intimate boundaries. We conclude that it is important to understand the potential importance some of these perceptions have on the recruitment of study participants and the acceptability of studies. The understanding of the socio-cultural context of clinical research is relevant for the programmatic planning of such research.

Citation: Kutalek R, Baingana F, Sevalie S, Broutet N, Thorson A (2020) Perceptions on the collection of body fluids for research on persistence of Ebola virus: A qualitative study. PLoS Negl Trop Dis 14(5): e0008327. https://doi.org/10.1371/journal.pntd.0008327

Editor: Abdallah M. Samy, Faculty of Science, Ain Shams University (ASU), EGYPT

Received: August 23, 2019; Accepted: April 27, 2020; Published: May 14, 2020

Copyright: © 2020 Kutalek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data cannot be made publicly available for ethical reasons (public availability would compromise study participants' privacy). Date can be accessed upon request at [email protected] .

Funding: This work was funded by Paul Allen Foundation and the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the World Health Organization (WHO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Sierra Leone was one of the countries most heavily impacted by the West African Ebola Virus Disease epidemic which saw an unprecedented number of survivors. By March 2016, when the WHO Director-General declared the end of the Public Health Emergency of International Concern, there had been 14,124 confirmed, probable and suspected cases and 3,956 deaths [ 1 ].

During and after the outbreak there have been several studies on the persistence of Ebola Virus (EBOV) in body fluids, especially in semen [ 2 – 4 ] suggesting sexual transmission of the virus from male survivors [ 5 , 6 ] or other forms of viral persistence-derived transmission [ 7 – 9 ].

In studies on viral persistence body fluids are sampled from male and female EVD survivors, often in resource poor settings. Broad acceptance and understanding of testing programs and research is essential for the success and sustainability of clinical studies, specifically for the enrolment and retention of study participants. It has been shown, for instance, that perceptions of blood sampling significantly influenced study uptake and loss to follow-up [ 10 – 12 ]. In many cultural contexts body fluids such as blood, menstrual blood, semen, urine, feces, or sweat are not “neutral substances” but endowed with meaning [ 13 , 14 ]. They may be considered as pure or polluted, as powerful substances, inflicting harm or as curative agents. From anthropological research we know that Muslim men may be especially conflicted about delivering semen samples in a clinical setting [ 15 ]. For female study participants it is important to understand how notions of purity and shame across different socio-economic, ethnic and religious groups might influence perceptions and acceptability e.g. of vaginal self-sampling [ 16 , 17 ]. These aspects, however, have so far rarely been considered in studies on viral persistence.

As we are faced with a growing number of EVD outbreaks (e.g. the current outbreak in DRC, as of 25 Feb 2020 3444 cases reported [ 18 ]) evidence on viral persistence e.g. of Zika virus is also increasing [ 19 ]. Clinical research in which body fluids play a role is becoming more important. Study participants’ perceptions on the collection of body fluids will therefore become more relevant for the programmatic planning and implementation of clinical studies.

In this qualitative study we aimed to explore the perceptions on bio-sampling in the Sierra Leone Ebola Virus Persistence Study (SLEVP study). The SLEVP study was established to investigate persistence of Ebola Virus (EBOV) in body fluids (semen, vaginal fluid, menstrual blood, urine, rectal fluid, sweat, tears, saliva, and breast milk when applicable) of 120 male and 120 female EVD survivors, and is described in detail in Deen et al. [ 20 ]. Participants received counseling prior to the sampling process, as well as two weeks later when they received their test results, described in detail in Abad et al. [ 21 ].

In this process evaluation we wanted to explore perceptions of study participants and study staff in the Sierra Leone Ebola Virus Persistence Study (SLEVP study) regarding the implementation of the study and the specimen process itself. Employing a meaning centered and critical approach, we were interested to understand how norms on gender and sexuality related to perceptions and experiences of study participants and staff, specifically, in what way perceptions of the body, on intimacy and on body fluids related to the study process. Furthermore we sought to explore how experiences of the Ebola epidemic impacted on the implementation of the study as well as on the perception of the sampling process.

Material and methods

The study was conducted between April and June 2017 at the two SLEVP study sites 34 Military Hospital (MH34) and Lungi Government Hospital (LGH). We invited all four counselors (2 from each site) and 13 purposively selected staff from all professions that were part of the SLEVP study, such as medical doctors, study nurses, lab technicians, cleaning personnel and security personnel for an interview. The selection took place in cooperation with WHO staff who were involved in the SLEVP study.

We purposively sampled former study participants with diverse religious background, age and marital status for in-depth interviews and focus-group discussions. By selecting participants with diverse social characteristic we expected to get a broader spectrum of perceptions regarding our research questions. For each study site four FGDs were conducted, one with older men, one with older women, one with younger men, and one with younger women. We aimed at homogenous groups in terms of gender and age so that group members would feel comfortable to answer our often intimate questions in the group. The FGDs were an important complement to in-depth interviews as some of the participants felt more at ease to talk in groups and/or were encouraged to tell their own perspective after having listened to their colleagues. Former study participants and study staff were informed about the evaluation study by the study receptionists and community liaison persons. Participants already knew them from the SLEVP study and trusted them.

Overall we conducted in-depth interviews and focus group discussions with 93 participants. We conducted in-depth interviews with all four counselors and 13 SLEVP study staff (doctors, nurses, lab technicians, community liaison persons, cleaning and security) ( Table 1 ) and 31 SLEVP study participants. Additionally we conducted eight focus group discussions with 45 SLEVP study participants ( Table 2 ).

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https://doi.org/10.1371/journal.pntd.0008327.t001

https://doi.org/10.1371/journal.pntd.0008327.t002

All interviews were carried out by experienced interviewers who were undergraduate university students in social work or social sciences. All interviewers spoke English and Krio, two also spoke Temne. The three male and one female interviewers had formerly been trained in and conducted qualitative health studies in Sierra Leone and were competent in qualitative interviewing. They received an additional two-day training by the study lead (RK) on principles of qualitative research, in-depth interviews, focus-group discussions and medical ethics. The training also entailed the use of the specific interview guidelines and the informed consent. The study lead closely supervised the interviewers in the field and gave them constant professional feedback on interview techniques and non-verbal communication skills.

The interview guides were co-developed by all five authors in a discursive process, guided by the research questions. They were translated into Krio by the interviewers, under close supervision of SS, FB and RK, and extensively discussed. They were then re-translated into English for quality control. The duration of the in-depth interviews was between 30–50 minutes. Focus group discussions lasted about 1.5 to 2 hours each and were carried out by 1–2 interviewers, depending on the availability of interviewers. All male groups were interviewed by male interviewers, the female groups were interviewed by our female interviewer. Most interviews with former study participants were conducted in Krio, some in English and two in Temne. In two of the focus groups one or two participants only spoke Temne; these FGDs were conducted bilingually by the Temne-Krio-speaking interviewers. Some of the fellow participants who were also bilingual supported with the translation. Most interviews with study staff were conducted in English. All interviews were voice-recorded with the consent of the interview partners.

Most transcriptions were conducted by a specifically hired research assistant who also translated the interviews from Krio to English. The Temne interviews were transcribed and translated into English by the Temne speaking interviewer. The other three interviewers transcribed two interviews each. All interviews were checked for completeness and accuracy and imported into the software atlas.ti for qualitative content analysis. Instead of names we used unique ID codes.

In a first phase we read through around one third of the transcribed interviews and assigned preliminary codes that emerged from the data to catch important concepts and categories. Then a very broad analysis was performed that summed up the main themes. With this preliminary analysis in hand we invited all study participants again and asked them on their feedback on these first results. As ownership and confidentiality of study participants is most important, we asked each interview partner how he or she would like to be informed about the preliminary results of the study and most agreed to be called again and informed in groups. At each study site we therefore held three separate dissemination meetings: one for the group of former study staff, one for female participants and one for male participants. We communicated these first results of the study and encouraged participants to discuss them with us. In this participatory approach we wanted to identify the most important themes for the participants, to clarify issues that may have been understood differently and to give participants the opportunity to air any concerns they had. The results of these meetings informed the second phase of analysis of the data and allowed a better definition and refinement of the codes and grouping in categories. Throughout the study ideas about the data were documented in theoretical memos. In an iterative and reflexive process of data immersion we searched for meaning and insightful findings [ 22 ].

In line with the analytical emphasis of this paper we identified three major themes: the understanding of the study and the recruitment process, the perceptions on and experiences of intimate sampling (semen, vaginal and rectal fluids) and the perceptions on and experiences of the sampling of blood and other body fluids.

Ethics statement

The research protocol was approved by the Sierra Leone Ethical Review Board and the WHO Ethical Review Committee. All data produced in the project are strictly confidential. We did not mention any real names, either in the transcriptions or in the publication. Prior to the interview all participants have been informed about the project and its objectives, the purpose of the interviews, and the use of the data for scientific purposes. Interviewers and the research assistant signed a confidentiality agreement.

The informed consent was read to them carefully in their preferred language and after agreeing to it participants and interviewers signed (or thumb marked) the informed consent form. All participants were informed about the voluntary character of this study and guaranteed strict confidentiality. They all consented that the interviews were being voice recorded. Study participants were compensated for their travel costs and time spent during the interview.

Understanding the viral persistence study and the recruitment process

Participants related to us how they were first informed of the study through information meetings, where aims and bio-sampling were explained. In the beginning of the recruitment process potential participants were concerned about confidentiality. There were also fears and rumors among survivors that study participants would be infected with EVD or that they would be used as guinea pigs in the study. Moreover there were rumors that the blood drawn in the study would be sold by the government, used during elections or as a treatment in case of another epidemic.

We never wanted to come. We were afraid. We just thought that because they missed to kill us at the [treatment] centers, it was through the test [study] they were going to get rid of us. (…) At first we were afraid, but thereafter we became confident. Onto the end I had no problem. Former SLEVP study participant IDI, male They said the blood they collected from us was going to be kept and used during elections. Some said they kept the blood perhaps another disease will come so that they could use it to treat the other patients. Those were some of the things they said. Former SLEVP study participant IDI, female

Several participants mentioned rumors they heard on the study that the blood collected would be sold, that they “would make money out of our fluids” or that body fluids would be kept for a future epidemic. Some said that they were afraid that “the white people wanted to use us” and “sell our lives”. Not all believed in these rumors but clearly there was quite some anxiety among the participants initially. Study staff related that they employed different strategies to overcome those concerns: they talked to the survivors, the community elders and other representatives and tried to convince them on the good intentions of the study and that they would themselves profit from knowing their status. Moreover, the very fact that several study participants knew the staff involved in the study from the EVD Treatment Unit (ETU) in which they were treated opened many doors. Study staff also mentioned that the very fact that survivors were employed as liaison officers was a trust building measure.

Staff as well as participants highly appreciated the confidentiality and privacy of the project which was realized at different levels. Participants received a unique ID number and were addressed only with this number instead of their names. On several occasions participants related to this measure as trust building. The study sites were separated from the main clinic buildings and according to our interview partners no one except study staff and participants had access. Moreover, care was taken not to disclose persons as participants in front of family or community. Several participants and staff mentioned that when they met accidentally outside the study compound they would not take notice of each other, or when participants were called and did not answer the call personally the reason for the call would not be disclosed. Furthermore, informing the public about the project, especially the detailed procedures of the project, e.g. what kind of samples were provided and in what way, was kept to a minimum; more information was only provided at the meetings where the recruitment took place and details were disclosed in the individual counseling sessions. Participants often stressed that the study “was a secret” or “like a secret society”. Many participants related that little was known about the study outside the survivor community, because they were asked to “keep the information to themselves”.

They told us earlier that we should not disclose any information to the community people and there is no need for us to explain to them that we are engaged in dry jack [masturbation], given out semen, and body water [body fluids] for test to be conducted. We felt the entire process should be a secret that we should not disclose to them. Former SLEVP study participant FGD, male group They told me that those of us registered for the study must not tell other people about it. When I returned home from the study, I was always with my children and I explained nothing to them. Former SLEVP study participant IDI, female

Participants greatly appreciated the friendly and cordial atmosphere of the project and that staff treated them in a kind and respectful manner. They also appreciated the free medical care and the reimbursements they received during the project.

Sampling of body fluids

From our interviews it became clear that counselors and nurses, but also lab technicians, doctors and liaison persons were important to inform the participants on the sampling of body fluids. For several reasons participants were sometimes reluctant or not able to provide a sample (the most problematic were semen, vaginal and blood samples) and staff negotiated their cooperation. Study staff were available to assist participants with providing samples and doing the self-swabs, especially when the participant did so for the first time. Inside the sampling tent posters explained the detailed procedures for each sample in pictographs. Our interview partners related that at the beginning of the study, staff would help with the sampling of vaginal and rectal fluid, saliva, tears, sweat and urine. At subsequent visits participants were more confident and often did the sampling without help. For providing the semen sample all staff would leave the tent after having instructed the male participant.

Specifically for the intimate sampling, privacy and confidentiality were of outmost importance. Overall study staff thought that most participants were fine with the sample taking and that participants were rather concerned about their health and knowing their status than with personal feelings of shame and fear. Most participants agreed on the principal necessity to test body fluids. However, there were certain sampling procedures of body fluids, such as the sampling of semen through masturbation or the sampling of vaginal fluids during menstruation, many participants felt very strongly about. They were unusual for most of the participants and initially led to fear, shame, reluctance and open opposition of some.

Male intimate sampling

Almost all the study staff acknowledged that the sampling procedure for semen was a challenge for most male participants. Staff mentioned several reasons why participants were not able to produce a semen sample. Some argued that it was because of religious reasons, some said that it was due to the sickness that made them impotent. Others argued that participants related to them that they would need their wives in the process. Staff occasionally also mentioned that contrary to what they had been advised, participants would often not abstain from sex before they were scheduled to come for the sampling.

Majority of the things went well except for the men, some will come and give all other body sample but when it comes to the semen, they will give an excuse that they are religious and don’t do such thing, especially the Muslims a lot of them were refusing to give a sample even when you booked an appointment with them. Former SLEVP study staff, female … some participants even when we advised them to abstain three days before sample collection they won’t adhere to that advice. They would have sexual intercourse the night before sample collection. When they came for the sample collection they won’t be able to give the sample. Former SLEVP study staff, female

For the participants religion was considered an important issue for the provision of semen samples in several aspects. Some men were highly uncomfortable to masturbate and considered it indecent and against their religion. Furthermore, especially during Ramadan, sexual intercourse and more so masturbation is considered haram (religiously forbidden). While many participants thought that the pornographic film greatly helped them during masturbation, some said they would not have needed it or that they didn’t want it for religious reasons. Some Muslim men openly objected to having pornographic movies shown.

Just as my brother has said, it [masturbation] is understandable in the urban centers a bit, but in the rural areas it is highly prohibited. In the village, they refer to anybody who does that as unreligious. Former SLEVP study participant FGD, male group We were not feeling fine because God does not permit us to take out [semen], without a woman, it is not decent at all, and we are just doing it because of our health and our status. Everything we were doing, we say it is confidential but it was painful. Former SLEVP study participant FGD, male group

Even though Muslims generally do not approve of masturbation, several staff and participants argued that it would be tolerated if it were done for a medical reason.

Normally especially the elderly people and the Muslims were not comfortable with it. Some people were saying it is forbidden but we had meetings with the Islamic council before we started the study. We asked them what Islam will tolerate. They told us that yes during Ramadan Islam will not tolerate such. But if it is not in Ramadan and it’s for your well being you are permitted to do it. And that was settled. Former SLEVP study staff, female For me, as long as it is for my health, (…) I just think God can understand because it is not something intentional, we were doing it for our health. To our people it is really something bad. Former SLEVP study participant FGD, male group

Participants often related that they are “not used” to masturbate and on several occasions they talked about loosing power or even becoming sick through masturbation, because they perceived masturbation as fundamentally different to having sexual intercourse. They said that in their communities people would not talk about it openly and they would consider it a sin. Three persons also explicitly mentioned that persons engaging in manual ejaculation are considered homosexuals by their communities.

For example, when we come and give the semen I will have to buy some drinks when I get home to replace what I have lost, that was how I used the money. Former SLEVP study participant IDI, male We were just doing but it weakened your system because when you jack your penis [masturbate] … when you engage in sex with a woman you feel relaxed on top of the lady the penis is controllable but when you ejaculate the penis gets weak. Former SLEVP study participant FGD, male group People who do masturbation are perceived badly by the community people, they will always class such person as unserious and being homosexual. Former SLEVP study staff, male

Reservations of participants towards providing semen samples on some occasions also led to open resistance. Staff argued that the withholding of semen samples was in some instances done deliberately because this did not only happen in the beginning of the study but also later, when participants were already accustomed to the procedures. They related that some patients realized they would still get reimbursed even when no sample was provided. In the view of staff resistance took different, more or less subtle forms, from the understandable rejection to give a sample e.g. due to religious reasons, to a coordinated collective form of resistance.

… some of them would say I would give blood but would not give the semen. Former SLEVP study staff, male Some followed their colleague who refused to give sample while others who were hesitating also joined their colleagues (…). In such cases when we noticed that some were only coming for the cash and not to give sample, we started withholding their cash and demanded they give the sample first because if such continues we cannot get the actual outcome of the research. With these methods we were able to solve some of the challenges. Former SLEVP study staff, female

Some male participants who were either not able or not willing to produce a semen sample were suspected to put gel or similar looking substances into the test tubes or bring a semen sample from outside. However, participants never said that they deliberately deceived study staff, but they knew that at least at the beginning of the study there would be no consequences when they were not able to produce a semen sample. This strategy, as also mentioned in the previous citation, was later changed.

(…) if you are not careful they bring the semen from home because they said unless there is a woman they can’t produce semen. Former SLEVP study staff, male We understood that some men because they were not ejaculating they were ashamed to come out without the semen sample. So, we speculated that they were putting the hand sanitizer in the test tube. Former SLEVP study staff, female If you could not produce for this week, they would encourage you; perhaps you could produce in another week. They gave the same transport refund even if you could not produce, or even if you produce only one fluid they would appreciate. Former SLEVP study participant FGD, male group

Female intimate sampling

Compared to the male participants, staff considered female participants to be unproblematic and cooperative in terms of intimate sampling (vaginal and rectal swabs). When relating to sampling in general, staff would usually highlight the challenges they had with male participants to collect semen. Some staff acknowledged that there was initial fear and shyness but overall staff were more occupied with male concerns, even though strong reservations towards intimate sampling were present in both sexes.

For the women there was no problem, they were so cooperative. Former SLEVP study staff, male For the eye water and breast milk there was no problem except for the vaginal fluid. Especially, for the aged women, they were a little bit shy. (…) They agreed when they understood the procedure. Initially, they thought that there will be a man present. Also we told them that they could even do it alone, and they would only be assisted by a nurse if they need it. We were not having any problems with the women. Former SLEVP study staff, female Some of them were afraid except when I explained to them that is so tiny like the feather of a chicken and this gave them confidence. (…) it was a mixed reaction, some accepted it whilst others rejected. Former SLEVP study staff, female

However, several female participants described their concerns quite differently. Many did not express their reluctance with sampling procedures openly but rather talked of having experienced fear, shame and embarrassment. One woman related that she did not want to disappoint the elders. Others were quite frank and described their struggle with the staff.

After the whole process was explained to us and what they will be taking from us I really felt bad and I didn’t want to reject my elders that’s why I participated in the study. And until it finished I did not encounter any problem. Former SLEVP study participant IDI, female The first time I came on this study I did not feel good especially the woman side. To be honest with you I was so much adamant with the nurse, but she encouraged me and even removed her pant for me as a way to give me more courage. I gave them the different samples they needed from me. Also the second time again when I came I was still adamant to give the samples. They still counseled me and I gave them the sample. The last time there was no problem between us because I realized that they were trying to help me know my status. Former SLEVP study participant FGD, female group

Some study participants were specifically concerned about the inclusion of elderly ladies into the study.

For instance a young nurse ordering an old woman to remove her pant is somehow embarrassing. Former SLEVP study participant FGD, female group

Some women considered the collection of menstrual fluids specifically difficult. Menstrual blood is considered unclean and participants on several occasions indicated that they were concerned what was done with the sample. One important strategy to overcome shame and embarrassment of the participants was to counsel and talk to the female participants, to treat them in a respectful way and by showing one’s own vulnerability and nakedness.

It was only for the collection of menstrual fluid I know that it was not fine because some women considered it as unclean. Former SLEVP study staff, female Part [A] As for me what I hate in the whole study process is the vaginal swabbing especially the menstruation. I always ask myself what they are going to do (with) it. (…) Part [B]: As my colleague said menstruation and the blood is the problem. We really want to know the reason for taken them. Because women find it very difficult to give it out especially to foreign people you don’t know. Former SLEVP study participant FGD, female group To do the menstruation test was the greatest difficulty I faced in the room. The nurse asked me to remove my pant in order to do the test I told her that I am ashamed to do it. Fortunately, for me the nurse also was on her menstruation period so as a result she removed her pant and shows me how to do the test. Former SLEVP study participant FGD, female group

Many women, especially the younger generation, had no problem whatsoever, either with the collection of menstrual blood or with the vaginal swabbing in general. At the second or third appointment most of them also got used to the procedures and did not need assistance from the nurses any more.

On the first day somebody did it for me and the second the third and forth I did it for myself. Former SLEVP study participant IDI, female When we come they will tell us not to me ashamed, they are female and am also a female so let me not be ashamed, so whatever they asked me to, let me do. They talk to us fine and encourage us, and we do what they told us, they gave us hot water to drink for us to sweat, so all that. Former SLEVP study participant IDI, female

The sampling of blood and other body fluids

Female and male participants likewise frequently mentioned the blood draw as a highly uncomfortable event, the experience of which clearly went beyond the mere pain–the drawing of blood was often related to the loss of strength and power. Participants not only mentioned the frequency of the blood draw but also the amount that they often considered “too much”. Female participants were specifically concerned about the “blood loss” that in their perception would cause headache and dizziness. Some male participants also felt that the blood draw would influence the semen sampling.

The only thing as I told you was the too much blood they removed from me. That gave me headache. They said if they did not remove enough blood from people they would not do the sample test, so they removed enough blood from people. That was the only problem I had with them. Former SLEVP study participant IDI, female When they remove their blood some men complain of shortage of blood which makes their heads spin it [and makes] dry jack [difficult]. We keep on telling them that the 1ml blood does not do anything to their health. Former SLEVP study staff, female

Participants often narrated that they had to replace the blood that was drawn with other substances such as ORS, “blood tonic”, “blood syrup” or some special drinks that are considered blood building.

There was a time I was seriously affected after donating my blood. There was a time I donated blood I felt a pain in such a way that I had to buy blood syrup. As for me, I drank raw eggs for three days before I came to normal, because I felt dizzy when I donated Former SLEVP study participant FGD, male group What we do not want is the removal of blood for test. If they come again and say blood test we will not take part. All of them mean the same. The blood test made us dizzy. Former SLEVP study participant FGD, female group

Staff also mentioned that even though participants had been informed of and had agreed to the blood draw (e.g. by signing the informed consent), when it came to the actual procedure many participants were reluctant and even resisted to undergo it. Some were quite firm in their opinion that if they were invited for another study they would not join if regular blood draws were a part of it.

They really do give us tough time. They lament to us after they have gone through and agreed to all what they have been told; when they reach to us to collect the specimen especially the blood then they start to grumble and say had I known I would not have come. Former SLEVP study staff, male They were afraid, they thought we were going to draw huge amount of blood from them except when we told them that we were going to take 5 ml of blood and that it would not exceed. We also show them the sample and they accepted it. Former SLEVP study staff, female

Staff and participants rarely mentioned challenges in collecting or self-swabbing of other body fluids. Only the sampling of tears was described as difficult to some of the staff and the participants. Uneasiness about the rectal swab was explicitly mentioned by three participants and one staff. Several participants were highly concerned where their samples would be taken. Most of these anxieties related to venous blood but three participants also mentioned other body fluids such as menstrual blood and semen.

What I want to say is about the blood collection. It is number one because every time we came was blood, every time we came was blood. Some of us were afraid because we did not know where our blood was taken to. (…) We were getting rumors that a ship was taking our blood away. For some of us we prayed that wherever our blood was taken to with negative intent let our blood be dark. Former SLEVP study participant FGD, female group I was thinking before when they came and collect our sperm, what are they doing with it? That what I was thinking. Where are they going with them? Because we are knowing the result but where are they going with them? Former SLEVP study participant IDI, male

This is the first study that analyzes perceptions on the collection of bio-samples in medical research on Ebola virus disease. It shows how important it is to understand broader socio-cultural contexts in which medical research is taking place. Perceptions of the body and on sexuality are socially and culturally constructed. They are deeply influenced by historical realities, by ethnic affiliation, power relations, gender roles, concepts of morality, education and religion. Moreover, medical studies that take place in or shortly after epidemics have to consider the specific governance dynamics of the response (or post-response efforts), as well as psychosocial implications of (post-)emergencies.

A study investigating Ebola viral persistence in body fluids is bound to be faced with many challenges. Sierra Leone experienced two years of a devastating epidemic, the impact of which has been disastrous economically and socially, resulting in significantly higher unemployment, lower schooling and less food consumption [ 23 ]. A fragile health system and the challenges related to the EVD response created fear and mistrust in many people [ 24 , 25 ]. This mistrust extended to everything that had to do with “Ebola” and could be clearly observed throughout our study. Moreover, the participants in the SLEVP study had recently survived a deadly disease and many had to deal with its psycho-social and economic consequences. It is well established that EVD survivors are more vulnerable to psychological distress caused by the disease experience as well as by stigmatization and social rejection [ 26 ].

Overall perception of the study

The SLEVP study team, as reflected in our interviews with study staff and study participants, overall showed high professionalism, high work ethics and excellent problem solving capacity, all of which generated an atmosphere of enthusiasm, respect and friendship and contributed to the success of the study. Study participants were especially fond of the respectful atmosphere and the strict confidentiality, study staff mentioned the good quality of the training which prepared them to tackle challenging situations and guided them through the sometimes difficult process of the project. Moreover, the very fact that some of the study staff were already known to the participants and that survivors were employed as liaison officers was an important trust-building measure. The success of these strategies can be seen in the overwhelmingly positive feedback we received from study participants on the study staff, and in the extremely low losses to follow-up [ 2 ]. Overall SLEVP study participants conceived the testing of their body fluids positively and saw it as a useful means to know their status and to be able to communicate the results to their partners or to the community, if they wished to. They were also glad for the financial remunerations they received and for the free medical care they were entitled during the study.

Nevertheless, as shown from our results, some study participants were ambivalent and sometimes reluctant towards sampling of certain body fluids (especially semen, blood and vaginal fluid). These reservations could eventually be overcome by guaranteeing confidentiality and privacy, by comprehensive professional counseling and arguments that stressed the benefits for the study participants. Moreover, many of the national SLEVP staff where either themselves survivors or were well acquainted with the clinical treatment of survivors. Still, there seemed to have been a cognitive gap between the signing of the informed consent and the actual sample taking, and between the understanding and perceptions of the study participants and the SLEVP study staff on the study process. To some study participants, the implications of sample taking were not completely clear and it seems that the way the informed consent was explained to the study participants could be improved upon.

The ambivalence and reluctance that were expressed by some of the study participants–the initial rumors that participants would be harmed in the study and that blood would be sold or used during political campaigning–revealed concerns that were present before the actual study process started and when informational meetings with key stakeholders were held. These rumors are indicative of the atmosphere in which the study was started, and, as mentioned above, the mistrust that was felt towards everything that had to do with “Ebola”. On a deeper level, these rumors may have been expressions of broader societal challenges and historical circumstances. They may have revealed uncertainties of who would really profit from the sampling of the body fluids, an issue that is broadly discussed within the scientific community as well. Ethical considerations of biobanking, especially in the context of disease outbreaks and under conditions of socioeconomic inequities, are hotly debated and the ethical adequacy of material transfer questioned [ 27 ]. The ownership of samples collected during the West African EVD outbreak is still unclear and an inventory on the location of samples lacking [ 28 ].

The sampling process and gendered dynamics

Ambivalences were expressed throughout the study process, in relation to male and female intimate sampling and to the sampling of blood. Self sampling and masturbation was described by study participants as unusual practices and the latter as prohibited. In the course of the sampling exercise, study participants were obliged to transgress cultural and intimate boundaries, exchanging “indecent” behavior for, in the eyes of the participants, useful health information. Initial consultations with the Islamic council did settle the concerns from the perspective of the study staff but not necessarily for the study participants. Intimate sampling remained deeply concerning for male and female participants alike. Reservations were expressed as fear and anger but also in feelings of loss or becoming sick. Several narratives were related to the loss of semen that would make men weak and powerless, or that the taking of blood would make especially pregnant and elderly women dizzy and sick. Participants were not only worried about the frequency of the blood draw but also of the amount which they often considered “too much”. The study added blood sampling relatively late in the study process and did only draw serum for serological analyses, which may in contrast be less than in other clinical studies. The „removal”narrative clearly goes beyond the simple drawing of a body fluid, creating an illness experience over something being taken away, albeit by consenting. It entangles the deeper meanings and symbolism of „too much blood”and „blood loss”as “blood being stolen”. Similar perceptions are well documented from anthropological research of clinical trials. Saethre and Stadler [ 29 ] call them “narratives of harm”. They are “a vehicle through which gender, cash, social reproduction, morality, and medicine were articulated” (p. 104). In their study on negotiating social relations during an HIV trial in South Africa, the authors also describe a similar cognitive gap between the informed consent which in detail explained procedures of taking blood and the feelings of trial participants that the blood taken was excessive and harmful. They contextualize these perceptions within postcolonial relationships of post-apartheid South Africa but clearly, unequal relationships between the global south and the global north, the researched and the researcher, can be observed in many African countries.

While females were depicted by staff as unproblematic and cooperative during intimate sampling, study participants themselves often felt fear, shame and embarrassment. This was overcome in often surprising ways, e.g. in that female staff showed their own nakedness and vulnerability. This gesture is also symbolic of the ambivalence of the study staff who advocated for a western biomedical conception of the naked human body as something natural in a medical encounter, often building a counter-narrative to the female participants who perceived nakedness as being indecent and immoral, the more so when being asked to put a swab into their vagina while menstruating. The discrepancy between staff perceptions of women as being “unproblematic and cooperative” and the women’s reported feelings of fear and shame seem to reflect larger societal gender dynamics. In the study, men may have been more successful to negotiate their position and articulate their needs than women. Even though gender sensitive trainings were part of the study protocol it seems that staff were not able to pick up on these issues in the counseling sessions.

Participants had very creative ways in re-gaining “control” over their body fluids and showing agency. Some male participants were not able or, on rare occasions, not willing to provide intimate sampling on several occasions. This was interpreted by study staff as either post-EVD related impotency or as a form of social resistance. In some instances staff suspected several male study participants to put gel into test tubes. The behavior was said by staff to have caused disturbances during the study process and was seen by some as abusing a system that was built on mutual trust. Still, the actual circumstances seem to tell another story, where missing samples for this reason was uncommon. Again, on a symbolic level very similar accusations are known from Saethre and Stadler [ 29 ], when women during the study were requested to apply microbicide gel vaginally. Some who were called “gel-dumpers” were suspected to only pretend the vaginal application in order to receive the remuneration. Gel dumping was considered “irresponsible because it endangered the scientific process” (p. 110).

Implications for medical studies

It is important to understand the potential importance some of these perceptions have on the recruitment of study participants and the acceptability of studies, first on the symbolic level: Body fluids may be considered as pure or polluted, as powerful substances, inflicting harm or as curative agents. Though not explicitly mentioned by the female participants themselves, female staff confirmed that some of the women considered menstrual blood as “unclean”. Several female participants were especially concerned where their menstrual blood samples would be taken, a worry that was also expressed for other body fluids in male and female participants, such as venous blood and semen. This could indicate a spiritual belief that body substances are generally considered as potentially powerful and able to inflict harm, and used against the person when in the wrong hands. These perceptions are wide-spread in many parts of Africa and have been described e.g. for blood donation in Sub-Saharan Africa [ 30 , 31 ], for blood draw in clinical research [ 10 ] and for semen collection in HIV studies [ 13 ].

On a structural level, reservations towards biomedical research in low-resourced settings in Sub-Saharan Africa that involves sample taking (usually blood) are not new and have been reported from several studies [ 10 , 32 , 33 ]. In a study by Newton et al. [ 12 ] blood drawn from infants in Ghana led to rumors that it would be used for transfusions for elderly people. These perceptions led to substantial loss to follow up. Similarly, in a study by Nchito et al. [ 11 ] in Zambia loss to follow up was partly attributed to the fear of a rumor of blood thefts. Perceptions on body fluids and sample taking can influence decisions of participants to take part in studies and to retain in a study. Yet in the specific cohort study here evaluated, study retention was close to 100%, meaning that especially for some men they remained over a long follow-up time (approaching two years). Factors that have influenced the high retention in the cohort, based on our findings, seem to have been the perceptions of a very high level of trust in the confidential handling of all results, the interest and engagement in knowing ones status as body fluid/semen positive or negative, and the professionalism paired with in-depth community belonging of staff involved. The targeted pre- and post- test counseling offered, as well as the fact that actual sampling of blood was reduced to a minimum, can also have influenced retention positively.

Rumors on medical research or public health interventions in low-income countries can also be seen as an expression of a potentially problematic relationship rooted in history between affected communities and researchers who are often from high-income countries [ 34 – 36 ]. Kovacic et al. [ 37 ] for instance found that in Uganda community experience with control programs on sleeping sickness remains in the memories of people for decades and may influence perceptions on medical research today. Feldman-Savelsberg et al. [ 35 ] in their research analyzed how colonial history, inter-country political conflicts, insensitive behavior of public health staff and not considering gender issues led to a disastrous chain reaction with rumors and subsequent resistance of girls and their parents towards a vaccination campaign against neonatal tetanus. The question how medical research is perceived in a particular socio-cultural setting has implications for the sustainability of research involving power dynamics between co-researchers and communities under study [ 34 ]. However, it is important to neither over- nor underestimate the power of rumors for medical research. While many of our study participants for instance articulated that they did not believe in the rumors, it is nevertheless important to not ignore them as they may pose a threat to medical research [ 36 ].

In our evaluation of a cohort study implemented during an EVD emergency, we found that attention to a very high level of confidentiality offered (ID, location of study, staff integrity etc.) as well as the attention to training and involvement of local staff and survivors’ representatives have contributed to the high retention in study and in general positive attitudes of participants. Further we identified challenges such as the need of continued attention to information and consent procedures, where in this study the purposive recruitment in the cohort was facilitated by information meetings and survivors’ liaison officers. Still, some participants felt they had initial doubts of study aims, which were overall resolved during the actual recruitment and consent processes.

It is important to conceive possible concerns towards sampling of body fluids early in the planning phases of a project and have these perspectives broadly discussed. In order to capture any reservations it is necessary to provide plenty of possibilities of information sharing and follow-up of continuous consent.

Study limitations

This study evaluation was conducted in a post-emergency. For data collection we had to follow a very strict and constrained time format. Interviews and focus group discussions at the two study sites had to take place in parallel, and interviewers sometimes had to conduct 2–3 interviews a day. This rapid study design did not allow for an in-depth ethnographic data collection and we may have missed important information, especially on such sensitive issues the study focused on. However, judging from the sometimes very personal and intimate information we received from our study participants, we got the overall impression that many interviewees were very open and frank when relating their opinions and stories.

Because study participants were invited to the same study site and by the same liaison officers as the viral persistence study, some study participants initially confused our process evaluation with the latter and thought we had come back to do a follow up. These confusions could be resolved by explaining that our study was a separate one and that we wanted to hear their opinion on the viral persistence study. Moreover, we also had different staff employed to do the interviews so as not create any biases regarding confidentiality.

For reasons of practicality, some interviews with female study participants had to be conducted by male interviewers. However, we specifically trained the male interviewers in gender sensitive questioning and RK supervised them closely in the field. All focus group discussions with female participants were conducted by a female interviewer and all focus group discussions with male participants were conducted by a male interviewer.

Conclusions

In clinical studies that involve the sampling of body fluids it should be part of the program to engage local communities, religious leaders and survivors. It is essential to take into account cultural and religious implications of the collection process and to understand underlying gender dynamics and vulnerabilities. All study staff should be trained in cultural and gender sensitive issues and it should be considered to include social science expertise in all phases of the study process.

Acknowledgments

We would like to thank Antoine Coursier, Philippe Gaillard and Gibrilla Fadlu Deen for helping with the design of this study and Elin Roos for valuable insights during the reflection process. We would also like to thank our research assistants Henry Gbettu, Samuel Harding, Miriam Hinton, Issa Kamara and Jacob Saad Kargbo.

The views expressed in this article are those of the authors and do not necessarily represent the official positions, decisions, policy or views of the Government of Sierra Leone Ministry of Health and Sanitation, Ministry of Defense or the World Health Organization.

• 1. WHO. Ebola Situation Report. 30 March 2016. https://apps.who.int/iris/bitstream/handle/10665/204714/ebolasitrep_30mar2016_eng.pdf?sequence=1
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Female ejaculation and squirting as similar but completely different phenomena: A narrative review of current research

Affiliation.

• 1 Obstetrics and Gynecology Department, University Hospital Motol and 2nd Medical Faculty of Charles University, Prague, Czech Republic.
• PMID: 35388532
• DOI: 10.1002/ca.23879

Women expel fluids of various quantities and compositions from the urethra during sexual arousal and orgasm. These are classified as either female ejaculation (FE) or squirting (SQ). The aim of our analysis was to present evidence that FE and SQ are similar but etiologically different phenomena. A review of studies was performed on fluids expelled from the urogenital tract during female sexual activities using the Web of Knowledge™ (Web of Science Core Collection) and MEDLINE (Ovid) databases from 1946 to 2021. Until 2011, all female orgasmic expulsions of fluids were referred to as FE. The fluid was known to be either from the paraurethral glands or as a result of coital incontinence. At present, SQ is considered as a transurethral expulsion of approximately 10 milliliters or more of transparent fluid, while FE is considered as a secretion of a few milliliters of thick fluid. The fluid in SQ is similar to urine and is expelled by the urinary bladder. The secretion in FE originates from the paraurethral glands and contains a high concentration of prostate-specific antigen. Both phenomena can occur simultaneously. The mechanisms underlying SQ and FE are entirely different. SQ is a massive transurethral orgasmic expulsion from the urinary bladder, while FE is the secretion of a very small amount of fluid from the paraurethral glands.

Keywords: female ejaculation; female prostate; orgasm; paraurethral glands; sexual arousal; squirting; urinary bladder.

© 2022 American Association for Clinical Anatomists and the British Association for Clinical Anatomists.

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Human Body Fluid

Shih-bin su.

1 Department of Occupational Medicine, Chi Mei Medical Center, Tainan 710, Taiwan

Terence Chuen Wai Poon

2 Department of Paediatrics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

Visith Thongboonkerd

3 Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, and Center for Research in Complex Systems Science, Mahidol University, Bangkok, Thailand

Human body fluids are considered as attractive sources for clinical markers. As for disease diagnosis and prognosis, advantages of body fluid testing include low invasiveness, low cost, and rapid sample collection and processing. Besides, altered protein expression profiles in body fluids reflect the change of physiological states and cellular networks of the diseased tissue/organ. Thus, analysis of human body fluid has become one of the most promising approaches to discover biomarkers or reveal pathophysiological mechanisms for human diseases. Human body fluid analysis is inherently challenging due to their unique characteristics such as protein complexity and the wide dynamic range of protein abundances. With the remarkable advances in the methods for sample preparation, proteomics technology, and quantitation, it is now possible to analyze body fluids with higher sensitivity and robust experimental design. As the recognition of the importance of “Translational Medicine” which is the process of turning appropriate biological discoveries into drugs and medical devices that can be used in the diagnosis and/or treatment of patients, a great quantity of researches were focusing on the human sample including human body fluids. Thus, it is conceivable that the new insight unveiled by human body fluid analysis will attract a wide audience abroad including researchers from the field of basic sciences, bioinformatics, analytical chemistry, molecular biology, and hospital.

In the study of H. Y. Wu et al., authors performed the first differential proteomic profiling between peritoneal dialysates from chronic glomerulonephritis (CGN) patients at the early and middle stage of continuous ambulatory peritoneal dialysis (CAPD) treatment. The changed proteins provide clues to the PD-induced loss of proteins from the peritoneum and assist the identification of potential biomarkers for noninvasive monitoring of peritoneal damage.

M. H. Yang et al. also characterized the peritoneal dialysate proteins from diabetes mellitus (DM) by proteomic tools. CGN peritoneal dialysate was used as control. Differentially expressed proteins in DM samples may indicate a situation for possible drug treatment and predictors of peritonitis for a validation study in the future.

P. Badiee reviewed the evaluation of different human body fluids, pleural Effusion, bronchoalveolar lavage fluid, peritoneal fluid, urine, pericardial effusion, blood, cerebrospinal fluid (CSF), synovial fluid, and saliva, for diagnosing fungal infections. Routine laboratory tests for the diagnosis of FI include urinalysis and blood analysis while analyses of both CSF and serum can improve the accuracy of the diagnosis.

K. Bořecká et al. studied the use of Coefficient of Energy Balance (CEB) values in a large CSF samples ( n = 8183) to demonstrate that CEB enables more exact assessment of actual energy state in the CSF compartment than glucose and lactate alone. This study suggested that CEB combined with CSF cytology has a great importance for diagnosis, differential diagnosis, and early therapy of CNS diseases.

H. C. Yen et al. discussed potential interferences on the analysis of F 2 -IsoPs and F 4 -NPs in CSF by GC/NICI-MS by present analytical methods. Proper TLC purification for obtaining reliable chromatograms for F 2 -IsoPs quantification in CSF is suggested as well as the necessity of adding additional holding of the column at 280°C for a period of time following data acquisition during F 2 -IsoPs and F 4 -NPs analysis to avoid potential interferences on subsequent F 4 -NPs quantification in CSF.

Acknowledgments

The guest editors of this special issue thank the reviewers and all authors for providing important contributions in this issue. The contributions in this issue discuss novel insights, advanced assessment as well as diagnosis. Of course, the selected topics and papers are not a comprehensive representation of the area of this special issue. Nonetheless, they represent the rich knowledge that we have the pleasure of sharing with the readers.

Shih-Bin Su Terence Chuen Wai Poon Visith Thongboonkerd

Dehydration

On this page, risk factors, complications.

Dehydration occurs when you use or lose more fluid than you take in, and your body doesn't have enough water and other fluids to carry out its normal functions. If you don't replace lost fluids, you will get dehydrated.

Anyone may become dehydrated, but the condition is especially dangerous for young children and older adults.

The most common cause of dehydration in young children is severe diarrhea and vomiting. Older adults naturally have a lower volume of water in their bodies, and may have conditions or take medications that increase the risk of dehydration.

This means that even minor illnesses, such as infections affecting the lungs or bladder, can result in dehydration in older adults.

Dehydration also can occur in any age group if you don't drink enough water during hot weather — especially if you are exercising vigorously.

You can usually reverse mild to moderate dehydration by drinking more fluids, but severe dehydration needs immediate medical treatment.

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Thirst isn't always a reliable early indicator of the body's need for water. Many people, particularly older adults, don't feel thirsty until they're already dehydrated. That's why it's important to increase water intake during hot weather or when you're ill.

The signs and symptoms of dehydration also may differ by age.

Infant or young child

• Dry mouth and tongue
• No tears when crying
• No wet diapers for three hours
• Sunken eyes, cheeks
• Sunken soft spot on top of skull
• Listlessness or irritability
• Extreme thirst
• Less frequent urination
• Dark-colored urine

When to see a doctor

Call your family doctor if you or a loved one:

• Has had diarrhea for 24 hours or more
• Is irritable or disoriented and much sleepier or less active than usual
• Can't keep down fluids
• Has bloody or black stool

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Sometimes dehydration occurs for simple reasons: You don't drink enough because you're sick or busy, or because you lack access to safe drinking water when you're traveling, hiking or camping.

Other dehydration causes include:

• Diarrhea, vomiting. Severe, acute diarrhea — that is, diarrhea that comes on suddenly and violently — can cause a tremendous loss of water and electrolytes in a short amount of time. If you have vomiting along with diarrhea, you lose even more fluids and minerals.
• Fever. In general, the higher your fever, the more dehydrated you may become. The problem worsens if you have a fever in addition to diarrhea and vomiting.
• Excessive sweating. You lose water when you sweat. If you do vigorous activity and don't replace fluids as you go along, you can become dehydrated. Hot, humid weather increases the amount you sweat and the amount of fluid you lose.
• Increased urination. This may be due to undiagnosed or uncontrolled diabetes. Certain medications, such as diuretics and some blood pressure medications, also can lead to dehydration, generally because they cause you to urinate more.

Anyone can become dehydrated, but certain people are at greater risk:

• Infants and children. The most likely group to experience severe diarrhea and vomiting, infants and children are especially vulnerable to dehydration. Having a higher surface area to volume area, they also lose a higher proportion of their fluids from a high fever or burns. Young children often can't tell you that they're thirsty, nor can they get a drink for themselves.
• Older adults. As you age, your body's fluid reserve becomes smaller, your ability to conserve water is reduced and your thirst sense becomes less acute. These problems are compounded by chronic illnesses such as diabetes and dementia, and by the use of certain medications. Older adults also may have mobility problems that limit their ability to obtain water for themselves.
• People with chronic illnesses. Having uncontrolled or untreated diabetes puts you at high risk of dehydration. Kidney disease also increases your risk, as do medications that increase urination. Even having a cold or sore throat makes you more susceptible to dehydration because you're less likely to feel like eating or drinking when you're sick.
• People who work or exercise outside. When it's hot and humid, your risk of dehydration and heat illness increases. That's because when the air is humid, sweat can't evaporate and cool you as quickly as it normally does, and this can lead to an increased body temperature and the need for more fluids.

Dehydration can lead to serious complications, including:

• Heat injury. If you don't drink enough fluids when you're exercising vigorously and perspiring heavily, you may end up with a heat injury, ranging in severity from mild heat cramps to heat exhaustion or potentially life-threatening heatstroke.
• Urinary and kidney problems. Prolonged or repeated bouts of dehydration can cause urinary tract infections, kidney stones and even kidney failure.
• Seizures. Electrolytes — such as potassium and sodium — help carry electrical signals from cell to cell. If your electrolytes are out of balance, the normal electrical messages can become mixed up, which can lead to involuntary muscle contractions and sometimes to a loss of consciousness.
• Low blood volume shock (hypovolemic shock). This is one of the most serious, and sometimes life-threatening, complications of dehydration. It occurs when low blood volume causes a drop in blood pressure and a drop in the amount of oxygen in your body.

To prevent dehydration, drink plenty of fluids and eat foods high in water such as fruits and vegetables. Letting thirst be your guide is an adequate daily guideline for most healthy people.

People may need to take in more fluids if they are experiencing conditions such as:

• Vomiting or diarrhea. If your child is vomiting or has diarrhea, start giving extra water or an oral rehydration solution at the first signs of illness. Don't wait until dehydration occurs.
• Strenuous exercise. In general, it's best to start hydrating the day before strenuous exercise. Producing lots of clear, dilute urine is a good indication that you're well-hydrated. During the activity, replenish fluids at regular intervals and continue drinking water or other fluids after you're finished.
• Hot or cold weather. You need to drink additional water in hot or humid weather to help lower your body temperature and to replace what you lose through sweating. You may also need extra water in cold weather to combat moisture loss from dry air, particularly at higher altitudes
• Illness. Older adults most commonly become dehydrated during minor illnesses — such as influenza, bronchitis or bladder infections. Make sure to drink extra fluids when you're not feeling well.

Oct 14, 2021

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• Thomas DT, et al. American College of Sports Medicine Joint Position Statement. Nutrition and Athletic Performance. Medicine and Science in Sports and Exercise. 2016;48:543.
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