The survival of a child with severe volume depletion at the emergency department depends on the competency of the first responder to recognize and promptly treat hypovolemic shock. Although the basic principles on fluid and electrolytes therapy have been investigated for decades, the topic remains a challenge, as consensus on clinical management protocol is difficult to reach, and more adverse events are reported from fluid administration than for any other drug. While the old principles proposed by Holliday and Segar, and Finberg have stood the test of time, recent systematic reviews and meta-analyses have highlighted the risk of hyponatraemia, and hyponatraemic encephalopathy in some children treated with hypotonic fluids. In the midst of conflicting literature on fluid and electrolytes therapy, it would appear that isotonic fluids are best suitable for the correction of hypotonic, isonatraemic, and hypernatraemic dehydration. Although oral rehydration therapy is adequate to correct mild to moderate isonatraemic dehydration, parenteral fluid therapy is safer for the child with severe dehydration and those with changes in serum sodium. The article reviews the pathophysiology of water and sodium metabolism and, it uses the clinical case examples to illustrate the bed-side approach to the management of three different types of dehydration using a pre-mixed isotonic fluid solution . When 3% sodium chloride is unavailable to treat hyponatraemic encephalopathy, 0.9% sodium chloride becomes inevitable, albeit, a closer monitoring of serum sodium is required. The importance of a keen and regular clinical and laboratory monitoring of a child being rehydrated is emphasized. The article would be valuable to clinicians in less-developed countries, who must use pre-mixed fluids, and who often cannot get some suitable rehydrating solutions. The survival of a child with severe volume depletion at the emergency department depends on the competency of the first responder to recognize and promptly treat hypovolemic shock . Poor tiAlthough the basic principles on fluid and electrolytes therapy have been investigated for decades, the topic remains a challenge, as consensus on clinical management protocol is difficult to reach, and more adverse events are reported from fluid administration than for any other drug , 7.While the maintenance fluid therapy promoted by Holliday and Segar in 1957 has stood the test of time ; recent Apart from unavailability of some desired fluids , the clinicians in developing countries are also plagued with dearth of randomized clinical studies on fluids and electrolytes therapy, and confusion arising from conflicting literature on fluids and electrolytes therapy from developed countries, as new research findings continue to confound the old understandings –22.For example, the comprehensive treatise by K. Powers on management of isonatraemic, hypotonic, and hypernatraemic dehydration published in Pediatric Review in 2015  was soonFurthermore, Kiguli et al. in 2011 , followiAlthough the FEAST study excluded children with severe malnutrition and gastroenteritis, and their study population could only meet 2% of the WHO criteria for shock ; the perVolume depletion denotes reduction of effective circulating volume in the intravascular space, and since sodium constitutes the main extracellular solute, sick children may have isonatraemic, hyponatraemic and hypernatraemic dehydration depending on the differential loss of sodium and water , 28. DehIn this article, the terms dehydration and volume depletion will be used interchangeably, even when they are not necessarily the same .The choice of either oral rehydration therapy (ORT) or intravenous (IV) therapy in a child depends on accurate assessment of the degree of dehydration . While OSince pediatric dehydration is frequently the result of gastroenteritis, characterized by vomiting and diarrhea , this arClinical conditions relating to dehydration from burns, severe malaria, anemia, diabetes ketoacidosis, sickle cell disease, total parenteral nutrition (TPN), severe acute malnutrition, septic shock, acute kidney injury are outside the scope of this article.Although variations exist in the methods available for assessing dehydration, and in correcting for fluid and electrolytes deficits –20, the Diarrhea: WHO defines diarrhea as the “passage of loose or watery stools at least three times in a 24 h period” but emphasizes the importance of change in stool consistency rather than frequency, and the usefulness of parental insight in deciding whether children have diarrhea or not . The episode may begin either as watery diarrhea or as dysentery  in a dehydrated state  (Hypernatremia is when serum sodium is greater than 145 mmol/L. It represents lack of free water in the extracellular space (ar space .Fluid and electrolyte deficit: a deficit is the amount of water (and electrolytes) lost before rehydrating treatment is begun. For practical purposes, it is a one-time estimate  is equal to the sum of the osmolality of individual solutes in the intravascular space  (mmol/kg) .The blood tonicity : this denotes the concentration of solutes  that are impermeable to cell membranes which are therefore restricted to the extracellular compartment  and decreases to two-thirds of body weight (67%) after the neonatal period. This decreases further to 60% by the age of 12 months, which is the same value we have in adult male  .The TBW is distributed in various locations throughout the body, known as the fluid compartments. The intracellular fluid (ICF) compartment is about 40% of the TBW. The remaining 20% of the TBW constitutes the ECF compartment. The ECF comprises the interstitial fluid (15% of the TBW) and the intravascular plasma which makes up about 5% of the TBW  , the juxtaglomerular apparatus, the renin-angiotensin system and others , 39 see.Because sodium intake is generally not affected by ECF volume, it means that the sodium in the ECF is controlled by an increase or a decrease in renal sodium excretion . The bodA low ECF volume is detected by cardiopulmonary baroreceptors located in the atria, ventricles, and pulmonary interstitial tissue . A low EOther mechanisms involved in sodium metabolism include redistribution of intra-renal blood flow and renal prostaglandins . The expWater balance is achieved by ensuring that the amount of water consumed in food and drink and that endogenously generated by metabolism equals the amount of water excreted . The conUnder normal physiologic conditions, the kidneys control the volume of bodily fluids by the amount of water excreted in the urine. The kidneys conserve water  by producing concentrated urine, relative to plasma, or they can rid the body of excess water by producing diluted urine, relative to plasma.The direct control of water excretion is exercised by antidiuretic hormone  , 34. AVPThirst-induced water craving is an important pathologic response to hyper-osmolality or hypovolemia . Thirst,When the mechanisms of restoring the ECF volume are compromised, end-organ hypo-perfusion leads to poor oxygenation and nutrient delivery and ultimately tissue acidosis , 38.Table In the midst of these compensatory mechanisms, and in the face of ongoing losses, dehydration may ensue, which when accompanied by proportionate loss of sodium from extracellular space results in isonatraemic dehydration. Isonatraemic dehydration is the commonest (70–80%) type of dehydration and the type with the best prognosis .In this state, the normal tonicity of body fluids at 275–290 mOsm/kg is maintained, and the serum sodium concentration remains at normal ranges of 135 and 145 mmol/L , 38.The fluid deficit in isonatraemic dehydration is 100% from the extracellular space and when replacing the fluid deficit, the sodium concentration in the repletion fluid should be similar to that of the serum (averages 154 mmol/L) , 28, 40.The classical features of dehydration are commonly seen in isotonic dehydration. These include thirst, decreased skin turgor, tachycardia, dry mucous membranes, sunken eyes, lack of tears when crying, a sunken anterior fontanel in infants, and oliguria. The severe features of dehydration include anuria, hypotension, feeble and very rapid radial pulse, cool and moist extremities, and diminished consciousness.It is seen in 10–15% of cases of dehydration. It occurs more frequently with bacillary dysentery or cholera. Hyponatraemia may develop or worsen if there is a considerable oral ingestion of water, low-electrolyte or electrolyte-free fluids, or diluted formula during diarrhea. It may also follow iatrogenic intravenous administration of hypotonic fluids at the hospital.The serum sodium is less than 135 mmol/L. The Sosm is less than 275 mOsm/Kg because serum sodium accounts essentially for Sosm. Table Since solute loss (in vomiting or diarrhea) almost always occurs in an isosmotic fluid that has a sodium and potassium concentration less than that of plasma, loss of these fluids cannot directly lower the plasma sodium except there is increased water intake, or when excess water is retained . Thus, wNausea and malaise are typically seen when sodium level acutely falls below 125–130 mmol/L . HeadachIt is seen in 10–20% of patients with diarrhea. It can occur when too much salt is ingested or due to water deficit. Most frequently, it is due to water deficit from increased water losses in diarrheal stools, and also due to reduced water intake during the illness. In rare cases, it is due to an increase in total body sodium following ingestion of concentrated formula, incorrectly prepared highly concentrated oral electrolyte solution, and administration of high solute containing beverages to a child with diarrhea . The potDehydration state in which serum sodium is greater than 145 mmol/L, and Sosm higher than 290 mOsm/kg . Mild hyThere is a fluid shift from the intracellular to the extracellular space to maintain intravascular volume (intracellular dehydration), therefore, the vascular volume is usually maintained until the degree of dehydration is quite severe , 4, 14. Children with hypernatremia tend to have a fever, very dried tongue, doughy feeling skin, and warm extremities , 41. TheThe maintenance fluid requirement is the daily water needed for well individual to excrete iso-osmotic urine. The needs for maintenance fluid and electrolytes arose from the need to eliminate heat and solutes , which are the two by-products of the basal metabolism , 36. MajBecause metabolic rate per unit of body weight declines with increasing age, children generate less heat and solute from basal metabolism than do infants and, therefore, require less fluid and electrolytes per unit of body weight , 36. WhiThe Holliday–Segar system has gained wide acceptance and has stood the test of time , 36. It The Holliday–Segar formula estimates kilocalories that can be equated with milliliters of fluid. For each 100 kcal expended, approximately 100 ml of fluid is required. The 100 ml is a rounded estimate from (a) 50 mL of fluid required to provide for skin, respiratory tract, and basal stool losses, and (b) 55 to 65 mL of fluid required for the kidneys to excrete an ultra-filtrate of plasma at 300 mOsm/L (with a specific gravity of 1.010) without having to concentrate the urine .average child can then be based on body weight , acetate (Ringer’s acetate), and with acetate and gluconate , these isotonic fluids are said to be balanced or buffered as they now have electro-neutrality   Table 77.Because 0.9% normal saline  has been shown to cause dilutional coagulopathy , 46, hypHowever, Ringer’s lactate and Hartmann’s solutions, respectively, contain sodium concentrations of 130 and 131 mmol/L which are relatively lower than the serum sodium and their use should also be closely monitored as they could adversely lower the patient’s serum sodium . In addiWhile the addition of 20 mmol/L of potassium chloride to IV fluid is generally permissible , the amount of potassium chloride should be individualized to the patient needs and should be closely monitored , 42, 50.Therefore, a preferred fluid solution to be used for maintenance fluid and electrolytes is 5% dextrose in 0.9% saline with 20 mmol/L of KCL , 42.Unless hypokalemia is present, there is no pressing reason to administer more than this quantity of potassium , 41.Another consideration worthy of note in the acutely ill child is that reduction in the excretion of free water makes these children have a reduced urinary output and expectedly, the total fluid required to maintain a normal intravascular volume is reduced , 38, 51.Hence, while the maintenance volumes should be the starting point for these acutely ill dehydrated children, adjustment (between 50 and 80% reductions in maintenance volumes) can be made based on the clinical response to fluids in these children , 38.In contrast, some sick children will have increased fluid requirements . These children may need more than the standard maintenance fluid rate to maintain normal intravascular volume , 51. RefAbove all, prescribing maintenance fluid for ill children requires regular assessments, including weight assessment in order to ensure that adequate hydration is achieved without putting children to hyponatraemia and or over-hydration , 51.A deficit is the amount of water (and electrolytes) lost before treatment is begun . For praAlthough acute weight change (each gram of weight loss corresponds to 1 mL of water loss) is the most direct basis for determining the amount of deficit fluid, however , this muFrom the foregoing, it is admissible that assessing the extent of volume depletion can be difficult. This difficulty is also compounded by the fact that in most cases, the pre-illness weight of a child is unknown and the clinician is constrained to use clinical signs and symptoms as well as laboratory data to assess the degree of dehydration , 4, 36. Generally, regardless of what scoring method is used, the severity of dehydration is classified as mild (3–5% volume loss), moderate (6–10% volume loss), or severe (9–15% volume loss) . From thInfants and children with mild dehydration often have minimal or no clinical changes other than dry mucous membranes . Early hg = 10,000 ml) is clinically estimated to be mildly dehydrated at 5%, the volume of deficit to be given is 500 ml.In the replacement for fluid deficit, it is important to remember that each gram of weight loss equals I milliliter of fluid , therefoFor a simple bedside calculation, a formula is easily derivable to give this estimate as follows; % dehydration × 10 × body weight (in kg).Traditionally, intravenous fluids to replace existing fluid deficit are given over the first 24 h, while the patient continues to get his maintenance fluid over the same 24-h period .However, many clinicians quickly administered the fluid deficit either in whole (100%) in the first 8 h  or in part  as a combined deficit/maintenance approach , 55. In The appropriate fluid to correct fluid deficit is isotonic fluid with glucose and KCl if required, (once urine output is established). A good example is 0.9% normal saline with 5% glucose with 20 mmol/L of KCl added  , 20. ThiWhile Moritz and Ayus have argued strongly against the use of isotonic saline in treating hyponatraemic encephalopathy ; normal saline has been inevitably used when 3% NaCl is not available , 41. ThiThe clinician must remember that the clinical assessment of dehydration is only an estimate; therefore, the child must be continually re-evaluated during therapy to ensure that adequate replacement volumes are administered.On-going losses represent fluid and electrolytes that are being lost, and which causes the state of volume depletion in the first place (vomiting and diarrhea from gastroenteritis)  ThereforNon-cholera diarrhea fluid contains sodium of 56 mmol/L and chloride of 95 mmol/L, cholera stool contains a higher sodium of 101 mmol/L, and chloride of 92 mmol/L. Table , data inDiarrheal stool can also be replaced with 10 mL/kg of ORS per episode of diarrheal stool or the rate of replacement can occur cumulatively every 1–6 h , 51.Volume deficit/degree of dehydration. The clinician must first determine if hypovolaemic shock is present  and must be treated as an emergency. A careful history and further physical examination can point to the possible types of dehydration . DetermiDoes osmolar disturbance exist? While it is not important to do elaborate laboratory investigations for mild dehydration, it is important to obtain the serum sodium, Sosm, urinary osmolality, urinary sodium, fractional excretion of sodium, and the urinary specific gravity for moderate to severe forms of dehydration . Serum gIn patients with hypernatremia, the normal response is an increase in ADH release, resulting in an increase in urinary osmolality that can reach up to 500 to 1200 mOsm/kg. The presence of this increase in urinary osmolality suggests that the water loss responsible for the hypernatremia (in the absence of osmotic diuresis) is coming from extra-renal  sources. In comparison, hypernatremia with urinary osmolality below 300 mOsm/kg is indicative of renal concentration defect. This could be due to diabetes insipidus (ADH deficiency or non-response to ADH) or other renal concentration defects seen in the polyuric phase of acute tubular necrosis and diuresis that may follow a relief of urinary obstruction . The distinction between central (ADH deficiency) and nephrogenic (non-response to ADH) diabetes insipidus can be made with the administration of desmopressin acetate (DDAVP), an analog of ADH. If the urine osmolality rise by at least 50% in the first 2 h of DDAVP , this has proven a state of ADH deficiency  , 34.In hyponatraemia, clinical evaluation of the intravascular volume, Sosm, urine osmolality, and urinary sodium are helpful for the specific diagnosis of the hyponatraemia . See FigCheck for acid-base disturbance by determining the blood pH, the serum PCO2 and the serum bicarbonate , 55. TheCheck the serum potassium. Serum potassium may be low following the loss in diarrheal stool . It may Renal function test. The kidney may fail following tissue hypo-perfusion resulting from prolonged uncorrected hypovolemia . It is iThe management of a child with dehydration must seek to answer the following questions :Volume It is important to emphasize that oral rehydration can be safely and effectively accomplished in children with mild-to-moderate dehydration and in those with normal serum sodium values. Children with more severe dehydration or with abnormal serum sodium values should be treated with intravenous infusions , 41, 42.The following discussion focuses on how to treat the different types and severity of dehydration that may be seen in diarrheal disease, and it also emphasizes on the necessary intensive monitoring required in all types of dehydration:Oral rehydration therapy either by mouth or through the nasogastric tube can safely and effectively restore intravascular volume in children with mild-to-moderate isonatraemic dehydration, in as much as the child can tolerate it . The AmeOral rehydration therapy works in the most severe form of diarrhea. Even with on-going diarrhea, water can be absorbed across the intestinal lumen by the co-transport of sodium and glucose via the SGLT1 protein and by active transport via the sodium-potassium ATPase pump . OptimalThe glucose: sodium ratio of rehydration fluids should not exceed more than 2:1 for effective fluid repletion . While cBeverages like apple juice, tea, ginger ale, colas, sports drinks, and chicken broth are inappropriate to use for rehydration because they do not contain the correct sodium and glucose ratio to promote salt and water reabsorption , 14, 55.Oral rehydration therapy is unsuitable in the following conditions; (a) severe dehydration, (b) circulatory instability or hypovolemic shock, (c) altered mental status, (d) intractable vomiting, (e) bloody diarrhea, (f) paralytic ileus/abdominal distension, (g) abnormal serum sodium values, (h) glucose mal-absorption, (i) lack of caregiver to give close attention during ORT, and in (j) those averse to the taste of oral rehydration solution or those not tolerating because of stomatitis or pharyngitis , 14.The amount of fluid deficit is calculated based on the change in weight (if pre-illness weight is known) or based on clinical signs. Generally, mild to moderate dehydration is assumed at 5% (50 ml/kg body weight) and this is replaced over 2–4 h , 14. UsiReplace ongoing losses with ORS. When possible and measurable, ongoing losses should be replaced volume for volume using appropriate fluid, or with ORS. When it is impossible to have a measurement of the vomitus or stool, replacing 10 mL/kg body weight for each watery stool or 2 mL/kg body weight for each episode of emesis should suffice .Breastfeeding/formula or age-appropriate complementary feed should not be stopped during ORT as they serve as maintenance. Small frequent feeds decrease vomiting. However, carbonated drinks and drinks or food with high concentrations of simple carbohydrates should be avoided during therapy, and patient should be reassessed regularly , 14, 60.E. Coli 25%, Campylobacter jejuni 10–18%, Shigella spp, and Salmonella spp 5% each), 35% of viral (15–25% rotavirus) origin, and in many the cause is unidentified or mixed  and hospital admission, and it does not have the extrapyramidal effects of promethazine , 67. TheChallenges in the administration of ORT include the perception that IV therapy is superior to ORT; ORT is time-consuming for both parents and doctors; parents expect IV therapy once they are on admission at the hospital; and parents expect IV therapy since they may have tried ORT at home, even when they have used poor technique .Some key measures to prevent diarrhea include: access to safe drinking-water, improvement in environmental sanitation, exclusive breastfeeding for the first 6 months of life, good personal, and food hygiene (hand washing), health education about how infectious diarrhea is spread and administration of rotavirus and typhoid vaccines to susceptible children .ORT involves the following:Once it is determined that a patient is in shock, the general principles of hypovolemic shock management per pediatric advanced life support should be followed including obtaining rapid vascular access, which may be in the form of peripheral intravenous access or an intraosseous route if peripheral access is not successful , 71. Thi❖What type and degree of dehydration is AB?❖Outline the fluid prescription for AB?AB, a 11- month old child presented at emergency unit with 3 days history of vomiting and diarrhea, physical examination revealed that the child was lethargic, dried mouth, tearing, sunken eyeballs and anterior fontanelle, pulse was rapid and weak, BP was 45mmHg/inaudible diastolic capillary refills was in excess of 4 s. Child is making urine, but mother has no need to change the nappies as she usually does before the illness. The child weighs 8 kg. The laboratory results revealed Na 138 mmol/L, K 1.8 mmol/L, Cl 95 mmol/LAB has severe isonatraemic dehydration with hypokalemia. AB also presented in hypovolaemic shock, so rapidly expand the intravascular space with 0.9% Normal saline, i.e., 20 mL/kg = 160 mL, given over 10 min as initial fluid therapy.Calculate the deficit at 15% because AB is an infant, i.e., 15 × 10 × 8 = 1,200 ml; however, 160 mL has been given as a volume expander, you are left with 1,040 mL as a remaining deficit volume.Calculate the maintenance fluid volume, i.e., 100 × 8 = 800 mLMeasure ongoing loss by possible recording volume of stool or vomitus and record the volume to be replaced volume for volume with ORS. If measurement is impossible give 10 mL/kg = 80 mL of ORS/loose stool and 2 mL/kg = 20 mL of ORS/vomitus❖For combined deficit/maintenance approach:You can either use the combined deficit/maintenance approach OR sequential deficit-maintenance approachGive 1/2 remaining deficit  + 1/3 maintenance (1/3 × 800 = 267 mL) = 787 mL in the first 8 h❖For sequential deficit/maintenance approach:Then, follow with 1/2 remaining deficit  + 2/3 maintenance (2/3 × 800 = 533) = 1,053 ml over the remaining 16 hGive 1,040 mL (remaining deficit) over the first 8 hGive 800 maintenance fluids over the remaining 16 hChoice of fluid for both maintenance and deficit is Isotonic Saline (0.9%) with 5% dextrose20 mmol of KCl into each liter of fluid could have been adequate but could be increased to 40 mmol/L because of the hypokalemia (1.8 mmol/L). Once the serum K rises to 3.5  decrease KCL to 20 mmol/L.Regular monitoring is requiredHypovolaemic shock must be treated once recognized regardless of whether the child is having isonatraemia, hyponatraemia, or hypernatremia , 38, 42.Initial fluid therapy/resuscitative fluid . Remember that this is part of deficit replacement.Subsequent therapy: replace deficit  + maintenance fluid volume + on-going losses.Final therapy: when patients return to normal composition/establish oral feeds/correct potassium deficitMonitor therapy continuously.Stages involved , 36, 55:SR, an 8 week old infant weighing 4 kg presented with 1 week history of vomiting and passage of loose stool. Mother was advised to give water as frequently as the child could tolerate it. He was found with moderate dehydration on examination. Laboratory results revealed Na 130 mmol/L, Cl 94 mmol/L, K 1.9 mmol/L, and HCo3 8 mmol/L.Deficit fluid volume: 10 × 10 × 4 = 400 mLMaintenance fluid volume: 100 × 4 = 400 mL❖For combined deficit/maintenance approach:Measure ongoing loss by possible recording volume of stool or vomitus and record the volume to be replaced volume for volume with ORS. If measurement is impossible give 10 mL/kg = 40 ml of ORS/loose stool and 2 mL/kg = 8 ml of ORS/vomitusGive 1/2 deficit (200 mL) + 1/3 of maintenance (133 mL) in the first 8 h, then 1/2 of remaining deficit (200 mL) and 2/3 of the remaining maintenance (267 mL) in the next 16 h❖For sequential deficit/maintenance approach:Regular monitoring is requiredGive 400 mL of deficit volume in the first 8 h❖Choice of fluid for both maintenance and deficit is Isotonic (0.9%) normal saline with 5% dextroseGive 400 mL of maintenance fluid in the next 16 h20 mmol of KCl into each liter of fluid could have been adequate but this could be increased to 40 mmol/L because of the hypokalemia (1.9 mmol/L). Once the serum K rises to 3.5, i.e., hypokalemia corrected) decrease KCL to 20 mmol/LRegular monitoring is required.For the most part, the following discussion will focus more on the management of hyponatraemia in a child with volume depletion.Hyponatraemia is seldom symptomatic unless the serum Na is < 120 and if the hyponatraemia occurs quickly . So, theJK is a 5 month old child brought to the emergency unit with a 7 day history of vomiting and diarrhea. JK had stopped breastfeeding in the last 48 h which made JK’s mother to institute tea and water which JK took poorly. 15 min before presentation, JK was said to have convulsed, generalized tonic-clonic which lasted for 15 min. On examination, JK was found with dried tongue, sunken eyes and depressed anterior fontanel and tenting of the skin, weight was 5 kg, pulse rate was 160 beat/min, cold and pale extremities. The blood pressure was 45 mmHg/inaudible diastolic. Laboratory evaluation revealed serum Na of 105 mmol/L, CL 95 mmol/L, K 3.5 mmol/L, serum HCO3 8 mmol/L. Outline the management approach of JK.JK is having severe hyponatraemic dehydration with serum Na < 120 mmol/L, and metabolic acidosis.Since JK is in shock give 20 mL/5 kg = 100 mL of Normal Saline.Calculate JK fluid deficit at 15% deficit = 15 × 10 × 5 = 750 mLActual deficit left is (750–100) = 650 mLCalculate JK Na deficit = 120–105 × 0.6 × body weight = 15 × 0.6 × 5 = 45 mmol of NaThis is equal to 90 mL of 3%NaCl, since 0.5 mmol of Na = 1 ml of 3% NaCl which should be given over 30 min. This dose can be repeated until the serum sodium becomes 120–125 mmol/L..Calculate JK maintenance fluid volume = 100 × 5 kg = 500 mLGive the remaining deficit, 560 mL (650–90 mL) to go in the first 8 hGive the maintenance of 500 ml to go over the remaining 16 hIt only makes sense that only the sequential deficit/maintenance approach can be used if there is a need to correct symptomatic hyponatraemiaThe fluid choice for the deficit and maintenance volume is isotonic saline (0.9%) with 5% glucose and the rate of rise in serum sodium should be monitored hourly as the serum sodium should not rise more than 0.5 mmol/L every hour or 12 mmol/L over 24 h Once child is making urine, add 20 mmol/L of KCL into isotonic saline with 5% dextrose.Regular monitoring is required.The initial goal in treating hyponatraemia is the correction of intravascular volume depletion with isotonic normal saline. Urgent treatment of hyponatraemia is however required in all patients who exhibit neurological changes including seizure, change in sensorium and if the serum sodium level is < 120 mmol/L . Most frThe formula for the Na deficit mmol = (120–current Na) × 0.6 × body weight in kg .The 0.6 is 60%, which is the volume of distribution of sodium. The mmol of Na required should ideally be gotten from 3% NaCl as it contains 513 mmol of Na/L or 1 mL = 0.5 mmol of Na. A rule of thumb is that 4 mL/kg of 3% NaCl increases serum Na by 3 mmol/L , 41.Although isotonic 0.9% saline is inappropriate for the treatment of hyponatraemic encephalopathy because it is insufficiently hypertonic to result in a consistent increase in plasma sodium; it may still be given if a hypertonic saline solution is unavailable, 1 mL of 0.9% saline contains 0.154 mmol of Na , 41. ThiAcute rapid correction of hyponatraemia to stop seizures or address neurological changes followed by a slower correction (10–12 mmol/L/day) to normal serum levels is essential to prevent central pontine myelinolysis (CPM). CPM although rare in children, is characterized by neurologic symptoms including confusion, agitation, flaccid or spastic quadriparesis, and death. CPM is also commoner in patients treated for chronic hyponatraemia than in those treated for acute hyponatraemia.Hypernatremia (serum sodium > 145 mmol/L) usually arises because too much of free water is lost which should be replaced gradually. It is moderate hypernatremia when serum sodium is 150–169 mmol/L and severe hypernatremia when serum sodium is > 169 mmol/L.The gradual rehydration protocol suggested by Finberg in 1973 remains valid up till today .After the administration of resuscitative isotonic saline for hypovolemic shock , the volume of free water deficit should be calculated and given slowly over 48 h in moderate hypernatremia and over 72 h in severe hypernatremia .At both rates (48 or 72 h) of rehydration, the caution is not to reduce the serum sodium by more than 0.5 mmol/L per hour and/or by more than 12 mmol/L over 24 h , 52. CloIt is the free water deficit volume that is spread over 48–72 h as the child continues to get his daily maintenance fluid and fluid is continuously being replaced for ongoing losses , 38, 52.The deficit volume in hypernatraemic dehydration is the free water and the formula for free water deficit is , 41:FreIdeally, the best fluid to give is water as it contains 100% free water . 0.45% nTP is a 3 month old child who presented at emergency pediatric unit (EPU) with 3 weeks history of fever and occasional vomiting. TP mother also noticed that the child has not been suckling well as before and she also felt light in her breasts. TP mother complained to her neighbor who advised her to buy infant formula as the child “may not like her breast milk again” TP mother was adding little water to many scoops of the infant formula, contrary to the instruction on the tin. However, TP continues to get worse and she was rushed to the EPU by 3 am. The house officer could not understand why the mother was worried as examination revealed only a dried tongue and doughy feeling skin. The weight was 5 kg. The house officer treated TP for malaria fever and asked the mother to come back later in the day. He also requested for E/Urea because of the history of vomiting. The result came out 1 h later revealing malaria parasitaemia of 1 + , Na of 170 mEq/L, K 3.7 mEq/L, Cl 104 mEq/L. When the senior doctor examined the child later, TP was confirmed to be in hypovolemic shock.The child had severe hypernatraemic dehydration and also in hypovolemic shockSo 20 mL/kg of NS was given over 20 min = 100 mLCalculated free water deficit = (170/145−1) × 0.6 × 5 = 0.52 L = 517 mLThe remaining deficit = 517 – 100 = 417 mLThe calculated maintenance = 100 mL × 5 = 500 mLChild received (1/3 of 417 mL) 139 mL of deficit + 500 mL of maintenance = 639 mL in the first 24 h (+ongoing losses)Another (1/3 of 417) 139 mL of deficit + 500 mL of maintenance = 639 mL in the next 24 h (+ongoing losses)Remaining (1/3 of 417 mL) 139 mL of deficit + 500 mL of maintenance = 639 mL in the next 24 h (+ongoing losses)In other word, the free water deficit was spread over 72 h  from the time of treatment commencement, while the child continued to receive his daily maintenance and ongoing lossesThe fluid choice is isotonic saline (0.9% NaCl with 5% glucose)20 mmol/L of KCL was added|Regular monitoring is required.Regular monitoring:It is important to remember that the bed-side assessment for dehydration remains at best clinical estimates; therefore, close monitoring of patients on rehydration is the key. In as much as the kidney is functioning optimally, errors of under and over estimation in the calculation of fluid estimates are often corrected by the kidney. While the cause of the dehydration is being treated and regardless of the type of dehydration, the clinician should pay attention to the following , 41, 52;Regular monitoring of the vital signs  and having a good record of the fluid intake and output  and close watch on the physical examination . The best monitoring “tests” are the simple ones that all too frequently are overlooked, such as the resolution of signs of dehydration apparent on physical examination Children receiving deficit fluid should be weighed at least every 6 hA daily increase in weight of 5% or more indicates fluid overload, provided there is no third-spacing. Manage by stopping IV fluids and measure serum sodiumA daily decrease in weight of 5% or more indicates dehydration. Pay a closer attention to fluid rates, to ensure adequate rehydrationDaily assess for edema (eyelid and lower limb swelling) and stop IV fluid if edema is identifiedCheck serum electrolytes and glucose dailyCheck serum electrolytes and glucose every 4 h, if there is hypo/hypernatraemic dehydration, until serum values become normalRed flag if serum sodium is ≤ 130 mmol/L or has fallen by > 0.5 mmol/L per hour or >12 mmol/L per day OR serum sodium is ≥ 150 mmol/L or has risen by > 0.5 mmol/L per hour or >12 mmol/L per dayIf sodium is correctly too rapidly in hyponatraemic dehydration, cerebral  demyelination, and permanent brain injury may occurIf sodium is corrected too rapidly in hypernatraemic dehydration, cerebral edema may occurThe closure of rehydration therapy is suggested by normalization of vascular status, restoration of normal mental status, lack of clinical signs, and symptoms of fluid deficit, and adequate urinary output of >0.5 mL/kg/h (1 mL/kg/h for an infant).Other endpoints include normalization of laboratory results including blood urea, serum creatinine, Sosm, urine osmolality, and urinary electrolytes.Normalization is impossible if ongoing losses continue and this should be corrected as well.Again, it appears that isotonic 0.9% normal saline with 5% dextrose is an appropriate fluid, and it is safe as a starting fluid in cases of hypernatraemic dehydration , 42, 52.Even though the deficit in hypernatremia is predominantly water, it is safe to use isotonic saline (0.9% with 5% glucose) for both maintenance and deficit volumes as isotonic fluids are superior to hypotonic fluids for the prevention of hyponatraemia and are not associated with an increase in the incidence of hypernatremia or fluid overload , 14.However, the clinician must ever remain vigilant and adjust appropriately the rate (reduce by 20%) of rehydration with isotonic saline as the reduction in serum sodium should not be more than 0.5 mmol/L per hour , 41, 52.Management of hyponatraemia involves the following:Give bolus of 0.9% saline 20 mL/kg if child is in shock and as required. In the child with hypernatraemic dehydration, as in any child with dehydration, the first priority is restoration of intravascular volume with isotonic fluidSubtract the bolus given for hypovolaemic shock from calculated deficit = remaining deficitCalculate maintenance fluid based on weight of the childGive 1/2 of remaining deficit over the first 24 h + 24 h maintenance fluid + ongoing lossesGive 1/2 of remaining deficit over the second 24 h + 24 h maintenance fluid + ongoing lossesFor mild/moderate hypernatremia;Give 1/3 of remaining deficit over the first 24 h+ 24 h maintenance fluid + ongoing lossesGive 1/3 of remaining deficit over the second 24 h + 24 h maintenance fluid + ongoing lossesGive 1/3 of remaining deficit over the third 24 h + 24 h maintenance fluid + ongoing lossesFor severe hypernatremia;The fluid of choice for correcting hypernatraemic dehydration is 0.9% NaCl with 5% glucoseThe management of a child with dehydration requires a regular and close clinical and laboratory monitoring. In as much as the kidneys are functioning optimally, errors resulting from over-hydration can be corrected by the kidneys. Onus is on the attending physician to ensure that hypovolaemic shock is reversed, while ongoing losses are replaced to remove the child from a perpetual state of dehydration.A preferred fluid solution to be used for maintenance fluid and electrolytes is 5% dextrose in 0.9% saline with 20 mmol/L of potassium chloride added.The maintenance fluid volumes are the starting point for acutely ill dehydrated children, adjustment (between 50–80% reductions in maintenance volumes) can be made based on the clinical response to fluids in these children who tend to have a reduced free water excretion from high levels of ADH hormones. Some children may, however, require more than the usual maintenance fluid volumes.Maintenance fluid containing less than 75 mmol/L of sodium should never be used for maintenance hydration. 0.18% sodium chloride  contains only 30 mmol/L of sodium and is not appropriate for maintenance hydration.Oral rehydration is most suitable for mild to moderate isonatraemic dehydration.0.9% saline with 5% glucose with 20 mmol/L of potassium chloride  is suitable for most isonatraemic, hypernatraemic, and hyponatraemic dehydration.The correction of the deficit-free water volume in hypernatraemic dehydration is spread over 48–72 h, as the child continues to get his daily maintenance fluid, and fluid is continuously being replaced for ongoing losses.If sodium is corrected too rapidly in hypernatremia, cerebral edema, and permanent brain injury may occur.If sodium is corrected too rapidly in hyponatraemia, cerebral  demyelination, and permanent brain injury may occur.Regular clinical and laboratory (serum electrolytes and glucose) monitoring every 4 h is required in hyponatraemic and hypernatraemic dehydration until serum values become normal.The rate of change in serum sodium should not be more than 0.5 mmol/L per hour and/or 12 mmol/L per day in hyponatraemic and hypernatraemic dehydration.Responsible for the conceptualization, literature review, and critical review of the manuscript.While the information contained in this article is scientifically correct, the author hereby disclaims any and all liability to all persons arising out of, or related to the content of this article. Readers are advised to seek the services of an experienced, competent professional if expert assistance is required in childhood fluid and electrolytes therapy.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


I consider how different co-precipitating DIC species affect aragonite B/Ca and also estimate the impact of variations in the B(OH)4−/co-precipitating DIC aragonite partition coefficient (KD), which may be associated with changes in the DIC and Ca2+ chemistry of the calcification fluid. The coral skeletal B/Ca versus calcification fluid pH relationships reported previously can be reproduced by estimating B(OH)4− and co-precipitating DIC speciation as a function of pHCF and assuming that KD are constant i.e. unaffected by calcification fluid saturation state. Assuming that B(OH)4− co-precipitates with CO32−, then observed patterns can be reproduced by a fluid with approximately constant [DIC] i.e. increasing pHCF concentrates CO32−, as a function of DIC speciation. Assuming that B(OH)4− co-precipitates with HCO3− only or CO32− + HCO3− then the observed patterns can be reproduced if [DIC]CF and pHCF are positively related i.e. if DIC is increasingly concentrated in the calcification fluid at higher pHCF probably by CO2 diffusion into the calcification site.The boron geochemistry of coral skeletons reflects the dissolved inorganic carbon (DIC) chemistry of the calcification fluid from which the skeletons precipitates and may be a valuable tool to investigate the effects of climate change on coral calcification. In this paper I calculate the predicted B/Ca of aragonite precipitating from seawater based fluids as a function of pH, [DIC] and [Ca Most reragonite  substitu lattice  and is do B(OH)3 . Hence aipitates  while  but does not affect total alkalinity. Bicarbonate anion transporters (BATs) convey HCO3− into the calcification fluid, likely in exchange for Cl−  and also decreases pHCF.The key processes affecting calcification fluid DIC chemistry and their effects are summarized in a-ATPase  which puhe fluid  so proto for Cl− . This in2.2CF. The details of the scenarios are as follows:I calculate the DIC chemistry of a seawater based calcification fluid and the B/Ca of aragonite precipitated from it under a range of different scenarios 4− in the aragonite  or is higher than this (the high DICCF scenario), CF is equivalent to that of seawater, I effectively calculate the DIC of the calcification fluid as a closed system. I do not infer that the fluid is closed to CO2 diffusion but rather that additions of CO2 to the calcification fluid by diffusion are balanced by loss of DIC to precipitation. This is supported by direct measurements of pHCF and [CO32−]CF which indicate that DICCF is approximately constant and equal to that of ambient seawater (2 (ambient seawater has pH 8 and [DIC] = 1796 μmol kg‐1) or 800 μatm CO2 (ambient seawater has pH 7.74 and [DIC] = 1911 μmol kg‐1). This doubling of seawater pCO2 indicates how DICCF is affected if the [CO2] of the coral tissue and body compartments is higher than that of ambient seawater  and that the [CO2] of the calcification fluid reflects that of ambient seawater brought to pHCF  and scale the addition of DIC to the calcification fluid over the full pH range at 400 and 800 μatm CO2 as a linear function of ΔCw. This calculation is shown in detail in Appendix 1. I assume that additional H+ extrusion compensates for the pH decrease associated with the ingress of CO2 so that pHCF is unaffected by this CO2 invasion. I calculate the final [DIC]CF as the [DIC]seawater plus CO2 added by diffusion  to apply in the calculations I combine data from two studies that measured boron partitioning in inorganic aragonite at ∼25 °C  for scenario 1a, [Ca2+][HCO3−] for scenario 1b and [Ca2+][HCO3− + CO32−] for scenario 1c. The experiments of To estimate the B(OH)t ∼25 °C . I excluturation , an indituration . I plot D B(OH)4−/CO32− is also positively correlated with precipitation rate in aragonite but KD B(OH)4−/HCO3− and KD B(OH)4−/(CO32− + HCO3−) do not show this relationship  I calculate calcification fluid saturation as [Ca2+]CF[CO32−]CF/K*sparagonite for scenario 1a, [Ca2+]CF[HCO3−]CF for scenario 1b and [Ca2+]CF[HCO3− + CO32−]CF for scenario 1c and then calculate KD from Eqs. D is independent of fluid saturation, I calculate the saturation state for a typical coral fluid based on direct measurements of [CO32−]CF at pHCF = 8.55 4−/CO32−, B(OH)4−/HCO3− and B(OH)4−/(CO32− + HCO3−) respectively. I apply these same KD to all scenarios in which I use a constant KD, irrespective of [co-precipitating DIC]CF, [Ca2+]CF or CO2 atmosphere.In the case that B(OH)d corals . I calcu2.2.42+]CF affects the saturation state of the calcification fluid and subsequently may influence the B(OH)4−:aragonite partition coefficient (see section 2.2.3). I adopt 2 approaches to estimate [Ca2+]CF. In scenario 5a I assume that all proton extrusion from the calcification fluid is mediated by Ca-ATPase. This enzyme pumps 2H+ out of the fluid for every Ca2+ pumped in, thereby increasing fluid total alkalinity and [Ca2+] in a 2:1 mole ratio. I use the total alkalinity of the calcification fluid  to infer the activity of the enzyme and to calculate fluid [Ca2+] (2+] of the fluid at pH 8 is that of ambient seawater (10 mmol kg‐1). Aragonite precipitation removes total alkalinity and Ca2+ in a 2:1 mole ratio so does not influence this approach. In scenario 5b I assume that proton extrusion is mediated by an alternative ATPase which does not affect fluid [Ca2+]. Direct measurements of coral calcification fluids suggest that fluid [Ca2+] is similar to seawater 4−/co-precipitating DIC aragonite partition coefficients (4−]CF using K*B = 2.527 × 10−9 (4−/co-precipitating DIC. I multiply fluid B(OH)4−/co-precipitating DIC by KD to calculate aragonite B/Ca.I calculate the B/Ca of aragonite precipitated from the calcification fluid under the various scenarios. Aragonite B/Ca equates to aragonite B(OH)mol kg−1 . I assumficients . I estim7 × 10−9  and calc33.111B of Porites spp. field corals suggests that mean coral pHCF is ∼8.5  between the coral tissue and the calcification fluid assuming that the [CO2] of the overlying tissue is the same as ambient seawater and that fluid [CO2] reflects that of ambient seawater brought to pHCF. The [CO2] of a fluid brought to pHCF is exponentially related to pHCF i.e. at high pHCF fluid [CO2] becomes progressively smaller  to ∼4100 μmol kg−1 and ∼6600 μmol kg‐1 at pHCF 9 for the 400 and 800 μatm CO2 high DIC scenarios respectively  or that other, non-Ca pumping, enzymes fulfil this role (resulting in no change to [Ca2+]CF). In the first scenario [Ca2+]CF increases by 5% and 6% above that of seawater at 400 and 800 μatm CO2 respectively at low DIC and by 23% and 42% respectively at high DIC  are associated with higher [co-precipitating DIC]CF than the low DIC at comparable pHCF. However while both [CO32−]CF and [CO32−+ HCO3−]CF are positively correlated with pHCF, [HCO3−]CF increases to a maximum at ∼ pH 8.3–8.5 and then begins to decrease again 4− speciation are illustrated in 4−/co-precipitating DIC ratios are illustrated in 4−/HCO3− and B(OH)4−/(CO32− + HCO3−) are positively correlated with pHCF in both the low and high DIC scenarios. As pHCF increases the increase in [B(OH)4−] (driven by the effect of pH on boron speciation) is larger than any increase in [HCO3−]CF and [CO32− + HCO3−]CF. In contrast, fluid B(OH)4−/CO32− is inversely correlated with pHCF at both low and high DIC. Here the proportional increase in [CO32−]CF at higher pHCF is larger than any increase in [B(OH)4−]CF. The high DIC scenarios generate lower B(OH)4−/co-precipitating DIC than the low DIC scenarios at comparable pH because [co-precipitating DIC]CF are higher in the high DIC scenarios. Likewise, [co-precipitating DIC] are higher at 800 μatm seawater pCO2 than at 400 μatm seawater pCO2 for comparable pHCF yielding lower B(OH)4−/[co-precipitating DIC] ratios at 800 μatm seawater pCO2 (B(OH)ter pCO2 c,d.Fig. 3.44−/co-precipitating DIC fluid compositions  with a constant KD (scenario 4b) as in setting a constant KD I do not require [Ca2+]CF to estimate calcification fluid saturation state. The constant and variable [Ca2+]CF scenarios generate broadly similar patterns in skeletal B/Ca. I illustrate the impact of this change at 400 μatm seawater pCO2 but calculate expected aragonite B/Ca at 800 μatm seawater pCO2 using variable [Ca2+]CF only.I calculate the B/Ca of aragonite precipitating from the fluids using the B(OH)ositions c,d and ctions 4−/co-precipitating DIC (CF if B(OH)4− co-precipitates with CO32− and is positively correlated with pHCF if B(OH)4− co-precipitates with HCO3− or (CO32−+ HCO3−). Higher [co-precipitating DIC]CF serves to dilute the calcification fluid B(OH)4− and generates lower skeletal B/Ca. For this reason the high DIC scenarios always generate lower skeletal B/Ca compared to the low DIC scenarios at comparable pHCF.ting DIC c,d are eD varies in response to calcification fluid saturation state then these patterns change significantly 4− incorporation in the precipitating aragonite. Although fluid B(OH)4−/[CO32−]CF decreases at high pH (4− incorporation at high fluid saturation state overrides this dilution of fluid B(OH)4− by CO32−. Put simply, over the pHCF range 8 to 9 at 400 μatm seawater pCO2, B(OH)4−/CO32− decreases by x0.7 and x0.3 in the low and high DIC scenarios respectively (D increases x8 and x22 (assuming a variable [Ca2+]CF) over the same pH range 4− incorporation in the aragonite) outweighs any B(OH)4− dilution by increased fluid [CO32−].Assuming that Kficantly g–o. KD i species . In the  high pH c, the inectively c but KD pH range b. So in rrelated g,j,m. HiD have a more subtle effect on aragonite B/Ca if B(OH)4− co-precipitates with either HCO3− only or CO32− + HCO3−. Assuming that B(OH)4− co-precipitates with HCO3−, then at low DIC both [HCO3−]CF and KD are relatively high at low pHCF and relatively low at high pHCF 4−/HCO3− (D and aragonite B/Ca and pHCF are positively correlated (D (driven by higher [HCO3−]CF compared to the low DIC scenario) is outweighed by the proportional decrease in fluid B(OH)4−/HCO3− (driven by increased [HCO3−]CF). Thus the high DIC scenarios generate lower aragonite B/Ca than the low DIC scenarios at comparable pHCF. Predicted aragonite B/Ca is broadly similar if B(OH)4− co-precipitates with both CO32− + HCO3− as HCO3− is usually the dominant DIC species over the range of pHCF. Once again aragonite B/Ca is positively correlated with pHCF in all scenarios and high DIC scenarios generate lower aragonite B/Ca than their low DIC counterparts 4− and decrease aragonite B/Ca. Over all co-precipitation scenarios, changes between predicted aragonite B/Ca at 400 and 800 μatm seawater pCO2 are almost imperceptible at low DIC and more significant at high DIC. When KD is variable, the increases in [co-precipitating DIC]CF generate higher KD. If B(OH)4− co-precipitates with CO32−, then the effect of increasing KD outweighs the effect of decreased fluid B(OH)4−/[CO32−] and aragonite B/Ca is higher at 800 μatm compared to 400 μatm seawater pCO2. If B(OH)4− co-precipitates with HCO3− or both CO32− + HCO3− then the effect of decreased fluid B(OH)4−/[co-precipitating DIC] outweighs the effect of increasing KD and aragonite B/Ca is lower at 800 μatm compared to 400 μatm seawater pCO2. Under all co-precipitation scenarios at variable KD changes between predicted aragonite B/Ca at 400 and 800 μatm seawater pCO2 are very subtle.Seawater pCOter pCO2 . At cons3.4.4D for all B(OH)4−/co-precipitating DIC species are much smaller than 1, B(OH)4− is preferentially discriminated against during aragonite formation. As precipitation proceeds, the B(OH)4−/co-precipitating DIC of the fluid remaining in the reservoir, and of the aragonite precipitated from it, increases. The final B/Ca of the precipitated aragonite reflects the proportion of the reservoir used in precipitation  and in this case it is likely that I have overestimated aragonite B/Ca at high pHCF in the high DIC scenario at 800 μatm seawater pCO2.In the scenario that (B(OH)on of KD . This ocerate KD  that exc3.52 conditions . Temperature also has no observable effect on boron partitioning in aragonite above fluid pH of 8.3 4− in the precipitating aragonite) counteracts the dilution of fluid B(OH)4− by high co-precipitating DICCF. In corals the observed skeletal B/Ca is relative constant regardless of inferred pHCF . This pattern cannot be reproduced by the variable KD scenarios either separately or in combination. I conclude that the coral data cannot be well described by any of the scenarios employing variable KD.Given the assumptions made in the calculations, e.g. in setting [DIC]rrelated g–o. FurtD generate wider ranges of aragonite B/Ca that are comparable to the skeletal B/Ca versus pHCF relationships observed in corals  and [DIC]CF (affecting [co-precipitating DIC]CF).The scenarios utilizing constant Kn corals a–f. The ion rate , it is uCF and skeletal B/Ca 4−]CF 4−]CF c. In thetal B/Ca b,c,e,f w4CF relationships can be reproduced by estimating B(OH)4− and co-precipitating DIC speciation as a function of pHCF and assuming that KD are constant i.e. unaffected by calcification fluid saturation state. Assuming that B(OH)4− co-precipitates with CO32−, then observed patterns can be reproduced by a fluid with approximately constant [DIC] i.e. increasing pHCF concentrates CO32−, as a function of DIC speciation. Assuming that B(OH)4− co-precipitates with HCO3− or CO32− + HCO3− then the observed patterns can be reproduced if [DIC]CF and pHCF are positively related i.e. if DIC is increasingly concentrated in the calcification fluid at higher pHCF probably by CO2 diffusion into the calcification site.Observed coral skeletal B/Ca versus pHNicola Allison: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.The authors declare no conflict of interest.This work was supported by the UK Natural Environment Research Council (award NE/I022973/1).No additional information is available for this paper.


Discussion. A small proportion of testicular cancer may present in an atypical manner. The scrotum and testicle have markedly different embryonic origins and therefore a distinct anatomic separation. As a result the scrotum is not a typical site of spread of testicular cancer. Case reports have been described that were managed in a similar manner with good outcomes. Therefore, even with significant scrotal involvement, if timely and appropriate treatment is administered, complete resolution of the tumour may be achieved.A 37-year-old male presented with a traumatic injury to the scrotal region necessitating emergency surgery. Evacuation of a haematoma and bilateral orchidectomy were performed. A left sided nonseminomatous germ cell tumour (NSGCT), predominantly yolk sac, was identified. Microscopic margins were positive for tumour. Initial tumour markers revealed an AFP of 22,854 ng/mL, HCG of <1 mIU/mL, and LDH of 463 IU/L. Eight weeks after surgery, AFP levels remained elevated at 11,646 ng/mL. Computed tomography (CT) scanning demonstrated left inguinal adenopathy, 1.5 cm in max dimension. On review, extensive evidence of scrotal involvement was evident. His tumour was staged as stage IIIC, poor risk NSGCT. He was treated with 4 cycles of bleomycin, etoposide, and cisplatin over a 12-week period. His tumour markers normalised after 3 cycles. There was a marked improvement noted clinically. Follow-up CT scans demonstrated complete resolution of his tumour. He later underwent further surgery to remove a small amount of remaining spermatic cord. Histology revealed no malignant tissue. The patient suffered many complications including testosterone deficiency, osteopenia, infertility, and psychological distress. A previously well, 37-year-old farmer presented after sustaining with a major traumatic injury to the scrotal region. This occurred as a consequence of a kick in the groin from a bull while he was tending to his livestock. Physical examination revealed extensive swelling and tenderness of the scrotum. He underwent emergency surgery for evacuation of a haematoma and debridement of necrotic tissue. He required a bilateral orchidectomy as the testicles were split at the time of the trauma. A scrotal approach to surgery was adopted. Unexpectedly, histology identified a left testicular pT4 nonseminomatous germ cell tumour (NSGCT), predominantly yolk sac with lymphovascular invasion. Scrotal and spermatic cord involvement was present. Resection margins were positive for residual microscopic tumour. Presurgery tumour markers, retrospectively analysed serum samples, revealed an alpha-fetoprotein (AFP) of 22854 ng/mL, human chorionic gonadotropin (HCG) of <1 mIU/mL, and LDH of 473 IU/L (10–250 IU/L).At 8-week follow-up after surgery the AFP level was noted to have remained significantly elevated at 11,646 ng/mL. The patient reported an increase in size of the scrotum in the postoperative weeks. Examination was suggestive of extensive scrotal involvement Figures . A firm The tumour was classified as stage IIIC, poor risk NSGCT , 2. The Given the incomplete resection he underwent further surgical intervention, by means of an inguinal approach, to remove a small amount of remaining spermatic cord after completing his chemotherapy. Histology on this occasion showed no malignant tissue. To date, 3.5 years out from chemotherapy, the patient remains in remission based on surveillance imaging, tumour marker monitoring, and physical examination. T score of −1.7. He was commenced on calcium and vitamin D supplementation as well as bisphosphonate therapy. Due to the urgent nature of his presentation sperm banking was not possible. As he was rendered infertile by the surgery he suffered significant psychological distress as he could not father children. This required referral to a clinical psychologist for evaluation and treatment.A number of other issues emerged from this case. These included lifelong testosterone deficiency necessitating supplementation under the supervision of an endocrinologist. A routine Dual-Energy X-Ray Absorptiometry (DEXA) scan identified osteopenia with aTesticular cancer is one of the most treatable solid tumours. The peak incidence is among young men between the ages of 20–40 years. The 5-year survival for nonseminomatous germ cell tumours can be stratified by risk: good risk 91%; intermediate risk 79%; poor risk 48% . DeviatiThe embryonic origins of the testicle and scrotum are different. The testicles develop from the mesonephros at the 10th thoracic level . They miScrotal involvement from testicular cancer is rare. It has, however, been described previously and is included in the staging of testicular cancer . The optGiven the rarity in this condition we feel this case outlines a reasonable approach to managing an individual who has confirmed scrotal involvement. Patients with proven scrotal involvement from germ cell tumour should be followed up on a regular basis as per the established guidelines for testicular cancer .


Should no difference in recurrence rates be observed when comparing irrigation-fluid temperatures, there is no need for warmed fluids during surgery. Our main aim is to investigate the effect of irrigation-fluid temperature on recurrence rates and clinical outcomes after cSDH evacuation using a multicenter randomized controlled trial design.Chronic subdural hematoma (cSDH) is one of the most common conditions encountered in neurosurgical practice. Recurrence, observed in 5–30% of patients, is a major clinical problem. The temperature of the irrigation fluid used during evacuation of the hematoma might theoretically influence recurrence rates since irrigation fluid at body temperature . The primary endpoint is recurrence rate of cSDH analyzed at 6 months post treatment. Secondary endpoints are mortality rate, complications and health-related quality of life.Irrigation-fluid temperature might influence recurrence rates in the evacuation of chronic subdural hematomas. We present a study protocol for a multicenter randomized controlled trial investigating our hypothesis that irrigation fluid at body temperature is superior to room temperature in reducing recurrence rates following evacuation of cSDH.NCT02757235. Registered on 2 May 2016.ClinicalTrials.gov, ID: The online version of this article (doi:10.1186/s13063-017-2194-y) contains supplementary material, which is available to authorized users. A chronic subdural hematoma (cSDH) consists of an accumulation of blood and degraded blood products located between the dura and the brain. cSDHs often expand over time causing progressive neurological symptoms due to brain compression. Symptoms include altered mental state, hemiparesis, headache and, in severe cases, loss of consciousness and even death. Chronic subdural hematomas mainly affect older people due to brain atrophy, an increased tendency to fall and a high prevalence of antithrombotic medications , 2.The incidence of cSDH in individuals over 70 years is approximately 58 per 100,000 per year . This maSymptomatic cSDH can, in the majority of cases, be treated by surgical evacuation, most often performed as surgical evacuation via one or more cranial burr holes , 5. ResuThe surgical procedure can be combined with intraoperative irrigation of the subdural space, and although potential benefits with this technique have not yet been ascertained in a controlled manner, there is evidence in favor of intraoperative irrigation , 8. Stilwww.neurosurgic.com addressed this particular question, the result of 620 respondents showed that 57% use irrigation fluid at body temperature and 40% use irrigation fluid at room temperature and 3% did not use any intraoperative irrigation.The irrigation-fluid temperature may have an impact on recurrence rates of cSDH, possibly due to negative effects on coagulation when using fluid at room temperature –12. It iThe aim of this multicenter randomized controlled study is to investigate whether irrigation-fluid temperature influences clinical outcome and recurrence rates in cSDH.The intraoperative use of irrigation fluid at body temperature results in lower recurrence rates when compared to irrigation fluid at room temperature.Consequently, the defined null hypothesis will be that there is no difference between the treatment groups.The primary aim is to investigate whether irrigation with body-temperature fluid reduces recurrence rates of cSDH compared to room-temperature fluid.Secondary aims include health-related quality of life, complication profile and frequency as well as mortality rate.oC, versus irrigation fluid at room temperature in burr-hole evacuation of cSDH , Karolinska University Hospital  and the Uppsala University Hospital .The recurrence rate of cSDH within a 6-month follow-up period.Mortality rateComplication profile and frequencyHealth-related quality of life at 6 months.Neurological function will be compared pre- and postoperatively and registered as improved/in status quo/worsenedThe study is registered at ClinicalTrials.gov and reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines  preoperatively, intraoperatively and within 24 h postoperatively by the attending neurosurgeon.Age, sex, limb weakness, Glasgow Coma Scale (GCS) score, disorientation, seizures, dysphasia, headache, gait disturbance, mid-line shift, maximal width of the hematoma on computed tomography (CT) and presence of unilateral or bilateral cSDH. Concomitant medication will also be recorded for aspirin, clopidogrel, warfarin and new oral anticoagulants (NOACs). Dexamethasone use will not be recorded since it is not used in the treatment of cSDH in SwedenPreoperative variables:Unilateral or bilateral surgery, general or local anesthesia, duration of surgery, irrigation fluid volumeIntraoperative variables:GCS, limb weakness, disorientation, dysphasia, headache, convulsions, gait disturbance, duration of postoperative drainagePostoperative variables (within 24 h)Current management of cSDH at all participating departments is burr-hole evacuation with intraoperative irrigation followed by active subgaleal drainage as described by Gazerri et al. .The patient will undergo surgery in the supine position under general or local anesthesia, and one to two burr holes are placed over the maximum width of the hematoma. The dura is opened in a cruciate fashion and coagulated by bipolar diathermia. The subdural space is irrigated with Ringer’s lactate at either body- or room temperature according to the result of the randomization. For irrigation, a 50-ml syringe and a soft catheter is used. When the irrigation fluid runs clear a subgaleal drainage is inserted over the burr hole and tunneled away from the skin incision. The drainage is connected to a collection bag with active suction ensuring continuous drainage. The patient is kept in the supine position until the drainage is removed the day after surgery.If the surgeon decides that a drain cannot be safely inserted the patient will be excluded from the study, although this should be a rare event due to the subgaleal location of the drainage.A total of 600 opaque envelopes (200 for each participating centers) with sequential study numbers containing randomly assigned irrigation-fluid temperatures will be prepared. Importantly, the envelopes are not transparent even under direct illumination and will be kept sealed until the patient is draped in the operation room. Also, the envelopes are interconnected so that it is impossible to open these in the wrong order by mistake or on purpose. The envelope will be opened at the time of surgery by the surgeon performing the procedure.The patient will not be informed of treatment allocationTo minimize detection and selection bias the treatment allocation will not be documented in medical recordsThe investigator performing the statistical analyses will be blinded to treatment assignment until the final analysis is completedIt will not be possible mask the treatment allocation from the treating surgeon; nevertheless, measures will be taken to minimize bias.Recurrence rate of same-sided cSDH requiring surgery within 6 monthsThe EuroQol 5D (version 3 L) (EQ-5D 3 L) is a generic measure of health-related quality of life (HRQL) . The queComplications within the follow-up period will be assessed using the Landriel Ibanez classification system . This syMortality will be analyzed as overall survival 6 months post treatmentThe follow-up period is 6 months. Within this period, recurrences requiring surgery are registered together with any complications and the mortality rate of the participants.At 2 months after surgery a CT scan is performed to assess any residual hematoma.At 6 months after surgery HRQL will be assessed using the EQ-5D 3 L questionnaire, mailed to each participant.Any loss to follow-up will be recorded.This is based on usual clinical practice and is consequently a decision made by the treating physician, often the neurosurgeon who is on-call. The indication for reoperation is typically based on the presence of significant residual or recurrent neurological symptoms . If symptoms are present, a CT scan is performed and if there is cSDH causing mass effect correlating with the symptoms the patient will undergo reoperation.p value of ≤ 0.05 is considered statistically significant.The total number of patients will be 496  for a power of 80%. The calculation is based on retrospective pilot study performed at Sahlgrenska University Hospital, 2013–2014, with a 5% versus 12% recurrence rate when comparing irrigation with body-temperature fluid versus room-temperature fluid, respectively (unpublished data). A To compensate for a loss to follow- up, we aim to include a total of 600 patients. Each center will recruit a number of 200 study participants ensuring homogenous recruitment between the participating centers. Although we do not anticipate a large loss to follow-up regarding the primary endpoint we believe that this may be the case for the secondary endpoints. Thus, we will mainly compensate for a loss to follow-up regarding the secondary outcome measures such as EQ-5D 3 L.A statistician blinded for treatment assignments will perform the analysis according to the intention-to-treat principle.Χ2 test for frequency comparison.The primary endpoint (rate of recurrences requiring surgery within 6 months) will be analyzed using the Χ2 test or Fisher’s exact test. Normally distributed numerical data will be analyzed using t test and the Mann-Whitney U test if skewed. Log-rank and Kaplan-Meier plots will be used for overall survival.Secondary endpoints will be analyzed using appropriate statistics. Categorical data will be compared using Data will be collected in the CRF and on password-protected computers. CRF and consent forms are stored in locked rooms at each department. Each study participant’s documents are identified by the randomization number, ensuring confidentiality.An interim analysis will be performed by an independent statistician when each site has 100 subjects with a completed 6-month follow-up. The interim analysis will focus on differences in mortality and recurrence rates (the primary endpoint) between study groups. In addition, each site will cross monitor each other regarding obtained consents and source of clinical data.The study has been approved by the Regional Ethics Committee in Gothenburg, Sweden on 19 January 2016 (reference number: 932-15) Additional file 2:Ethics approval from the regional Ethical Review Board of Gothenburg, Sweden. Approved funds of 203,000 SEK from the regional R&D grant. Approved funds of 20,000 SEK from the Hjalmar Svensson research grant. Approved funds of 50,000 SEK from the Edit Jacobsson research grant. (DOC 120 kb)


Gliomas are devastating brain cancers that have poor prognostic outcomes for their patients. Short overall patient survival is due to a lack of durable, efficacious treatment options. Such therapeutic difficulties exist, in part, due to several glioma survival adaptations and mechanisms, which allow glioma cells to repurpose paracrine signalling pathways and ion channels within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space or promote evasion from anti-cancer defence mechanisms. Ultimately, this culminates in glioma repopulation and migration at distances beyond the original tumour site, which is a considerable obstacle for effective treatment. After an era of failed phase II trials targeting individual signalling pathways, coupled to our increasing knowledge of glioma sub-clonal divergence, combinatorial therapeutic approaches which target multiple molecular pathways and mechanisms will be necessary for better treatment outcomes in treating malignant gliomas. Furthermore, next-generation therapy which focuses on infiltrative tumour phenotypes and disruption of the vascular and perivascular microenvironments harbouring residual disease cells offers optimism for the localised control of malignant gliomas. High-grade gliomas remain one of the most aggressive and difficult to treat cancers in adults, with a very poor prognosis of 14 months . HoweverGlioma aggressiveness and therapeutic resistance has led to many transcriptome- or genome-wide studies aiming to unravel the complex molecular pathways of gliomas to better understand disease progression and to design novel targeted therapeutic agents. For instance, efforts have been made to research and analyse thousands of genetic profiles of tumour samples uploaded in a shared online space called The Cancer Genome Atlas Research Network in order to identify appropriate tumour targets ,11,12. AThe invasive ability of gliomas has been the focus of pathologists since 1938, when German neuropathologist Hans Joachim Scherer suggested that the tumour cells of glioma malignancies infiltrate the normal brain parenchyma with distinct morphological patterns . Of thesAmong all spaces provided by the Scherer model of invasion, the perivascular space has the major share of glioma invasion, and more than 85% of the invading malignant cells migrate around blood vessels to form the satellite tumour shape ,27. Furt2+ concentrations through inositol-1,4,5-triphosphate receptor 3 [2+ oscillations [2+ resulted in the activation of ion channels necessary for volume and morphology changes of glioma cells during migration through narrow spaces. Calcium oscillations results in reprogramming of the Cl− and K+ channels which are normally set to regulate neural membrane potential. This enables the glioma cell to reduce its volume down to 33% of its original size, and thus facilitating the infiltration through small compartments by removing free cytoplasmic water outside the cell via Cl− efflux [2+ which, in turn, induces the contraction of cellular cytoskeleton, cytosolic flow and ultimately the formation of bleb protrusions at glioma cell membranes. Both BK receptor 2 inhibitor, Hoe-140, and bleb retraction blocker, blebbistatin, were both effective in inhibiting glioma cell invasion [2+ levels, but it can also enhance human and rat glioma cell migration in vitro via binding to BK receptor 1. This leads to the activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT cascade signalling pathway [Despite a predilection in gliomas to vascularity, it is not clear yet whether glioma cells infiltrate this perivascular space preferentially as a response to appropriate nutrients and environmental cues which promote tumour survival and growth, or whether this space represents the least physical barrier that resists tumour cell propagation to surroundings. According to our current knowledge, this question is yet to be answered and therefore needs to be comprehensively addressed, as it affects the trends and the prioritisation of tumour treatment modalities. It could be argued that the availability of certain chemo-attractive molecules in the perivascular and endothelial cell niches could explain the preferential habitation of glioma cells around the vascular tree . For exaceptor 3 ,36. Calcceptor 3 ; i.e., lceptor 3 ,37, wherllations ,38. Thes− efflux ,39. Seif pathway , involve pathway , or the  pathway ,45,46,47 pathway .As a consequence of the significant role of BK in glioma perivascular satellitosis, a BK receptor inhibitor, Icatibant , has been tested in preclinical studies using glioma rat models and shown to be effective in impairing the migration of glioma cells through cerebral parenchyma and ultimately resulting in a smaller tumour mass . SimilarIntegrins likely also promote perivascular invasion through the activation of the chemokine (C-X-C motif) ligand 12 (CXCL12)/CXCR4) signalling pathway . CXCL12,+/CD133+ GSCs are located around CD31+ endothelial cells [The GSC theory postulates an explanation for tumour aetiology, albeit the dynamic nature of GSC subpopulations cautions against reductionist descriptions of static populations. It suggests that the bulk of genotypically diverse tumour could be generated by a small population of self-renewing cancer stem-like cells that in turn can differentiate into multiple tumour cell lineages . Howeveral cells ; likewisal cells . Recentlal cells . In addiDespite the anti-tumour activity of endothelial cells advocated by studies conducted in other tumours such as colorectal and prostate cancers ,59, seveCurrent consensus in the glioma field suggests that GSC are located within two main compartments; firstly, GSC could be located where hypoxia is evident, and pseudopalisading glioma cells  are gathered with this characteristic form around the necrotic regions in the glioma core ; the sec2+-dependant release of K+. Moreover, this also leads to several dysfunctional consequences on the delicate neurovascular unit such as the decrement of shuttling energetic metabolites such as lactate from astrocytes to neurons [Current studies indicate that the infiltration of glioma cells through the perivascular space of the adjacent surrounding parenchyma has several dismal effects on the locally invaded niche of brain tissue. In normal physiological conditions, astrocytic end-feet circumferentially covers almost the entire surface of blood vessels  to form  neurons , and the neurons . The rep neurons . The dis neurons .Although the definitive mechanism of glioma invasion through the perivascular space is largely unclear, we advocate that gliomas and GSC seek to invade the perivascular compartment to reach the abluminal surface of the blood vessels via tracking different chemotactic ligands, activating signalling pathways, expressing extracellular adhesive molecules, and even reprogramming the normal protective mechanisms towards tumour benefit. Such mechanisms hint at the adaptive nature of glioma cells as the perivascular compartment provides several advantages for the tumour, in addition to nutrients provided in the serum leaked trough fragile basement membranes of the invaded blood vessels. For instance, the generation of new vascular stem microenvironments by the migrating GSC could lead to considerable repopulation of tumour, with a completely distinct genetic and epigenetic profile and facilitate further tumour growth and invasion at the new site . This ni


E-cigarettes have rapidly increased in popularity in recent years, driven, at least in part, by marketing and word-of-mouth discussion on Twitter. Given the rapid proliferation of e-cigarettes, researchers need timely quantitative data from e-cigarette users and smokers who may see e-cigarettes as a cessation tool. Twitter provides an ideal platform for recruiting e-cigarette users and smokers who use Twitter. Online panels offer a second method of accessing this population, but they have been criticized for recruiting too few young adults, among whom e-cigarette use rates are highest.This study compares effectiveness of recruiting Twitter users who are e-cigarette users and smokers who have never used e-cigarettes via Twitter to online panelists provided by Qualtrics and explores how users recruited differ by demographics, e-cigarette use, and social media use.Participants were adults who had ever used e-cigarettes  and smokers  with public Twitter profiles. Participants were recruited via online panel (n=190) or promoted tweets using keyword targeting for e-cigarette users (n=190). Predictor variables were demographics , e-cigarette use , social media use behaviors , and days to final survey completion from survey launch for Twitter versus panel. Recruitment method  was the dependent variable.P=.02) than panel. Compared with young adult e-cigarette users (age 18-24 years), e-cigarette users aged 25 to 34 years  and 35 to 44 years  were more likely to be recruited via Twitter than panel. Smokers aged 35 to 44 years were less likely than those aged 18 to 24 years to be recruited via Twitter than panel . E-cigarette users who reported a greater number of e-cigarette puffs per day were more likely to be recruited via Twitter than panel compared to those who reported fewer puffs per day . With each one-unit increase in Twitter usage, e-cigarette users were 9.55 times  and smokers were 4.91 times  as likely to be recruited via Twitter than panel.Across the total sample, participants were recruited more quickly via Twitter (incidence rate ratio=1.30, Twitter ads were more time efficient than an online panel in recruiting e-cigarette users and smokers. In addition, Twitter provided access to younger adults, who were heavier users of e-cigarettes and Twitter. Recruiting via social media and online panel in combination offered access to a more diverse population of participants. E-cigarettes have rapidly increased in popularity in recent years. In the United States, 13% of adults are e-cigarette users . AwareneThe proliferation of e-cigarettes in the United States has been driven, at least in part, by marketing and word-of-mouth discussion on Twitter . TwitterTwitter provides a free and efficient means of sharing and accessing information about e-cigarettes, making it a unique and informative vantage point from which to understand how people are using, selling, buying, accessing, and sharing information about these emerging products. At the same time, a growing body of literature demonstrates that social media provides an efficient and cost-effective space for recruiting hard-to-reach populations for survey research -20.Social media sites, such as Facebook, Instagram, and Twitter, offer powerful targeting capabilities that aid in recruiting hard-to-reach populations ,22, suchThe majority of published studies that explore the use of social media for participant recruitment have used Facebook ,16-20. FGiven the rapid proliferation of e-cigarettes, researchers need timely data from e-cigarette users and smokers who have never used e-cigarettes, but may seek out e-cigarettes for cessation. Twitter provides an efficient and effective recruitment method because it allows for access to Twitter users’ public Twitter data and survey data and because it is a space where many conversations about e-cigarettes are occurring, both marketing and organic word-of-mouth conversations ,12. AlthTwitter is more popular among people who are younger , thus weEligible participants were adults who reported having ever used e-cigarettes  and adult current smokers who reported current smoking every day or some days, having smoked ≥100 cigarettes in their lifetime, and having never used e-cigarettes . All participants also had public Twitter profiles, lived in the United States, and gave permission to monitor their public Twitter profile. People with public Twitter profiles were recruited to explore patterns of information sharing and consumption related to e-cigarettes on Twitter, which will be reported in a forthcoming paper. The majority of e-cigarette users in the sample  were also current smokers. It is important to note that in this study e-cigarette users who were smokers were classified as e-cigarette users so that exposure to and sharing of e-cigarette tweets could be assessed for smokers who had not tried e-cigarettes, but may be using Twitter to learn about e-cigarettes. The study was approved by RTI International’s Institutional Review Board.Equal numbers of participants were intentionally recruited via Qualtrics’ panel aggregator (n=190) or promoted tweets (n=190).Qualtrics panel aggregator was used to recruit online panel participants for this study. The Qualtrics panel aggregator provides clients with access to members of a number of market research panels and uses digital fingerprinting technology and IP address checks to ensure that participants’ data are as valid and reliable as possible. Participants recruited via panel received an email from Qualtrics inviting them to participate in the study by clicking on a link to a screening questionnaire to assess eligibility. Participants recruited via the Qualtrics panel aggregator were targeted based on profiling attributes that are included in online panels that are used to guarantee that data about panel respondents are detailed and accurate. We used the following profiling attributes provided previously by participants to target participants for the survey: age, being a smoker, and being part of an online social network. Qualtrics did not have the capability to target e-cigarette users; thus, participants were not targeted based on their e-cigarette use , an image , and a link to the screening questionnaire (see Twitter ad examples in Twitter ads provide a number of targeting capabilities for reaching a specific target audience. Targeting features used for ads included (1) age targeting ads to adults aged 18 or older, and (2) keyword and hashtag targeting for words and hashtagged words that Twitter users have tweeted or searched for on Twitter related to e-cigarettes and smoking  for completed surveys was the dependent variable.Qualtrics sent email invitations to panel members who met the targeting recruitment criteria . The email invitation included a link to the screening questionnaire that participants then clicked and completed to assess their eligibility for participating in the survey. A feature was enabled in the survey that prevented any person with the same IP address from completing the survey more than once to prevent duplicate responses. As an added precaution to prevent duplicate responses, respondent email addresses were cross-checked for both exact email address matches and similar name matches  with a database of emails from participants who had already completed the survey  to prevent participants who completed the survey multiple times from receiving multiple incentives and from being included in the final sample. Participants determined to be eligible based on their responses to screening questions related to age, having a public Twitter profile, and being e-cigarette users or smokers were presented with a brief consent form. Individuals who consented to participate in the study continued directly to the 20-minute Web survey where they answered questions about their demographic characteristics, tobacco product use , cessation behaviors, e-cigarette-related perceptions, social media and Internet use, and exposure to/recall of e-cigarette content on social media. Participants who completed the survey were compensated with the standard Qualtrics panel incentive, which can be redeemed for rewards and had an estimated value of approximately US $1.50. This incentive structure and amount is standard procedure for what Qualtrics and other survey panels provide to participants as compensation for this length of survey.Initial contact with potential participants occurred through Twitter ads  targeted at participants who were likely to be eligible using age and keyword targeting. Participants recruited via Twitter clicked on a promoted tweet in their Twitter feed and were then directed to a Web link for the screening questionnaire. The same feature was enabled in the survey that prevented any person with the same IP address from completing the survey more than once to prevent duplicate responses. The same email cross-checking procedure was used as a second precaution to prevent duplicate respondents from receiving multiple incentives and being included in the final sample. Participants then completed the same screening questionnaire as those recruited via panel, and eligible participants completed the same consent form and survey instrument as panel participants. Participants recruited via Twitter who completed the survey were compensated with a US $10 digital gift card incentive. Qualtrics incentives were the standard incentive provided for the length of survey administered and could not be altered to match incentives for Twitter participants.Independent variables were demographics , e-cigarette use , and social media use .Unpaired sample means tests were used to compare the percentage of people from Twitter versus the panel who completed each stage of the recruitment process. To determine which recruitment method was more efficient in recruiting participants, a series of Poisson regression analyses were conducted on the number of eligible participants who completed the full survey and provided public Twitter data and the recruitment method (Twitter vs panel) with days to survey completion  for each recruitment method included as an offset variable . Using tP<.25) were included in multivariate logistic regression models [A series of bivariate analyses were conducted to determine which variables differed between people recruited via Twitter and online panel. Variables related to recruitment source  with 395,035 and 195,919 impressions generated from the smoker and e-cigarette targeted ad campaigns, respectively. Ads resulted in 2691 total clicks, with 1718 clicks on smoker-targeted ads  and 973 clicks on e-cigarette user-targeted ads . Total cost of ads was US $6848.25 (US $4206.23 for smoker-targeted ads and US $2642.02 for e-cigarette user-targeted ads). Qualtrics panel sent 152,221 email invitations to panel members who met the target recruitment criteria and 15,262 panel members clicked on the survey link, demonstrating that emails sent via panel resulted in a 10.00% survey click rate. Cost comparisons could not be made between the two recruitment methods because Qualtrics was used for both panel recruitment and for programming and managing the survey  and they do not provide a cost breakdown that separates out these overlapping costs to determine the cost of panel recruitment in isolation.P=.02) when including only survey completes that were received during active recruitment for both Twitter and panel, and 2.13 times faster (P<.001) when also including survey completes from the 2-week panel soft launch that occurred before the Twitter ads launched. Although participants were recruited in equal numbers via panel and Twitter (n=190 each), results demonstrated that the IRR for time to completion was 1.30 times faster for Twitter participants than panel participants (P=.02) (see P<.001). Compared with participants recruited via Twitter, a larger percentage of participants recruited via panel (1) provided their Twitter handle and consented to share their public Twitter data (P=.002), and (2) consented to complete the online survey (P<.001). Finally, compared to those recruited via panel, a larger proportion of participants recruited via Twitter (1) provided a public Twitter handle that we were able to use to extract their Twitter data (P<.001), and (2) completed the baseline survey (P<.001). Taken together, these findings show that Twitter recruitment resulted in a higher proportion of useable data and completed surveys from Twitter.A larger percentage of people recruited via panel completed the screener than people recruited via Twitter , with a larger percentage of white, non-Hispanic smokers  compared with e-cigarette users . Among the 16.6% (63/380) of Hispanics (vs 17.6% in 2015 US census) in the sample, a larger percentage were e-cigarette users  than were smokers . Among the 5.8% (22/380) of black, non-Hispanic participants (vs 12.6% in 2015 US census), a larger percentage were smokers  than e-cigarette users . Overall, the sample was almost evenly split by gender , but a larger percentage of e-cigarette users were male  and a larger percentage of smokers were female . A smaller percentage of participants had a college degree or higher ; this was true of both e-cigarette users  and smokers .The majority of e-cigarette users reported using their first e-cigarette 30 minutes or less after waking . On average, e-cigarette users reported using e-cigarettes on a mean 13.99 (SD 11.99) days of the past 30 days and taking a mean 54.68 (SD 139.66) puffs per day on their e-cigarette.P<.001). More than one-third of participants reported that they post and share information about e-cigarettes online , and this number was higher among e-cigarette users  than smokers  (P<.001).On average, participants were most likely to report using Twitter daily or several times per day , with smokers reporting slightly higher mean Twitter use rates on average  than e-cigarette users , although this difference was not statistically signitifcant. Less than half of the sample reported using Twitter to give and receive advice about e-cigarettes  and to learn about e-cigarettes ; these percentages were higher among e-cigarette users  than smokers . Also in line with expectations, e-cigarette users were more likely to be recruited via Twitter  than panel .As predicted, smokers were more likely to be recruited via panel  than via Twitter , 35 to 44 years , 45 to 54 years , and 55 years or older  were less likely to be recruited via Twitter (than panel) compared with young adult e-cigarette users aged 18 to 24 years. Male e-cigarette users  and smokers  were more likely than women to be recruited by Twitter than panel. E-cigarette users who reported a college education or greater were less likely to be recruited via Twitter than panel  compared to those with less education. E-cigarette users who reported using e-cigarettes on more days of the past 30 , who took more puffs on their e-cigarette per day , and who used e-cigarettes more than 30 minutes after waking  were more likely to be recruited via Twitter than panel.Overall, e-cigarette users and smokers tended to be older and male. More specifically, bivariate analyses showed that adult e-cigarette users and smokers aged 25 to 34 years , and smokers were 3.69 times as likely to be recruited via Twitter than panel . E-cigarette users who reported using Twitter to give or receive advice about e-cigarettes were less likely to be recruited via Twitter than panel .As expected, e-cigarette users and smokers who reported using Twitter more frequently were more likely to be recruited via Twitter than panel, such that with each one-unit increase in Twitter usage, e-cigarette users were 1.93 times as likely to be recruited via Twitter than panel  [P=.03) and 35 to 44 years  were less likely to be recruited via Twitter than panel compared with e-cigarette users aged 18 to 24 years. This difference did not emerge when comparing the 18 to 24 group to older adults (older than 45 years). Similarly, in line with our hypotheses, smokers aged 35 to 44 years were less likely than those aged 18 to 24 years to be recruited via Twitter than panel . E-cigarette users who reported a greater number of puffs on their e-cigarette per day were more likely to be recruited via Twitter than panel compared with e-cigarette users who reported fewer puffs per day . In addition, with each one-unit increase in Twitter usage, e-cigarette users were 9.55 times  and smokers were 4.91 times  as likely to be recruited via Twitter than panel.Logistic regression models were used to compare the demographic characteristics, e-cigarette use, and social media use between people recruited via Twitter and panel . VariablP<.25) . As hypoFor both e-cigarette users and smokers, those aged 18 to 24 years and individuals who were heavier users of Twitter were more likely to be recruited via Twitter than adults aged between 35 and 44 years. E-cigarette users aged between 18 and 24 years were also more likely than those aged between 25 and 35 years to be recruited via Twitter, but the same was not true of smokers.E-cigarette users and smokers were recruited more quickly via Twitter than online panel. A larger percentage of people recruited via Twitter were eligible to participate in the study based on their e-cigarette use or smoking behavior compared with participants recruited via panel, suggesting that Twitter recruitment provided a more direct way  to reach the target populations. Participants recruited via panel were more likely to consent to participate in the survey than those recruited via Twitter, which makes sense because panel members are already experienced with completing online surveys for incentives. In contrast, a larger percentage of participants recruited via Twitter completed the survey and provided public Twitter handles (which was an eligibility requirement for accessing their Twitter data) compared to those recruited via panel.Consistent with our predictions, as well as research suggesting that smoking rates are highest among adults aged between 25 and 44 years  and thatTwitter and online panel recruitment methods provided access to different subgroups of e-cigarette users and smokers. Consistent with our predictions and research showing that Twitter is more popular among younger adults , TwitterOverall, findings from this study suggest that recruiting participants directly from Twitter provided the most effective means of accessing people who would both complete a survey and a provide public Twitter handles for extracting Twitter data. In addition, participants recruited via Twitter reported being heavier users of Twitter, suggesting that recruiting participants in this way provides access to a population for whom questions about e-cigarette information exposure and sharing on Twitter are most relevant.Twitter provides highly specific targeting features that allow users to be targeted based on demographics, interests, and other characteristics, which in the case of this research included age and use of keywords related to e-cigarettes and smoking. These features make Twitter a more efficient resource for reaching the target population than an online panel because panel participants could only be targeted based on age, membership in any online social network, and smoking behavior (and could not be targeted based on e-cigarette use).This study expands the literature on using social media to recruit hard-to-reach populations in several ways. First, this study demonstrates the efficacy of using Twitter for participant recruitment, which has been shown in few published research studies to date . Second,Although this study provides important insights into the usefulness of online panels and Twitter for recruiting hard-to-reach participant populations, this research has several limitations. First, both samples recruited for this study are not representative of the US population of e-cigarette users and smokers, and findings may not generalize to a national sample of e-cigarette users and smokers. Second, only one online panel provider was compared to Twitter recruitment and, thus, findings may not generalize to recruitment efforts using other online panels. Third, people could have been exposed to both Twitter and panel recruitment materials because recruitment efforts for the study were conducted simultaneously. Fourth, panel and Twitter incentives provided to participants were not equivalent  suggesting the possibility that the findings reported here may be driven by differences in incentives received by participants between the two recruitment methods. Fifth, cost comparisons could not be made between the two recruitment methods to determine whether one method is more cost efficient for participant recruitment. A final limitation of this research, and any research conducted using social media to recruit participants , is thatOur findings demonstrate that Twitter ads were more efficient than an online panel in recruiting e-cigarette users and smokers with a substantially larger number of eligible participants completing surveys and other eligibility requirements. In addition, Twitter and online panels provide access to different subgroups of these hard-to-reach populations. Twitter provided access to younger adults, who were heavier users of Twitter and e-cigarettes (e-cigarette users only). Recruiting participants via social media along with online panel offered access to a broader population from which to understand e-cigarette use than would one of the two recruitment sources alone.