Comparison of Ringer Lactate and Isotonic Acetate Solution as Perioperative Maintenance Fluid for Children
Comparison of Ringer Lactate and Isotonic Acetate Solution as Perioperative Maintenance Fluid for Children
In children fluids are supplemented during surgery to provide volume, to maintain blood
 glucose levels, electrolyte balance and to meet the ongoing fluid losses during surgery.
 Fluid replacement during surgery since decades has been based on the Holliday and Segar
 method.These authors proposed that water maintenance in children includes: 100 millilitre
 (ml)/100 kilocalorie (kcal) for the first 10 kg of body weight, 50mL/100 kcal for 11-20 kg
 and 20mL/100 kcal for every kilogram of body weight above 20 kg. The maintenance electrolyte
 requirements of 3 mEq/100 kcal for sodium and 2 mEq/100 kcal for potassium per day, were
 based upon the electrolyte composition of breast and cow's milk. Based on these
 recommendations hypotonic fluid (0.45% saline) was considered as the ideal fluid for
 maintenance in children undergoing surgery.

 Since the past many years there have been many documented cases of hyponatremia after
 administration of hypotonic fluids with potential for serious neurological injury in this
 group of patients.The use of Holliday and Segar's formula to calculate the maintenance fluid
 regimen in postoperative children leads to an overestimation of the volume of fluid needed,
 as there is a low urine output in this period. The postoperative period is at risk for
 non-osmotic secretion of anti-diuretic hormone (ADH), which reduces the ability of kidney to
 excrete free water and carries risk for development of hyponatraemia.Authors in favour of
 hypotonic solutions feel that hyponatremia results from excessive volume of fluid and
 isotonic solutions have risk of hypernatremia, interstitial fluid overload, excessive sodium
 excretion, and hyperchloremic metabolic acidosis.

 Based on the increased incidence of hyponatremia in children undergoing surgery, the
 paediatric anaesthesia societies [Society of Paediatric Anesthesia (SPA), Paediatric
 Anaesthesia Society of Great Britain and European society of Paediatric Anesthesia (ESPA)]
 put forward guidelines for the type and amount of fluid to be administered during
 surgery.Since then normal saline is the commonly used fluid during the perioperative
 period.However recent studies have shown that the use of normal saline is associated with
 development of hyperchloremic metabolic acidosis and poor outcome.

 Ringer lactate (RL) is a commonly used intravenous fluid during surgery and has been found to
 have decreased possibility of producing hyponatremia although it is a slightly hypotonic
 solution.Plasmalyte is an isotonic fluid which has been shown to maintain electrolyte balance
 and prevent hyponatremia as well as hyperchloremic acidosis in adult population.However
 plasmalyte has been less frequently used in paediatric population.Therefore this study is
 planned with the aim of comparing intravenous fluids, ringer lactate and plasmalyte in the
 perioperative period regarding the incidence of hyponatremia produced by these solutions,
 their effect on electrolytes and blood gases in children undergoing elective surgery.
Fluid therapy is aimed to compensate for fasting which is required for surgery, to meet the
 ongoing fluid losses and to maintain electrolyte balance during surgery. Fluid deficit of a
 healthy child who is not fed parenterally may be estimated by multiplying hourly maintenance
 requirement for fluid by number of hours since the child's last oral intake (50% of deficit +
 maintenance in first hour, 25% of deficit + maintenance in second hour). Maintenance fluid
 therapy represents the volume of fluids and amount of electrolytes and glucose needed to
 replace anticipated physiological losses from breath, sweat and urine and to prevent
 hypoglycaemia. This maintains homeostasis while an individual is unable to control his/her
 own fluid intake while being operated. Replacement fluid represents the volume of fluid given
 to replace the volume lost during the surgical procedure. For 50 years, this therapy was
 based on Holliday and Segar's formula.

 In 1957, Malcolm Holliday and William Segar published fluid management guide-lines for
 hospitalized children, which proposed to match children's water and electrolyte requirements
 on a weight-based calculation using: 100 ml/100 kcal for the first 10 kg of body weight, 50
 ml/100 kcal for 11-20 kg and 20 ml/100 kcal for every kilogram of body weight above 20 kg.
 Their proposed maintenance electrolyte requirements of 3 meq/100 kcal of sodium (Na) per day
 and 2 meq/100 kcal of potassium (K) per day, were based upon the electrolyte composition of
 breast and cow's milk.

 Once applied, these recommendations identified hypotonic fluid as the ideal maintenance fluid
 choice in hospitalized children, leading to the widespread use of 0.225% and 0.45% saline in
 this population. However, the widely used recommendations of Holliday and Segar did not
 consider the changing fluid and electrolyte requirements of a sick or postoperative child.
 Hypotonic fluid with a low sodium content (77 meq/l) and high percentage of electrolyte free
 water (78% EFW) can cause dilutional hyponatremia.Along with this, non-osmotic stimuli of
 anti-diuretic hormone (ADH) secretion in postoperative period makes the patient more
 vulnerable to hyponatremia. The primary stimulus for ADH release is an increase in osmolality
 however, many non-osmotic stimuli like nausea have also been identified as a potent
 non-osmotic stimulus for ADH release.Non osmotic causes of ADH release are broadly divided
 into hemodynamic and non-hemodynamic stimuli for its release. Hypovolemia, hypotension,
 hypoalbuminemia, congenital heart failure are some hemodynamic causes of non-osmotic
 secretion of ADH. Pneumonia, bronchitis, hypoxia, meningitis and brain tumour are some of the
 non-hemodynamic causes of ADH release.

 Anti-diuretic hormone (ADH), is a neurophysial hormone which is synthesised in the supraoptic
 nuclei of the hypothalamus and released from the posterior pituitary gland. It binds to
 vasopressin V2 receptor in the basolateral membrane of the collecting duct, which leads to
 the insertion of aquaporin-2 receptors for retaining water in the body. By retaining water
 and decreasing urine output it increases the electrolyte free water in vascular compartment
 causing hyponatremia.Hyponatremia leads to hypotonicity of extracellular fluid (ECF)
 resulting in movement of water into intracellular space hence cell swells and cerebral edema
 occurs.Clinical presentation of acute hyponatremia (decrease in Na over ≤48 hours to
 <135meq/L) includes headache, lethargy and seizures, and potentially even respiratory and
 cardiac arrest secondary to brain stem herniation.2,3 These outcomes are more likely to be
 seen with severe acute hyponatremia (Na <130 mmol/L) and because of their higher
 brain/intracranial volume ratio, children are at increased risk for these sequelae compared
 with adults.Several studies have consistently showed that postoperative patients have an
 increased risk of developing hyponatremia.The incidence of hyponatremia after administration
 of hypotonic solutions varies from 11 to 31%.

 Arieff et al, conducted a prospective clinical case study of 16 children and reviewed 24,412
 children admitted for surgery. The main objective was to find out whether hyponatremia causes
 permanent brain damage or not. Over a period of 6 years, 16 children admitted in 5 tertiary
 hospitals and 9 community hospitals developed hyponatremia within 5 days of admission. At
 admission the sodium levels were 138 mmol/l. Patients became progressively lethargic,
 complained of nausea and vomiting after 2 hours of hypotonic fluid infusion. After 37 hours
 serum sodium was 115 mmol/l and urine osmolality was 676 mmol/kg. Among 16 patients, one was
 mentally retarded, 10 died and 5 were in permanent vegetative state. Four patients treated
 with IV sodium chloride (154 mmol/l and 512 mmol/l) showed an increase in sodium level from
 108 to 138 mmol/l in 44 hours. Among 24,412 patients 83 patients developed postoperative
 hyponatremia out of which 7 died.

 Grissenger, published case reports of hyponatremia and death in two healthy children who were
 administered plain dextrose and hypotonic saline after surgery. First child underwent
 tonsillectomy and adenoidectomy. The child was given maintenance fluid of 5% Dextrose
 200ml/hr instead of 75ml/hr due to calculation error. The child vomited several times, became
 lethargic and threw seizures. The secondchild underwent repair of coarctation of aorta and
 was given IV frusemide 1mg/hr as the child's urine output was low. On postoperative day-2
 child developed hyponatremia and sodium chloride infusion was started as per physician's
 order. In the morning the child became less responsive and by afternoon he developed seizures
 and vomiting. In both cases by the time the intensivist could recognize hyponatremia and
 start treatment, the child became unresponsive to pain stimuli. Despite intubation,
 ventilatory support, aggressive sodium correction and treatment of cerebral edema both the
 children died.

 Eulmesekianet al, conducted a prospective observational study on postoperative patients
 admitted in paediatric intensive care unit to establish incidence and factors associated with
 hospital acquired hyponatremia. A total of 81 patients having serum sodium in normal range
 (136-146 mmol/l) and requiring IV fluid in the post-operative period were included in the
 study. The incidence of hospital-acquired hyponatremia at 12 hrs was 21% [95% CI (3.7-38.3)],
 at 24 hrs it was 31% [95% Confidence interval (CI)(11.4-50.6)]. At 12 hrs, relative risk of
 developing hyponatremia was 11.55 (95% CI [ 2.99-44.63]; p =0.0004) for Na loss of >0.5
 mmol/kg/hr, RR=10 (95% CI, 2.55-39.15; p=0.0009) for a negative Na balance of >0.3
 mmol/kg/hr, and RR=4.25 (95% CI,1.99-9.08; p=0.0002) for a urine output >3.4 mL/kg/hr. At 24
 hrs, relative risk for hyponatremia was 3.25 (95% CI [1.2-8.77]; p =0.0201) for a positive
 fluid balance of > 0.2 mL/kg/hr.

 Choong et al, conducted a randomized controlled study involving 258 patients aged 6 months to
 16 yrs of age with expected postoperative stay of >24hrs. Patients with uncorrected plasma
 sodium level, abnormal ADH secretion, recent diuretic use, on total parenteral nutrition were
 excluded from study. Patients were randomized into hypotonic perioperative maintainence
 solution(PMS) (n=130) or isotonic PMS (n=128) group by a computer generated randomization
 sequence. The primary outcome was hyponatremia occurring during study intervention and
 secondary outcomes were severe hyponatremia, hypernatremia, and plasma ADH levels. This study
 showed that the risk of hyponatremia was greater for patients who received hypotonic PMS,
 compared with isotonic PMS (40.8% vs 22.7%; RR: 1.82 [95% CI: 1.21-2.74]; P=0.004). Eight
 patients (6.2%) developed severe hyponatremia following hypotonic PMS, compared with 1
 patient (0.8%) in the isotonic PMS group (RR: 7.21 [95% CI:0.93-55.83]; P =0.059). The risk
 of hypernatremia was not significantly different between the 2 groups.

 Saba et al, conducted a randomized controlled trial involving 59 children aged 3 months to 18
 years of age. They were randomized into isotonic and hypotonic groups. The study showed that
 24% of the patients in the 0.45% saline group experienced a drop in serum [Na], compared with
 19% of those in the 0.9% saline group (p = 0.7). The lowest exit Na (133 mmol/L) and maximum
 rate of fall (-0.52 mmol/L/h) were in a surgical patient receiving 0.45% saline. This patient
 had 380 ml of oral fluid intake during the study interval. The second lowest exit Na (135
 mmol/L) and next fastest rate of fall (-0.40 mmol/L/h) were in a medical patient receiving
 0.9% saline; oral intake was 82 ml. There were no adverse events. No participant developed
 hypertension.

 Neville et al, conducted a prospective randomized study involving 124 children aged 6 months
 to 15 years admitted for surgery. They received isotonic or hypotonic fluid at 100% or 50%
 maintenance rate. Plasma electrolytes, osmolality and ADH at induction of anesthesia were
 compared with values at 8 hours (T8), and 24 hours (T24) after surgery.Blood glucose and
 ketones were measured every 4 hours. Electrolytes and osmolality were measured in urine
 samples. The study showed that plasma sodium concentrations fell in both N/2 groups at T8
 (100%: -1.5mmol/L, 50%: -1.9 mmol/L; [P < 0.01]) with hyponatremia more common than in the NS
 groups at T8 (30% vs 10%;[P = 0.02]) but not T24. Median plasma antidiuretic hormone
 concentration increased 2 to 4 fold during surgery (P <0.001) and only reattained levels at
 induction of anesthesia by T24 in the N/2 100% group. Two children on 100% developed syndrome
 of inappropriate ADH secretion (SIADH) (1NS). Fourteen children (23%; 7NS) on 50% maintenance
 were assessed as dehydrated. Dextrose content was increased in 18 for hypoglycemia or
 ketosis.

 Friedman et al, conducted a randomized controlled trial involving 110 patients aged 1 month
 to 18 years of age. Patients were randomized into 0.9% saline (isotonic) group and 0.45%
 saline (hypotonic) group.The primary outcome was to measure mean sodium level at 48 hours.The
 secondary outcomes were mean sodium level at 24 hours, hyponatremia, hypernatremia, weight
 gain, edema and hypertension. The mean Na levels in isotonic and hypotonic group were
 similar. Two of the 56 patients developed hyponatremia in hypotonic group (serum sodium
 levels of 134meq/l after 24 hours). Mean serum sodium levels at 24 hours did not differ
 between the groups (140.5 [2.7] vs 139.6 [2.7] meq/l respectively, [95% CI:-0.22 to 2.02
 meq/l]; p=0.14. One patient in each group developed hypernatremia with serum sodium levels of
 147meq/l at 24 hours. Two patients in each group developed hypertension and 2 patients in the
 isotonic group developed edema.

 Valadaoa et al, conducted a randomized controlled trial involving 57 children aged 1 to 14
 years with acute appendicitis and eligible for appendectomy. They were randomized to receive
 intravenous isotonic or hypotonic maintenance solutions. Samples were collected for measuring
 electrolytes, urea, creatinine at the start of the infusion, 24 hours and 48 hours after
 surgery and then analysed. The primary end point of the study was serum sodium levels during
 the intervention and at the end of 48 hours of the protocol. At admission, 49% patients had
 moderate hyponatremia (Na=130-135 meq/L) and 51% had normal sodium (Na >136 mEq/L). After 24
 hours, 12 patients had hyponatremia of whom 7 had received hypotonic solution. After 48
 hours, 17 children had hyponatremia of whom ten had received hypotonic solution. Between the
 initial Na and final Na levels, there was an increase of 0.9 mEq/L sodium in the isotonic
 group and of 0.4 mEq/L sodium in hypotonic group. In the group of eight patients with normal
 initial sodium (>136 mEq/L) and low final sodium (<135 mEq/L) three had received isotonic and
 five had received hypotonic saline solution with an initial variation of 136 to 140 mEq/L and
 of 132 to 135 meq/l at 48 h. In the group admitted with low sodium (130-135 mEq/L), nine
 children remained hyponatremic (132-135 mEq/L) at the end, of whom four had received isotonic
 solution and five hypotonic solution. Of the 15 patients who had initial hyponatremia
 (130-135 mEq/L) and normal Na at 48 h (136-140 meq/l) seven received isotonic solution and
 eight hypotonic solution.

 Mc Nab et al, conducted a meta-analysis which included randomized controlled trials comparing
 isotonic vs hypotonic IV fluids as maintenance fluid in children involving 1109 children aged
 3 months to 18 y. The intervention group received isotonic fluid (sodium >125 - 160 meq/l)
 while the other group received hypotonic fluid (sodium <125 meq/l). The primary outcome of
 the study was to measure proportion of patients in each treatment group with hyponatremia or
 hypernatremia at any time point while receiving intravenous fluids. Anti-diuretic hormone
 level, plasma and urine osmolarity, electrolytes were also measured. A total of 449 patients
 in the analysis received isotonic fluid, while 521 received hypotonic fluid. Those who
 received isotonic fluid had substantially lower risk of hyponatraemia (17% versus 34%; RR
 0.48; 95% CI 0.38 to 0.60). It was not clear whether there is an increased risk of
 hypernatraemia when isotonic fluids are used (4% versus 3%; RR 1.24; 95% CI 0.65 to 2.38),
 although the absolute number of patients developing hypernatraemia was low.

 Based on the findings of various studies isotonic fluid like 0.9% normal saline was
 introduced in clinical practice in paediatric patients undergoing surgery.

 Ringer lactate (273 mosm/l) is mildly hypotonic to plasma (294 milliosmol/l) and has been
 used as maintenance fluid in few studies. These studies showed reduced incidence of
 hyponatremia and metabolic acidosis when ringer lactate was used as a maintenance fluid.

 Zunini et al,retrospectively studied 122 children undergoingcraniofacial surgery. Out of 122
 patients 63 received only Normal saline (NS group) whereas 59 received Ringer lactate (RL
 group). Acid-base balance and electrolytes were measured at 1-2 hrs post-induction (P1) and
 2-4 hrs post induction (P2). This study showed that the incidence of metabolic acidosis was
 45% (44 patients) in P-1 and 60% (61 patients) in P-2 time period. Acidosis was more frequent
 in NS group than in the RL group in both periods: 66% and 80% in NS versus 26% and 37% in RL
 group (P = 0.015 for P-1 and P = 0.027 for P-2). The incidence of severe acidosis (pH <=
 7.25) was also larger in those receiving NS (39%) than in those receiving RL (8%).
 Hyponatremia (Na <135 mmol/L) was observed in 40% (NS) and 26% (RL) of the cases during P-1
 and in 52% (NS) and 50% (RL) of the cases during P-2 time period. No statistically
 significant difference was found in the incidence of hyponatremia between the groups. Overall
 the incidence of metabolic acidosis and hyponatremia was less in RL group compared to NS
 group.

 Coulthard et al, conducted a randomized controlled trial involving 82 patients undergoing
 spinal instrumentation, craniotomy for tumor resection or cranial vault remodelling. Children
 were randomized to receive Hartman's solution with 5% dextrose or 0.45% saline with 5%
 dextrose. The primary outcome was to measure sodium at 16-18 hours postoperatively. Thirty
 nine children received Hartman's solution and 40 received hypotonic saline. The result showed
 mean postoperative plasma sodium levels of children receiving 0.45% saline and 5% dextrose
 were 1.4 mmol/l (95% CI [0.4 to 2.5]) lower than those receiving Hartmann's and 5% dextrose
 (p=0.008). In the 0.45% saline group, seven patients (18%) became hyponatraemic (Na <135
 mmol/l) at 16-18 postoperatively; in the Hartmann's group no patient became hyponatraemic
 (p=0.01). No child in either fluid group became hypernatraemic.

 Plasmalyte is balanced salt solution with constituents similar to that of plasma, with an
 osmolality of 294 mosmol/l. In adults, studies using plasmalyte have shown decreased
 incidence of hyponatremia and metabolic acidosis when compared to hypotonic saline.

 McNab et al conducted a randomized controlled double blind study in paediatric population
 aged 3 months to 18 years of age, comparing plasmalyte and hypotonic saline as maintenance
 fluid. The patients were randomly assigned into NA-140 and NA-77 group by a computer
 generated online randomization system. Study investigators, treating clinicians, nurses, and
 patients were masked to assigned fluid type throughout the study. Eligible patients were
 started on NA-140 or NA-70 and continued till the maintenance requirement became 50% of
 standard maintenance rate. When a patient had a surgical procedure before the start of
 intravenous maintenance fluid, the serum sodium was taken at the end of the procedure and
 serum electrolytes, urea, creatinine were measured after 6, 24, 48 and 72 h of treatment,
 until the study fluid was stopped. This study showed that 4% of participants (12 out of 322 )
 allocated to Na140 developed hyponatraemia whereas 11% of participants (35 out of 319)
 developed hyponatremia in Na77 group (odds ratio 0.31,p=0.001). Seven patients developed
 severe hyponatraemia during the study with little evidence of a difference between the two
 treatment groups (odds ratio of 0.35, 95% confidence interval of 0.07-1.8; p=0.2). None of
 these children developed severe hyponatraemia. The occurrence of hypernatraemia was similar
 in the two groups: 14 (4%) participants developed hypernatraemia in the Na140 group, compared
 with 18 (6%) in the Na77 group (odds ratio of 0.80, 95% CI of 0.39-1.65,p=0.55).

 Since very few studies have been conducted in paediatric population using Ringer Lactate and
 isotonic acetate solution, this study was planned.
Inclusion Criteria:

 -  Age: 2 - 8 years

 -  American society of anesthesiologist (ASA) - 1

 -  Laparoscopic surgical procedure of 2 hours duration requiring IV fluid administration
 for at least 24 hours

 Exclusion Criteria:

 -  Uncorrected plasma sodium level before surgery

 -  Diseases which cause abnormal ADH secretion

 -  Renal and cardiac disease

 -  Chronic lung disease

 -  Cranial/thoracic surgery

 -  Recent loop diuretics use