Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02936167 |
| Other study ID # |
NK/2181/MD/11192-93 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
October 12, 2016 |
| Last updated |
October 14, 2016 |
| Start date |
September 2016 |
| Est. completion date |
February 2017 |
Study information
| Verified date |
October 2016 |
| Source |
Postgraduate Institute of Medical Education and Research |
| Contact |
Neerja Bhardwaj, MD |
| Phone |
9815174439 |
| Email |
neerja.bhardwaj[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
India: Indian Council of Medical Research |
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
