Glucose for Children during Surgery: Pros, Cons, and Protocols: A Postgraduate Educational Review.

The question of whether glucose supplementation is required in children during surgery is still under debate. The impact of perioperative glucose supplementation, or its restriction, on their metabolism remains unclear. We discuss the findings of various studies that have addressed this question and the rationale for current recommendations.

INTRODUCTION

The routine use of intraoperative glucose-containing fluids in children has declined over the years owing to evidence that normal-to-high blood glucose levels are maintained during surgery even with the infusion of glucose-free fluids, probably as a result of stress-induced hyperglycemia and insulin resistance.[1]

The situation is different in newborns. They need 4–8 mg/kg/min (approximately 300 mg/kg/h) of glucose for sustaining brain development,[2] deprivation of which may adversely affect neurodevelopmental outcome.[34] Neonates are susceptible to develop hypoglycemia due to low glycogen reserves. Hence, they need glucose as a part of their maintenance fluid during surgery. However, how much glucose neonates need during surgery is still open to debate.

Hyperglycemia too may be detrimental to neonates. Adverse clinical outcomes associated with neonatal hyperglycemia include intraventricular hemorrhage, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, osmotic diuresis, impaired immunity, delayed wound healing, renal injury, and neuronal lactic acidosis.[567891011121314]

Neonates are capable of mounting substantial neuroendocrine response to both surgical stress and decreased glucose supply. This manifests as a rise in cortisol, glucagon, catecholamines, and vasopressin, along with fall in insulin. The result is a rise in blood glucose concentration through gluconeogenesis, fat mobilization, and protein catabolism.[151617] However, such compensation occurs at the expense of valuable energy reserves, namely, glycogen, fat, and proteins.

Any fluid used intraoperatively should aim at keeping this stress response to a minimum by providing adequate glucose to suppress gluconeogenesis and fat mobilization. At the same time, it should maintain normal plasma osmolarity, electrolyte balance, and hemodynamic stability. The major concerns regarding neonatal fluid management are hypoglycemia, hyperglycemia, hyponatremia, and volume overload.[218]

NEONATAL EUGLYCEMIC RANGE

There has been considerable debate about the threshold of neonatal hypoglycemia. It was commonly believed that neonates can tolerate episodes of asymptomatic moderate hypoglycemia. However, Lucas et al. (1988)[3] demonstrated neurodevelopmental impairment in infants with recurrent episodes of asymptomatic moderate hypoglycemia (blood glucose <2.6 mmol/L). Koh et al. (1988)[4] also demonstrated abnormal sensory evoked potentials in children with blood glucose <2.6 mmol/L. Subsequently, WHO designated a blood glucose “operational threshold”[1920] of ≤2.6 mmol/L (45 mg/dL) as requiring treatment in neonates, both term and preterm.

On the other hand, the threshold for significant neonatal hyperglycemia is unclear. Various studies have reported adverse outcomes at blood glucose level >8.3 mmol/L (150 mg/dL).[5678] More severe outcomes were reported with prolonged hyperglycemia.

NEONATAL RESPONSE TO SURGICAL AND METABOLIC STRESS

Neonatal response to anesthesia and surgical stress has been extensively studied. Anand et al.[151617] observed that the neonates are capable of mounting a substantial endocrine and metabolic response to surgical stress, the main features of which are increase in plasma epinephrine, norepinephrine, cortisol, glucagon, and beta-endorphin levels; fall in plasma insulin: glucagon ratio; and accompanying hyperglycemia and hyperlactatemia. Their research revealed that neonates develop significant perioperative hyperglycemia, the level of which correlates strongly with plasma glucagon and epinephrine levels. This is accompanied by rise in free fatty acids (FFAs) and ketone bodies (KBs). The insulin: glucagon ratio is significantly reduced at the end of surgery. Thus, they concluded that stress-related hormonal changes in preterm and term neonates may precipitate a catabolic state characterized by glycogenolysis, gluconeogenesis, lipolysis, and mobilization of gluconeogenic substrates in the immediate postoperative period. A higher intraoperative stress response was associated with a higher postoperative mortality and poorer prognosis.

Glucose deprivation or restriction during surgery may amount to metabolic stress in a neonate prompting a brisk metabolic response. The response of young infants to fasting has been described by Leon et al.[21] as a sequence starting with an initial fall in blood glucose followed by a fall in the concentration of gluconeogenic substrates (lactose and alanine). Thereafter occurs a brisk rise in free fatty acids (FFA) beta-hydroxy butyrate (3-HOB) as lipolysis and hepatic ketogenesis are initiated. The resultant alterations in biochemical parameters include a fall in pH, base excess (BE) and bicarbonate, and rise in anion gap (high anion gap metabolic acidosis). These changes are brought about by a fall in plasma insulin level, followed by a rise in plasma glucagon, epinephrine, and growth hormone.

NEED FOR PERIOPERATIVE GLUCOSE

Fujino et al.[22] and Yamasaki et al.[23] have observed that intraoperative glucose supplementation reduces ketogenesis, attenuates postoperative insulin resistance, and suppresses protein catabolism in adults. However, the role of intraoperative glucose supplementation in neonates is still controversial, and there is no consensus yet as to the amount of glucose that is optimal for neonates during surgery.

Various studies have investigated the effect of different glucose-containing fluids in pediatric populations during surgery. Their findings, with respect to different metabolic and biochemical parameters, have been discussed below and summarised in Table 1.

Table 1

Summary of findings of various studies comparing the use of intraoperative dextrose-containing fluids in pediatric patients

GLUCOSE HOMEOSTASIS

A rise in blood glucose was observed in most neonates undergoing surgery, even with the intraoperative use of plain Ringer acetate (RA).[242526] Among studies in older infants and children, although net rise in blood glucose was observed with the use of plain Ringer lactate (RL) during surgery,[27282930] fall in blood glucose was noted in isolated cases with the use of dextrose-free fluids.[2728]

Sümpelmann et al.[31] used 1% dextrose-containing isotonic balanced salt solution in neonates undergoing major surgeries at a mean infusion rate of 10 ml/kg/min. Blood glucose was maintained in the normoglycemic range, and there was no incidence of hypoglycemia or hyperglycemia with the use of this regimen. Studies on the effect of 1% dextrose-containing intraoperative fluid in older infants and children have demonstrated a net rise in blood glucose during surgery,[272830] which returned to normal by 1 h after surgery.[30]

The use of 2%–2.5% dextrose-containing fluids during surgery in pediatric patients has been shown to cause a rise in blood glucose.[242829303233] The rise was significantly greater with 2.5% dextrose in RL as compared to 1% dextrose in RL.[30]

The use of 5% dextrose-containing fluid during surgery in pediatric patients has invariably produced hyperglycemia.[272933]

Larsson et al.[25] and Sandström et al.[26] have studied the effect of continuing 10% dextrose at standard maintenance rate during surgery in neonates, with additional losses being replaced with plain RA. Both studies reported a rise in blood glucose at the end of surgery which remained significantly elevated above baseline even 8 h after surgery.[26] The rise in blood glucose is explained by the metabolic and endocrine response of the children to surgical stress resulting in an increase in counter-regulatory hormones, mainly epinephrine and glucagon, as described by Anand et al.[1617]

A fall in blood glucose was observed in patients who received glucose-containing fluids in the preoperative period and was subsequently switched to glucose-free fluid during surgery. With intraoperative dextrose supplementation, blood glucose level was maintained in these patients.[2526]

ELECTROLYTE BALANCE

Postoperative hyponatremia is a major concern in neonates with the use of hypotonic fluids during surgery. Dubois et al.[30] and Hongnat et al.[32] found hyponatremia during the postoperative period using hypotonic fluids.

Dubois et al.[30] compared RL (Na+ = 130 mmol/L) to a combination of RL and D5 (resultant Na+ 65 mmol/L) in children aged 3 months to 10 years and found that serum sodium concentration is maintained in patients receiving RL as compared to patients receiving the combination of RL and D5 who show a fall in serum sodium.

Hongnat et al.[32] compared two fluids, one having 46 mmol/L and the other 62 mmol/L sodium in children aged 3 months to 10 years. They observed a fall in serum sodium concentration at the end of surgery in both groups, the change being greater in the group receiving the fluid with the lower concentration of sodium.

Sümpelmann et al.[31] used isotonic balanced salt solution with 140 mmol/L sodium in neonates. No change in serum sodium concentration was reported in the postoperative period with the use of this fluid.

ACID-BASE STATUS

Studies that scrutinized the effect of intraoperative dextrose supplementation on acid-base balance yielded conflicting results. Nishina et al.[33] reported a fall in pH and BE at the end of surgery in infants receiving dextrose-free solution during surgery, which they attributed to ketosis due to glucose deprivation. Sümpelmann et al.[31] used 1% glucose-containing solution in neonates and noted a statistically significant decrease in bicarbonate and BE. However, the reported changes in both the parameters were clinically insignificant. On the contrary, Sandström et al.[26] reported no change in pH during the use of dextrose-free fluid during surgery in neonates. The change in pH may not have been evident due to the smaller sample size of their study.

METABOLIC PARAMETERS

The effect of intraoperative glucose supplementation on the production of KB and FFA in pediatric patients has been studied. Mikawa et al.[29] reported no change in the levels of KB and FFA in children aged 1.5–9 years with the use of dextrose-free fluids. On the other hand, Sandström et al.[26] and Nishina et al.[33] observed a rise in KB and FFA in infants. There was no rise in KB and FFA in patients receiving glucose supplementation during surgery in any of the studies.

The production of KB appears to be promoted by preoperative fasting and intraoperative use of glucose-free fluids, especially in infants.

ENDOCRINE PARAMETERS

Mikawa et al.[29] observed insulin levels in patients aged 1.5–9 years and reported no significant difference at the end of surgery among those receiving plain RL and those receiving 2% or 5% dextrose in RL. On the other hand, Nishina et al.[33] reported a fall in insulin levels at the end of surgery in infants receiving plain RL, unlike those given 2% and 5% dextrose in RL during surgery. The difference in their findings can be attributed to the difference in age groups of the study populations.

In a recent study comparing 1%, 2%, and 4% dextrose-containing solutions for intraoperative use in neonates,[34] we observed that blood glucose increased in all three groups at the end of surgery, with no significant difference in blood glucose and incidence of hyperglycemia among them. BE, bicarbonate, and pH showed a significant fall at the end of surgery in patients receiving 1% dextrose. Serum insulin was significantly lower and glucagon: insulin ratio was higher in patients receiving 1% dextrose. At 24 h after surgery, blood glucose and incidence of hyperglycemia were significantly higher in patients receiving 1% dextrose. Thus, although 1% dextrose-containing solution appears as effective as higher glucose concentrations in maintaining blood glucose level and preventing hypoglycemia during surgery in neonates, there is evidence to suggest increased catabolism in these patients compared to those receiving glucose at a higher rate that is closer to the physiological requirement of glucose in neonates. No significant difference in glucose homeostasis, electrolyte balance, metabolic parameters, and endocrine parameters was observed between neonates given 2% and 4% dextrose-containing fluids.

Keeping such evidence in view, the Association of Paediatric Anaesthetists of Great Britain and Ireland issued consensus guidelines (2007)[35] stating that maintenance fluid in term neonates should be 10% dextrose at 2–3 ml/kg/h in the first 48 h of life, followed by 10% dextrose in N/5 saline at 4 ml/kg/h from the 3rd day of life onward. Any fluid deficit or surgical loss should be corrected with isotonic fluids. Children who warrant glucose in their intraoperative fluids are neonates in their first 48 h of life and children on dextrose-containing fluids or parenteral nutrition preoperatively. Children of low birth weight, prolonged surgery (more than 3 h), or under extensive regional anesthesia should have serial monitoring of blood glucose or should receive a 1%–2.5% dextrose-containing maintenance fluid.

The German Scientific Working Group for Paediatric Anaesthesia published the European Consensus Statement[36] in 2011 stating that intraoperative infusions in children should have an osmolarity and sodium concentration close to the physiological range to avoid hyponatremia, an addition of 1%–2.5% glucose to avoid hypoglycemia, lipolysis, or hyperglycemia, and should include metabolic anions (i.e., lactate, acetate, or malate) as bicarbonate precursors to avoid acid-base disturbances. These recommendations have been further consolidated in the recent perioperative fluid therapy guidelines[37] by the Association of the Scientific Medical Societies in Germany.

CONCLUSION

Evidence suggests that neonates and infants need dextrose supplementation during surgery, albeit at a lower rate than their normal maintenance requirement. The interruption of glucose supply in children of this age group during the perioperative period can result in hypoglycemia, hypercatabolism, ketogenesis, and delayed hyperglycemia. The exact amount of dextrose needed in the perioperative period is still under consideration. The rate at which glucose is being supplied depends both on the dextrose concentration of the maintenance fluid and the rate of infusion and must be adjusted according to individual surgical needs. Although intraoperative dextrose supplementation in infants has demonstrated better biochemical and metabolic stability, definite benefit in terms of improvement in surgical outcomes is still to be proven and warrant larger trials. Till such time that further definitive evidence comes to light, the use of 1%–2.5% dextrose-containing isotonic fluids for intraoperative maintenance in neonates and infants appears to be most prudent.

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