hyperglycemia in critically ill children,should it be treat agressively

8/10/2019 Hyperglycemia in Critically Ill Children,Should It Be Treat Agressively

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Munar Lubis

Division of Pediatric Emergency, Department of Child HealthUniversity of Sumatera Utara, Haji Adam Malik Hospital

Medan, Indonesia

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Hyperglycemia occurs frequently among critically ill nondiabetic

children and is correlated with a greater in-hospital mortality rate

and longer lengths of stay

There are no specific criteria for defining hyperglycemia among

acutely ill, non diabetic children. Some studies chose various

cutoff values, ie. 110, 120 and 126 mg/dl

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Introduction


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Faustino & Apkon:

Prevalence: 16,7% - 75% (cutoff values: 120, 150 & 200 mg/dl)

Relative Risk (RR) for dying increased for maximum glucosewithin 24 hr > 150mg/dl and highest glucose within 10 days >

120mg/dl

Faustino EV, Apkon M, J Pediatr 2005;14630-4


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Stress hyperglycemia

Multifactorial: neuroendocrine response & insulin resistance

Critically ill patients in ICU setting who are exposed to acute and

chronic stress often develop hyperglycemia through multiple

proposed mechanisms:

counterregulatory hormone-mediated upregulation of gluconeogenesis

and glycogenolysis

downregulation of glucose transporters with decreased peripheralutilization of glucose by tissues such as skeletal muscle and liver

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Historically, the accepted benefit of this altered glucosehomeostasis:

to increase energy substrate to vital organs such as the brain and

myocardium

to compensate for volume loss by promoting the movement of cellularfluid into the intravascular compartment or liberating water bound to

glycogen

Challenges to this belief have emerged from studies examiningclinical morbidity and mortality outcomes

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Srinivasan et al: Peak BG of > 126 mg/dl occurred in 86% of patients

Peak BG and duration of hyperglycemia are independentlyassociated with mortality in PICU

Insulin infusion use was not associated with a significantly higherrisk of hypoglycemia of < 50 mg/dl compared with those who did not

receive insulin

Srinivasan et al, Pediatr Crit Care Med 2004;5:329-36

Wintergerst et al: mortality rate increased as patientsmaximal glucose levels increased, reaching 15,2% amongpatients with the greatest degree of hyperglycemia

Wintergerst et al, Pediatrics 2006;118:173-9

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Branco et al: In children with septic shock, a peak glucose

level of > 178 mg/dl is associated with an increased risk ofdeath

Branco RG et al, Pediatr Crit Care Med 2005;6:470-2

Yates et al: hyperglycemia in the post operative period was

associated with increased morbidity and mortality in

postoperative pediatric cardiac patient

Yates et al, Pediatr Crit Care Med 2006;7:351-5

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The mechanisms mentioned specifically in the pediatric literature

include oxidative damage and deficiency in antioxidant protectionin

patients with type 1 diabetes and altered cytokine levelsin pediatric

patients with meningococcal sepsis and septic shock

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Klein et al, Curr Opin Clin Nutr Metab Care 2007;10:187-92

Mechanism by which hyperglycemia causes cell injury


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Hyperglycemia

Polyol pathway Protein Kinase C Pathway

Advanced Glycation

Pathway

Reactive Oxygen

Species Pathway

Activation of cell signaling molecules

Altered gene expression and protein function

Cellular Dysfunction and Damage

Srinivasan et al, Pediatr Crit Care Med 2004;5:329-36


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Polyol pathway unused glucose enters the polyol pathway

Glucose + NADPH Aldose Reductase Sorbitol + NADP

Sorbitol + NAD Sorbitol Dehydrogenase Fructose + NADH


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Activation of the polyol pathway

decrease of reduced NADP+ and oxidized NAD+

(necessary cofactors in redox reactions throughout the body)

decreased synthesis of

reduced glutathione, nitric oxide, myoinositol, & taurine

Myoinositol normal function of nerves


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Sorbitol may also glycate nitrogens on proteins, such as

collagen, and the products of these glycations are referred-to

as AGEsadvanced glycation endproducts

AGEsare thought to cause disease in the human body, one

effect of which is mediated by receptor mediators cytokines

effects and the inflammatory responses induced


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Hyperglycemic state the affinity of aldose reductase for

glucose

much sorbitol to accumulate

using much more NADPH

leaving less NADPH

The NADPH acts to promote nitric oxide and glutathione

production, and its conversion during the pathway leads to

reactive oxygen species


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Excessive activation of the polyol pathway

Increases intracellular and extracellular sorbitol, reactive

oxygen species

decreased concentration of nitric oxide and glutathione

damage cells


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Intracellular hyperglycemia in the endothelium, which occurs

because glucose transporters in these cells are not

downregulated in the face of hyperglycemia, also causes an

increase in diacylglycerol, which, in turn, activates several

isoforms of protein kinase C (PKC)

This inappropriate activation of PKC alters blood flow and

changes endothelial permeability, in part via efffects on nitric

oxide pathways


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Table 1 Compilation of mechanisms for cell injury in the hyperglycemic/insulin resistant state

Oxidative stress (increased oxidative damage to lipids,proteins, DNA, and to cells via apoptosis)a

Increased reactive oxygen species

Glucose autoxidationPolyol pathway

Protein glycation

Decreased antioxidant protection/disposal

Lower levels of glutathione peroxidase, superoxide dismutase (enzymatic)

Lower levels of plasma antioxidant capacity, i.e. vitamins C, E, A (nonenzymatic)Increased rate of muscle protein catabolism

Increased phenylalanine release

Altered balance in immune system regulationa

Decreased innate immunity in animal models

Impaired phagocytosis

Impaired neutrophil function

Increased deactivation of monocytes and neutrophils during infection

(immunoparalysis)

Excessive and unchecked cytokine production (may be caused by oxidative stress) and

increased C-reactive protein have a role in microvascular injury and organ failure

IL-6, TNF-a, IL-18


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Association with dyslipidemia of the critically illDysregulation of lipid homeostasis

Elevated triglycerides

Elevated VLDL

Decreased LDL and HDL

May result in decreased scavenging of endotoxinMay decrease cholesterol transport (substrate) to the cell membrane

Cardiac dysfunction

Nitric oxide mediated myocyte damage

Reactive oxygen species-mediated myocardial apoptosis

Increased angiotensin-II

Increased systemic vascular resistance

Decreased cardiac output, cardiac index, stroke volume

Table 1 Cont..


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18Klein et al, Curr Opin Nutr Metab Care 2007; 10: 187-92

Cerebral ischemia

Worsened intracellular acidosis

Increased brain edema

Disruption of bloodbrain barrier

Endothelial activation and damage

Excessive nitric oxide concentrations can be proinflammatory and cause ischemia and

cell damage

Adhesion molecule activation attracts leukocytesActivated leukocytes can release reactive oxygen species

Excessive leukocyte adhesion can hamper perfusion

Mitochondrial abnormalities

Dysfunction in respiratory chain and energy production

Ultrastructural damage to hepatocyte mitochondria

aDenotes pathways that have been demonstrated in studies in children.

IL, interleukin; TNF, tumor necrosis factor; VLDL, very low-density lipoprotein; LDL, low-density lipoprotein; HDL,

high-density lipoprotein

Table 1 Cont..


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Studies on critically ill adults demonstrate the benefits of

glycemic control

There is a paucity of data in pediatric intensive care setting

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Van den Berghe et al (Adult study):

Conventional-treatment group: continuous insulin infusion was started only

when the BG level > 215mg/dl and was adjusted to maintain a BG level of

180-200 mg/dl

Intensive-treatment group: insulin infusion was started when the BG level >

110mg/dl and was adjusted to maintain normoglycemia (80-110mg/dl). The

maximal continuous IV insulin infusion was arbitrarily set as 50 IU per hour

Intensive insulin therapy significantly reduced morbidity but not

mortality among all patients in the medical ICU

Previous study in the surgical ICU: intensive insulin therapy reduces

morbidity and mortality among critically ill patients

Van den Berghe et al, N Engl J Med 2006; 354: 449-6220

VS


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The pathophysiologic response to stress and the effects of

hyperglycemia on tissues are not well delineated

Uncertainty regarding acceptable age-related norms for

euglycemia in ill children

The traditional fear of hypoglycemia

The potential for complications related to hypoglycemia is

highest in the youngest children less than 3-5 years of age whoare undergoing critical brain development

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Klein et al, Curr Opin Clin Nutr Metab Care 2007;10:187-92

Challenge in pediatrics


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Physicians typically treat hyperglycemia only after blood glucose

concentrations exceed the renal threshold for resorption of glucose

(200-250 mg/dl), resulting in an osmotic diuresis

perception that avoidance hypoglycemia and its potentialconsequences are more important than glycemic control

There is still insufficient data to extrapolate to children that strict glucose

control is beneficial

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MANAGEMENT


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Severe hyperglycemia may occur with severe gastroenteritis

Treatment of shock and ongoing fluid replacement lead to resolution

of hyperglycemia

Insulin therapy is required occasionally but should be used

cautiouslyat a dose of 0,025 U/kg/hour because these children

often are extremely sensitive to insulin and may become

hypoglycemic very rapidly

The dose can becautiouslyincreased if no response is seen

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Diabetic Ketoacidosis (DKA):

Fluid & electrolyte therapy

Insulin therapy:

Regular Insulin

Starting dose: 0,1 U/kg/hr, sometimes can be decreased to 0,05 U/kg/hr if the

patient is very young or is particularly insulin sensitive Rate: should be adjusted to decrease plasma glucose by approxymately

100mg/dl/hr until BG reaches approximately 200 to 300 mg/dl adding 5%glucose to the rehydration fluids is appropriate

Glucose infusion rate should be adjusted to maintain plasma glucose in

the 100 to 150 mg/dl range

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Richards GE. Diabetic Ketoasidosis. In: Fuhrman BP, Zimmerman J, eds.

Pediatric critical care. 3rd ed. Philadelphia: Elsevier 2006. p. 1125-34


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Hyperglycemia is common in critically ill children

Recent studies have linked hyperglycemia to worse outcome in

critically ill childrenAdditional studies in the pediatric population, with due

consideration of the risk of hypoglycemia and glucose variability,

are needed to elucidate the effects that strict glucose controlmay have on morbidity and mortality rates in the PICU

SUMMARY

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Hydration

Rapid replacement of volume is necessary to stabilize if patient is truly in shock.

Use 10-20 ml/kg of NS or LR as rapidly as possible until hypotension and perfusion are

improved. If patient is not in shock, use 10-20 ml/kg once

Continually assess results of fluid boluses and stop once circulatory failure is reversed (to

avoid too rapid correction of hyperosmolar state)

Be sure to take into account fluids administered prior to transfer and reduce calculatedneeds by that amount

Correct remaining fluid deficit over 36-48 hours.

Maintenance fluids must also be provided during this period

It is usually not necessary to replace urine output, monitor output, and folow hydration status.

There are hidden sources of water in DKA from oxidation of glucose and ketones, and ADH iselevated. Osmotic diuresis should subside once glucose is normalized (


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Glucose/electrolyte/correction

Use of bicarbonate is only indicated for patients in shock, unresponsive to fluid resuscitation,or hyperalkemia with ECG changes (1-3 mEq/kg to raise pH to >7,2). Bicarbonate should be

administered only when perfusion and ventilation can be assured

Electrolyte replacement

Insulin administration

Initial insulin therapy is usually 0,05-0,1 U/kg/hour IV continuous drip (up to 7 U/hour)

Standard solution is 50 U regular insulin in 250 ml NS so that 0,1 U/kg/hour=0,2

ml/kg/hour

Monitor serum glucose every 30-60 minutes as ordered Serum glucose should not fall faster than 100 mg/dl/hour

Typically, when blood sugar reaches < 200-300, rather than reducing or discontinuing the

insulin infusion,dextrose is added to maintenance fluids until metabolic acidosis and ketonuria

are resolved

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Conversion from IV to subcutaneous insulin

Subcutaneous insulin may be considered when

Serum glucose falls below 250 mg/dl

Acidosis is resolved (HCO3>20)

Ketones are absent

ADA PO is initiated

There should be a 1-hour overlap between administration of

first dose of subcutaneous regular insulin (15-30 minutes iflispro insulin will be given) and discontinuing insulin infusion

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For a child with previously diagnosed diabetes, return to the childs previous insulin regimen,

with supplemental rapid-acting insulin for hyperglycemia and/or ketonuria. Insulin

requirements may be higher during the first day post DKA

If patient was not on subcutaneous insulin previously, a typical conversion pattern:

Daily requirement of 0,5-1 U/kg/day

Divide 2/3 of the dose for AM and 1/3 of the dose for PM

Each dose may be split 2/3 intermediate-acting (NPH on lente) and 1/ 3 short-acting(regular or lispro). Supplemental doses of short-acting insulin (generally 10% of total daily

dose) may also be used to help stabilize the patients blood sugar and calculate

permanent insulin dose

Do not treat aggressively during the night or when child is not eating during the day

Supplemental doses should be approximately 10% to 15% of total daily dose (or 0,1-0,2U/kg/dose). Humalog insulin, because of its rapid action and short duration,is recommended

in this situation

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hyperglycemia in critically ill children,should it be treat agressively

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