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Insulin Therpay In I C U

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Insulin replacement therapy in ICU Roz Elliott CNC The Royal North Shore Hospital
Transcript
Page 1: Insulin Therpay In  I C U

Insulin replacement therapy in ICU

Roz Elliott

CNC

The Royal North Shore Hospital

Page 2: Insulin Therpay In  I C U

Session outline• What is insulin?• Action of insulin• Insulin receptors• Pharmacokinetics• Indications for insulin therapy in ICU• Insulin resistance/hyperglycaemia in ICU

patients • Recent developments• Intravenous administration• Future developments

Page 3: Insulin Therpay In  I C U

What is insulin?

• Naturally occurring hormone produced by the cells in the Islets of Langerhans in the pancreas in response to– Increase blood glucose level (>3.9mmol/l)– Increase blood amino acid level– Secretion of gastric hormones eg secretin, gastric

inhibitory peptide• A polypeptide molecule (A and B chain joined by

disulphide bonds)• Complex structure which varies from species to

species (chains have different sequencing on A chain at 8, 9 & 10 and B chain at 30)

Page 4: Insulin Therpay In  I C U

What is insulin? Naturally occurring human insulin molecule (mole wgt 5808)

S S

Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Asn

Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Pro-Lys-Thr

S

S

S

S

A CHAIN

B CHAIN

Page 5: Insulin Therpay In  I C U

Actions of insulin

• Instrumental in fat, carbohydrate and protein metabolism

• Has rapid, intermediate and delayed actions– Rapid (seconds) = transport of glucose, K+ and amino

acids into cells– Intermediate (minutes) = Stimulation of protein synthesis– Delayed (hours) = Increase in mRNAs for lipogenic

enzymes

Page 6: Insulin Therpay In  I C U

Actions of insulin

• Glucose entry to the cell – fat, muscles and other tissues by facilitated diffusion as

insulin the number of glucose transporters (GLUT 1 to 5) – small intestine and renal tubule cells by active transport

via SGLT 1 receptors– (certain cells are not insulin dependant for glucose entry)

• Synthesis and inhibition of degradation of protein– Protein sparing action of glucose for energy production– Increased entry of amino acids to cells– Increased enzyme stores

• Increased fat deposition (lipid synthesis)– Increased mRNA lipogenic enzyme stores related to

increased entry of amino acids to cells

Page 7: Insulin Therpay In  I C U

Insulin receptors

• Large complex protein found on many different cells even cells in which insulin does not increase glucose uptake

• Insulin joins to the subunit which causes autophosphorylation of the subunit – Leads to phosphorylation and dephosphorylation of

other proteins in the cell resulting in biological effects of insulin

– e.g. increased numbers of glucose transporters (GLUT 1 to 5)

• When insulin binds to its receptors the receptors aggregate and are taken into the cell by endocytosis

Page 8: Insulin Therpay In  I C U

Pharmacokinetics

• ½ life of insulin in human circulation is approximately 5 minutes

• Maximum decline in plasma glucose occurs 30 minutes after IV administration of insulin

• 20% of insulin is destroyed by endosomes (principle enzyme is insulin protease) found in many cells

• 80% of secreted insulin degraded by liver and kidneys

Page 9: Insulin Therpay In  I C U

Indications for insulin therapy in ICU

• Diabetic patients (type I and type II)

• Diabetic ketoacidosis

• Mild to severe hyperglycaemia in seriously ill patients

Page 10: Insulin Therpay In  I C U

Insulin resistance/hyperglycaemia in ICU patients

• Total glucose uptake by cells is massively increased in seriously ill patients however hyperglycaemia is a common finding (even in the absence of diabetes)

• Insulin levels may be normal or even above normal

Page 11: Insulin Therpay In  I C U

Insulin resistance/hyperglycaemia in ICU patients

• Proposed mechanisms for hyperglycaemia in seriously patients– Peripheral insulin resistance (high cortisol, cytokine,

adrenaline & glucagon levels inhibit phosphorylation in the subunit )

– Increased endogenous glucose production (liver glycogen is converted to glucose)

– No exercise-stimulated glucose uptake in skeletal muscle

– Glucose intolerance • Impaired insulin-stimulated glucose uptake by Glucose

transporter 4 (skeletal & cardiac muscle, adipose tissue) • Impaired glycogen synthase activity (impaired synthesis of

glycogen from glucose)

Page 12: Insulin Therpay In  I C U

Insulin resistance/hyperglycaemia in ICU patients

• Adverse patient outcomes associated with prolonged hyperglycaemia and high blood glucose levels on admission to hospital– Brain injury patients reduced survival/poorer functional

outcomes– Higher mortality in children with burn injury– Higher mortality in trauma patients– MI patients higher risk of cardiogenic shock and in-

hospital mortality– Higher mortality in stroke patients– Higher mortality in non-diabetic paediatric critically

patients

Page 13: Insulin Therpay In  I C U

Insulin resistance/hyperglycaemia in ICU patients

• Hyperglycaemia appears to be more toxic to seriously ill patients than healthy people

• Proposed mechanisms by which hyperglycaemia adversely affects outcomes– Cells that are insulin independent for glucose uptake

are exposed to high glucose levels leading to• Oxidative stress causing mitochondrial dysfunction especially

in organs = risk of organ failure

– White cell function impaired (abnormal granulocyte adhesion, phagocytosis and inappropriate cell killing)= infection risk

Page 14: Insulin Therpay In  I C U

Recent developments

• Proposed mechanisms for improved outcomes of insulin replacement in seriously ill non-diabetic patients:– Improved neutrophil function– Reduced infection risk and incidence of

sepsis– Prevention of hyperglycaemia-induced

mitochondrial dysfunction reducing the risk of organ failure

Page 15: Insulin Therpay In  I C U

Recent developments

• Normoglycaemia in Intensive Care Evaluation (NICE) study– Based on the Belgium RCT

• 1548 pts randomised to intensive insulin group (BGL 4.4-6.1mmol/L) or conventional insulin group (BGL 10-11.1mmol/L)

• Significant reduction hospital mortality in intensive insulin group (7.2% vs 10.9%, p= 0.01)

• Some methodological areas for improvement

Van Den Berghe et al. 2001

Page 16: Insulin Therpay In  I C U

Recent developments

• NICE– Multi-centre (ANZICS CTG) open label RCT

of glucose management in ICU– Aim: ‘to compare the effects of two glucose

targets on 90 day all-cause mortality in ICU patients who are predicted on admission to stay in the ICU for at least one full calendar day’

– Planned enrolment of 4000 patients

Page 17: Insulin Therpay In  I C U

Intravenous administration

• Human sequence insulin for replacement therapy may be produced semisynthetically by enzymatic modification of porcine insulin (emp) or biosynthetically by recombinant DNA technology using bacteria (crb, prb) or yeast (pyr) e.g. Actrapid (human, pyr)

Page 18: Insulin Therpay In  I C U

Intravenous administration

• Usual type of insulin used in ICU is the short acting soluble form e.g. Actrapid (human)

• Local administration (RNSH) guide– 100iu mixed in 500mls Saline 0.9% (1ml= 0.2iu)– Administration set primed and 100mls solution run

through (20-80% of insulin may be taken up by plastic)

– Administered using a volumetric pump, ideally via a dedicated lumen/cannula

– Titrated using 0.5 to 10 iu/hr to BGL– BGL measured every 1 to 2 hours

Page 19: Insulin Therpay In  I C U

Intravenous administration

• Dangers/complications– Abrupt interruption or cessation in diabetic

patients will result in acidosis– Cessation of feeding without concomitant

reduction in insulin will result in hypoglycaemia

– Decreased catecholamine infusion rate without concomitant reduction in insulin will result in hypoglycaemia

Page 20: Insulin Therpay In  I C U

Future developments

• NICE study will provide more evidence to support or refute intensive insulin therapy in seriously ill patients

• Further work is being conducted to identify the beneficial and harmful (neuro) endocrine responses to critical illness and suitable interventions

Page 21: Insulin Therpay In  I C U

Summary

• Insulin acts on cells to increase glucose uptake and protein and amino acid synthesis

• Intensive insulin therapy for the seriously ill remains controversial

• Future metabolic interventions will be based on the neuroendocrine reactions which are found to be harmful


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