High dose insulin Infusion Arrowe park ICU Journal Club Will Angus – November 2017

Contents A bit about insulin Calcium channel blocker overdose Beta blocker overdose Quite a lot of “borrowed” diagrams High dose insulin therapy

Insulin Peptide hormone Produced in beta cells of pancreatic islets Main anabolic hormone in the human body

Insulin

Insulin release Glucose enters B-cell through GLUT-2 channel Low affinity for glucose, ensures rate of entry proportional to extracellular concentration Glucose phosphorylated to glucose-6-phosphate Then enters glycolytic pathway, subsequent oxidation of acetyl CoA produces ATP This closes K+ channels preventing efflux Build up of K+ ions makes inside less negative Leads to depolarisation and opening of voltage sensitive Ca2+ channels

Insulin release Stimulated by beta-2 adrenergic fibres Inhibited by alpha-2 adrenergic fibres Net effect of catecholamines is to inhibit insulin release due to dominance of alpha receptors

High dose insulin therapy First used to treat verapamil overdose in 1993 Has theoretical benefits for calcium channel blocker and beta blocker overdose Can lead to slightly terrifying doses… For example, for 70kg patient: Loading dose of 70 units (1u/kg) Infusion of 35-700 units per hour (0.5-10u/kg/hr) Need a lot of glucose e.g. glucose 50%: 50ml bolus and start at 50ml/hr

Calcium channel blocker overdose Verapamil and diltiazem most lethal (though in overdose receptor selectivity is lost) CCBs bind to alpha-1 subunit of L-type calcium channels, preventing the intracellular influx of calcium Functionally important in cardiac myocytes, vascular smooth muscle cells, and islet beta cells

Calcium channel blocker overdose Cardiac: Excessive negative inotropy, negative chronotropy, negative dromotropy Impaired utilisation of glucose by cardiac myocytes: Impaired uptake of glucose and free fatty acids by cardiac myocytes Inhibition of calcium-dependent mitochondrial activity required for glucose catabolism Decreased vascular smooth muscle tone: Decreased afterload, systemic hypotension, coronary vasodilation Metabolic: Hypoinsulinaemia as insulin release is dependent on calcium influx into islet beta cells through L-type calcium channels

Calcium Channel blocker overdose

Beta blocker overdose Cardiac Bradycardia, AV block Decreased contractility Hypotension Metabolic Hypoglycaemia (inhibition of gluconeogensis) Hypoinsulinaemia (inhibition of beta-2 mediated pancreatic insulin release) Other Bronchospasm Seizures, coma

Beta blocker overdose

Basically CCBs and BBs both reduce available calcium within myocytes (e.g. myocardial and smooth muscle) Leads to cardiogenic shock Bad news bears

High dose insulin A stressed myocardium wants to metabolise glucose instead of fatty acids Insulin facilitates the intracellular transport of glucose Therefore more insulin means more glucose for the heart Positive inotrope

Engebretson 2011 Review article Published in Clinical Toxicology in 2011 Methods Literature search of published articles between 1975 and 2010 485 articles identified 72 included considered relevant and included in review Animal studies, case reports and case series No available clinical trials

Mechanism of high dose insulin benefit Increased inotropy Increased intracellular glucose transport Vascular dilatation

Dysregulated PI3K pathway seen in CCB overdose Insulin: Re-activates PI3K pathway Increases calcium entry Increases translocation of GLUT-4 from organelles onto cell membrane Increases glucose entry

Insulin causes vasodilation due to enhancement of endothelial nitric oxide synthase This improves microvascular dysfunction seen in cardiogenic shock Decreased afterload will also increase cardiac output

Efficacy ….it also works in pigs In dogs poisoned with verapamil: Improved survival with HDI compared to adrenaline or glucagon Improved LV function In dogs poisoned with propranolol: HDI improved myocardial contractility Restored responsiveness to beta-agonists Sustained improvements compared to adrenaline Improved survival compared to glucagon ….it also works in pigs

Efficacy Potentially higher doses of insulin required when vasopressors used Need to overcome increased SVR caused by vasopressors to enhance cardiac output Consider weaning off vasopressor therapy if initiated prior to HDI once stable (No evidence vasopressors are beneficial in drug-induced cardiogenic shock)

Clinical experience All case reports or case series HDI safe when used carefully Often a rapid haemodynamic improvement Treatment failure may be associated with: Use of vasopressors Inadequate insulin dosing Delayed administration of HDI Inadequate duration of HDI Pathophysiology unresponsive to HDI

25 years of literature summarised in 5 sarcastic minutes Treatment Protocols 25 years of literature summarised in 5 sarcastic minutes

Treatment protocols Initial measures: IV fluids Trial of vasopressors IV calcium Supportive care …consider OGD in massive overdose?

Treatment protocols Glucose 25g bolus Give if: only if BM <11.1, only if BM <22, give to everyone regardless of BM or do whatever you feel like Insulin bolus 1u/kg to 10u/kg Higher bolus seems more effective in severe cases and works faster Somebody accidentally got 1000 units and was fine Insulin infusion 0.5u/kg/hr to 10u/kg/hr (…somebody accidentally got 22u/kg/hr and was fine) Titrate to effect Concomitant glucose infusion Give whatever concentration at whatever rate you feel like. Genuinely just choose a random selection and someone has done it

Treatment protocols Onset of action usually stated as 45-60 minutes No evidence of this ever being measured Improvements seen in around 5 minutes in canine models

Treatment goals Aims to maintain perfusion of critical vascular beds, not increase MAP Monitor skin warmth, mental state, urine output, peripheral pulses etc Using BP alone may be misleading This value does not reflect cardiac output and perfusion, particularly when vasopressors are used Increases in SVR may decrease tissue perfusion and decrease survival Cardiac output monitoring probably a good idea Bedside echo for the win

Monitoring Serum glucose Check every 10 minutes initially Once stable can check hourly Serum potassium Check every hour initially while titrating insulin Once stable can check every six hours Avoid over correcting, consider supplementing when <3mmol/L Monitor magnesium and phosphate concentrations

Tapering treatment Nobody knows Once cardiac function has improved: The infusion must be gradually tapered and discontinued Alternatively the insulin infusion can be stopped abruptly Glucose infusion will be required up to 24 hours post-discontinuation Again, pick a random concentration at a random rate and somebody has done it Monitor blood glucose

Adverse effects Hypoglycaemia Not actually as common as you might think Rarely clinically significant (at least as far as what is reported in the literature) Hypokalaemia Average serum potassium during HDI therapy around 2.7 to 3mmol/L Many patients do not require potassium supplementation No reported ECG signs of hypokalaemia or arrhythmias No irreversible adverse effects have been reported

Conclusion The authors conclude: HDI a promising treatment for beta blocker and calcium channel blocker poisoning It’s use is supported by experimental evidence and case reports Insulin bolus followed by infusion with glucose supplementation Glucose and potassium concentrations must be monitored closely

You should probably just do what Debbie says Conclusion My conclusions: It’s a scary thing to prescribe, but also pretty cool Nobody is 100% sure how it works, or indeed how to use it definitively It works in anaesthetised dogs and pigs really well which is nice In terms of treatment protocols there is not a lot of evidence to back up your choice Blood pressure shouldn’t be used as a treatment target You should probably just do what Debbie says

How to do it Glucose 50% infusion at 50ml/hr Check BM, if <10 give 50ml Glucose 50% Insulin bolus: 1 unit/kg Insulin infusion start at 0.5 units/kg/hr Can be increased by 0.5 units/kg/hr every ten minutes as needed

How to do it Check BM every 20 minutes when starting the infusion, or after changing rate Once stable (i.e. three stable results) can check every three hours Treat hypoglycaemia with 50ml Glucose 50% bolus Continue glucose infusion for 24 hours after discontinuing insulin infusion The potassium will drop, avoid replacing unless <3.5mmol/L Easy peasy

37 year old male Deliberate overdose: 4g propranolol 5g quetiapine 1.6g lofepramine On arrival to A&E: BP 70/40 HR 50 Unrousable GCS 4 (E2 V1 M1)

37 year old male Intubated for airway protection Very haemodynamically unstable Glucagon bolus and infusion Requiring dobutamine 20ml/hr, adrenaline 15ml/hr, noradrenaline 20ml/hr for a systolic of 90mmHg Oliguric

37 Year old Male Decision to start high dose insulin Glucose 50% infusion commenced at 50mls/hr Insulin 70 unit bolus and then infusion started at 35 units per hour Increased by 0.5u/kg/hr until more stable and vasopressors could be weaned down Maximum insulin requirement was 380 units per hour Lowest BM was 7 High dose insulin infusion weaned after 48 hours Extubated uneventfully Lived happily ever after