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

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

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

4. Insulin

6. 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

7. 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

8. 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 units per hour (0.5-10u/kg/hr)
Need a lot of glucose e.g. glucose 50%: 50ml bolus and start at 50ml/hr

9. 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

10. 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

11. Calcium Channel blocker overdose

12. 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

13. Beta blocker overdose

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

15. 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

17. 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

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

19. 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

20. 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

21. 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

22. 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)

23. 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

24. 25 years of literature summarised in 5 sarcastic minutes
Treatment Protocols
25 years of literature summarised in 5 sarcastic minutes

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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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. 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

38. 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