HYPOGLYCEMIA MANAGEMENT IN THE EMERGENCY DEPARTMENT

Silu Zuo, Pharm.D.

PGY1 Pharmacy Resident

UW Medicine

Patient Case

CC: JT is a 53 y/o female presenting to ED with profound hypoglycemia and unresponsiveness during nuclear medicine study

HPI: Progressive hypoglycemia over past several

years, at times resulting in loss of consciousness Recent CT scan showed possible neuroendocrine

tumor on pancreas nuclear medicine study to further assess

At nuclear medicine, was unresponsive with BG of 20

Patient Case

PMH: Epilepsy, complex partial Turner's syndrome Hypoglycemia Osteoporosis Macrocytic anemia

Patient Case

Medications: Alendronate 70 mg PO Q7 days Benztropine 0.5 mg PO BID Carbamazepine 400 mg PO BID Depakote 500 mg PO EC BID Glucagon 1mg Injection PRN hypoglycemia Glucose 40% oral gel 15 gram tube PO PRN

hypoglycemia Olanzapine 15 mg PO QHS Potassium chloride ER 20 MEQ PO daily Sertraline Hcl 100mg PO daily Topiramate 25 mg PO BID

Patient Case

Vitals BP 102/53 HR 88 RR 18 SpO2 100% RA

To be continued….

Glucose Homeostasis

Glucose Homeostasis

↓ blood glucose

↑ blood glucose

Glucose Homeostasis

The pancreas is a major player Alpha cells: secrete glucagon Beta cells: secrete insulin Delta cells: secrete somatostatin

Important role in maintaining balance of both insulin and glucagon

Other counter-regulatory hormones Adrenaline (epinephrine) Cortistol

Glucose Homeostasis

Hypoglycemia

Normal blood glucose (fasting): 70-110 mg/dL

Small excursions above range post-prandially

Hypoglycemia – “Whipple’s triad” 1) Symptoms consistent with hypoglycemia 2) Low plasma glucose concentration (<70

mg/dL) 3) Relief of those symptoms after the

plasma glucose level is raised

Harper's Illustrated Biochemistry, 29e. New York, NY: McGraw-Hill; 2012.

Hypoglycemia

Hypoglycemia

Hypoglycemia can be very dangerous if untreated Brain cannot make glucose or store very

much glycogen requires a continuous supply of glucose from blood circulation

Serious hypoglycemia Seizure, loss of consciousness, coma, death

Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.

Hypoglycemia

Causes Drugs

Insulin or insulin secretagogue, alcohol Gatifloxacin (removed from market), pentamidine,

quinine, indomethacin, others Critical illness

Hepatic, renal or cardiac failure, sepsis Hormone deficiency

Cortisol, glucagon, epinephrine (in insulin-deficient diabetes)

Non–islet cell tumor

J Clin Endocrinol Metab 94:709, 2009.

Hypoglycemia

Causes Endogenous hyperinsulinism

Insulinoma Functional beta-cell disorder

(noninsulinoma pancreatogenous hypoglycemia, post gastric bypass)

Insulin or insulin receptor antibody Insulin autoimmune hypoglycemia

Accidental, surreptitious, or malicious hypoglycemia

J Clin Endocrinol Metab 94:709, 2009.

Treatment

Oral carbohydrate replacement IV glucose/dextrose Glucagon Octreotide Diazoxide

UWMC Hypoglycemia Protocol

UWMC Hypoglycemia Protocol

UWMC Hypoglycemia Protocol

Oral Carbohydrates

Glucose 15-20 g orally – preferred initial treatment in conscious individual with hypoglycemia

Examples of 15 g of carbohydrates: 4 ounces of juice 4 ounces of nondiet soda 8 ounces of skim milk 3-4 glucose tablets 5-6 Life Savers candies

After treatment, eat snack with protein/fat to prevent recurrence

Clinical Diabetes 2012 Jan;30(1):38

IV Glucose/Dextrose

“IV glucose” = IV dextrose 50% (50g/100mL) Dose = 12.5-25 g (25 g/50 mL = 1 amp) IV

push Dextrose 5%, 10%, 20%, 30%, 40%, 50%,

70% 5-10% can give via peripheral IV

10% at fast rate may cause irritation and ↑ risk of extravasation

Concentrations >10% (hypertonic) may cause thrombosis if infused via peripheral veins administer via central line

AVOID extravasation (vesicant)

UpToDate.

Glucagon

Dose: 1 mg IV/IM/SQ, may repeat in 15 mins

IV dextrose should be administered as soon as it is available; if patient fails to respond to glucagon, IV dextrose must be given.

Role: patients without IV access (especially severe hypoglycemia, unconscious patients

Glucagon Emergency KitGlucagon HypoKitGlucaGen HypoKit (glucagon) [prescribing information]. Glucagon Emergency Kit [prescribing information].

Patient, Case Cont’d

Time

Blood Glucose

Notes

1214 165 After IV glucose 12.5 g

1250 17 D50% 12.5 g, D5/NS 100 mL/hr

1326 76

1348 33 D50% 12.5 g

1413 168

1428 134

1452 107

1536 99

1600 114 Central line placed, D10 100 mL/hr

Octreotide

Somatostatin analogue Provides more potent inhibition of growth

hormone, glucagon, and insulin as compared to endogenous somatostatin

May reduce recurrent hypoglycemia as with dextrose-alone therapy

Should be used with IV dextrose/oral carbohydrates

Dose: (ideal dose not well established) SQ: 50-100 mcg, repeat every 6 hours PRN IV: up to 125 mcg/hour has been usedPharmacol Rev. 2003 Mar;55(1):105-31.

Ann Emerg Med, 2000, 36(2):133-6.

Octreotide

Design Prospective, double-blind, placebo-controlled trial

Patients • 40 adult patients presenting to ED with hypoglycemia (BG≤60 mg/dL)• Taking a sulfonylurea or a combination of insulin and sulfonylurea• Admitted to hospital for at least 24 hrs• Exclusions: pregnancy, not taking insulin/SU

Intervention/Comparator

Intervention (N=22)Standard treatment (1 ampule of 50% dextrose IV and oral carbs) + 1 dose of octreotide 75 mcg SQ

Comparator (N=18)Standard treatment + placebo (1 mL of 0.9% NS SQ)

Ann Emerg Med 2008; 51(4):400-406.

Octreotide

Results

Reduced rate of recurrent hypoglycemia

Ann Emerg Med 2008; 51(4):400-406.

Octreotide

Warnings/precautions: Cholelithiasis – may inhibit gallbladder

contractility Glucose regulation Hypothyroidism – may suppress TSH

secretion Pancreatitis – may change absorption of

fats Adverse effects: bradycardia, dizziness,

hyperglycemia, diarrhea, constipation

Sandostatin [prescribing information].

Diazoxide

Antidote for hypoglycemia due to hyperinsulinemia; vasodilator

Opens ATP-dependent K+ channels on pancreatic beta cells hyperpolarization of the beta cell inhibition of insulin release

Binds to a different site on the potassium channel than the sulfonylureas

Dose: 3-8 mg/kg/day PO in divided doses Q8H Starting dose 3 mg/kg/day PO divided in 2-

3 doses

Diazoxide

No randomized, controlled studies Few case reports

Pentamidine-induced hypoglycemia Sulfonylurea-induced hypoglycemia

Pharmacol Rev. 2003 Mar;55(1):105-31.

Diazoxide

Contraindications: hypersensitivity to diazoxide or to other thiazides

Warnings/precautions: Heart failure – antidiuretic actions, may ↑

fluid retention Gout – may cause hyperuricemia Renal dysfunction

Adverse effects: hypotension, hyperglycemia

Diazoxide [prescribing information].

Patient Case, Cont’d

Time Blood Glucose

Notes

1633 131 Diazoxide __ mg

1817-2012 84-111 Transferred to MICU

2117-2353 61/55/78 D50% 25 g x 3 amps

0246 74 D50% 25 g x 1 amp, changed to D20%

1345 73 D50% 25 g x 1 amp, changed to to D50%/0.45%NS

Patient Case, Cont’d

Post-ED, admitted to MICU with close follow-up from Endocrinology

Continued to IV dextrose infusion with PRN D50% and Q3-6H BG checks

Extensive workup for neuroendocrine tumor: Labs:

Low insulin, c-peptide, and high betahydroxybutyrate does not suggest insulinoma

High pro-insulin may mimic effects of insulin and likely cause of low BG

Octreotide scan – negative findings Endoscopic US Biopsy of pancreatic mass: Positive for

neoplasia neuroendocrine tumor Sent to Harborview for surgical management

References Bender DA, Mayes PA. Chapter 20. Gluconeogenesis & the Control of Blood Glucose. In: Murray RK,

Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil P. eds. Harper's Illustrated Biochemistry, 29e. New York, NY: McGraw-Hill; 2012.

Cryer PE, Davis SN. Chapter 345. Hypoglycemia. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.

Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009 Mar;94(3):709-28.

American Diabetes Association. Hypoglycemia? Low Blood Glucose? Low Blood Sugar? Clinical Diabetes 2012 Jan;30(1):38.

UptoDate. Instant glucose and intravenous dextrose: Drug information. LexiComp.

GlucaGen HypoKit (glucagon) [prescribing information]. Princeton, NJ: Novo Nordisk Inc; December 2011.

Glucagon Emergency Kit [prescribing information]. Indianapolis, IN: Eli Lilly and Company; February 18, 2005.

Doyle ME, Egan JM. Pharmacological agents that directly modulate insulin secretion. Pharmacol Rev. 2003 Mar;55(1):105-31.

McLaughlin SA, Crandall CS, and McKinney PE, “Octreotide: An Antidote for Sulfonylurea-Induced Hypoglycemia,” Ann Emerg Med, 2000, 36(2):133-6.

Fasano CJ, O'Malley G, Dominici P, et al: Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea-induced hypoglycemia. Ann Emerg Med 2008; 51(4):400-406.

Sandostatin [prescribing information]. East Hanover, NJ: March 2012.

Diazoxide [prescribing information]. Baker Norton Pharmaceuticals, Miami, FL, 1997.