• Steroid administration should be considered in patients with hypoglycemia that is either resistant to aggressive glucose replacement therapy or associated with the signs of adrenal insufficiency. In addition to hypoglycemia, adrenal insufficiency is characterized by profound weakness, hypothermia, hypotension poorly responsive to crystalloid and vasopressor infusions, and various metabolic abnormalities (hyponatremia, hyperkalemia, and azotemia). Initial, ED steroid replacement includes the rapid administration of hydrocortisone via the IV route: 100-200 mg in the adult and 1-2 mg/kg in children.
• Consider Sepsis
• C-Peptide is suppressed in exogenous insulin use

Pathophysiology

Decline in insulin release at 8o mg/dl, counterregulatory hormone release at 65, symptoms at 55, and cognitive dysfunction at 45.  Hypoglycemia can result from increased endogenous or exogenous insulin, blunter counterregulatory response, impaired gluconeogenesis.  ETOH causes rise in NADH/NAD ratio stealing oxaloacetate and therefore decreasing hepatic gluconeogenesis.

 

if blood tubes sit before testing, glucose will decrease ~7% an hour. (Irwin & Rippe)

 

Consider obtaining Cortisol level during hypoglycemia if adrenal suppression is suspected.  Also consider ETOH level.

 

other causes of fasting hypoglycemia

which my old Oxford Handbook explains as:

EXPLAINS

• Exogenous drugs — insulin, oral hypoglycemics, quinine, chloroquine, beta-blocker overdose, valproate overdose, salicylate overdose, pentamidine.
• Pituitary insufficiency
• Liver disease — hepatocellular cancer, hepatitis and rare genetic defects.
• Addison’s disease
• Islet cell tumours — insulinomas;
  Immune hypoglycemia — e.g. anti-insulin receptor antibodies in Hodgkin’s disease or anti-insulin antibodies that release insulin when insulin levels are relatively low;
  Infection — e.g. severe sepsis, malaria
• Non-pancreatic neoplasms — fibromas, sarcomas, mesotheliomas, and small cell carcinomas that produce IGF-2; extensive metastases that overwhelm the body’s ability to produce glucose;
  Nesidioblastosis or Noninsulinoma pancreatogenous hypoglycemia (NIPH) syndrome — islet cell hyperplasia, which can be congenital or acquired, e.g. post-gastric surgery
• Starvation and malnutrition

 

 

 

Insulins

If suspect surreptitious use, get c-peptide which is only released in endogenous insulin

Oral Agents

Sulfonylureas

Work by increasing insulin production.  Since increase secretion and action of insulin in response to sugar/food, feeding/sugar infusions exacerbate the problem.

Toxicity can last as long as 72 hours, even with shorter acting agents

Can have disulfiram reactions, especially with chlorpropamide

AC

Octreotide 50 ug SC Q6

Kiddies 1-1/5 ug/kg SC Q6

Must be admitted for 24 hours if using octreotide.  Octreotide works by inhibiting insulin secretion from the pancreas.

(Ann Emerg Med 36(2):133, August, 2000)

Review (Crit Care 2005;9)

RCTof octreotide vs. placebo (Ann Emerg Med 2008;  ) used 75 mcg. probably need to be dosed Q 8 hours

 

NSAIDs, Sulfonylureas, & Hypoglycemia

Sulfonylurea agents for type 2 diabetes include glimepiride, glipizide, and glyburide. The hypoglycemic action of sulfonylureas are well known to be potentiated by nonsteroidal anti-inflammatory agents, especially in elderly patients.  In one report, aspirin administration resulted in a 29% increase in glyburide free fraction (1).  Many other NSAIDs, including ibuprofen, have been associated with sulonylrea-induced hypoglycemia (2).

Emergency Physicians should be aware of this interaction for two reasons: (1) As NSAIDs are prescribed frequently in the ED, adding an NSAID to a patient taking a sulfonylurea can result in hypoglycemia and (2) a patient presenting to the ED with sulfonylurea-induced hypoglycemia should be asked about recent initiation of NSAID use.

References:(1) Kubacka RT, et al. Effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy subjects Ann Pharmacother 1996;30:20. (2) Sone H, et al.  Ibuprofen-related hypoglycemia in a patient receiving sulfonylureaAnn Intern Med. 2001;134(4):344. (3).Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York: © McGraw-Hill; 2001.

 

 

Treatment

Patients presenting soon after a potentially dangerous sulfonylurea ingestion should be given oral activated charcoal.  Further management after sulfonylurea exposure depends on the presence of symptoms and level of serum glucose.

 

Asymptomatic + normal glucose:  Patients with normal serum glucose levels do not necessarily require treatment or hospital admission.  Because all currently available sulfonylurea agents have a time to peak effect of approximately 4-6 hours, patients who develop toxicity after exposure will invariably become hypoglycemic within eight hours.  Therefore, patients who remain euglycemic and asymptomatic for an eight-hour period of observation may be considered safe for discharge home directly from the emergency department.  During this period of observation, patients should be monitored continuously for changes in mental status with blood glucose checked at least hourly.  Oral intake should not effect evaluation, however any intravenous administration of dextrose may postpone the onset of hypoglycemia and therefore necessitates a longer period of observation (up to 18-24 hours).

 

Symptoms/hypoglycemia:  Patients who develop hypoglycemia after sulfonylurea exposure require hospital admission for at least 24 hours.  Hypoglycemia should initially be treated with intravenous dextrose boluses to restore normal blood glucose levels (>60 mg/dL).  Serum glucose should be monitored every 15 to 60 minutes.  Since patients with poorly controlled diabetes may experience hypoglycemic symptoms with blood glucose levels of 60-80 mg/dL, these patients may require treatment despite a “normal” blood glucose.

 

 

Octreotide (Somatostatin), a synthetically derived hormone that suppresses insulin release from beta islet cells, can act as a specific sulfonylurea antidote and can be administered either subcutaneously or intravenously to patients exhibiting hypoglycemia following sulfonylurea poisoning.  In studies comparing treatments for sulfonylurea-induced hypoglycemia, octreotide was shown to improve hypoglycemia and decrease the need for dextrose administration.  The dose of octreotide is 50–100 mcg given IV or SQ every 8 to 12 hours.  Some sources have recommended more frequent dosing or a continuous infusion of octreotide. When used for short-term therapy, as in the treatment of sulfonylurea overdose, octreotide has essentially no side effects.  Pediatric dosing is not well established.  Because octreotide is dispensed in 50 mcg vials, use of 50 mcg per dose in children (regardless of size) is reasonable.  The long-acting preparation of octreotide, Sandostatin LAR, should not be used in the management of sulfonylurea poisoning.

 

As stated above, intravenous dextrose boluses should be initiated promptly upon recognition of hypoglycemia.  For adults, 1-2 ampules (0.5-1 g/kg, or 1-2 mL/kg) of 50% dextrose solution may be given.  Pediatric patients are treated with 2-4 mL/kg of 25% dextrose solution.   A 10% dextrose infusion may be instituted in patients with persistent hypoglycemia or in those refractory to octreotide.  Due to an unfavorable risk/benefit profile, diazoxide is no longer indicated.

 

Summary and discussion of case questions

1.    All available sulfonylurea agents have a similar time of onset (around 4-6 hours), but some, like chlorpropamide, may last considerably longer than others.  Emergency department disposition without treatment may be considered for patients who remain euglycemic and asymptomatic for at least eight hours after ingestion, provided no parenteral dextrose or octreotide was administered during or previous to the period of observation.

2.    Hospital admission and institution of therapy should be initiated in all patients with documented hypoglycemia, regardless of current symptoms.

3.    Early decontamination of large or potentially dangerous ingestions may be attempted with oral activated charcoal.  Hypoglycemia should initially be treated with dextrose bolus therapy (D50 or D25).  Octreotide is a synthetic somatostatin analog that inhibits insulin release from pancreatic beta islet cells, and therefore acts as a specific antidote in sulfonylurea toxicity.  Parenteral octreotide should be administered to all patients manifesting hypoglycemia after sulfonylurea exposure.  Continuous dextrose infusion is only necessary in those patients refractory to octreotide therapy. (From Atlanta Poison Center?)

 

Biguanides

Work by blocking hepatic release of glucose

Metformin (Glucophage), phenformin (removed from market), buformin

Do not cause hypoglycemia, but instead lactic acidosis.

Type II Lactic Acidosis which means true production of lactate, as opposed to Type I in which the defect is  lactate from shock state

Action is to block gluconeogenesis and possibly fat mobilization

MALA (metformin associated lactic acidosis)

Seen c renal failure, hepatic dysfunction, and low flow states

May increase gut production of lactate or prevent hepatic use of endogenous lactate production

Can see malaise, myalgia, decreased LOC, resp distress, systemic failure, shock, cardiac dysrhythmia

Usually levels >5.0 mcg/ml

Use Hemodialysis or CVVH not to lower metformin levels (though there will be some effect), but to take off the lactate.

Bicarb treatment may have a role

This summary is from the always amazing Poison Review

Alpha-Glucosidase Inhibitors

Blocks digestion of starchs

Acarbose

No hypoglycemia

Miglitol

No hypoglycemia

Glitazones

Rezulin (removed from market), Actos, Avandia

Increases peripheral insulin sensitivity

Hepatotoxicity and neutropenia

Check LFTs and observe

Repaglinide

Prandin

Stimulates insulin release

Admit for observation

Nateglinide

Starlix

Admit for observation

Thiazolidinediones

Lower insulin resistance at the tissues, no hypoglycemia

Rosiglitazone

Pioglitazone

Exenatide

experimental drug which causes new beta cells to be produced

Other Agents

Ackee fruit

hypoglycin A affects carnitine transport, treat with glucose and carnitine

B blockers

increase toxicity of other agents by preventing hepatic glucose release

 

Extraneal peritineal dialysis fluid can give false high readings on glucose dehydrogenase finger stick machines, blood glucose will be accurate

 

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