History

Fact Explanation
Tiredness Lethargy and tiredness are neuroglycopenic symptoms that occur due to a reduction, in cerebral glucose. [1]
Inappropriate behavior A neuroglycopenic symptom, however sympatho-adrenal activation can cause anxiety that may also manifest as a change in behavior. [1]
Blurred vision Diplopia and blurred vision occurs as a neuroglycopenic symptom in hypoglycemia. [2,3,4]
Seizures Insulinomas may present as a recurrent seizure disorder. A neuroglycopenic symptom that occurs due to a lack of glucose needed in the function of cerebral neurons. Delay in diagnosis/misdiagnosis of hypoglycemic seizures can lead to permanent neurological damage or coma. [2]
Palpitations Palpitations occur due to the activation of the sympatho-adrenal system, in response to the hypoglycemia. Other sympatho-adrenal symptoms include: tremors and diaphoresis. Usually sympatho-adrenal symptoms precede neuroglycopenic sypmtoms. However in tumor induced hypoglycemia (TIH) commonly due to an insulinoma, neuroglycopenia may occur first.[3,4]
Coma Prolonged periods of hypoglycemia can cause a coma, which occurs due to a reduction in cerebral glucose that is essential for the function of neurons. [2]
Death Prolonged periods of hypoglycemia leads to non reversible brain damage, and results in death. [4]
History of heavy ethanol ingestion Heavy ethanol ingestion induces hypoglycemia by inhibiting gluconeogenesis. [4]
History of starvation Patients who have undertaken hunger strikes or been deprived of food for long periods (elderly, the critically ill, fasting for religious festivals and hostage victims) are at risk of hypoglycemia due to reduced intake of glucose. [4,5,6]
History of attempted suicide/ poisining A psychiatric history should be elicited. A history of depression or previous attempts of deliberate self harm (DSH) should raise the possibility of attempted suicide. This possibility should especially be entertained in health workers and those with access to insulin (relatives, caregivers of diabetics) . Other drugs used are: sulfonylureas and meglitinides [4,5]
History of inherited metabolic disease Inborn errors of metabolism, most of which have a recessive inheritance, are an important cause of hypoglycemia in the non diabetic. They can be classified in to three groups: intoxication diseases (i.e., amino-acidopathies, organic aciduria, fructose intolerance and galactosaemia, iron and copper overload, porphyria); diseases linked to energy deficiency (i.e., glycogenolysis, mitochondrial diseases, disorders of fatty acid oxidation and ketogenesis, congenital lactic acidosis); and diseases due to degradation or synthesis defect of complex molecules (i.e.lysosomal or peroxisomal diseases, and congenital disorders of glycosylation.) [7]
References
  1. LIN YY, HSU CW, SHEU WH, CHU SJ, WU CP, TSAI SH. Risk factors for recurrent hypoglycemia in hospitalized diabetic patients admitted for severe hypoglycemia. Yonsei Med J [online] 2010 May, 51(3):367-74 [viewed 03 June 2014] Available from: doi:10.3349/ymj.2010.51.3.367
  2. CORREIA P, PANCHANI R, RANJAN R, AGRAWAL C. Insulinoma presenting as refractory seizure disorder F1000Res [online] :15 [viewed 03 June 2014] Available from: doi:10.12688/f1000research.1-15.v1
  3. OKABAYASHI T, SHIMA Y, SUMIYOSHI T, KOZUKI A, ITO S, OGAWA Y, KOBAYASHI M, HANAZAKI K. Diagnosis and management of insulinoma World J Gastroenterol [online] 2013 Feb 14, 19(6):829-837 [viewed 03 June 2014] Available from: doi:10.3748/wjg.v19.i6.829
  4. MUKHERJEE E, CARROLL R, MATFIN G. Endocrine and Metabolic Emergencies: Hypoglycaemia Ther Adv Endocrinol Metab [online] 2011 Apr, 2(2):81-93 [viewed 03 June 2014] Available from: doi:10.1177/2042018811401644
  5. GUNDGURTHI A, KHARB S, DUTTA MK, PAKHETRA R, GARG MK. Insulin poisoning with suicidal intent Indian J Endocrinol Metab [online] 2012 Mar, 16(Suppl1):S120-S122 [viewed 03 June 2014] Available from: doi:10.4103/2230-8210.94254
  6. CHENTLI F, AZZOUG S, AMANI MEL A, ELGRADECHI A. Diabetes mellitus and Ramadan in Algeria. Indian J Endocrinol Metab [online] 2013 Oct, 17(Suppl 1):S295-8 [viewed 03 June 2014] Available from: doi:10.4103/2230-8210.119622
  7. DOUILLARD C, MENTION K, DOBBELAERE D, WEMEAU JL, SAUDUBRAY JM, VANTYGHEM MC. Hypoglycaemia related to inherited metabolic diseases in adults Orphanet J Rare Dis [online] :26 [viewed 04 June 2014] Available from: doi:10.1186/1750-1172-7-26

Examination

Fact Explanation
Confusion A neuroglycopenic symptom, that occurs due to a reduction in glucose concentration, which is vital for the function of cerebral neurons. [1]
Diaphoresis Occurs due to the activation of the sympatho-adrenal system in response to hypoglycemia. [2]
Tremors A sympatho-adrenal symptom of hypoglycemia. [2]
Arterial hypertension Adrenergic overactivity, due to activation of the sympatho-adrenal system. [3]
Irregular pulse Severe hyperinsulinemic hypoglycemia can cause cardiac arrhythmia due to hypokalemia, as insulin causes potassium influx into the cells. [4]
References
  1. LIN YY, HSU CW, SHEU WH, CHU SJ, WU CP, TSAI SH. Risk factors for recurrent hypoglycemia in hospitalized diabetic patients admitted for severe hypoglycemia. Yonsei Med J [online] 2010 May, 51(3):367-74 [viewed 03 June 2014] Available from: doi:10.3349/ymj.2010.51.3.367
  2. OKABAYASHI T, SHIMA Y, SUMIYOSHI T, KOZUKI A, ITO S, OGAWA Y, KOBAYASHI M, HANAZAKI K. Diagnosis and management of insulinoma World J Gastroenterol [online] 2013 Feb 14, 19(6):829-837 [viewed 03 June 2014] Available from: doi:10.3748/wjg.v19.i6.829
  3. DOUILLARD C, MENTION K, DOBBELAERE D, WEMEAU JL, SAUDUBRAY JM, VANTYGHEM MC. Hypoglycaemia related to inherited metabolic diseases in adults Orphanet J Rare Dis [online] :26 [viewed 04 June 2014] Available from: doi:10.1186/1750-1172-7-26
  4. RENO CM, DAPHNA-IKEN D, CHEN YS, VANDERWEELE J, JETHI K, FISHER SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes [online] 2013 Oct, 62(10):3570-81 [viewed 04 June 2014] Available from: doi:10.2337/db13-0216

Differential Diagnoses

Fact Explanation
Epilepsy Severe hypoglycemia can cause seizures, that mimic epilepsy. Seizures in hypoglycemia is of the generalized tonic clonic type, assessment of CBS will reveal hypoglycemia. [1]
Transient Ischemic Attack (TIA) Hypoglycemia may present with slurred speech and focal deficits, which may be easily confused for a TIA. A rapid CBS test will confirm hypoglycemia, and there is recovery following dextrose infusion. [2]
Cardiac arrythmias Severe hyperinsulinemic hyperglycemia can precipitate cardiac arrhythmia due to the associated hypokalemia. Differentiation will require assessment of plasma glucose and an electrocardiogram. [3]
Substance abuse A history of substance abuse must be elicited in every patient presenting with change in behavior, disorientation and coma. Some centers advocate routine screening for alcohol and drugs. [4]
Pheochromocytoma A pheochromocytoma will mimic the adrenergic symptoms and signs of hypoglycemia such as tremors, sweating and even episodic hypertension. However, there is usually no loss of consciousness, drowsiness or other neuroglycopenic symptoms. Laboratory investigation will confirm the diagnosis. [5]
Addison's disease Primary adrenal insufficiency can cause hypoglycemia due to a deficiency of cortisol. Neuroglycopenic symptoms are predominant, as adrenal deficiency virtually abolishes the adrenergic response to hypoglycemia. These patients are at higher risk of hypoglycemia, and also of severe hypoglycemia and its complications; due to the lack of the cortisol counter regulatory mechanism. [6]
References
  1. YıLMAZ AğLADıOğLU S, SAVAş ERDEVE Ş, ÇETINKAYA S, BAş VN, PELTEK KENDIRCI HN, ÖNDER A, AYCAN Z. Hyperinsulinemic Hypoglycemia: Experience in A Series of 17 Cases J Clin Res Pediatr Endocrinol [online] 2013 Sep, 5(3):150-155 [viewed 04 June 2014] Available from: doi:10.4274/Jcrpe.991
  2. MUKHERJEE E, CARROLL R, MATFIN G. Endocrine and Metabolic Emergencies: Hypoglycaemia Ther Adv Endocrinol Metab [online] 2011 Apr, 2(2):81-93 [viewed 03 June 2014] Available from: doi:10.1177/2042018811401644
  3. RENO CM, DAPHNA-IKEN D, CHEN YS, VANDERWEELE J, JETHI K, FISHER SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes [online] 2013 Oct, 62(10):3570-81 [viewed 04 June 2014] Available from: doi:10.2337/db13-0216
  4. DUNHAM CM, CHIRICHELLA TJ. Trauma activation patients: evidence for routine alcohol and illicit drug screening. PLoS One [online] 2012, 7(10):e47999 [viewed 04 June 2014] Available from: doi:10.1371/journal.pone.0047999
  5. TANAKA Y, ISOBE K, MA E, IMAI T, KIKUMORI T, MATSUDA T, MAEDA Y, SAKURAI A, MIDORIKAWA S, HATAYA Y, KATO T, KAMIDE K, IKEDA Y, OKADA Y, ADACHI M, YANASE T, TAKAHASHI H, YOKOYAMA C, ARAI Y, HASHIMOTO K, SHIMANO H, HARA H, KAWAKAMI Y, TAKEKOSHI K. Plasma free metanephrines in the diagnosis of pheochromocytoma: diagnostic accuracy and strategies for Japanese patients. Endocr J [online] 2014 May 28 [viewed 04 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24871964
  6. MEYER G, HACKEMANN A, REUSCH J, BADENHOOP K. Nocturnal hypoglycemia identified by a continuous glucose monitoring system in patients with primary adrenal insufficiency (Addison's Disease). Diabetes Technol Ther [online] 2012 May, 14(5):386-8 [viewed 04 June 2014] Available from: doi:10.1089/dia.2011.0158

Investigations - for Diagnosis

Fact Explanation
Capillary Blood Sugar (CBS) Diagnosis of pathological hypoglycemia is confirmed by the Whipple triad: symptoms of hypoglycemia, a low plasma glucose level and resolution of symptoms and signs once normoglycemia is achieved. Though CBS is not always accurate, it provides rapid results (as delaying treatment can disastrous consequences) and a low CBS should be followed by subsequent laboratory investigation of plasma glucose. A glucose level of less than 55mg/dl (3 mmol/L) supported by the Whipple triad establishes the diagnosis of hypoglycemia in a non diabetic. [1,2]
References
  1. MUKHERJEE E, CARROLL R, MATFIN G. Endocrine and Metabolic Emergencies: Hypoglycaemia Ther Adv Endocrinol Metab [online] 2011 Apr, 2(2):81-93 [viewed 03 June 2014] Available from: doi:10.1177/2042018811401644
  2. IGLESIAS P., DIEZ J. J.. MANAGEMENT OF ENDOCRINE DISEASE: A clinical update on tumor-induced hypoglycemia. European Journal of Endocrinology [online] December, 170(4):R147-R157 [viewed 03 June 2014] Available from: doi:10.1530/EJE-13-1012

Investigations - Fitness for Management

Fact Explanation
Full Blood Count Important baseline investigation, symptoms of severe anemia may mimic hypoglycemia and cause lethargy, weakness. In addition a leucocytocis is suggestive of an infection that will also cause hypoglycemia. [1]
C Reactive Protein To asses the presence of an infective process, that may have precipitated the hypoglycemia. [1]
Serum Insulin In exogenous hypoglycemia, the level of insulin is elevated (more than 3 micoIU/ml). [2]
C Peptide In hypoglycemia due to exogenous insulin despite an elevated insulin level, C-peptide is low (less than 0.6 ng/mL). This helps exclude DSH using sulfonylureas as this causes increased secretion of endogenous insulin, thus there is an increase in both insulin and C-peptide. [2]
Serum Cortisol The possibility of primary adrenal insufficiency should be entertained. As it can cause symptoms of hypoglycemia due to cortisol deficiency. [3]
TSH/fT4/fT3 Should be performed in the investigation of non diabetic hypoglycemia for several reasons. Firstly hypothyroidism may mimic symptoms of hypoglycemia. Secondly, pituitary insufficiency can lead to hypoglycemia, due to inactivation of the hypothalamo-pituitary-adrenal axis, thyroid hormone secretion will be depressed in this situation. Rarely a thyrotoxic crisis can precipitate hypoglycemia, (though it commonly causes impaired glucose tolerance). [4]
Liver Enzymes/Liver Function Tests Liver failure is a cause for hypoglycemia, as it depresses hepatic gluconeogenesis during periods of fasting. Therefore assessment of the liver enzymes and liver function tests is needed. [1]
CT Abdomen For the diagnosis of an insulinoma, they are hypervascular and, as a result, demonstrate a greater degree of enhancement than normal pancreatic parenchyma during the arterial and capillary phases of contrast. [5]
MRI Abdomen The sensitivity and specificity of MRI is higher than CT for the diagnosis of an insulinoma, despite its advantages it is the second line investigation in current practice.[5]
References
  1. MUKHERJEE E, CARROLL R, MATFIN G. Endocrine and Metabolic Emergencies: Hypoglycaemia Ther Adv Endocrinol Metab [online] 2011 Apr, 2(2):81-93 [viewed 03 June 2014] Available from: doi:10.1177/2042018811401644
  2. GUNDGURTHI A, KHARB S, DUTTA MK, PAKHETRA R, GARG MK. Insulin poisoning with suicidal intent Indian J Endocrinol Metab [online] 2012 Mar, 16(Suppl1):S120-S122 [viewed 03 June 2014] Available from: doi:10.4103/2230-8210.94254
  3. MEYER G, HACKEMANN A, REUSCH J, BADENHOOP K. Nocturnal hypoglycemia identified by a continuous glucose monitoring system in patients with primary adrenal insufficiency (Addison's Disease). Diabetes Technol Ther [online] 2012 May, 14(5):386-8 [viewed 04 June 2014] Available from: doi:10.1089/dia.2011.0158
  4. NAKATANI Y, MONDEN T, SATO M, DOMEKI N, MATSUMURA M, BANBA N, NAKAMOTO T. Severe Hypoglycemia Accompanied with Thyroid Crisis Case Rep Endocrinol [online] 2012:168565 [viewed 04 June 2014] Available from: doi:10.1155/2012/168565
  5. OKABAYASHI T, SHIMA Y, SUMIYOSHI T, KOZUKI A, ITO S, OGAWA Y, KOBAYASHI M, HANAZAKI K. Diagnosis and management of insulinoma World J Gastroenterol [online] 2013 Feb 14, 19(6):829-837 [viewed 03 June 2014] Available from: doi:10.3748/wjg.v19.i6.829

Management - General Measures

Fact Explanation
Secure Airway, Breathing and Circulation Initial management and resuscitation of any unconscious patient should involve management of airway, breathing and circulation. Decision to intubate should be made with assessment of the Glasgow Coma Scale (GCS); if less than 8 elective intubation should be performed as the patient's airway protection reflexes are absent. [1] Supplemental oxygen and IV fluids can be administered, in pre-hospital care or when encountered at the emergency department.
Continous monitoring Continuous monitoring of the patient should occur during the initial assessment and resuscitation. This should include monitoring of pulse, blood pressure, oxygen saturation and capillary blood sugar (CBS). [2]
References
  1. ROBINSON N, MACLEOD KG. Airway management in the transfer of the unconscious patient. Ann R Coll Surg Engl [online] 1983 Nov, 65(6):372-3 [viewed 04 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/6638851
  2. SACKS Z, VAIDYA A, SHARMA N, GOTTLIEB B. Interactive medical case. A patient found unresponsive. N Engl J Med [online] 2012 Dec 13, 367(24):e36 [viewed 04 June 2014] Available from: doi:10.1056/NEJMimc1204403

Management - Specific Treatments

Fact Explanation
Pre-hospital care If possible an oral carbohydrate dose should be administered, prior to hospital admission. Initial load can be provided with oral glucose, a 15-20g dose will maintain euglycemia for approximately 2 hours. Therefore it should be followed by a complex carbohydrate meal, to maintain euglycemia for a longer period. [1,2]
Admission criteria Admission to a hospital is mandatory in a non diabetic patient with hypoglycemia, where a secondary cause is suspected. This is for further investigation in to the etiology. Non response to treatment at primary care is another indication. [1]
Intravenous Thiamine In a patient presenting with chronic malnutrition or alcohol abuse, IV Thiamine should be administered prior to dextrose therapy to prevent Wernicke's encephalopathy. Bolus of 1-2 mg/kg. [2]
Dextrose Management of hypoglycemia is with dextrose. When the plasma insulin level reach 50-60microIU/ml, hepatic gluconeogensis becomes completely suppressed. Thus dextrose is necessary. The objective of an acute intervention is to minimize cerebral damage, therefore dextrose infusion should commence once it is suggested by a low CBS (save plasma for a late laboratory investigation of venous glucose). Initial administration of 25-50 ml of 50% Dextrose, should be followed by a saline flush. Subsequent 10% dextrose should be titrated according to clinical response, plasma venous glucose levels and food intake. [2,3]
Glucagon Glucagon stimulates hepatic gluconeogenesis, and an emergency dose of IM/SC Glucagon 1 mg can be administered. This unhelpful where hepatic function is depressed, i.e. liver failure, ethanol induced hypoglycemia and adrenal insufficiency. [3]
Subsequent measures following stabilization Following stabilization, management should be aimed at maintaining euglycemia and on investigating the cause of hypoglycemia. [3]
References
  1. ANYANWU AC, ODENIYI IA, FASANMADE OA, ADEWUNMI AJ, ADEGOKE O, MOJEED AC, OLOFIN KE, OHWOVORIOLE AE. Endocrine-related diseases in the emergency unit of a Tertiary Health Care Center in Lagos: A study of the admission and mortality patterns. Niger Med J [online] 2013 Jul, 54(4):254-7 [viewed 03 June 2014] Available from: doi:10.4103/0300-1652.119651
  2. MUKHERJEE E, CARROLL R, MATFIN G. Endocrine and Metabolic Emergencies: Hypoglycaemia Ther Adv Endocrinol Metab [online] 2011 Apr, 2(2):81-93 [viewed 03 June 2014] Available from: doi:10.1177/2042018811401644
  3. GUNDGURTHI A, KHARB S, DUTTA MK, PAKHETRA R, GARG MK. Insulin poisoning with suicidal intent Indian J Endocrinol Metab [online] 2012 Mar, 16(Suppl1):S120-S122 [viewed 03 June 2014] Available from: doi:10.4103/2230-8210.94254