Hypoglycaemia Treatment Algorithm

Definition

• as per http://content.nejm.org/cgi/content/full/360/2/190: UK Hypoglycaemia Study defined hypoglycaemic event as 20min or more with BG<3.0mM/L[54mg/dL], reflecting duration and BG levels at which cognitive fx deteriorates in physiological studies
• Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 2005;22:749-755. [Medline]
• UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007;50:1140-1147. [Medline]
• Deary IJ. Effects of hypoglycaemia on cognitive function. In: Frier BM, Fisher BM, eds. Hypoglycaemia and diabetes: clinical and physiological aspects. London: Edward Arnold, 1993:80-92.
• Evans ML, Pernet A, Lomas J, Jones J, Amiel SA. Delay in onset of awareness of acute hypoglycemia and of restoration of cognitive performance during recovery. Diabetes Care 2000;23:893-897. [Abstract] [pdf]
• 8 healthy volunteers, 1 x hyperinsulinaemic [vs 1 x euglycaemic] clamp to dcr PG rapidly to 2.65 for 90mins; Results: immediate impairm of cognitive fx; counterreg hormone responses (Adr, NA, Glucagon, cortisol, GH) and symptomatic awareness after 20min after onset of hypoglycaemia; during recovery, 4-choice reaction time remained abnl even after resolution of symptomatic awareness
• symptoms questionnaire [scale 1-7: absent - max.]: (A: 7 autonomic symptoms:) •sweating, •warmth, •palpitations, •tingling, •anxiety, •trembling, •hunger, (B: 8 neuroglycopenic symptoms:) •blurred vision, •tiredness/drowsiness, •confusion, •weakness, •headache, •difficulty in speaking, •dizziness, •irritability;
• cognitive fx tests: 1) 4-choice reaction time, 2) Stroop word subtest, 3) color-word subtest, 4) trail-making B test;

Practice Guideline

• ENDO: JCEM
• Whipple's triad:
1. symptoms/signs
• adrenergic: palpitations, tremor, arousal/anxiety
• cholinergic: sweating, hunger, paraesthesias
• neuroglycopenic: behavioural changes, fatigue, confusion, seizure, loss of consciousness
2. P-Glu<3.0mM/L=55mg/dL [cf. unequivocally nml P-Glu>3.9mM/L=70mg/dL]
• NB: symptom threshold may be lower with recurrent hypoglycaemia or extended fasting, after exercise or sleep
• NB: beware false-positives: e.g. without inhibitors of glycolysis, or delayed separation of plasma/serum from formed elements, esp. with erythrocytosis, leukocytosis, thrombocytosis
3. resolution of symptoms/signs with P-Glu normalization
• Evaluation strategy in non-diabetic adults:
• first consider :
1. drugs
2. critical illness
3. hormone deficiencies
4. non-islet cell tumours
• if neg: accidental/surreptitious/malicious hyperinsulinism or endogenous hyperinsulinism
• if suspected endogenous: measure during episode of hypoglycaemia (*ref. values assume no intercurr illness/renal insuff), if needed provoked by up-to-72h fast (2/3 <24h, vast majority<48h) or mixed meal test over 5h with a meal most likely to cause hypo; NB: NEVER use oGTT)
• glucose < 3.0mM/L=55ng/dL* (rise by >=1.4mM/L=25mg/dL after 1.0mg iv glucagon indicate mediation by insulin/insulin-like growth factor);
• insulin (>=18pM/L=3.0mcU/mL* in endogenous hyperinsulinism, although may occas. be false-neg);
• C-peptide (>=0.2nM/L=0.6ng/mL* in endogenous hyperinsulinism);
• proinsulin (>=5.0pM/L* in endogenous hyperinsulinism);
• beta-hydroxybutyrate (<=2.7mM/L indicates mediation by insulin/insulin-like growth factor; NB: rising levels indicate a negative fast!);
• circulating oral hypoglycaemic agents (need to exclude before insulinoma localisation);
• insulin antibodies (any time) (need to exclude before insulinoma localisation);

Table 1. Causes of hypoglycemia in adults:

• Ill or medicated individual
• Drugs
• Insulin or insulin secretagogue
• Alcohol
• Antihyperglycaemic agents
• Others (Table 2)--according to quality of evidence:
• moderate: Cibenzoline, Gatifloxacin, Pentamidine, Quinine, Indomethacin, Glucagon (during endoscopy)
• low: Chloroquineoxaline sulfonamide, Artesunate/Artemisin/Artemether, IGF-I, Lithium, [Dextro-]Propoxyphene
• very low (but >25 cases reported): ACEI, ARA, beta-blockers, levofloxacin, mifepristone, disopyramide, Trimethoprim-Sulfamethoxazole, Heparin, 6-Mercaptopurin
• Critical illnesses
• Hepatic, renal, or cardiac failure
• Sepsis (including malaria)
• Inanition
• Hormone deficiency
• Cortisol [, GH]
• Glucagon and epinephrine (in insulin deficient diabetes mellitus)
• Nonislet cell tumor hypoglycaemia=NICTH (usu. large mesenchymal tumours, causing overproduction of [incompletely processed] IGF-II (NB: may be nml IGF-II level, but hi pro-IGF-II/IGF-II ratio, and usu. hi IGF-II/IGF-I ratio due to suppressed GH secretion and therefore low IGF-I), also reported hi IGF-I)
• Seemingly well individual
• Endogenous hyperinsulinism
• Insulinoma (usu. fasting hypoglycaemia, but may also be postprandial; incidence 1/250k pt-yrs; <10%malignant/multiple/MEN-I; often <1.0cm; CT/MRI detection ~ 70/85%; somatostatin receptor scintigraphy=SRS: ~50[-80]% sens.; endoscopic pancr US +-FNA: up to 90% sens. in some centres; selective pancreatic arterial calcium injection with >2[-5]fold icr in hepatic venous insulin levels regionalizes insulinoma with hi sens. and Ix of choice for functional β-cell disorders; ?role of PET); intraop. pancr US: almost invariably localizes tu.)
• Functional β-cell disorders (nesidioblastosis) [treatment: dietary, medical: alpha-glucosidase inhibitor, diazoxide, octreotide, or steroids, growth hormone, else partial pancreatectomy]
• Noninsulinoma pancreatogenous hypoglycemia=NIPHS (usu. postprandial due to diffuse islet hypertrophy/-plasia; confirmation: selective arterial calcium stimulation test)
• Post gastric bypass hypoglycemia (usu. postprandial, usu. many mths after surgery)
• Insulin autoimmune hypoglycemia
• Antibody to insulin [rare, usu. Jap/Kor: Insulin binds to antibody, and released later in unregulated fashion, causing lo Glu]
• Antibody to insulin receptor (due to agonist properties; NB: usu hi Insulin levels due to dcrd clearance, but appropriately suppressed C-peptide levels; often female African-American with autoimmune diseases)
• Insulin secretagogue
• Other
• Accidental, surreptitious, or malicious hypoglycemia

Hypoglycaemia: Overview

• Symptoms if <=3.9mM/L (i.e. <="4") (Cox(1993)DiabetesCare: Perceived symptoms in the recognition of hypoglycemia.)
• autonomic response: pallor, palpitations, sweating, shaking/trembling, hunger
• neuroglycopaenic response: feeling light-headed, confusion, altered behaviour, paraesthesia, drowsiness, coma

• Lucozade 95±10, Cornflakes 81±3, Mars bar 65±3, Digestive biscuits 59±2, Coca Cola 58±5, Honey 55±5, Orange juice 50±4, Milk chocolate 43±3, Full-fat milk 27±4, Multi-grain bread 43, Ryvita 74 (?), [Jan Watson, J Diabetes Nursing 2008]

• 20-30g of hi GI carbohydrate food: 3-5 glucose tablets, 50mL Lucozade, glass of ordinary cola or fruit juice, or proprietary glucose gel

Severity

• Grade 1 hypoglycaemia: transitory symptoms not affecting normal activity
• G2: temporarily incapacitated but patient able to control symptoms without help
• G3: incapacitated and required assistance to control symptoms without help
• G4: required medical attention or glucagon injection
• Src: eg;

Hypobox (FGH)

• BG<4, unconscious:
• 20mL 20%  or {1mg   + 10mg   
• 20mL [BNF: 50mL] 20% Dextrose IV [=4g[10g] Dextrose], or
• glucagon 1mg IM [+Metoclopramide 10mg PO/IM/IV: before low GI food], provided no prior alcohol
• BG<4, losing consciousness:
• 
• Glycogel massaged into cheek, followed by food;
• if no effect after 5 min: as above
• BG<4, conscious:
•  120 / 200 / 200 
  4 / 4
• 120mL Lucozade original (1/2 tea cup); or:
• 200mL fruit juice , 200mL Coca Cola (non-diet), 4 jelly babies , 4 dextrose tablets ;
• recheck BM after 5mins: if <5: repeat Lucozade
• 2 / 2
• 2 digestive biscuits ; or: 2 slices granary/wholemeal bread

Hypo-unawareness

• can often be restored with meticulous avoidance of hypoglycaemia over a 2-3 week period!
• src: ENDO: JCEM Hypoglycaemia guideline:  7914259; 7895957; 8405713;

Systematic: Hypoglycaemia