Hyperglycemia

by Toh Hong Chuen

Case Presentation

A 58-year-old lady presented with right foot pain for 3 days, associated with high fever, lethargy, polyuria, and polydipsia. At triage, air hunger was noted. Her vital signs were: BP 82/46 mmHg, PR 131/min, RR 28/min, T 38.7 and SpO2 98%. She was brought to the resuscitation room for further management.

Clinically, she was dehydrated and confused with GCS E4V4M6. Her neck was supple, and lungs were clear. Crepitus was noted on the dorsum of the right foot. Point of care blood tests showed: capillary glucose 40 mmol/L, capillary ketone 7.2 mmol/L, pH 7.22, HCO3 8 mmol/L, pCO2 20 mmHg, Na 130 mmol/L, Cl 95 mmol/L, K 5.5 mmol/L and lactate 6.9 mmol/L.

A diagnosis of septic shock secondary to gas gangrene complicated by diabetic ketoacidosis was made. She was aggressively resuscitated with fluid and started on IV insulin infusion. Potassium replacement was withheld as K was elevated. Urinary catheterization was performed for strict input-output monitoring. Broad-spectrum antibiotics and intramuscular tetanus toxoid were given. X-ray of right foot confirmed subcutaneous air.

The patient was sent directly to the theatre and underwent extensive debridement for the gas gangrene. She had an uneventful recovery and was discharged 1 week later.

Critical Bedside Actions and General Approach

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are potentially life-threatening diabetic emergencies. In acutely ill patients with hyperglycemia, blood and urine tests must be performed, preferably at the point of care, to evaluate for the presence of DKA or HHS (Table 1).

Key management principles for DKA and HHS include initiation of IV fluid therapy and IV insulin infusion while ensuring normokalemia and avoiding hypoglycemia. The precipitating cause should be identified and treated. Patient’s vital signs, mental status and biochemical response to therapy (glucose, ketones, Na and K) and input-output must be closely monitored. As DKA and HHS resolve, overlap with s/c insulin prior to stopping the insulin infusion. See appendix 1 for management details.

Differential Diagnoses

Diagnostic Criteria For DKA And HHS

Criteria	DKA Mild	DKA Moderate	DKA Severe	HHS
Serum glucose (mmol/L)	≥14	≥14	≥14	≥33
pH	7.25-7.30	7.00-7.24	<7.00	>7.3
HCO3 (mmol/L)	15-18	10-14	<10	>18
Anion gap (mmol/L)	>10	>12	>12	Variable
Serum ketone (mmol/L)	≥0.6	≥0.6	≥0.6	Small/none
Urine ketone	Positive	Positive	Positive	Small/none
Effective serum osmolality (mOsm/kg)	Variable	Variable	Variable	>320

Adapted from Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343. doi:10.2337/dc09-9032. Please read the article for more information.

 

DKA and HHS are distinguished as follow:

• Hallmarks of DKA are anion-gap acidosis, ketosis, and hyperglycemia.
  • Usually associated with type 1 diabetes; can occur in type 2 diabetes during a serious illness.
  • A short duration of symptoms, usually <1-2 days.
  • Up to 10% of DKA are “euglycaemic” (glucose <14). They can be seen in pregnant patients, those with restricted food intake, or had initiated insulin therapy (though insufficient) prior to presentation.
• Hallmarks of HHS are profound hyperosmolality, hyperglycemia, and dehydration.
  • Associated with type 2 diabetes; can occur with type 1 as a simultaneous occurrence with DKA.
  • Like DKA, the circulating amount of insulin is inadequate to prevent hyperglycemia. Unlike DKA, this amount is sufficient to prevent lipolysis and ketoacidosis.
  • Without significant ketoacidosis, HHS develops slowly and subtly over several days, contributing to more severe water deficit at around 7-12 L, compared to 4-6 L in DKA.
  • The older terms “hyperglycemic hyperosmolar nonketotic coma” (HHNK) and “hyperglycemic hyperosmolar nonketotic state” (HHNS) should not be used. Patients often present without coma, and ketonemia may found in some.
• Up to 1/3 of patients have an overlap of DKA and HHS.
• Any significant stress can precipitate DKA/HHS, remembered as “7 ‘I’s have bled!”.
  • Iatrogenic (drug interaction, e.g. steroids)
  • Idiopathic (new onset DM)
  • Illegal (substance abuse)
  • Infarction (e.g. AMI, stroke, bowel ischemia)
  • Infection (e.g. pneumonia, UTI, cellulitis)
  • Infraction (i.e. noncompliance)
  • IUP (i.e. pregnancy)
  • Bleeding GI

History and Physical Examination Hints

1. DKA and HHS can present similarly with malaise, anorexia, thirst, polyuria, and polydipsia. In addition, they can be triggered by similar precipitants. Differences include a longer presentation and more severe dehydration in HHS.
2. Neurological symptoms
   • HHS patients often have some degree of altered mental state or other neurological disturbances. These are related to the severity and rate of development of hyperosmolality.
   • Conversely, since hyperosmolality is absent or insignificant, DKA patients have normal neurological status. Only severe DKA presents with coma.
3. Respiratory symptoms
   • DKA patients often present with air hunger and kussmaul’s breathing secondary to acidosis, unlike HHS.
4. Abdominal symptoms
   • In DKA, nausea, vomiting and abdominal pain are associated with the severity of ketoacidosis.
   • Conversely, an acute abdominal process such as pancreatitis can precipitate DKA. Search for intraabdominal precipitants if abdominal pain when DKA is mild, persistent pain despite improvement of acidosis or signs of peritonism.
   • HHS (no significant ketoacidosis) is not associated with abdominal pain. Evaluate for an abdominal precipitant if there are abdominal symptoms.
5. Physical findings may be unreliable for estimating the degree of dehydration, particularly in children
   • In DKA, patients may appear more dehydrated from the drying of oral mucosa due to Kussmaul’s respiration.
   • Hyperosmolality in HHS may “preserve” intravascular volume (even though it leads to urinary losses) and mask signs of volume depletion until hemodynamic deterioration suddenly occur.

Emergency Diagnostic Tests and Interpretation

1. High Anion Gap Metabolic Acidosis (HAGMA)
   • The most important feature of DKA.
   • Anion gap = Na – (Cl + HCO3). Use measured sodium in the calculation of anion gap.
   • pH in venous blood gas is sufficient as it correlates with arterial pH. Perform arterial blood gas only if concomitant respiratory failure is suspected.
   • Note that the severity of metabolic acidosis can be masked by metabolic alkalosis from vomiting.
   • Interestingly, most patients change from HAGMA to NAGMA while recovering from treatment. This is due to urinary loss of ketones earlier during osmotic diuresis. Ketones can be metabolized to bicarbonate when adequate insulin is provided; hence the loss of urinary ketones is equivalent to losing bicarbonate, resulting in NAGMA.
2. Ketosis
   • The small amount of ketones is normally present (<0.6 mmol/L) acting as an alternative energy source if glucose is not available.
   • In DKA, relative or absolute insulin deficiency and the surge of counterregulatory hormones (especially glucagon and catecholamines) cause unrestrained ketogenesis. All three ketones, acetone (Ac), acetoacetate (AAc) and beta-hydroxybutyrate (BHB) are elevated.
   • AAc and BHB fully dissociate in physiological pH and contribute to HAGMA. Ac, which does not dissociate, does not.
   • BHB is the most abundant ketone in DKA, with a ratio of 10:1 compared to Aac, and Ac is least abundant.
   • Insulin reduces overall ketone level but also converts BHB AAc. As nitroprusside-based urine test detects only Ac and AAc, urinary ketones may not improve or paradoxically worsen with treatment. Therefore, serum BHB should be used to monitor resolution of ketosis.
   • Note that blood test for ketones can be falsely positive in a patient taking sulfhydryl drugs.
3. Serum osmolality
   • The effective serum osmolality should be used in the diagnosis of HHS, not measured osmolality. Measured Na should be used to determine the osmolality.
   • Effective serum osmolality = 2 x Na (mmol/L) + Glucose (mmol/L).
   • Urea travels freely across a cell membrane and does not contribute to osmolality in vivo.
4. Serum potassium
   • Check K before and after starting insulin.
   • Total body potassium depletion occurs through urinary (and occasionally gastrointestinal) loss. Serum K, however, may be normal or paradoxically elevated due to transcellular shift (acidosis, insulin deficiency), volume contraction and reduced renal function.
   • Hypokalemia at presentation signifies profound K loss. This generally worsens with treatment and may precipitate threatening arrhythmia and profound respiratory muscle weakness.
5. Serum sodium
   • As hyperglycemia draws fluid into the intravascular space, most patients have low normal or mild hyponatremia (dilutional). Hypernatraemia, therefore, signifies severe dehydration.
   • Use the measured Na when calculating the anion gap and serum osmolality.
   • Corrected Na = serum Na + 2 [ (serum glucose – 5.5)/5.5 ]
   • After the initial fluid challenge with 0.9% NaCl, use corrected sodium to decide on the choice of saline for infusion.
6. Others
   • Leukocytosis is present due to the elevated levels of stress hormones. Up to 15K may be expected for DKA.
   • Serum amylase, lipase, hepatic enzymes, creatinine kinase and CRP, can be mildly elevated. These are nonspecific findings.

Emergency Treatment Options

1. Fluids
   • Patients with DKA and HHS are invariably volume depleted. Start IV 0.9% NaCl at 10-20 mmol/kg/hr during the first hour.
   • After BP and perfusion normalizes, continue infusion at a rate of 250-500 ml/hr with 0.45% NaCl if the calculated Na is normal or high; or 0.9% NaCl if the calculated Na is low
   • The total body fluid deficit should be slowly corrected over 24 hrs.
2. IV insulin
   • Mainstay treatment of DKA and HHS.
   • Before initiating IV insulin,
     • Initiate fluid replacement. With insulin, glucose is taken up by cells, drawing fluid out of intravascular space and can cause hypotension.
     • Correct hypokalemia, if present, with IV KCl at 20-30 mmol/hr until K>3.3 mmol/L.
   • Give as a continuous infusion of 0.1 U/kg/hr, and not as a bolus as this may cause severe hypokalemia and may risk hypoglycemia.
   • Resolution of DKA as indicated by serum glucose <11 mmol/L plus any 2 of the following:
     • pH >7.3,
     • HCO3 >18 mmol/L
     • Anion Gap ≤ 12 mmol/L
   • As the resolution of ketoacidosis in DKA often lack behind hyperglycemia (mean duration of 12 hours versus 6 hours respectively), IV insulin should be continued with dextrose replacement to clear the ketones. When capillary glucose reaches 11 mmol/L:
     • Reduce IV insulin rate to 0.02-0.5 U/kg/hr
     • Add D5% to replacement fluid, keep serum glucose between 8-11 mmol/L until ketoacidosis resolves.
     • Once resolved and the patient is able to take orally, start subcutaneous rapid-acting insulin at 0.1 U/kg around 30-60 min before stopping the insulin infusion, given the delayed onset of the s/c preparation, to prevent rebound hyperglycemia.
   • Similarly in HHS, when capillary glucose reaches 16 mmol/L:
     • Reduce IV insulin rate to 0.02-0.5 U/kg/hr, keep serum glucose between 11-16 mmol/L.
     • IV insulin can be stopped once the patient is alert, taking orally and started on their oral hypoglycemic or subcutaneous insulin.
3. Potassium
   • Correct hypokalemia if present as above.
   • Add 20-30 mmol of K in each liter of fluid to maintain normokalemia.
     • Withhold K is elevated above the upper limit (or >5.2 mmol/L).
   • Check K 2 hourly after initiating fluid and insulin therapy
4. Phosphate
   • DKA patients have total body phosphate though serum levels may be normal or elevated. Treatment with insulin drives phosphate intracellularly and worsens hypophosphatemia.
     • However, routine phosphate replacement is not indicated as no studies demonstrated benefit. Treatment could also precipitate hypocalcemia.
   • Consider phosphate replacement (IV K2PO4 at 4.5 mmol/hr) in DKA if:
     • Cardiac dysfunction
     • Respiratory depression
     • Anemia
     • Severe hypophosphatemia (<1 mg/dL).
   • Unlike DKA, there is no evidence for replacement of phosphate in HHS.
5. Sodium Bicarbonate
   • NaHCO3 should not be given in DKA as it is Independent risk factor for cerebral edema, and can worsen hypokalemia, create excessive sodium load, induce paradoxical CSF acidosis or even impairing release of O2 to tissues via shifting the oxygen-hemoglobin curve to left.
   • Consider only if the patient is severely acidotic (pH <6.9).

Pediatric, Geriatric, Pregnant Patient and Other Considerations

Pregnancy (DKA)

• Low maternal mortality (<1%), but perinatal mortality can be as high as 35%.
• Presents similarly to non-pregnant women, but 1/3 of patients may have euglycaemic DKA.
• Treated similarly, but include fetal monitoring.

Pediatric (DKA)

• As the clinical judgment of dehydration is unreliable, set maintenance fluids based on of 6% total water deficit.
• The most feared complication is cerebral edema
• Occurs in 1% of DKA episodes, but high mortality of 40-90%.
• Major risk factors include treatment with sodium bicarbonate and severe hypocapnia and high urea at presentation.
• Typically presents 4-12 hours after initiating treatment, but can be delayed up to 48 hours. Once recognized: elevate the head of the bed and reduce IV fluids by 1/3. If BP is normal, start IV mannitol (0.5-1 g/kg over 20 min). If patient is hypotensive, use IV 3% NaCl (5-10 ml/kg over 30 min).

Geriatric (HHS)

• Prone to develop HHS due to altered thirst mechanism, restricted access to water and decreased pancreatic reserve. Always check blood sugar in patients, especially the elderly, with an altered mental state.
• Managed similarly to other population.

Disposition Decisions

All patients with DKA or HHS should be admitted. They should be sent to the ICU or high dependency unit if there were severe symptoms, refractory hypotension, refractory oliguria or persistent mental state changes.

Appendix 1

References and Further Reading

• Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343. doi:10.2337/dc09-9032.
• Maletkovic J, Drexler A. Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Endocrinol Metab Clin North Am. 2013;42(4):667-695. doi:10.1016/j.ecl.2013.07.001.
• Wachtel T. The diabetic hyperosmolar state. Clin Geriatr Med. 1990;6(4):797-806.
• Palevsky PM. Hypernatremia. Semin Nephrol. 1998;18(1):20-30. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9459286. Accessed December 18, 2015.
• Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care. 2002;17(1):63-67. doi:10.1053/jcrc.2002.33030.
• Beck LH. Q: Should the actual or the corrected serum sodium be used to calculate the anion gap in diabetic ketoacidosis? Cleve Clin J Med. 2001;68(8):673-674.
• Brandenburg M a, Dire DJ. Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis. Ymem. 1998;31(4):459-465. Available at: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=9546014&retmode=ref&cmd=prlinks\npapers2://publication/uuid/6216F196-EC44-4CE0-ABDF-E64E845AE6BE.
• Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15(6):412-426. doi:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8.
• Uptodate: Plasma sodium concentration correction for hyperglycemia. Available at: http://www.uptodate.com.libproxy1.nus.edu.sg/contents/calculator-plasma-sodium-concentration-correction-for-hyperglycemia?source=search_result&search=corrected+sodium+calculator&selectedTitle=1~150. Accessed December 20, 2015.
• Carroll M, Yeomans E. Diabetic ketoacidosis in pregnancy. Crit Care Med. 2005;33((10 Suppl): S347). doi:10.1016/j.ogc.2007.08.001.
• Cullen MT, Reece EA, Homko CJ, Sivan E. The changing presentations of diabetic ketoacidosis during pregnancy. Am J Perinatol. 1996;13(7):449-51. doi:10.1055/s-2007-994386.
• Olivieri L, Chasm R. Diabetic Ketoacidosis in the Pediatric Emergency Department. Emerg Med Clin North Am. 2013;31(3):755-773. doi:10.1016/j.emc.2013.05.004.
• Glaser N, The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344(4):264-269.
• George Bakris M, Lawrence Blonde, MD F, Andrew J.M. Boulton M, et al. American Diabetes Association. Standards of Medical in Diabetes 2015. J Clin Appl Res Educ. 2015;38(January):99. doi:10.2337/dc15-S005.