Each year, roughly 10,000 patients present to the Emergency Department in diabetic ketoacidosis (DKA). Prior to the advent of insulin, the mortality rate of DKA was 100% although in recent years, that rate has dropped to approximately 5%.1 Despite clinical advances, the mortality rate has remained constant over the last 10 years. With aggressive resuscitative measures and appropriate continued management this trend may change.
DKA is defined as:
- Hyperglycemia (glucose > 250 mg/dl)
- Acidosis (pH < 7.3)
Severity of DKA:
- Mild – pH 7.25-7.3
- Moderate – pH 7.0-7.24
- Severe – pH < 7.0
In the absence of insulin, serum glucose rises leading to osmotic diuresis. This diuresis leads to loss of electrolytes including sodium, magnesium, calcium and phosphorous. The resultant volume depletion leads to impaired glomerular filtration rate (GFR) and acute renal failure.
In patients with DKA, fatty acid breakdown produces 2 different ketone bodies, first acetoacetate, which then further converts to beta-hydroxybutyrate, the latter being the ketone body largely produced in DKA patients.
With this background in mind, let’s take a look at some urban legends in the management of DKA and the evidence that dispels these legends.
Here’s a case:
58 year old woman with DM I presents with nausea and vomiting Vitals: 121/72, 129, 95%, 97.8oF, BS > 388
Although this presentation may represent DKA, further testing is obtained to confirm the diagnosis. Often, the question arises as to whether an arterial or venous blood gas is adequate.
#1 – An ABG is not necessary for the diagnosis and treatment of DKA
- ABG gets you pH, PaO2, PaCO2, HCO3, Lactate, electrolytes and O2Sat
- VBG gets all this except for PaO2 (but we have pulse ox so this isn’t really an issue) – Question is, is it accurate?
There’s a lot of literature on the use of VBG instead of ABG.2-6 Here’s the summary:
- pH ABG – VBG: 0.03 – 0.05
- HCO3 ABG – VBG: – 1.5 – 2.0
- CO2 ABG – VBG: – 6 mm Hg
The Joint British Diabetes Society 2011 Guidelines endorse the use of VBG instead of ABG for initial assessment of acid/base status as well as continued monitoring during management.7
Bottom Line: VBG just as good as ABG in the diagnosis and management of DKA.
Let’s return to our patient. The VBG: 7.01, Bicarb 12, K = 3.6. IV fluids have been started and the nurse asks you if you can start the insulin drip.
#2 – Try and avoid Normal Saline
A common phenomenon observed when starting a DKA resuscitation with normal saline (NS) is worsening of the patient’s acidosis with decreasing bicarbonate levels (example below). This occurs despite an improvement in the anion gap, and is explained by a hyperchloremic metabolic acidosis caused by bolusing with NS. This could be a real problem for a patient whose initial bicarbonate level is extremely low.1
There is a randomized controlled trial comparing NS to LR for resuscitation in DKA (Zyl et al, 2011). These authors found a trend towards faster improvement in pH when using LR compared to NS (p = 0.076). They also found that patients in the NS group experienced a decrease in average serum bicarbonate during the first hour of treatment (from 8.86 to 8.21 mEq/L), whereas patients in the LR group experienced an increase in average serum bicarbonate during the first hour of treatment (from 7.71 mEq/L to 8.83 mEq/L). Although the authors concluded that this was a negative study, the data suggests an advantage of using LR in correcting the acidosis.
The Bottom Line: Normal saline induces a hyperchloremic acidosis which drops bicarbonate levels in the initial phase of DKA resuscitation, and is probably not the ideal fluid to use. LR is a better choice.2
#3 – After fluids, the next most critical step in treatment…
The pathophysiology in DKA involves osmotic diuresis and extensive electrolyte loss. Total body potassium can be severely depleted but extracellular potassium levels can be falsely reassuring as acidosis leads to shift of potassium out of cells. Regardless, hypokalemia is a critical cause of morbidity and mortality and should be immediately addressed.
Insulin administration can exacerbate serum hypokalemia by shifting potassium intracellularly. Thus, potassium replacement should always be considered prior to starting insulin. About 5-10% of patients with DKA will present with hypokalemia (K < 3.3 mEq/L).8 Insulin therapy should be held until a serum potassium > 3.5 mEq/L is documented. If the potassium is < 5.5 mEq/L but > 3.5 mEq/L, it’s safe to start both IV and PO (if patient tolerates) potassium repletion along with your insulin.
Potassium Replacement in DKA
- Sodium – Serum concentration diluted as a result of osmotic gradient of glucose pulling more water into extracellular space.
- Phosphate – If < 1.0 mEq/L, start repletion.
- Magnesium – All patients who are hypokalemic are hypomagnesemic. Replete together as long as kidney function is intact.
The Bottom Line: Electrolyte replacement, particularly potassium is more critical early in DKA management than insulin.
In addition to the severe hypokalemia, our patient is markedly acidemic. Guidelines recommend administration of bicarbonate when the pH falls below 7.1 or 7.0.9
#4 – Once the pH falls below 7.1/7.0, bicarbonate infusion is likely detrimental
A number of studies have retrospectively examined patients with DKA looking for differences in groups that got bicarbonate versus those that did not.10-12 Patients in these studies, some with pH as low as 6.9, had no benefit from bicarbonate therapy. In order for bicarbonate to increase the serum pH, the lungs have to blow off CO2. Patients with DKA are already maximally ventilating CO2 and are not able to increase this rate. Thus, the administration of bicarbonate does not significantly raise the serum pH. Additionally, there is harm to administration of bicarbonate as well. Bicarbonate administration delays the improvement of ketosis13 and worsens hypokalemia and intracellular acidosis.14
Bottom Line: There is no established role for administration of sodium bicarbonate to patients with DKA regardless of their pH.
Back to our patient… Bicarbonate therapy is held and repeat potassium comes back at 3.9 mEq/L. The insulin drip is ready to hang and the patient’s nurse asks you how much of a bolus you would like to give.
#5 – A bolus of insulin should not be given along with the infusion
Insulin is administered to stop ketosis and eventually, will aid in “closing the gap.” What we would like to do is to give insulin in a way that leads to near normal circulating levels of around 150 – 200 microunits/ml. Giving a bolus and infusion, however, leads to a high peak insulin level with a low plateau. With an infusion rate of around 0.14 units/kg, the patient will reach a steady plateau state that is near the normal circulating level.15
As far as outcomes, Goyal et al found no difference in glucose change or anion gap change in the patients who received a bolus of insulin followed by an infusion.16 Additionally, the bolus insulin group had longer lengths of stay and a 6-fold increase in hypoglycemic episodes (6% vs. 1%).
Bottom Line: Bolus insulin does not result in a more rapid improvement of the patient and is associated with more episodes of hypoglycemia and a longer length of stay.
#6– Avoid Intubation if Possible
When approaching a critically ill patient, securing the airway is often an initial consideration. However, in DKA this is fraught with hazard and often destabilizes the patient. With the exception of a patient who has truly developed respiratory muscle fatigue (and lost the ability to generate a compensatory respiratory alkalosis), intubation will typically worsen the patient.
First, the act of intubation is dangerous. Sick DKA patients typically have extremely low bicarbonate levels, for which they are compensating with a respiratory alkalosis (for example, consider a patient with bicarbonate of 2 mEq/L, PaCO215 mm, and pH 6.75). If there is difficulty intubating this patient and the PaCO2 rises to, say, 60mm then the pH will fall to 6.15. Approaches to mitigate this risk include attempting to mask-ventilate the patient in the peri-intubation period or awake intubation. It should be noted that DKA patients may develop gastroparesis and are at risk for aspiration. Even if the patient has an anatomically normal airway, the physiology of DKA makes this a dangerous procedure. This is a case of resuscitate and try not to intubate…
Second, if the patient was generating a reasonable compensatory alkalosis then the PaCO2 is usually higher on the ventilator than prior to intubation. The ET tube adds resistance to the respiratory circuit. If the patient is passive on the ventilator, the ventilator only provides active inhalation with passive exhalation (compared to the patient prior to intubation who was actively inhaling and exhaling). In practice it is generally impossible to achieve the same level of respiratory alkalosis on the ventilator than a strong non-intubated patient can generate.
For a patient with mental status alteration due to the DKA, it may be best to avoid intubation as long as the patient is protecting their airway (noting that traditional criteria to evaluate airway protection such as absence of a gag reflex or GCS scoring are not supported by evidence).4 If mental status changes are due to DKA, improvement often occurs rapidly. Ultimately this is a clinical decision which must be made at the bedside. If there is doubt, close observation and serial evaluation may be helpful.
#7– DKA is typically precipitated by other etiologies
Two of the most common causes of DKA are infection and inadequate insulin therapy. However, DKA can also be precipitated by several drug classes. Some of the common drug culprits and the mechanisms by which they can lead to DKA:
Corticosteroids (e.g.prednisone,hydrocortisone) Steroids are notorious for causing hyperglycemia and making it difficult to maintain good glucose control. They primarily increase post-prandial glucose levels via increased insulin resistance and can also increase hepatic gluconeogenesis – the creation of glucose from non-carbohydrate building blocks, such as fat or protein, a process that occurs in DKA.22 The risk increases with larger doses and a longer duration of use and can even be seen with use of topical steroids.23
Thiazide diuretics (e.g. hydrochlorothiazide, chlorthalidone) Thiazides are suspected to cause increased glucose intolerance through direct toxic effects on the pancreas and through their propensity to cause hypokalemia, which can lead to decreased insulin secretion.23 They can additionally increase hepatic glucose production and cause decreased insulin sensitivity. A higher dose may confer an increased risk. The risk of DKA is noted to be lower with loop diuretics
SGLT2 inhibitors (e.g. canagliflozin, empagliflozin) Sodium glucose cotransporter 2 inhibitors are a newer class of antihyperglycemic agents, so it may be counterintuitive that these agents can lead to DKA. However, they can cause a specific type of DKA known as “euglycemic ketoacidosis,” in which patients present with near normal plasma glucose levels, most likely due to their increase in urinary glucose excretion. The mechanism of precipitation of DKA is multifactorial and still somewhat unclear, but they may cause an increase in glucagon levels and retention of ketones.24 Additionally, when used in combination with insulin, the dose of insulin is usually lowered to prevent hypoglycemia. The resulting lower levels of circulating insulin may not be enough to suppress ketogenesis.
Atypical antipsychotics (olanzapine, clozapine) The mechanism by which these agents increase the risk of DKA is also somewhat unclear, but may be linked to their adverse effect of weight gain. This may occur through development of insulin resistance and altered leptin levels, which is a hormone usually responsible for appetite suppression and fat breakdown.22,25 The risk differs with each agent, but a higher risk has been noted with clozapine and olanzapine. The effects are reversible upon discontinuation of the drug.
When a patient presents with DKA, it’s important that, as pharmacists, we analyze a patient’s medication regimen to identify any medications that may have contributed to the development of DKA. It may be beneficial to switch to a different drug or drug class that has a lower risk of DKA in order to avoid hospital readmission and increased healthcare costs.
- VBG as good as ABG for diagnosis and treatment
- Aggressively replete potassium prior to starting insulin when clinically indicated
- Bicarbonate is unnecessary in DKA treatment and potentially harmful
- A bolus of insulin is unnecessary in DKA treatment and potentially harmful
- Avoid normal saline
- Avoid Intubation if possible
- Look for a precipitating etiology
Hijinio Carreon DO, FAAEM
- Lebovitz HE: Diabetic ketoacidosis. Lancet 1995; 345: 767-772.
- Brandenburg, Mark A, Dire, Daniel J: Comparison of Arterial and Venous Blood Gas Values in the Initial Emergency Department Evaluation of Patients with Diabetic Ketoacidosis. Annals of Emergency Medicine 1998; 31:4: 459-465.
- Gokel, Yuksel; Paydas, Saime; Koseoglu, Zikret; Alparslan, Nazan; Seydaoglu, Gulsah: Comparison of Blood Gas and Acid-Base Measurements in Arterial and Venous Blood Samples in Patients with Uremic Acidosis and Diabetic Ketoacidosis in the Emergency Room. American Journal of Nephrology 2000; 20:319-323.
- Malatesha G, Singh N, Bharija A, Rehani B, Goel A. Comparison of arterial and venous pH, bicarbonate, PCO2 and PO2 in initial emergency department assessment. Emergency Medicine Journal 2007. 24: 569-571.
- Middleton P, Kelly A-M, Brown J. Agreement between arterial and central venous values for pH, bicarbonate, base excess, and lactate. Emergency Medicine Journal 2006 23: 622-624.
- Ma JO, Rush MD, Godfrey MM, Gaddis G. Arterial blood gas results rarely influence emergency physician management of patients with suspected diabetic ketoacidosis. AEM 2003; 10: 836-41.
- Savage MW, Datary KK, Culvert A, Ryman G, Rees JA, Courtney CH, Hilton L, Dyer PH, Hamersley MS; Joint British Diabetes Societies. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabet Med. 2011 May;28(5):508-15.
- Aurora S, Cheng D, Wyler B, Menchine M. Prevalence of hypokalemia in ED patients with diabetic ketoacidosis. Am J Emerg Med 2012; 30: 481-4.
- Kitabchi AE, Umpierrez GE, Murphy MB et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabet Care 2006; 29 (2): 2739-2748.
- Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med. 1986;105(6):836.
- Duhon B, Attridge RL, Franco-Martinez AC, Maxwell PR, Hughes DW. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother 2013; 47: 970-5.
- Green SM, Rothrock SG, Ho JD et al. Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emergency Medicine 1998; 31: 41-48.
- Okuda Y, Drogue HJ, Field JB et al. Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. J Clinical Endocrinology Metabolism 1996; 81: 314-320.
- Villon A, Zuni F, Plafond P et al. Does bicarbonate therapy improve management of severe diabetic ketoacidosis? Crit Care Med 1999; 27: 2690-2693.
- Kitabchi AE, Murphy MB, Spencer J, Matteri R, Karas J, Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes Care. 2008;31(11):2081.
- Goyal N, Miller J, Sankey S, Mossallam U. Utility of Initial Bolus insulin in the treatment of diabetic ketoacidosis. Journal of Emergency Medicine, Vol 20:10, p30.
- Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes Care. 2009;32(7):1335-43.
- Rehman A, Setter SM, Vue MH. Drug-Induced Glucose Alterations Part 2: Drug-Induced Hyperglycemia. Diabetes Spectrum. 2011;24(4):234-8.
- Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Annals of Internal Medicine. 1993;118(7):529-39.
- Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. The Journal of Clinical Endocrinology & Metabolism. 2015;100(8):2849-52.
- Lean MEJ, Pajonk F-G. Patients on Atypical Antipsychotic Drugs. Another high-risk group for type 2 diabetes. 2003;26(5):1597-605.