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Hyperglycemic Emergencies in Adults

      Key Messages
      • Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) should be suspected in ill patients with diabetes. If either DKA or HHS is diagnosed, precipitating factors must be sought and treated.
      • DKA and HHS are medical emergencies that require treatment and monitoring for multiple metabolic abnormalities and vigilance for complications.
      • A normal blood glucose does not rule out DKA in pregnancy.
      • Ketoacidosis requires insulin administration (0.1 U/kg/h) for resolution; bicarbonate therapy should be considered only for extreme acidosis (pH ≤7.0).
      • Note to readers: Although the diagnosis and treatment of diabetic ketoacidosis (DKA) in adults and in children share general principles, there are significant differences in their application, largely related to the increased risk of life-threatening cerebral edema with DKA in children and adolescents. The specific issues related to treatment of DKA in children and adolescents are addressed in the Type 1 Diabetes in Children and Adolescents chapter, p. S153.

      Introduction

      Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are diabetes emergencies with overlapping features. With insulin deficiency, hyperglycemia causes urinary losses of water and electrolytes (sodium, potassium, chloride) and the resultant extracellular fluid volume (ECFV) depletion. Potassium is shifted out of cells, and ketoacidosis occurs as a result of elevated glucagon levels and absolute insulin deficiency (in the case of type 1 diabetes) or high catecholamine levels suppressing insulin release (in the case of type 2 diabetes). In DKA, ketoacidosis is prominent, while in HHS, the main features are ECFV depletion and hyperosmolarity.
      Risk factors for DKA include new diagnosis of diabetes mellitus, insulin omission, infection, myocardial infarction, abdominal crisis, trauma and, possibly, treatment with insulin infusion pumps, thyrotoxicosis, cocaine, atypical antipsychotics and, possibly, interferon. HHS is much less common than DKA (
      • Hamblin P.S.
      • Topliss D.J.
      • Chosich N.
      • et al.
      Deaths associated with diabetic ketoacidosis and hyperosmolar coma, 1973-1988.
      ,
      • Holman R.C.
      • Herron C.A.
      • Sinnock P.
      Epidemiologic characteristics of mortality from diabetes with acidosis or coma, United States, 1970-78.
      ). In addition to the precipitating factors noted above for DKA, HHS also has been reported following cardiac surgery and with the use of certain drugs, including diuretics, glucocorticoids, lithium and atypical antipsychotics.
      The clinical presentation of DKA includes symptoms of hyperglycemia, Kussmaul respiration, acetone-odoured breath, ECFV contraction, nausea, vomiting and abdominal pain. There also may be a decreased level of consciousness. In HHS, there is often more profound ECFV contraction and decreased level of consciousness (proportional to the elevation in plasma osmolality). In addition, in HHS, there can be a variety of neurological presentations, including seizures and a stroke-like state that can resolve once osmolality returns to normal (
      • Holman R.C.
      • Herron C.A.
      • Sinnock P.
      Epidemiologic characteristics of mortality from diabetes with acidosis or coma, United States, 1970-78.
      ,
      • Wachtel T.J.
      • Tetu-Mouradjian L.M.
      • Goldman D.L.
      • et al.
      Hyperosmolarity and acidosis in diabetes mellitus: a three year experience in Rhode Island.
      ,
      • Malone M.L.
      • Gennis B.
      • Goodwin J.S.
      Characteristics of diabetic ketoacidosis in older versus younger adults.
      ). In both conditions, there also may be evidence of a precipitating condition.

      Prevention

      Sick day management that includes capillary beta-hydroxybutyrate monitoring reduces emergency room visits and hospitalizations in young people (
      • Laffel L.M.
      • Wentzell K.
      • Loughlin C.
      • et al.
      Sick day management using blood 3-hydroxybutyrate (3-OHB) compared with urine ketone monitoring reduces hospital visits in young people with T1DM: a randomized clinical trial.
      ).

      Diagnosis

      DKA or HHS should be suspected whenever patients have significant hyperglycemia, especially if they are ill or highly symptomatic (see above). As outlined in Figure 1, to make the diagnosis and determine the severity of DKA or HHS, the following should be assessed: plasma levels of electrolytes (and anion gap), glucose, creatinine, osmolality and beta-hydroxybutyric acid (beta-OHB) (if available), blood gases, serum and urine ketones, fluid balance, level of consciousness, precipitating factors and complications (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ). Arterial blood gases may be required for sicker patients, when knowing the adequacy of respiratory compensation and the A-gradient is necessary. Otherwise, venous blood gases are usually adequate—the pH is typically 0.015 to 0.03 lower than arterial pH (
      • Malatesha G.
      • Singh N.K.
      • Bharija A.
      • et al.
      Comparison of arterial and venous pH, bicarbonate, PCO2 in initial emergency department assessment.
      ,
      • Brandenburg M.A.
      • Dire D.J.
      Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis.
      ,
      • Ma O.J.
      • Rush M.D.
      • Godfrey M.M.
      • Gaddis G.
      Arterial blood gas results rarely influence emergency physician management of patients with suspected diabetic ketoacidosis academic.
      ).
      Figure thumbnail gr1
      Figure 1Management of diabetic ketoacidosis (DKA) in adults.Anion gap = Plasma [Na+] – Plasma [Cl] – Plasma [HCO3]. Corrected plasma [Na+] = Measured [Na+] + [3/10 × ([Glucose (mmol/L)] − 5)]. Effective plasma osmolality = ([Na+] × 2) + [Glucose (mmol/L)] + [Urea (mmol/L)] reported as mmol/kg. Beta-OHB, beta-hydroxybutyric acid; ECFV, extracellular fluid volume; IV, intravenous.
      Point-of-care capillary blood beta-hydroxybutyrate measurement in emergency is sensitive and specific for DKA and, as a screening tool, may allow more rapid identification of hyperglycemic patients at risk for DKA (
      • Charles R.A.
      • Bee Y.M.
      • Eng P.H.
      • Goh S.Y.
      Point-of-care blood ketone testing: screening for diabetic ketoacidosis at the emergency department.
      ,
      • Naunheim R.
      • Jang T.J.
      • Banet G.
      • et al.
      Point-of-care test identifies diabetic ketoacidosis at triage.
      ,
      • Sefedini E.
      • Prasek M.
      • Metelko Z.
      • et al.
      Use of capillary beta-hydroxybutyrate for the diagnosis of diabetic ketoacidosis at emergency room: Our one-year experience.
      ,
      • MacKay L.
      • Lyall M.J.
      • Delaney S.
      • et al.
      Are blood ketones a better predictor than urine ketones of acid base balance in diabetic ketoacidosis?.
      ,
      • Bektas F.
      • Eray O.
      • Sari R.
      • Akbas H.
      Point of care blood ketone testing of diabetic patients in the emergency department.
      ,
      • Harris S.
      • Ng R.
      • Syed H.
      • Hillson R.
      Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis.
      ).
      There are no definitive criteria for the diagnosis of DKA. Typically, the arterial pH is ≤7.3, serum bicarbonate is ≤15 mmol/L, and the anion gap is >12 mmol/L with positive serum and/or urine ketones (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ,
      • Lebovitz H.E.
      Diabetic ketoacidosis.
      ). Plasma glucose is usually ≥14.0 mmol/L but can be lower (
      • Munro J.F.
      • Campbell I.W.
      • McCuish A.C.
      • et al.
      Euglycemic diabetic ketoacidosis.
      ). DKA is more challenging to diagnose in the presence of the following conditions: 1) mixed acid-base disorders (e.g. associated vomiting, which will raise the bicarbonate level); 2) if there has been a shift in the redox potential favouring the presence of beta-OHB (rendering serum ketone testing negative); or 3) if the loss of keto anions with sodium or potassium in osmotic diuresis has occurred, leading to a return of the plasma anion gap toward normal. It is, therefore, important to measure ketones in both the serum and urine. If there is an elevated anion gap and serum ketones are negative, beta-OHB levels should be measured. Measurement of serum lactate should be considered in hypoxic states. In HHS, a more prolonged duration of relative insulin insufficiency and inadequate fluid intake (or high glucose intake) results in higher glucose levels (typically ≥34.0 mmol/L) and greater ECFV contraction, but minimal acid-base disturbance (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ).
      Pregnant women in DKA typically present with lower glucose levels than nonpregnant women (
      • Guo R.X.
      • Yang L.Z.
      • Li L.X.
      • Zhao X.P.
      Diabetic ketoacidosis in pregnancy tends to occur at lower blood glucose levels: case-control study and a case report of euglycemic diabetic ketoacidosis in pregnancy.
      ), and there are case reports of euglycemic DKA in pregnancy (
      • Oliver R.
      • Jagadeesan P.
      • Howard R.J.
      • Nikookam K.
      Euglycaemic diabetic ketoacidosis in pregnancy: an unusual presentation.
      ,
      • Chico A.
      • Saigi I.
      • Garcia-Patterson A.
      • et al.
      Glycemic control and perinatal outcomes of pregnancies complicated by type 1 diabetes: Influence of continuous subcutaneous insulin infusion and lispro insulin.
      ).

      Management

      Objectives of management include restoration of normal ECFV and tissue perfusion; resolution of ketoacidosis; correction of electrolyte imbalances and hyperglycemia; and the diagnosis and treatment of coexistent illness. The issues that must be addressed in the patient presenting with DKA or HHS are outlined in Table 1. A summary of fluid therapy is outlined in Table 2, and a management algorithm and formulas for calculating key measurements are provided in Figure 1.
      Table 1Priorities
      Severity of issue will dictate priority of action.
      to be addressed in the management of patients presenting with hyperglycemic emergencies
      MetabolicPrecipitating cause of DKA/HHSOther complications of DKA/HHS
      • ECFV contraction
      • Potassium deficit and abnormal concentration
      • Metabolic acidosis
      • Hyperosmolality (water deficit leading to increased corrected sodium concentration plus hyperglycemia)
      • New diagnosis of diabetes
      • Insulin omission
      • Infection
      • Myocardial infarction
      • ECG changes may reflect hyperkalemia
        • Bellazzini M.A.
        • Meyer T.
        Pseudo-myocardial infarction in diabetic ketoacidosis with hyperkalemia.
        ,
        • Petrov D.
        • Petrov M.
        Widening of the QRS complex due to severe hyperkalemia as an acute complication of diabetic ketoacidosis.
      • A small increase in troponin may occur without overt ischemia
        • Geddes J.
        • Deans K.A.
        • Cormack A.
        • et al.
        Cardiac troponin I concentrations in people presenting with diabetic ketoacidosis.
      • Thyrotoxicosis
        • Talapatra I.
        • Tymms D.J.
        Diabetic ketoacidosis precipitated by subacute (De Quervain's) thyroiditis.
      • Drugs
      • Hyper/hypokalemia
      • ECFV overexpansion
      • Cerebral edema
      • Hypoglycemia
      • Pulmonary emboli
      • Aspiration
      • Hypocalcemia (if phosphate used)
      • Stroke
      • Acute renal failure
      • Deep vein thrombosis
      ECFV, extracellular fluid volume; ECG, electrocardiographic; DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state.
      Severity of issue will dictate priority of action.
      Table 2Summary of fluid therapy for DKA and HHS in adults
      • 1.
        Administer IV normal saline initially. If the patient is in shock, give 1–2 L/h initially to correct shock; otherwise, give 500 mL/h for 4 hours, then 250 mL/h for 4 hours.
      • 2.
        Add potassium immediately if patient is normo- or hypokalemic. Otherwise, if initially hyperkalemic, only add potassium once serum potassium falls to <5 to 5.5 mmol/L and patient is diuresing.
      • 3.
        Once plasma glucose reaches 14.0 mmol/L, add glucose to maintain plasma glucose at 12.0–14.0 mmol/L.
      • 4.
        After hypotension has been corrected, switch normal saline to half-normal saline (with potassium chloride). However, if plasma osmolality is falling more rapidly than 3 mmol/kg/h and/or the corrected plasma sodium is reduced, maintain IV fluids at higher osmolality (i.e. may need to maintain on normal saline).
      DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; IV, intravenous.
      Patients with DKA and HHS are best managed in an intensive care unit or step-down setting (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ,
      • Lebovitz H.E.
      Diabetic ketoacidosis.
      ) with specialist care (
      • May M.E.
      • Young C.
      • King J.
      Resource utilization in treatment of diabetic ketoacidosis in adults.
      ,
      • Levetan C.S.
      • Jablonski K.A.
      • Passaro M.D.
      • et al.
      Effect of physician specialty on outcomes in diabetic ketoacidosis.
      ). Protocols, when followed, may be beneficial (
      • Bull S.V.
      • Douglas I.S.
      • Foster M.
      • Albert R.K.
      Mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care unit and hospital lengths of stay: results of a nonrandomized trial.
      ,
      • Waller S.L.
      • Delaney S.
      • Strachan M.W.
      Does an integrated care pathway enhance the management of diabetic ketoacidosis?.
      ), but there can be challenges with achieving adherence (
      • Devalia B.
      Adherence to protocol during the acute management of diabetic ketoacidosis: would specialist involvement lead to better outcomes?.
      ,
      • Salahuddin M.
      • Anwar M.N.
      Study on effectiveness of guidelines and high dependency unit management on diabetic ketoacidosis patients.
      ). Volume status (including fluid intake and output), vital signs, neurological status, plasma concentrations of electrolytes, anion gap, osmolality and glucose need to be monitored closely, initially as often as every 2 hours (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ,
      • Lebovitz H.E.
      Diabetic ketoacidosis.
      ). Precipitating factors must be diagnosed and treated (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ,
      • Lebovitz H.E.
      Diabetic ketoacidosis.
      ).

      ECFV contraction

      The sodium deficit is typically 7-10 mmol/kg in DKA (
      • Kreisberg R.A.
      Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment.
      ) and 5 to 13 mmol/kg in HHS (
      • Ennis E.D.
      • Stahl E.J.
      • Kreisberg R.A.
      The hyperosmolar hyperglycemic syndrome.
      ), which, along with water losses (100 mL/kg and 100 to 200 mL/kg, respectively), results in decreased ECFV, usually with decreased intracellular fluid volume (
      • Kreisberg R.A.
      Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment.
      ,
      • Ennis E.D.
      • Stahl E.J.
      • Kreisberg R.A.
      The hyperosmolar hyperglycemic syndrome.
      ). Restoring ECFV improves tissue perfusion and reduces plasma glucose levels both by dilution and by increasing urinary glucose losses. ECFV re-expansion, using a rapid rate of initial fluid administration, was associated with an increased risk of cerebral edema (CE) in 1 study (
      • Mahoney C.P.
      • Vlcek B.W.
      • DelAguila M.
      Risk factors for developing brain herniation during diabetic ketoacidosis.
      ) but not in another (
      • Rosenbloom A.L.
      Intracerebral crises during treatment of diabetic ketoacidosis.
      ). In adults, one should initially administer intravenous (IV) normal saline 1 to 2 L/h to correct shock, otherwise 500 mL/h for 4 hours, then 250 mL/h of IV fluids (
      • Adrogue H.J.
      • Barrero J.
      • Eknoyan G.
      Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis.
      ,
      • Fein I.A.
      • Rackow E.C.
      • Sprung C.L.
      • et al.
      Relation of colloid osmotic pressure to arterial hypoxemia and cerebral edema during crystalloid volume loading of patients with diabetic ketoacidosis.
      ).

      Potassium deficit

      The typical potassium deficit range is 2 to 5 mmol/kg in DKA and 4 to 6 mmol/kg in HHS (
      • Ennis E.D.
      • Stahl E.J.
      • Kreisberg R.A.
      The hyperosmolar hyperglycemic syndrome.
      ,
      • Mahoney C.P.
      • Vlcek B.W.
      • DelAguila M.
      Risk factors for developing brain herniation during diabetic ketoacidosis.
      ). There have been no randomized trials that have studied strategies for potassium replacement. Typical recommendations suggest that potassium supplementation should be started for plasma potassium <5.0 to 5.5 mmol/L once diuresis has been established, usually with the second litre of saline. If the patient at presentation is normo- or hypokalemic, potassium should be given immediately, at concentrations in the IV fluid between 10 and 40 mmol/L, at a maximum rate of 40 mmol/h. In the case of frank hypokalemia (potassium <3.3 mmol/L), insulin should be withheld until potassium replacement at 40 mmol/h has restored plasma potassium to ≥3.3 mmol/L (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ). It is reasonable to treat the potassium deficit of HHS in the same way.

      Metabolic acidosis

      Metabolic acidosis is a prominent component of DKA. Patients with HHS have minimal or no acidosis. Insulin is used to stop ketoacid production; IV fluid alone has no impact on parameters of ketoacidosis (
      • Owen O.E.
      • Licht J.H.
      • Sapir D.G.
      Renal function and effects of partial rehydration during diabetic ketoacidosis.
      ). Short-acting insulin (0.1 U/kg/h) is recommended (
      • Kitabchi A.E.
      • Ayyagari V.
      • Guerra S.M.
      • et al.
      The efficacy of low dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis.
      ,
      • Heber D.
      • Molitch M.E.
      • Sperling M.A.
      Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with “conventional” insulin therapy.
      ,
      • Butkiewicz E.K.
      • Leibson C.L.
      • O'Brien P.C.
      • et al.
      Insulin therapy for diabetic ketoacidosis. Bolus insulin injection versus continuous insulin infusion.
      ). Although the use of an initial bolus of IV insulin is recommended in some reviews (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ), there has been only 1 randomized controlled trial (RCT) in adults examining the effectiveness of this step (
      • Kitabchi A.E.
      • Murphy M.B.
      • Spencer J.
      • et al.
      Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis?.
      ). In this study, there were 3 arms: a bolus arm (0.07 units/kg, then 0.07 units/kg/h), a low-dose infusion group (no bolus, 0.07 units/kg/h), and a double-dose infusion group (no bolus, 0.14 units/kg/h). Outcomes were identical in the 3 groups, except 5 of 12 patients needed extra insulin in the no-bolus/low-dose infusion group, and the double dose group had the lowest potassium (nadir of 3.7 mmol/L on average). Unfortunately, this study did not examine the standard dose of insulin in DKA (0.1 units/kg/h). In children, using an initial bolus of IV insulin does not result in faster resolution of ketoacidosis (
      • Fort P.
      • Waters S.M.
      • Lifshitz F.
      Low-dose insulin infusion in the treatment of diabetic ketoacidosis: bolus versus no bolus.
      ,
      • Lindsay R.
      • Bolte R.G.
      The use of an insulin bolus in low-dose insulin infusion for pediatric diabetic ketoacidosis.
      ) and increases the risk of CE. The use of subcutaneous boluses of rapid-acting insulin analogues at 1- to 2-hour intervals results in similar duration of ketoacidosis with no more frequent occurrence of hypoglycemia compared to short-acting IV insulin 0.1 U/kg/h (
      • Della Manna T.
      • Steinmetz L.
      • Campos P.R.
      • et al.
      Subcutaneous use of a fast-acting insulin analog: an alternative treatment for pediatric patients with diabetic ketoacidosis.
      ,
      • Umpierrez G.E.
      • Latif K.
      • Stoever J.
      • et al.
      Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis.
      ,
      • Umpierrez G.E.
      • Cuervo R.
      • Karabell A.
      • et al.
      Treatment of diabetic ketoacidosis with subcutaneous insulin aspart.
      ). The dose of insulin should subsequently be adjusted based on ongoing acidosis (
      • Wiggam M.I.
      • O'Kane M.J.
      • Harper R.
      • et al.
      Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management.
      ), using the plasma anion gap or beta-OHB measurements. Plasma glucose levels will fall due to multiple mechanisms, including ECFV re-expansion (
      • Waldhäusl W.
      • Kleinberger G.
      • Korn A.
      • et al.
      Severe hyperglycemia: effects of rehydration on endocrine derangements and blood glucose concentration.
      ), glucose losses via osmotic diuresis (
      • Owen O.E.
      • Licht J.H.
      • Sapir D.G.
      Renal function and effects of partial rehydration during diabetic ketoacidosis.
      ), insulin-mediated reduced glucose production and increased cellular uptake of glucose. Once plasma glucose reaches 14.0 mmol/L, IV glucose should be started to prevent hypoglycemia, targeting a plasma glucose of 12.0 to 14.0 mmol/L.
      Similar doses of IV insulin can be used to treat HHS, although subjects are not acidemic, and the fall in plasma glucose concentration is predominantly due to re-expansion of ECFV and osmotic diuresis (
      • Waldhäusl W.
      • Kleinberger G.
      • Korn A.
      • et al.
      Severe hyperglycemia: effects of rehydration on endocrine derangements and blood glucose concentration.
      ). Insulin has been withheld successfully in HHS (
      • Gerich J.E.
      • Martin M.M.
      • Recant L.L.
      Clinical and metabolic characteristics of hyperosmolar nonketotic coma.
      ), but generally its use is recommended to reduce plasma glucose levels (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ).
      Use of IV sodium bicarbonate to treat acidosis did not affect outcome in RCTs (
      • Morris L.R.
      • Murphy M.B.
      • Kitabchi A.E.
      Bicarbonate therapy in severe diabetic ketoacidosis.
      ,
      • Gamba G.
      • Oseguera J.
      • Castrejon M.
      • et al.
      Bicarbonate therapy in severe diabetic ketoacidosis: a double blind, randomized placebo controlled trial.
      ,
      • Hale P.J.
      • Crase J.
      • Nattrass M.
      Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis.
      ). Sodium bicarbonate therapy can be considered in adult patients in shock or with arterial pH ≤7.0. For example, one can administer 1 ampoule (50 mmol) sodium bicarbonate added to 200 mL D5W (or sterile water, if available) over 1 hour, repeated every 1 to 2 hours until pH is ≥7.0 (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ). Potential risks associated with the use of sodium bicarbonate include hypokalemia (
      • Soler N.G.
      • Bennet M.A.
      • Dixon K.
      • et al.
      Potassium balance during treatment of diabetic ketoacidosis with special reference to the use of bicarbonate.
      ) and delayed occurrence of metabolic alkalosis.

      Hyperosmolality

      Hyperosmolality is due to hyperglycemia and a water deficit. However, serum sodium concentration may be reduced due to shift of water out of cells. The concentration of sodium needs to be corrected for the level of glycemia to determine if there is also a water deficit (Figure 1). In patients with DKA, plasma osmolality is usually ≤320 mmol/kg. In HHS, plasma osmolality is typically >320 mmol/kg. Because of the risk of CE with rapid reductions in osmolality (
      • Carlotti A.P.
      • Bohn D.
      • Mallie J.P.
      • et al.
      Tonicity balance, and not electrolyte-free water calculations, more accurately guides therapy for acute changes in natremia.
      ), it has been recommended that the plasma osmolality be lowered no faster than 3 mmol/kg/h (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ). This can be achieved by monitoring plasma osmolality, by adding glucose to the infusions when plasma glucose reaches 14.0 mmol/L to maintain it at that level and by selecting the correct concentration of IV saline. Typically, after volume re-expansion, IV fluid is switched to half-normal saline because urinary losses of electrolytes in the setting of osmotic diuresis are usually hypotonic. The potassium in the infusion will also add to the osmolality. If osmolality falls too rapidly despite the administration of glucose, consideration should be given to increasing the sodium concentration of the infusing solution (
      • Kitabchi A.E.
      • Umpierrez G.E.
      • Murphy M.B.
      • et al.
      Management of hyperglycemic crises in patients with diabetes.
      ,
      • Chiasson J.L.
      • Aris-Jilwan N.
      • Belanger R.
      • et al.
      Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
      ). Water imbalances can also be monitored using the corrected plasma sodium. Central pontine myelinolysis has been reported in association with overly rapid correction of hyponatremia in HHS (
      • O'Malley G.
      • Moran C.
      • Draman M.S.
      • et al.
      Central pontine myelinolysis complicating treatment of the hyperglycaemic hyperosmolar state.
      ).

      Phosphate deficiency

      There is currently no evidence to support the use of phosphate therapy for DKA (
      • Keller U.
      • Berger W.
      Prevention of hypophosphatemia by phosphate infusion during treatment of diabetic ketoacidosis and hyperosmolar coma.
      ,
      • Wilson H.K.
      • Keuer S.P.
      • Lea A.S.
      • et al.
      Phosphate therapy in diabetic ketoacidosis.
      ,
      • Fisher J.N.
      • Kitabchi A.E.
      A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis.
      ), and there is no evidence that hypophosphatemia causes rhabdomyolysis in DKA (
      • Singhal P.C.
      • Abromovici M.
      • Ayer S.
      • et al.
      Determinants of rhabdomyolysis in the diabetic state.
      ). However, because hypophosphatemia has been associated with rhabdomyolysis in other states, administration of potassium phosphate in cases of severe hypophosphatemia may be considered for the purpose of trying to prevent rhabdomyolysis.

      Complications

      In Ontario, in-hospital mortality in patients hospitalized for acute hyperglycemia ranged from <1% at ages 20 to 49 years to 16% in those over 75 years (
      • Booth G.L.
      • Fang J.
      Acute complications of diabetes.
      ). Reported mortality in DKA ranges from 0.65% to 3.3% (
      • Holman R.C.
      • Herron C.A.
      • Sinnock P.
      Epidemiologic characteristics of mortality from diabetes with acidosis or coma, United States, 1970-78.
      ,
      • May M.E.
      • Young C.
      • King J.
      Resource utilization in treatment of diabetic ketoacidosis in adults.
      ,
      • Bagg W.
      • Sathu A.
      • Streat S.
      • et al.
      Diabetic ketoacidosis in adults at Auckland Hospital, 1988-1996.
      ,
      • Umpierrez G.E.
      • Kelly J.P.
      • Navarrete J.E.
      • et al.
      Hyperglycemic crises in urban blacks.
      ,
      • Musey V.C.
      • Lee J.K.
      • Crawford R.
      • et al.
      Diabetes in urban African-Americans. I. Cessation of insulin therapy is the major precipitating cause of diabetic ketoacidosis.
      ). In HHS, recent studies found mortality rates to be 12% to 17%, but included patients with mixed DKA and hyperosmolality (
      • Hamblin P.S.
      • Topliss D.J.
      • Chosich N.
      • et al.
      Deaths associated with diabetic ketoacidosis and hyperosmolar coma, 1973-1988.
      ,
      • Wachtel T.J.
      • Tetu-Mouradjian L.M.
      • Goldman D.L.
      • et al.
      Hyperosmolarity and acidosis in diabetes mellitus: a three year experience in Rhode Island.
      ,
      • Wachtel T.J.
      • Silliman R.A.
      • Lamberton P.
      Predisposing factors for the diabetic hyperosmolar state.
      ). About 50% of deaths occur in the first 48 to 72 hours. Mortality is usually due to the precipitating cause, electrolyte imbalances (especially hypo- and hyperkalemia) and CE.
      Recommendations
      • 1.
        In adult patients with DKA, a protocol should be followed that incorporates the following principles of treatment: 1) fluid resuscitation, 2) avoidance of hypokalemia, 3) insulin administration, 4) avoidance of rapidly falling serum osmolality, and 5) search for precipitating cause (as illustrated in Figure 1) [Grade D, Consensus].
      • 2.
        In adult patients with HHS, a protocol should be followed that incorporates the following principles of treatment: 1) fluid resuscitation, 2) avoidance of hypokalemia, 3) avoidance of rapidly falling serum osmolality, 4) search for precipitating cause, and 5) possibly insulin to further reduce hyperglycemia (as illustrated in Figure 1) [Grade D, Consensus].
      • 3.
        Point-of-care capillary beta-hydroxybutyrate may be measured in the hospital in patients with type 1 diabetes with capillary glucose >14.0 mmol/L to screen for DKA, and a beta-hydroxybutyrate >1.5 mmol/L warrants further testing for DKA [Grade B, Level 2 (
        • Charles R.A.
        • Bee Y.M.
        • Eng P.H.
        • Goh S.Y.
        Point-of-care blood ketone testing: screening for diabetic ketoacidosis at the emergency department.
        ,
        • Naunheim R.
        • Jang T.J.
        • Banet G.
        • et al.
        Point-of-care test identifies diabetic ketoacidosis at triage.
        ,
        • Sefedini E.
        • Prasek M.
        • Metelko Z.
        • et al.
        Use of capillary beta-hydroxybutyrate for the diagnosis of diabetic ketoacidosis at emergency room: Our one-year experience.
        ,
        • MacKay L.
        • Lyall M.J.
        • Delaney S.
        • et al.
        Are blood ketones a better predictor than urine ketones of acid base balance in diabetic ketoacidosis?.
        ,
        • Bektas F.
        • Eray O.
        • Sari R.
        • Akbas H.
        Point of care blood ketone testing of diabetic patients in the emergency department.
        ,
        • Harris S.
        • Ng R.
        • Syed H.
        • Hillson R.
        Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis.
        )].
      • 4.
        In individuals with DKA, IV 0.9% sodium chloride should be administered initially at 500 mL/h for 4 hours, then 250 mL/h for 4 hours [Grade B, Level 2 (
        • Adrogue H.J.
        • Barrero J.
        • Eknoyan G.
        Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis.
        )] with consideration of a higher initial rate (1–2 L/h) in the presence of shock [Grade D, Consensus]. For persons with a HHS, IV fluid administration should be individualized based on the patient's needs [Grade D, Consensus].
      • 5.
        In individuals with DKA, an infusion of short-acting IV insulin of 0.10 U/kg/h should be used ([Grade B, Level 2 (
        • Heber D.
        • Molitch M.E.
        • Sperling M.A.
        Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with “conventional” insulin therapy.
        ,
        • Butkiewicz E.K.
        • Leibson C.L.
        • O'Brien P.C.
        • et al.
        Insulin therapy for diabetic ketoacidosis. Bolus insulin injection versus continuous insulin infusion.
        )]. The insulin infusion rate should be maintained until the resolution of ketosis [Grade B, Level 2 (
        • Umpierrez G.E.
        • Latif K.
        • Stoever J.
        • et al.
        Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis.
        )] as measured by the normalization of the plasma anion gap [Grade D, Consensus]. Once the plasma glucose concentration reaches 14.0 mmol/L, IV dextrose should be started to avoid hypoglycemia [Grade D, Consensus].
      • Abbreviations:
        DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; IV, intravenous.

      Other Relevant Guidelines

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