Hyperglycemic Emergencies in Adults

Abstract

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. •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. 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 (1Hamblin P.S. Topliss D.J. Chosich N. et al.Deaths associated with diabetic ketoacidosis and hyperosmolar coma, 1973-1988.Med J Aust. 1989; 151: 439-444PubMed Google Scholar, 2Holman R.C. Herron C.A. Sinnock P. Epidemiologic characteristics of mortality from diabetes with acidosis or coma, United States, 1970-78.Am J Public Health. 1983; 73: 1169-1173Crossref PubMed Scopus (18) Google Scholar). 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 (2Holman R.C. Herron C.A. Sinnock P. Epidemiologic characteristics of mortality from diabetes with acidosis or coma, United States, 1970-78.Am J Public Health. 1983; 73: 1169-1173Crossref PubMed Scopus (18) Google Scholar, 3Wachtel T.J. Tetu-Mouradjian L.M. Goldman D.L. et al.Hyperosmolarity and acidosis in diabetes mellitus: a three year experience in Rhode Island.J Gen Med. 1991; 6: 495-502Google Scholar, 4Malone M.L. Gennis B. Goodwin J.S. Characteristics of diabetic ketoacidosis in older versus younger adults.J Am Geriatr Soc. 1992; 40: 1100-1104Crossref PubMed Scopus (111) Google Scholar). In both conditions, there also may be evidence of a precipitating condition. Sick day management that includes capillary beta-hydroxybutyrate monitoring reduces emergency room visits and hospitalizations in young people (5Laffel 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.Diabet Med. 2006; 23: 278-284Crossref PubMed Scopus (118) Google Scholar). 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar). 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 (7Malatesha G. Singh N.K. Bharija A. et al.Comparison of arterial and venous pH, bicarbonate, PCO2 in initial emergency department assessment.Emerg Med J. 2007; 24: 569-571Crossref PubMed Scopus (103) Google Scholar, 8Brandenburg M.A. Dire D.J. Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis.Ann Emerg Med. 1998; 31: 459-465Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 9Ma 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.Emerg Med. 2003; 10: 836-841Google Scholar). 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 (10Charles 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.Singapore Med J. 2007; 48: 986-989PubMed Google Scholar, 11Naunheim R. Jang T.J. Banet G. et al.Point-of-care test identifies diabetic ketoacidosis at triage.Acad Emerg Med. 2006; 13: 683-685Crossref PubMed Google Scholar, 12Sefedini 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.Diabetol Croat. 2008; 37: 73-78Google Scholar, 13MacKay L. Lyall M.J. Delaney S. et al.Are blood ketones a better predictor than urine ketones of acid base balance in diabetic ketoacidosis?.Pract Diabetes Int. 2010; 27: 396-399Crossref Scopus (9) Google Scholar, 14Bektas F. Eray O. Sari R. Akbas H. Point of care blood ketone testing of diabetic patients in the emergency department.Endocr Res. 2004; 30: 395-402Crossref PubMed Scopus (48) Google Scholar, 15Harris S. Ng R. Syed H. Hillson R. Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis.Diabet Med. 2004; 22: 221-224Crossref Scopus (41) Google Scholar). 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar, 17Lebovitz H.E. Diabetic ketoacidosis.Lancet. 1995; 345: 767-772Abstract PubMed Google Scholar). Plasma glucose is usually ≥14.0 mmol/L but can be lower (18Munro J.F. Campbell I.W. McCuish A.C. et al.Euglycemic diabetic ketoacidosis.BMJ. 1973; 2: 578-580Crossref PubMed Scopus (177) Google Scholar). 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar). Pregnant women in DKA typically present with lower glucose levels than nonpregnant women (19Guo 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.J Obstet Gynaecol Res. 2008; 34: 324-330Crossref PubMed Scopus (60) Google Scholar), and there are case reports of euglycemic DKA in pregnancy (20Oliver R. Jagadeesan P. Howard R.J. Nikookam K. Euglycaemic diabetic ketoacidosis in pregnancy: an unusual presentation.J Obstet Gynaecol. 2007; 27: 308Crossref PubMed Scopus (9) Google Scholar, 21Chico 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.Diabetes Technol Ther. 2010; 12: 937-945Crossref PubMed Scopus (32) Google Scholar). 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 emergenciesMetabolicPrecipitating 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 57Bellazzini M.A. Meyer T. Pseudo-myocardial infarction in diabetic ketoacidosis with hyperkalemia.J Emerg Med. 2010; 39: e139-e141Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 58Petrov D. Petrov M. Widening of the QRS complex due to severe hyperkalemia as an acute complication of diabetic ketoacidosis.J Emerg Med. 2008; 34: 459-461Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar•A small increase in troponin may occur without overt ischemia 59Geddes J. Deans K.A. Cormack A. et al.Cardiac troponin I concentrations in people presenting with diabetic ketoacidosis.Ann Clin Biochem. 2007; 44: 391-393Crossref PubMed Scopus (13) Google Scholar•Thyrotoxicosis 60Talapatra I. Tymms D.J. Diabetic ketoacidosis precipitated by subacute (De Quervain's) thyroiditis.Pract Diabetes Int. 2006; 23: 76-77Crossref Scopus (3) Google Scholar•Drugs•Hyper/hypokalemia•ECFV overexpansion•Cerebral edema•Hypoglycemia•Pulmonary emboli•Aspiration•Hypocalcemia (if phosphate used)•Stroke•Acute renal failure•Deep vein thrombosisECFV, extracellular fluid volume; ECG, electrocardiographic; DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state.∗ Severity of issue will dictate priority of action. Open table in a new tab Table 2Summary of fluid therapy for DKA and HHS in adults1.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. Open table in a new tab ECFV, extracellular fluid volume; ECG, electrocardiographic; DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state. 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar, 17Lebovitz H.E. Diabetic ketoacidosis.Lancet. 1995; 345: 767-772Abstract PubMed Google Scholar) with specialist care (22May M.E. Young C. King J. Resource utilization in treatment of diabetic ketoacidosis in adults.Am J Med Sci. 1993; 306: 287-294Crossref PubMed Scopus (41) Google Scholar, 23Levetan C.S. Jablonski K.A. Passaro M.D. et al.Effect of physician specialty on outcomes in diabetic ketoacidosis.Diabetes Care. 1999; 22: 1790-1795Crossref PubMed Scopus (98) Google Scholar). Protocols, when followed, may be beneficial (24Bull 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.Crit Care Med. 2007; 35: 41-46Crossref PubMed Scopus (80) Google Scholar, 25Waller S.L. Delaney S. Strachan M.W. Does an integrated care pathway enhance the management of diabetic ketoacidosis?.Diabet Med. 2007; 24: 359-363Crossref PubMed Scopus (29) Google Scholar), but there can be challenges with achieving adherence (26Devalia B. Adherence to protocol during the acute management of diabetic ketoacidosis: would specialist involvement lead to better outcomes?.Int J Clin Pract. 2010; 64: 1580-1582Crossref PubMed Scopus (22) Google Scholar, 27Salahuddin M. Anwar M.N. Study on effectiveness of guidelines and high dependency unit management on diabetic ketoacidosis patients.J Postgrad Med Inst. 2009; 23: 120-123Google Scholar). 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar, 17Lebovitz H.E. Diabetic ketoacidosis.Lancet. 1995; 345: 767-772Abstract PubMed Google Scholar). Precipitating factors must be diagnosed and treated (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar, 17Lebovitz H.E. Diabetic ketoacidosis.Lancet. 1995; 345: 767-772Abstract PubMed Google Scholar). The sodium deficit is typically 7-10 mmol/kg in DKA (28Kreisberg R.A. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment.Ann Intern Med. 1978; 88: 681-695Crossref PubMed Scopus (144) Google Scholar) and 5 to 13 mmol/kg in HHS (29Ennis E.D. Stahl E.J. Kreisberg R.A. The hyperosmolar hyperglycemic syndrome.Diabetes Rev. 1994; 2: 115-126Google Scholar), 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 (28Kreisberg R.A. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment.Ann Intern Med. 1978; 88: 681-695Crossref PubMed Scopus (144) Google Scholar, 29Ennis E.D. Stahl E.J. Kreisberg R.A. The hyperosmolar hyperglycemic syndrome.Diabetes Rev. 1994; 2: 115-126Google Scholar). 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 (30Mahoney C.P. Vlcek B.W. DelAguila M. Risk factors for developing brain herniation during diabetic ketoacidosis.Pediatr Neurol. 1999; 2: 721-727Abstract Full Text Full Text PDF Scopus (122) Google Scholar) but not in another (31Rosenbloom A.L. Intracerebral crises during treatment of diabetic ketoacidosis.Diabetes Care. 1990; 13: 22-33Crossref PubMed Scopus (258) Google Scholar). 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 (32Adrogue H.J. Barrero J. Eknoyan G. Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis.JAMA. 1989; 262: 2108-2113Crossref PubMed Scopus (75) Google Scholar, 33Fein 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.Ann Intern Med. 1982; 96: 570-575Crossref PubMed Scopus (81) Google Scholar). The typical potassium deficit range is 2 to 5 mmol/kg in DKA and 4 to 6 mmol/kg in HHS (29Ennis E.D. Stahl E.J. Kreisberg R.A. The hyperosmolar hyperglycemic syndrome.Diabetes Rev. 1994; 2: 115-126Google Scholar, 30Mahoney C.P. Vlcek B.W. DelAguila M. Risk factors for developing brain herniation during diabetic ketoacidosis.Pediatr Neurol. 1999; 2: 721-727Abstract Full Text Full Text PDF Scopus (122) Google Scholar). 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar). It is reasonable to treat the potassium deficit of HHS in the same way. 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 (34Owen O.E. Licht J.H. Sapir D.G. Renal function and effects of partial rehydration during diabetic ketoacidosis.Diabetes. 1981; 30: 510-518Crossref PubMed Scopus (74) Google Scholar). Short-acting insulin (0.1 U/kg/h) is recommended (35Kitabchi A.E. Ayyagari V. Guerra S.M. et al.The efficacy of low dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis.Ann Intern Med. 1976; 84: 633-638Crossref PubMed Scopus (148) Google Scholar, 36Heber D. Molitch M.E. Sperling M.A. Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with “conventional” insulin therapy.Arch Intern Med. 1977; 137: 1377-1380Crossref PubMed Scopus (35) Google Scholar, 37Butkiewicz E.K. Leibson C.L. O'Brien P.C. et al.Insulin therapy for diabetic ketoacidosis. Bolus insulin injection versus continuous insulin infusion.Diabetes Care. 1995; 18: 1187-1190Crossref PubMed Scopus (31) Google Scholar). Although the use of an initial bolus of IV insulin is recommended in some reviews (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar), there has been only 1 randomized controlled trial (RCT) in adults examining the effectiveness of this step (38Kitabchi 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?.Diabetes Care. 2008; 31: 2081-2085Crossref PubMed Scopus (76) Google Scholar). 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 (39Fort P. Waters S.M. Lifshitz F. Low-dose insulin infusion in the treatment of diabetic ketoacidosis: bolus versus no bolus.J Pediatr. 1980; 96: 36-40Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 40Lindsay R. Bolte R.G. The use of an insulin bolus in low-dose insulin infusion for pediatric diabetic ketoacidosis.Pediatr Emerg Care. 1989; 5: 77-79Crossref PubMed Scopus (33) Google Scholar) 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 (41Della 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.Diabetes Care. 2005; 28: 1856-1861Crossref PubMed Scopus (83) Google Scholar, 42Umpierrez 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.Am J Med. 2004; 117: 291-296Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 43Umpierrez G.E. Cuervo R. Karabell A. et al.Treatment of diabetic ketoacidosis with subcutaneous insulin aspart.Diabetes Care. 2004; 27: 1873-1888Crossref PubMed Scopus (156) Google Scholar). The dose of insulin should subsequently be adjusted based on ongoing acidosis (44Wiggam 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.Diabetes Care. 1997; 20: 1347-1352Crossref PubMed Scopus (99) Google Scholar), using the plasma anion gap or beta-OHB measurements. Plasma glucose levels will fall due to multiple mechanisms, including ECFV re-expansion (45Waldhäusl W. Kleinberger G. Korn A. et al.Severe hyperglycemia: effects of rehydration on endocrine derangements and blood glucose concentration.Diabetes. 1979; 28: 577-584Crossref PubMed Scopus (156) Google Scholar), glucose losses via osmotic diuresis (34Owen O.E. Licht J.H. Sapir D.G. Renal function and effects of partial rehydration during diabetic ketoacidosis.Diabetes. 1981; 30: 510-518Crossref PubMed Scopus (74) Google Scholar), 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 (45Waldhäusl W. Kleinberger G. Korn A. et al.Severe hyperglycemia: effects of rehydration on endocrine derangements and blood glucose concentration.Diabetes. 1979; 28: 577-584Crossref PubMed Scopus (156) Google Scholar). Insulin has been withheld successfully in HHS (46Gerich J.E. Martin M.M. Recant L.L. Clinical and metabolic characteristics of hyperosmolar nonketotic coma.Diabetes. 1971; 20: 228-238Crossref PubMed Scopus (158) Google Scholar), but generally its use is recommended to reduce plasma glucose levels (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar). Use of IV sodium bicarbonate to treat acidosis did not affect outcome in RCTs (47Morris L.R. Murphy M.B. Kitabchi A.E. Bicarbonate therapy in severe diabetic ketoacidosis.Ann Intern Med. 1986; 105: 836-840Crossref PubMed Scopus (205) Google Scholar, 48Gamba G. Oseguera J. Castrejon M. et al.Bicarbonate therapy in severe diabetic ketoacidosis: a double blind, randomized placebo controlled trial.Rev Invest Clin. 1991; 43: 234-248PubMed Google Scholar, 49Hale P.J. Crase J. Nattrass M. Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis.Br Med J Clin Res Ed. 1984; 289: 1035-1038Crossref PubMed Scopus (102) Google Scholar). 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar). Potential risks associated with the use of sodium bicarbonate include hypokalemia (50Soler N.G. Bennet M.A. Dixon K. et al.Potassium balance during treatment of diabetic ketoacidosis with special reference to the use of bicarbonate.Lancet. 1972; 2: 665-667Abstract PubMed Scopus (62) Google Scholar) and delayed occurrence of metabolic alkalosis. 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 (51Carlotti 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.Intensive Care Med. 2001; 27: 921-924Crossref PubMed Scopus (53) Google Scholar), it has been recommended that the plasma osmolality be lowered no faster than 3 mmol/kg/h (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar). 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 (6Kitabchi A.E. Umpierrez G.E. Murphy M.B. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (454) Google Scholar, 16Chiasson J.L. Aris-Jilwan N. Belanger R. et al.Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.CMAJ. 2003; 168: 859-866PubMed Google Scholar). 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 (52O'Malley G. Moran C. Draman M.S. et al.Central pontine myelinolysis complicating treatment of the hyperglycaemic hyperosmolar state.Ann Clin Biochem. 2008; 45: 440-443Crossref PubMed Scopus (36) Google Scholar). There is currently no evidence to support the use of phosphate therapy for DKA (53Keller U. Berger W. Prevention of hypophosphatemia by phosphate infusion during treatment of diabetic ketoacidosis and hyperosmolar coma.Diabetes. 1980; 29: 87-95Crossref PubMed Scopus (71) Google Scholar, 54Wilson H.K. Keuer S.P. Lea A.S. et al.Phosphate therapy in diabetic ketoacidosis.Arch Intern Med. 1982; 142: 517-520Crossref PubMed Scopus (103) Google Scholar, 55Fisher J.N. Kitabchi A.E. A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis.J Clin Endocrinol Metab. 1983; 57: 177-180Crossref PubMed Scopus (167) Google Scholar), and there is no evidence that hypophosphatemia causes rhabdomyolysis in DKA (56Singhal P.C. Abromovici M. Ayer S. et al.Determinants of rhabdomyolysis in the diabetic state.Am J Nephrol. 1991; 11: 447-450Crossref PubMed Scopus (40) Google Scholar). 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. 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 (61Booth G.L. Fang J. Acute complications of diabetes.in: Hux J.E. Booth G.L. Slaughter P.M. Diabetes in Ontario: An ICES Practice Atlas. Institute for Clinical Evaluative Sciences, Toronto, ON2003: 2.19-2.50http://www.ices.on.caGoogle Scholar). Reported mortality in DKA ranges from 0.65% to 3.3% (2Holman R.C. Herron C.A. Sinnock P. Epidemiologic characteristics of mortality from diabetes with acidosis or coma, United States, 1970-78.Am J Public Health. 1983; 73: 1169-1173Crossref PubMed Scopus (18) Google Scholar, 22May M.E. Young C. King J. Resource utilization in treatment of diabetic ketoacidosis in adults.Am J Med Sci. 1993; 306: 287-294Crossref PubMed Scopus (41) Google Scholar, 62Bagg W. Sathu A. Streat S. et al.Diabetic ketoacidosis in adults at Auckland Hospital, 1988-1996.Aust N Z J Med. 1998; 28: 604-608Crossref PubMed Scopus (19) Google Scholar, 63Umpierrez G.E. Kelly J.P. Navarrete J.E. et al.Hyperglycemic crises in urban blacks.Arch Intern Med. 1997; 157: 669-675Crossref PubMed Google Scholar, 64Musey 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.Diabetes Care. 1995; 18: 483-489Crossref PubMed Scopus (112) Google Scholar). In HHS, recent studies found mortality rates to be 12% to 17%, but included patients with mixed DKA and hyperosmolality (1Hamblin P.S. Topliss D.J. Chosich N. et al.Deaths associated with diabetic ketoacidosis and hyperosmolar coma, 1973-1988.Med J Aust. 1989; 151: 439-444PubMed Google Scholar, 3Wachtel T.J. Tetu-Mouradjian L.M. Goldman D.L. et al.Hyperosmolarity and acidosis in diabetes mellitus: a three year experience in Rhode Island.J Gen Med. 1991; 6: 495-502Google Scholar, 65Wachtel T.J. Silliman R.A. Lamberton P. Predisposing factors for the diabetic hyperosmolar state.Arch Intern Med. 1987; 147: 499-501Crossref PubMed Scopus (58) Google Scholar). 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.Recommendations1.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 (10Charles 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.Singapore Med J. 2007; 48: 986-989PubMed Google Scholar, 11Naunheim R. Jang T.J. Banet G. et al.Point-of-care test identifies diabetic ketoacidosis at triage.Acad Emerg Med. 2006; 13: 683-685Crossref PubMed Google Scholar, 12Sefedini 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.Diabetol Croat. 2008; 37: 73-78Google Scholar, 13MacKay L. Lyall M.J. Delaney S. et al.Are blood ketones a better predictor than urine ketones of acid base balance in diabetic ketoacidosis?.Pract Diabetes Int. 2010; 27: 396-399Crossref Scopus (9) Google Scholar, 14Bektas F. Eray O. Sari R. Akbas H. Point of care blood ketone testing of diabetic patients in the emergency department.Endocr Res. 2004; 30: 395-402Crossref PubMed Scopus (48) Google Scholar, 15Harris S. Ng R. Syed H. Hillson R. Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis.Diabet Med. 2004; 22: 221-224Crossref Scopus (41) Google Scholar)].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 (32Adrogue H.J. Barrero J. Eknoyan G. Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis.JAMA. 1989; 262: 2108-2113Crossref PubMed Scopus (75) Google Scholar)] 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 (36Heber D. Molitch M.E. Sperling M.A. Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with “conventional” insulin therapy.Arch Intern Med. 1977; 137: 1377-1380Crossref PubMed Scopus (35) Google Scholar, 37Butkiewicz E.K. Leibson C.L. O'Brien P.C. et al.Insulin therapy for diabetic ketoacidosis. Bolus insulin injection versus continuous insulin infusion.Diabetes Care. 1995; 18: 1187-1190Crossref PubMed Scopus (31) Google Scholar)]. The insulin infusion rate should be maintained until the resolution of ketosis [Grade B, Level 2 (42Umpierrez 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.Am J Med. 2004; 117: 291-296Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar)] 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. 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 (10Charles 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.Singapore Med J. 2007; 48: 986-989PubMed Google Scholar, 11Naunheim R. Jang T.J. Banet G. et al.Point-of-care test identifies diabetic ketoacidosis at triage.Acad Emerg Med. 2006; 13: 683-685Crossref PubMed Google Scholar, 12Sefedini 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.Diabetol Croat. 2008; 37: 73-78Google Scholar, 13MacKay L. Lyall M.J. Delaney S. et al.Are blood ketones a better predictor than urine ketones of acid base balance in diabetic ketoacidosis?.Pract Diabetes Int. 2010; 27: 396-399Crossref Scopus (9) Google Scholar, 14Bektas F. Eray O. Sari R. Akbas H. Point of care blood ketone testing of diabetic patients in the emergency department.Endocr Res. 2004; 30: 395-402Crossref PubMed Scopus (48) Google Scholar, 15Harris S. Ng R. Syed H. Hillson R. Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis.Diabet Med. 2004; 22: 221-224Crossref Scopus (41) Google Scholar)].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 (32Adrogue H.J. Barrero J. Eknoyan G. Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis.JAMA. 1989; 262: 2108-2113Crossref PubMed Scopus (75) Google Scholar)] 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 (36Heber D. Molitch M.E. Sperling M.A. Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with “conventional” insulin therapy.Arch Intern Med. 1977; 137: 1377-1380Crossref PubMed Scopus (35) Google Scholar, 37Butkiewicz E.K. Leibson C.L. O'Brien P.C. et al.Insulin therapy for diabetic ketoacidosis. Bolus insulin injection versus continuous insulin infusion.Diabetes Care. 1995; 18: 1187-1190Crossref PubMed Scopus (31) Google Scholar)]. The insulin infusion rate should be maintained until the resolution of ketosis [Grade B, Level 2 (42Umpierrez 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.Am J Med. 2004; 117: 291-296Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar)] 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. Type 1 Diabetes in Children and Adolescents, p. S153