Treatment consists of rehydration with intravenous fluids, the administration of insulin, and replacement of electrolytes.
General medical care and close supervision by trained medical and nursing staff is of paramount importance in the management of patients with DKA. A treatment flowchart (Table 1.3) should be used and updated meticulously. A urine catheter is necessary if the patient is in coma or if no urine is passed in the first 4 hours….
Patients with DKA have severe dehydration. The amount of fluid needing to be administered depends on the degree of dehydration (Table 1.4). Fluid replacement aims at correction of the volume deficit and not to restore serum osmolality to normal. Isotonic solution NaCl (0.9%) (normal saline; osmolality 308 mOsm/kg) should be administered even in patients with high serum osmolality since this solution is hypotonic compared to the extracellular fluid of the patient. 10
The initial rate of fluid administration depends on the degree of volume depletion and underlying cardiac and renal function. In a young adult with normal cardiac and/or renal function 1 L of normal saline is administered intravenously within the first half- to one hour. In the second hour administer another 1 L, and between the third and the fifth hours administer 0.5–1 L per hour. Thus, the total volume in the first 5 hours should be 3.5–5 L . If the patient is in shock or blood pressure does not respond to normal saline infusion, colloid solutions together with normal saline may be used.1,6
Some authors suggest replacement of normal saline with hypotonic (0.45%) saline solution after stabilization of the hemodynamic status of the patient and when corrected serum sodium levels are normal.8 However, this approach may result in rapid movement of extracellular water into cells as blood glucose and osmolality fall with treatment; such shifts have been implicated in the pathogenesis of cerebral edema. 6,10 Hypotonic saline solution can be used when serum osmolality is very high; this is rare in DKA but common in HHS.
When the blood glucose level falls below 250 mg/dl (13.9 mmol/L), or according to other authors 200 mg/dl (11.1 mmol/L), normal saline should be discontinued and replaced immediately by dextrose 5% solution at a rate of 250 ml per hour. Alternatively infusion of a mixture of 5% dextrose with 0.45% NaCl, instead of dextrose 5%, can be used. 9 Glucose infusion together with insulin administration suppresses lipolysis and ketogenesis and maintains blood glucose levels at near normal (120–180 mg/dl [6.6–10 mmol/L]) levels. Intravenous glucose is given without interruption until the patient is eating again and subcutaneous insulin resumed. 1,6,8,10
In total, 6–12 L of fluid may be required in the first 24 hours for the correction of dehydration. 6 The duration of intravenous fluid administration is on average 48 hours. Restoration of water deficit requires special attention not only to the ongoing loss of fluid in the urine because hyperglycemia continues for several hours after starting treatment but also to avoid overhydration, particularly in patients with impaired cardiac or renal function. Urine output monitoring is very important for such patients.
Intravenous soluble insulin infusion
Administration of insulin is the etiologic treatment of DKA because it reduces blood glucose levels by inhibiting hepatic glucose production, increasing glucose uptake and utilization in peripheral tissues and inhibiting lipolysis and ketogenesis. Insulin administration must begin in parallel with fluid replacement therapy.
As recently as the early 1970s, large doses of insulin were administered for the treatment of DKA. Then several randomized trials showed that the administration of small doses of insulin is effective in the resolution of DKA and reduces the risk of hypoglycemia and hypokalemia. 20,21 Nowadays, according to most protocols, 1,6,8 the administration of an initial intravenous bolus of soluble rapid-acting insulin is recommended. Some suggest a bolus administration of insulin (usually 0.1 IU/kg) followed by infusion of 0.1 IU/kg per hour (usually 5–7 IU per hour). Others suggest infusion of insulin at a higher dose (0.14 IU/kg per hour) without an initial bolus administration. The infusion solution is usually prepared by adding 100 IU of insulin to 250 ml normal saline and is administered with special infusion pumps. If such pumps are not available, 50 IU of rapid-acting soluble insulin can be diluted in 500 ml normal saline, thus creating a solution with a concentration of 1 IU of insulin for every 10 ml solution, and then infusing at the desired rate (for example 50–70 ml/h if 5–7 IU per hour are needed) in parallel with the normal saline administered for the correction of dehydration using a Y connector or preferably via a separate venous line. The addition of albumin to the solution to discourage insulin absorption to the walls of the infusion device is not necessary. 22
Other routes of insulin administration
Instead of continuous infusion, insulin can be administered subcutaneously or intramuscularly with equally good results, providing that the patient is hemodynamically stable. Intermittent intramuscular soluble insulin administration in the deltoid muscle (5 IU) every 2 hours after an initial loading dose of 20 IU is acceptable for the treatment of uncomplicated DKA.
If subcutaneous insulin is to be used, patients typically receive an initial dose of 0.2 IU/kg (for example 16 IU in an 80 kg person) followed by 0.1 IU/kg every hour (for example 8 IU for an 80 kg person) or an initial dose of 0.3 IU/kg and subsequently 0.2 IU/kg every 2 hours while blood glucose remains above 250 mg/dl (13.9 mmol/L). When glucose levels fall to below 250 mg/dl (13.9 mmol/L) the insulin dose may be decreased by half and administered every 1 or 2 hours until resolution of DKA. Subcutaneous or intramuscular insulin is indicated for the management of DKA in centers where it is difficult to monitor low–dose intravenous infusions and may be associated with a lower cost of hospitalization by avoiding intensive care unit placement. 19 Milder forms of DKA can also be treated safely with subcutaneous or intramuscular insulin. Comparison of subcutaneous, intramuscular, and intravenous regimens for treatment of DKA has shown no significant difference in outcomes, except for a more rapid decline in glucose and ketones in the first 2 hours with the intravenous infusion. 22,23
Recently, treatment with subcutaneous rapid-acting insulin analogs (lispro or aspart every 1 or 2 hours in non-intensive care unit settings) was shown to be an effective alternative to the use of intravenous regular insulin in the treatment of DKA. 24,25 The rate of decline of blood glucose concentration and the mean duration of treatment until correction of ketoacidosis were similar among patients treated with subcutaneous insulin analogs every 1 or 2 hours or with the intravenous regular insulin. An initial intramuscular or subcutaneous dose of 0.3 IU/kg (for example, 24 IU in an 80 kg person), followed by 0.1 IU/kg every hour (for example, 8 IU every hour in an 80 kg person), can be used. However, it is recommended that until more data on efficacy are available, patients with severe DKA, hypotension, edema, or associated severe critical illness are managed with intravenous soluble insulin. 9
Some doctors prefer the repetitive-bolus intravenous administration of insulin: specifically the administration of 20–50 IU every 2 hours is recommended. 10 When glucose levels fall below 250 mg/dl (13.9 mmol/L), the treatment changes to subcutaneous administration every 4–6 hours. However, because intravenous insulin has a plasma half-life of about 8–9 minutes, intermittent intravenous administration may lead to unpredictable and fluctuating insulin concentrations. In addition, high insulin doses may lead to hypokalemia and late hypoglycemia.
It should be noted that the protocols of fluid administration may vary depending on the clinic, but their basic principles and therapeutic goals remain the same. Insulin administration should produce a steady and predictable fall in blood glucose levels averaging 50–70 mg/dl per hour (2.8–3.9 mmol/L per hour). If blood glucose does not fall by at least 10% in the first hour (or less than 50 mg/dl [2.8 mmol/L per hour]) on the insulin infusion rate, the insulin dose should be doubled or increased by 0.05–0.1 IU/kg every 1–2 hours (or 1–2 IU every 1–2 hours), providing that other causes for lack of response have been excluded. These include worsening of acidosis or inadequate hydration.6 When blood glucose is below 250 mg/dl (13.9 mmol/L) and/or there is improvement in clinical status with decrease in blood glucose greater than 75 mg/dl (4.2 mmol/L), the rate of insulin infusion should be decreased by 0.05–0.1 IU/kg per hour (or 1–2 IU per hour). In any case, the rate of insulin infusion should not be less than 1 IU per hour. If blood glucose has fallen to below 80 mg/dl (4.5 mmol/L), insulin infusion should be discontinued for no more than 1 hour and restarted at a lower infusion rate. During insulin infusion after the first few hours the blood glucose levels should be maintained between 140 and 180 mg/dl (7.8–10 mmol/L).1,6,10
The intravenous infusion of insulin can be stopped when DKA has been corrected (blood glucose is less than 200 mg/dl [11 mmol/L], HCO 3 − is above 18 mEq/L, pH is higher than 7.3, and anion gap is normal). Then, feeding and per os hydration as well as subcutaneous administration of insulin can be initiated. 8
Patients are given soluble insulin or rapid – acting insulin analogs 1–2 hours before discontinuation of intravenous insulin to allow sufficient time for the injected insulin to start to work and before each meal. In parallel, injection of intermediate- or long-acting insulin should be initiated to provide the basal insulin requirement. It is not recommended that patients in transition from intravenous to subcutaneous insulin only are placed on short-acting insulin using sliding scales. If patients used insulin before admission, the same dose can be restarted in the hospital. Newly diagnosed patients with Type 1 diabetes require a total daily dose of 0.5–0.8 IU/kg, divided as 30–50% basal insulin and the remainder as rapid-acting insulin before each meal. Fingerstick glucose measurements before meals and at night should be done to correct for possible fluctuations in insulin needs.8,10
In patients with KPD, long-term management can be guided rationally by accurate classification based upon assessment of β-cell functional reserve, β-cell autoantibodies, and in some instances, HLA allelotyping. Although assessment of these parameters in all patients presenting with DKA is ideal, cost constraints and assay availability may make it prohibitive in some regions.
At presentation the type of diabetes is unknown and it is advisable that all patients continue subcutaneous insulin administration on discharge from the hospital until further testing (β-cell functional reserve and pancreatic autoantibodies) is performed. Assessment of β-cell secretory reserve and β-cell autoimmunity can be performed 1-3 weeks after resolution of ketoacidosis, to minimize the acute effects of glucose toxicity or desensitization on β-cell function. β-cell secretory reserve (as measured by fasting plasma C-peptide, C-peptide response to glucagon stimulation, and C-peptide to glucose ratio) following DKA resolution is the strongest predictor of long-term glycemic control and insulin dependence.26 Patients are classifi ed as “β−” if the fasting serum C-peptide concentration is less than 1 ng/ml (0.33 nmol/L) and the peak serum C-peptide response to glucagon (measured at 5 and 10 minutes after intravenous injection of 1 mg glucagon) is less than 1.5 ng/ml (0.5 nmol/L).11 Although these cut-off points do not independently predict the potential for successful and safe withdrawal of insulin, a high ratio (>11) of fasting C-peptide (in nmol/L) to glucose (in mmol/L) at 6 months predicts such a course among β+ patients.26
Patients with poor β-cell function (β−) after resolution of the DKA event typically require long-term exogenous insulin therapy, regardless of autoantibody status. Patients with β-cell secretory reserve who are antibody negative (A− β+) are often able to discontinue insulin, especially if they had unprovoked DKA as the initial manifestation of diabetes. The duration of the process of insulin withdrawal is variable and may range from 10 to 14 weeks to longer. If, after discontinuation of insulin, blood glucose values increase without development of ketosis, treatment with oral or injectable agents to lower blood glucose is required. If the patient develops ketosis upon decreasing the insulin dose, insulin should be intensified. In this setting, attempting to withdraw insulin a second time is not suggested. Patients with preserved β-cell function who have autoantibodies (A+ β+) have a variable course, with some demonstrating progressive β-cell deterioration and others long-term preservation. This group of individuals requires more careful monitoring, and these patients may benefit from HLA genotyping to provide additional prognostic markers of clinical behavior.
Ketonemia and ketonuria may continue for up to 36 hours because of the slow elimination of ketone bodies. 6 When ketonemia is used to assess response to therapy, Determination of β-OHB in blood is recommended.
Next Issue: Clinical Management of Diabetic Ketoacidosis in adults. – Treatment of acidosis – Electrolyte replacement – Patient monitoring – Complications – Preventing DKA
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Nikolaos Katsilambros, MD, PhD, FACP
SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 by John Wiley & Sons, Ltd.
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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.
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