Evaluation When evaluating a patient for hyperglycemia, the focus should be on the patient's cardiorespiratory status, mental status, and volume status.

Goals of Treatment Treatment goals are to reduce the following complications associated with hyperglycemia: Kidney and eye disease by regulation of blood pressure and lowering hyperglycemia. Ischemic heart disease, stroke, and peripheral vascular disease by control of hypertension, hyperlipidemia, and cessation of smoking.

Reduce the risk of metabolic syndrome and stroke by control of body weight and control of hyperglycemia. Differential Diagnosis There are many conditions that can present with hyperglycemia.

Differential diagnosis of hyperglycemia include: Diabetes mellitus type 1 and 2. Prognosis The prognosis of individuals with hyperglycemia depends on how well the levels of blood glucose are controlled. Complications Complications of untreated or uncontrolled hyperglycemia over a prolonged period of time include: Microvascular Complications Retinopathy.

Postoperative and Rehabilitation Care Hyperglycemia is common postoperatively. Consultations Hyperglycemia can be managed by internists but if remains uncontrolled then consultation with endocrinology is needed. Following specialties are involved in the management of diabetes and its complications Endocrinologist.

Deterrence and Patient Education Patients diagnosed with diabetes need comprehensive care in the first few months of the diagnosis as management can be overwhelming and time-consuming.

Pearls and Other Issues Patients with severe hyperglycemia should be assessed for clinical stability including mentation and hydration. Enhancing Healthcare Team Outcomes Diabetes management is very complex and time-consuming.

Review Questions Access free multiple choice questions on this topic. Comment on this article. References 1. Villegas-Valverde CC, Kokuina E, Breff-Fonseca MC.

Strengthening National Health Priorities for Diabetes Prevention and Management. MEDICC Rev. Hammer M, Storey S, Hershey DS, Brady VJ, Davis E, Mandolfo N, Bryant AL, Olausson J.

Hyperglycemia and Cancer: A State-of-the-Science Review. Oncol Nurs Forum. Yari Z, Behrouz V, Zand H, Pourvali K. New Insight into Diabetes Management: From Glycemic Index to Dietary Insulin Index.

Curr Diabetes Rev. Simon K, Wittmann I. Can blood glucose value really be referred to as a metabolic parameter? Rev Endocr Metab Disord. Bashir M, Naem E, Taha F, Konje JC, Abou-Samra AB.

Outcomes of type 1 diabetes mellitus in pregnancy; effect of excessive gestational weight gain and hyperglycaemia on fetal growth. Diabetes Metab Syndr.

Jacobsen JJ, Black MH, Li BH, Reynolds K, Lawrence JM. J Diabetes Complications. Rawlings AM, Sharrett AR, Albert MS, Coresh J, Windham BG, Power MC, Knopman DS, Walker K, Burgard S, Mosley TH, Gottesman RF, Selvin E.

The Association of Late-Life Diabetes Status and Hyperglycemia With Incident Mild Cognitive Impairment and Dementia: The ARIC Study. Diabetes Care. Kubis-Kubiak AM, Rorbach-Dolata A, Piwowar A.

Crucial players in Alzheimer's disease and diabetes mellitus: Friends or foes? Mech Ageing Dev. Shakya A, Chaudary SK, Garabadu D, Bhat HR, Kakoti BB, Ghosh SK. A Comprehensive Review on Preclinical Diabetic Models. Elgebaly MM, Arreguin J, Storke N.

Targets, Treatments, and Outcomes Updates in Diabetic Stroke. J Stroke Cerebrovasc Dis. Yayan EH, Zengin M, Erden Karabulut Y, Akıncı A. The relationship between the quality of life and depression levels of young people with type I diabetes.

Perspect Psychiatr Care. Duggan EW, Carlson K, Umpierrez GE. Perioperative Hyperglycemia Management: An Update. Goswami G, Scheinberg N, Schechter CB, Ruocco V, Davis NJ. Endocr Pract. Copyright © , StatPearls Publishing LLC. Bookshelf ID: NBK PMID: PubReader Print View Cite this Page Mouri MI, Badireddy M.

In: StatPearls [Internet]. In this Page. Bulk Download. Bulk download StatPearls data from FTP. Related information. PMC PubMed Central citations. Similar articles in PubMed. Report of the Committee on the classification and diagnostic criteria of diabetes mellitus.

Your body cannot tolerate large amounts of ketones and will try to get rid of them through the urine. Unfortunately, the body cannot release all the ketones and they build up in your blood, which can lead to ketoacidosis.

Many people with diabetes, particularly those who use insulin, should have a medical ID with them at all times. In the event of a severe hypoglycemic episode, a car accident, or other emergency, the medical ID can provide critical information about the person's health status, such as the fact that they have diabetes, whether or not they use insulin, whether they have any allergies, etc.

Emergency medical personnel are trained to look for a medical ID when they are caring for someone who can't speak for themselves. Medical IDs are usually worn as a bracelet or a necklace. Traditional IDs are etched with basic, key health information about the person, and some IDs now include compact USB drives that can carry a person's full medical record for use in an emergency.

Your best bet is to practice good diabetes management and learn to detect hyperglycemia so you can treat it early—before it gets worse. Breadcrumb Home Life with Diabetes Get the Right Care for You Hyperglycemia High Blood Glucose.

What causes hyperglycemia? A number of things can cause hyperglycemia: If you have type 1, you may not have given yourself enough insulin. If you have type 2, your body may have enough insulin, but it is not as effective as it should be.

You ate more than planned or exercised less than planned. You have stress from an illness, such as a cold or flu. This may result from a plasma insulin concentration as determined by baseline and stimulated C-peptide [ Table 2 ] adequate to prevent excessive lipolysis and subsequent ketogenesis but not hyperglycemia 4.

The key diagnostic feature in DKA is the elevation in circulating total blood ketone concentration. Assessment of augmented ketonemia is usually performed by the nitroprusside reaction, which provides a semiquantitative estimation of acetoacetate and acetone levels.

Although the nitroprusside test both in urine and in serum is highly sensitive, it can underestimate the severity of ketoacidosis because this assay does not recognize the presence of β-hydroxybutyrate, the main metabolic product in ketoacidosis 4 , If available, measurement of serum β-hydroxybutyrate may be useful for diagnosis Accumulation of ketoacids results in an increased anion gap metabolic acidosis.

Hyperglycemia is a key diagnostic criterion of DKA; however, a wide range of plasma glucose can be present on admission.

Elegant studies on hepatic glucose production rates have reported rates ranging from normal or near normal 38 to elevated 12 , 15 , possibly contributing to the wide range of plasma glucose levels in DKA that are independent of the severity of ketoacidosis This could be due to a combination of factors, including exogenous insulin injection en route to the hospital, antecedent food restriction 39 , 40 , and inhibition of gluconeogenesis.

On admission, leukocytosis with cell counts in the 10,—15, mm 3 range is the rule in DKA and may not be indicative of an infectious process. In ketoacidosis, leukocytosis is attributed to stress and maybe correlated to elevated levels of cortisol and norepinephrine The admission serum sodium is usually low because of the osmotic flux of water from the intracellular to the extracellular space in the presence of hyperglycemia.

An increased or even normal serum sodium concentration in the presence of hyperglycemia indicates a rather profound degree of free water loss. To assess the severity of sodium and water deficit, serum sodium may be corrected by adding 1.

Studies on serum osmolality and mental alteration have established a positive linear relationship between osmolality and mental obtundation 9 , Serum potassium concentration may be elevated because of an extracellular shift of potassium caused by insulin deficiency, hypertonicity, and acidemia Patients with low normal or low serum potassium concentration on admission have severe total-body potassium deficiency and require careful cardiac monitoring and more vigorous potassium replacement because treatment lowers potassium further and can provoke cardiac dysrhythmia.

Pseudonormoglycemia 44 and pseudohyponatremia 45 may occur in DKA in the presence of severe chylomicronemia. The admission serum phosphate level in patients with DKA, like serum potassium, is usually elevated and does not reflect an actual body deficit that uniformly exists due to shifts of intracellular phosphate to the extracellular space 12 , 46 , Insulin deficiency, hypertonicity, and increased catabolism all contribute to the movement of phosphate out of cells.

A serum lipase determination may be beneficial in the differential diagnosis of pancreatitis; however, lipase could also be elevated in DKA in the absence of pancreatitis Not all patients with ketoacidosis have DKA.

DKA must also be distinguished from other causes of high—anion gap metabolic acidosis, including lactic acidosis; ingestion of drugs such as salicylate, methanol, ethylene glycol, and paraldehyde; and acute chronic renal failure 4. Because lactic acidosis is more common in patients with diabetes than in nondiabetic persons and because elevated lactic acid levels may occur in severely volume-contracted patients, plasma lactate should be measured on admission.

A clinical history of previous drug abuse should be sought. Measurement of serum salicylate and blood methanol level may be helpful. Ethylene glycol antifreeze is suggested by the presence of calcium oxalate and hippurate crystals in the urine. Paraldehyde ingestion is indicated by its characteristic strong odor on the breath.

Because these intoxicants are low—molecular weight organic compounds, they can produce an osmolar gap in addition to the anion gap acidosis A recent report states that active cocaine use is an independent risk factor for recurrent DKA Recently, one case report has shown that a patient with diagnosed acromegaly may present with DKA as the primary manifestation of the disease In addition, an earlier report of pituitary gigantism was presented with two episodes of DKA with complete resolution of diabetes after pituitary apoplexy Successful treatment of DKA and HHS requires correction of dehydration, hyperglycemia, and electrolyte imbalances; identification of comorbid precipitating events; and above all, frequent patient monitoring.

Protocols for the management of patients with DKA and HHS are summarized in Fig. Protocol for management of adult patients with DKA or HHS. Bwt, body weight; IV, intravenous; SC, subcutaneous. Initial fluid therapy is directed toward expansion of the intravascular, interstitial, and intracellular volume, all of which are reduced in hyperglycemic crises 53 and restoration of renal perfusion.

In the absence of cardiac compromise, isotonic saline 0. Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output.

In general, 0. Fluid replacement should correct estimated deficits within the first 24 h. In patients with renal or cardiac compromise, monitoring of serum osmolality and frequent assessment of cardiac, renal, and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload 4 , 10 , 15 , Aggressive rehydration with subsequent correction of the hyperosmolar state has been shown to result in a more robust response to low-dose insulin therapy During treatment of DKA, hyperglycemia is corrected faster than ketoacidosis.

The mainstay in the treatment of DKA involves the administration of regular insulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular injections 4 , 56 , Randomized controlled studies in patients with DKA have shown that insulin therapy is effective regardless of the route of administration The administration of continuous intravenous infusion of regular insulin is the preferred route because of its short half-life and easy titration and the delayed onset of action and prolonged half-life of subcutaneous regular insulin 36 , 47 , Numerous prospective randomized studies have demonstrated that use of low-dose regular insulin by intravenous infusion is sufficient for successful recovery of patients with DKA.

Until recently, treatment algorithms recommended the administration of an initial intravenous dose of regular insulin 0. A recent prospective randomized study reported that a bolus dose of insulin is not necessary if patients receive an hourly insulin infusion of 0.

If plasma glucose does not decrease by 50—75 mg from the initial value in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved Fig.

Treatment with subcutaneous rapid-acting insulin analogs lispro and aspart has been shown to be an effective alternative to the use of intravenous regular insulin in the treatment of DKA. Treatment of patients with mild and moderate DKA with subcutaneous rapid-acting insulin analogs every 1 or 2 h in non—intensive care unit ICU settings has been shown to be as safe and effective as the treatment with intravenous regular insulin in the ICU 60 , 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 h or with intravenous regular insulin.

However, until these studies are confirmed outside the research arena, patients with severe DKA, hypotension, anasarca, or associated severe critical illness should be managed with intravenous regular insulin in the ICU.

Despite total-body potassium depletion, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises. Insulin therapy, correction of acidosis, and volume expansion decrease serum potassium concentration.

To prevent hypokalemia, potassium replacement is initiated after serum levels fall below the upper level of normal for the particular laboratory 5. Generally, 20—30 mEq potassium in each liter of infusion fluid is sufficient to maintain a serum potassium concentration within the normal range.

Rarely, DKA patients may present with significant hypokalemia. The use of bicarbonate in DKA is controversial 62 because most experts believe that during the treatment, as ketone bodies decrease there will be adequate bicarbonate except in severely acidotic patients.

Severe metabolic acidosis can lead to impaired myocardial contractility, cerebral vasodilatation and coma, and several gastrointestinal complications A prospective randomized study in 21 patients failed to show either beneficial or deleterious changes in morbidity or mortality with bicarbonate therapy in DKA patients with an admission arterial pH between 6.

Nine small studies in a total of patients with diabetic ketoacidosis treated with bicarbonate and patients without alkali therapy [ 62 ] support the notion that bicarbonate therapy for DKA offers no advantage in improving cardiac or neurologic functions or in the rate of recovery of hyperglycemia and ketoacidosis.

Moreover, several deleterious effects of bicarbonate therapy have been reported, such as increased risk of hypokalemia, decreased tissue oxygen uptake 65 , cerebral edema 65 , and development of paradoxical central nervous system acidosis.

Despite whole-body phosphate deficits in DKA that average 1. Phosphate concentration decreases with insulin therapy. Prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA 46 , 67 , and overzealous phosphate therapy can cause severe hypocalcemia 46 , The maximal rate of phosphate replacement generally regarded as safe to treat severe hypophosphatemia is 4.

No studies are available on the use of phosphate in the treatment of HHS. Patients with DKA and HHS should be treated with continuous intravenous insulin until the hyperglycemic crisis is resolved.

Resolution of HHS is associated with normal osmolality and regain of normal mental status. When this occurs, subcutaneous insulin therapy can be started. To prevent recurrence of hyperglycemia or ketoacidosis during the transition period to subcutaneous insulin, it is important to allow an overlap of 1—2 h between discontinuation of intravenous insulin and the administration of subcutaneous insulin.

Patients with known diabetes may be given insulin at the dosage they were receiving before the onset of DKA so long as it was controlling glucose properly. In insulin-naïve patients, a multidose insulin regimen should be started at a dose of 0.

Human insulin NPH and regular are usually given in two or three doses per day. More recently, basal-bolus regimens with basal glargine and detemir and rapid-acting insulin analogs lispro, aspart, or glulisine have been proposed as a more physiologic insulin regimen in patients with type 1 diabetes.

A prospective randomized trial compared treatment with a basal-bolus regimen, including glargine once daily and glulisine before meals, with a split-mixed regimen of NPH plus regular insulin twice daily following the resolution of DKA. Hypoglycemia and hypokalemia are two common complications with overzealous treatment of DKA with insulin and bicarbonate, respectively, but these complications have occurred less often with the low-dose insulin therapy 4 , 56 , Frequent blood glucose monitoring every 1—2 h is mandatory to recognize hypoglycemia because many patients with DKA who develop hypoglycemia during treatment do not experience adrenergic manifestations of sweating, nervousness, fatigue, hunger, and tachycardia.

Hyperchloremic non—anion gap acidosis, which is seen during the recovery phase of DKA, is self-limited with few clinical consequences This may be caused by loss of ketoanions, which are metabolized to bicarbonate during the evolution of DKA and excess fluid infusion of chloride containing fluids during treatment 4.

Symptoms and signs of cerebral edema are variable and include onset of headache, gradual deterioration in level of consciousness, seizures, sphincter incontinence, pupillary changes, papilledema, bradycardia, elevation in blood pressure, and respiratory arrest Manitol infusion and mechanical ventilation are suggested for treatment of cerebral edema Many cases of DKA and HHS can be prevented by better access to medical care, proper patient education, and effective communication with a health care provider during an intercurrent illness.

Paramount in this effort is improved education regarding sick day management, which includes the following:. Emphasizing the importance of insulin during an illness and the reasons never to discontinue without contacting the health care team.

Similarly, adequate supervision and staff education in long-term facilities may prevent many of the admissions for HHS due to dehydration among elderly individuals who are unable to recognize or treat this evolving condition.

The use of home glucose-ketone meters may allow early recognition of impending ketoacidosis, which may help to guide insulin therapy at home and, possibly, may prevent hospitalization for DKA.

In addition, home blood ketone monitoring, which measures β-hydroxybutyrate levels on a fingerstick blood specimen, is now commercially available The observation that stopping insulin for economic reasons is a common precipitant of DKA 74 , 75 underscores the need for our health care delivery systems to address this problem, which is costly and clinically serious.

The rate of insulin discontinuation and a history of poor compliance accounts for more than half of DKA admissions in inner-city and minority populations 9 , 74 ,

Data adapted from ref. Recent epidemiological studies indicate that hospitalizations for DKA in the U. are increasing. DKA is the most common cause of death in children and adolescents with type 1 diabetes and accounts for half of all deaths in diabetic patients younger than 24 years of age 5 , 6.

Death in these conditions is rarely due to the metabolic complications of hyperglycemia or ketoacidosis but relates to the underlying precipitating illness 4 , 9.

The prognosis of both conditions is substantially worsened at the extremes of age in the presence of coma, hypotension, and severe comorbidities 1 , 4 , 8 , 12 , The events leading to hyperglycemia and ketoacidosis are depicted in Fig.

In DKA, reduced effective insulin concentrations and increased concentrations of counterregulatory hormones catecholamines, cortisol, glucagon, and growth hormone lead to hyperglycemia and ketosis. Hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues 12 , , , , — This is magnified by transient insulin resistance due to the hormone imbalance itself as well as the elevated free fatty acid concentrations 4 , The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to the release of free fatty acids into the circulation from adipose tissue lipolysis and to unrestrained hepatic fatty acid oxidation in the liver to ketone bodies β-hydroxybutyrate and acetoacetate 19 , with resulting ketonemia and metabolic acidosis.

Increasing evidence indicates that the hyperglycemia in patients with hyperglycemic crises is associated with a severe inflammatory state characterized by an elevation of proinflammatory cytokines tumor necrosis factor-α and interleukin-β, -6, and -8 , C-reactive protein, reactive oxygen species, and lipid peroxidation, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of obvious infection or cardiovascular pathology All of these parameters return to near-normal values with insulin therapy and hydration within 24 h.

The procoagulant and inflammatory states may be due to nonspecific phenomena of stress and may partially explain the association of hyperglycemic crises with a hypercoagulable state The pathogenesis of HHS is not as well understood as that of DKA, but a greater degree of dehydration due to osmotic diuresis and differences in insulin availability distinguish it from DKA 4 , Although relative insulin deficiency is clearly present in HHS, endogenous insulin secretion reflected by C-peptide levels appears to be greater than in DKA, where it is negligible Table 2.

Insulin levels in HHS are inadequate to facilitate glucose utilization by insulin-sensitive tissues but adequate to prevent lipolysis and subsequent ketogenesis IRI, immunoreactive insulin.

Adapted from ref. The most common precipitating factor in the development of DKA and HHS is infection 1 , 4 , Other precipitating factors include discontinuation of or inadequate insulin therapy, pancreatitis, myocardial infarction, cerebrovascular accident, and drugs 10 , 13 , In addition, new-onset type 1 diabetes or discontinuation of insulin in established type 1 diabetes commonly leads to the development of DKA.

Factors that may lead to insulin omission in younger patients include fear of weight gain with improved metabolic control, fear of hypoglycemia, rebellion against authority, and stress of chronic disease.

Before , the use of continuous subcutaneous insulin infusion devices had also been associated with an increased frequency of DKA 23 ; however, with improvement in technology and better education of patients, the incidence of DKA appears to have reduced in pump users.

However, additional prospective studies are needed to document reduction of DKA incidence with the use of continuous subcutaneous insulin infusion devices Underlying medical illness that provokes the release of counterregulatory hormones or compromises the access to water is likely to result in severe dehydration and HHS.

In most patients with HHS, restricted water intake is due to the patient being bedridden and is exacerbated by the altered thirst response of the elderly.

Elderly individuals with new-onset diabetes particularly residents of chronic care facilities or individuals with known diabetes who become hyperglycemic and are unaware of it or are unable to take fluids when necessary are at risk for HHS 10 , Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, sympathomimetic agents, and pentamidine, may precipitate the development of HHS or DKA 4.

Recently, a number of case reports indicate that the conventional antipsychotic as well as atypical antipsychotic drugs may cause hyperglycemia and even DKA or HHS 26 , An increasing number of DKA cases without precipitating cause have been reported in children, adolescents, and adult subjects with type 2 diabetes.

Observational and prospective studies indicate that over half of newly diagnosed adult African American and Hispanic subjects with unprovoked DKA have type 2 diabetes 28 , , , — The clinical presentation in such cases is acute as in classical type 1 diabetes ; however, after a short period of insulin therapy, prolonged remission is often possible, with eventual cessation of insulin treatment and maintenance of glycemic control with diet or oral antihyperglycemic agents.

In such patients, clinical and metabolic features of type 2 diabetes include a high rate of obesity, a strong family history of diabetes, a measurable pancreatic insulin reserve, a low prevalence of autoimmune markers of β-cell destruction, and the ability to discontinue insulin therapy during follow-up 28 , 31 , This unique, transient insulin-requiring profile after DKA has been recognized mainly in blacks and Hispanics but has also been reported in Native American, Asian, and white populations Some experimental work has shed a mechanistic light on the pathogenesis of ketosis-prone type 2 diabetes.

At presentation, they have markedly impaired insulin secretion and insulin action, but aggressive management with insulin improves insulin secretion and action to levels similar to those of patients with type 2 diabetes without DKA 28 , 31 , The process of HHS usually evolves over several days to weeks, whereas the evolution of the acute DKA episode in type 1 diabetes or even in type 2 diabetes tends to be much shorter.

Occasionally, the entire symptomatic presentation may evolve or develop more acutely, and the patient may present with DKA with no prior clues or symptoms.

For both DKA and HHS, the classical clinical picture includes a history of polyuria, polydipsia, weight loss, vomiting, dehydration, weakness, and mental status change. Physical findings may include poor skin turgor, Kussmaul respirations in DKA , tachycardia, and hypotension. Mental status can vary from full alertness to profound lethargy or coma, with the latter more frequent in HHS.

Focal neurologic signs hemianopia and hemiparesis and seizures focal or generalized may also be features of HHS 4 , Although infection is a common precipitating factor for both DKA and HHS, patients can be normothermic or even hypothermic primarily because of peripheral vasodilation.

Severe hypothermia, if present, is a poor prognostic sign Caution needs to be taken with patients who complain of abdominal pain on presentation because the symptoms could be either a result of the DKA or an indication of a precipitating cause of DKA, particularly in younger patients or in the absence of severe metabolic acidosis 34 , Further evaluation is necessary if this complaint does not resolve with resolution of dehydration and metabolic acidosis.

The diagnostic criteria for DKA and HHS are shown in Table 1. The initial laboratory evaluation of patients include determination of plasma glucose, blood urea nitrogen, creatinine, electrolytes with calculated anion gap , osmolality, serum and urinary ketones, and urinalysis, as well as initial arterial blood gases and a complete blood count with a differential.

An electrocardiogram, chest X-ray, and urine, sputum, or blood cultures should also be obtained. The severity of DKA is classified as mild, moderate, or severe based on the severity of metabolic acidosis blood pH, bicarbonate, and ketones and the presence of altered mental status 4.

Significant overlap between DKA and HHS has been reported in more than one-third of patients Severe hyperglycemia and dehydration with altered mental status in the absence of significant acidosis characterize HHS, which clinically presents with less ketosis and greater hyperglycemia than DKA.

This may result from a plasma insulin concentration as determined by baseline and stimulated C-peptide [ Table 2 ] adequate to prevent excessive lipolysis and subsequent ketogenesis but not hyperglycemia 4.

The key diagnostic feature in DKA is the elevation in circulating total blood ketone concentration. Assessment of augmented ketonemia is usually performed by the nitroprusside reaction, which provides a semiquantitative estimation of acetoacetate and acetone levels.

Although the nitroprusside test both in urine and in serum is highly sensitive, it can underestimate the severity of ketoacidosis because this assay does not recognize the presence of β-hydroxybutyrate, the main metabolic product in ketoacidosis 4 , If available, measurement of serum β-hydroxybutyrate may be useful for diagnosis Accumulation of ketoacids results in an increased anion gap metabolic acidosis.

Hyperglycemia is a key diagnostic criterion of DKA; however, a wide range of plasma glucose can be present on admission. Elegant studies on hepatic glucose production rates have reported rates ranging from normal or near normal 38 to elevated 12 , 15 , possibly contributing to the wide range of plasma glucose levels in DKA that are independent of the severity of ketoacidosis This could be due to a combination of factors, including exogenous insulin injection en route to the hospital, antecedent food restriction 39 , 40 , and inhibition of gluconeogenesis.

On admission, leukocytosis with cell counts in the 10,—15, mm 3 range is the rule in DKA and may not be indicative of an infectious process. In ketoacidosis, leukocytosis is attributed to stress and maybe correlated to elevated levels of cortisol and norepinephrine The admission serum sodium is usually low because of the osmotic flux of water from the intracellular to the extracellular space in the presence of hyperglycemia.

An increased or even normal serum sodium concentration in the presence of hyperglycemia indicates a rather profound degree of free water loss. To assess the severity of sodium and water deficit, serum sodium may be corrected by adding 1.

Studies on serum osmolality and mental alteration have established a positive linear relationship between osmolality and mental obtundation 9 , Serum potassium concentration may be elevated because of an extracellular shift of potassium caused by insulin deficiency, hypertonicity, and acidemia Patients with low normal or low serum potassium concentration on admission have severe total-body potassium deficiency and require careful cardiac monitoring and more vigorous potassium replacement because treatment lowers potassium further and can provoke cardiac dysrhythmia.

Pseudonormoglycemia 44 and pseudohyponatremia 45 may occur in DKA in the presence of severe chylomicronemia. The admission serum phosphate level in patients with DKA, like serum potassium, is usually elevated and does not reflect an actual body deficit that uniformly exists due to shifts of intracellular phosphate to the extracellular space 12 , 46 , Insulin deficiency, hypertonicity, and increased catabolism all contribute to the movement of phosphate out of cells.

A serum lipase determination may be beneficial in the differential diagnosis of pancreatitis; however, lipase could also be elevated in DKA in the absence of pancreatitis Not all patients with ketoacidosis have DKA.

DKA must also be distinguished from other causes of high—anion gap metabolic acidosis, including lactic acidosis; ingestion of drugs such as salicylate, methanol, ethylene glycol, and paraldehyde; and acute chronic renal failure 4. Because lactic acidosis is more common in patients with diabetes than in nondiabetic persons and because elevated lactic acid levels may occur in severely volume-contracted patients, plasma lactate should be measured on admission.

A clinical history of previous drug abuse should be sought. Measurement of serum salicylate and blood methanol level may be helpful.

Ethylene glycol antifreeze is suggested by the presence of calcium oxalate and hippurate crystals in the urine. Paraldehyde ingestion is indicated by its characteristic strong odor on the breath.

Because these intoxicants are low—molecular weight organic compounds, they can produce an osmolar gap in addition to the anion gap acidosis A recent report states that active cocaine use is an independent risk factor for recurrent DKA Recently, one case report has shown that a patient with diagnosed acromegaly may present with DKA as the primary manifestation of the disease In addition, an earlier report of pituitary gigantism was presented with two episodes of DKA with complete resolution of diabetes after pituitary apoplexy Successful treatment of DKA and HHS requires correction of dehydration, hyperglycemia, and electrolyte imbalances; identification of comorbid precipitating events; and above all, frequent patient monitoring.

Protocols for the management of patients with DKA and HHS are summarized in Fig. Protocol for management of adult patients with DKA or HHS.

Bwt, body weight; IV, intravenous; SC, subcutaneous. Initial fluid therapy is directed toward expansion of the intravascular, interstitial, and intracellular volume, all of which are reduced in hyperglycemic crises 53 and restoration of renal perfusion.

In the absence of cardiac compromise, isotonic saline 0. Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output. In general, 0. Fluid replacement should correct estimated deficits within the first 24 h.

In patients with renal or cardiac compromise, monitoring of serum osmolality and frequent assessment of cardiac, renal, and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload 4 , 10 , 15 , Aggressive rehydration with subsequent correction of the hyperosmolar state has been shown to result in a more robust response to low-dose insulin therapy During treatment of DKA, hyperglycemia is corrected faster than ketoacidosis.

The mainstay in the treatment of DKA involves the administration of regular insulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular injections 4 , 56 , Randomized controlled studies in patients with DKA have shown that insulin therapy is effective regardless of the route of administration The administration of continuous intravenous infusion of regular insulin is the preferred route because of its short half-life and easy titration and the delayed onset of action and prolonged half-life of subcutaneous regular insulin 36 , 47 , Numerous prospective randomized studies have demonstrated that use of low-dose regular insulin by intravenous infusion is sufficient for successful recovery of patients with DKA.

Until recently, treatment algorithms recommended the administration of an initial intravenous dose of regular insulin 0. A recent prospective randomized study reported that a bolus dose of insulin is not necessary if patients receive an hourly insulin infusion of 0.

If plasma glucose does not decrease by 50—75 mg from the initial value in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved Fig.

Treatment with subcutaneous rapid-acting insulin analogs lispro and aspart has been shown to be an effective alternative to the use of intravenous regular insulin in the treatment of DKA. Treatment of patients with mild and moderate DKA with subcutaneous rapid-acting insulin analogs every 1 or 2 h in non—intensive care unit ICU settings has been shown to be as safe and effective as the treatment with intravenous regular insulin in the ICU 60 , 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 h or with intravenous regular insulin.

However, until these studies are confirmed outside the research arena, patients with severe DKA, hypotension, anasarca, or associated severe critical illness should be managed with intravenous regular insulin in the ICU.

Despite total-body potassium depletion, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises.

Insulin therapy, correction of acidosis, and volume expansion decrease serum potassium concentration. To prevent hypokalemia, potassium replacement is initiated after serum levels fall below the upper level of normal for the particular laboratory 5.

Generally, 20—30 mEq potassium in each liter of infusion fluid is sufficient to maintain a serum potassium concentration within the normal range. Rarely, DKA patients may present with significant hypokalemia. The use of bicarbonate in DKA is controversial 62 because most experts believe that during the treatment, as ketone bodies decrease there will be adequate bicarbonate except in severely acidotic patients.

Severe metabolic acidosis can lead to impaired myocardial contractility, cerebral vasodilatation and coma, and several gastrointestinal complications A prospective randomized study in 21 patients failed to show either beneficial or deleterious changes in morbidity or mortality with bicarbonate therapy in DKA patients with an admission arterial pH between 6.

Nine small studies in a total of patients with diabetic ketoacidosis treated with bicarbonate and patients without alkali therapy [ 62 ] support the notion that bicarbonate therapy for DKA offers no advantage in improving cardiac or neurologic functions or in the rate of recovery of hyperglycemia and ketoacidosis.

Moreover, several deleterious effects of bicarbonate therapy have been reported, such as increased risk of hypokalemia, decreased tissue oxygen uptake 65 , cerebral edema 65 , and development of paradoxical central nervous system acidosis.

Despite whole-body phosphate deficits in DKA that average 1. Phosphate concentration decreases with insulin therapy. Prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA 46 , 67 , and overzealous phosphate therapy can cause severe hypocalcemia 46 , The maximal rate of phosphate replacement generally regarded as safe to treat severe hypophosphatemia is 4.

No studies are available on the use of phosphate in the treatment of HHS. Patients with DKA and HHS should be treated with continuous intravenous insulin until the hyperglycemic crisis is resolved. Resolution of HHS is associated with normal osmolality and regain of normal mental status.

When this occurs, subcutaneous insulin therapy can be started. To prevent recurrence of hyperglycemia or ketoacidosis during the transition period to subcutaneous insulin, it is important to allow an overlap of 1—2 h between discontinuation of intravenous insulin and the administration of subcutaneous insulin.

Patients with known diabetes may be given insulin at the dosage they were receiving before the onset of DKA so long as it was controlling glucose properly. In insulin-naïve patients, a multidose insulin regimen should be started at a dose of 0. Human insulin NPH and regular are usually given in two or three doses per day.

More recently, basal-bolus regimens with basal glargine and detemir and rapid-acting insulin analogs lispro, aspart, or glulisine have been proposed as a more physiologic insulin regimen in patients with type 1 diabetes.

A prospective randomized trial compared treatment with a basal-bolus regimen, including glargine once daily and glulisine before meals, with a split-mixed regimen of NPH plus regular insulin twice daily following the resolution of DKA. Hypoglycemia and hypokalemia are two common complications with overzealous treatment of DKA with insulin and bicarbonate, respectively, but these complications have occurred less often with the low-dose insulin therapy 4 , 56 , Frequent blood glucose monitoring every 1—2 h is mandatory to recognize hypoglycemia because many patients with DKA who develop hypoglycemia during treatment do not experience adrenergic manifestations of sweating, nervousness, fatigue, hunger, and tachycardia.

Hyperchloremic non—anion gap acidosis, which is seen during the recovery phase of DKA, is self-limited with few clinical consequences This may be caused by loss of ketoanions, which are metabolized to bicarbonate during the evolution of DKA and excess fluid infusion of chloride containing fluids during treatment 4.

Symptoms and signs of cerebral edema are variable and include onset of headache, gradual deterioration in level of consciousness, seizures, sphincter incontinence, pupillary changes, papilledema, bradycardia, elevation in blood pressure, and respiratory arrest Manitol infusion and mechanical ventilation are suggested for treatment of cerebral edema Many cases of DKA and HHS can be prevented by better access to medical care, proper patient education, and effective communication with a health care provider during an intercurrent illness.

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In: Feingold KR, Anawalt B, Blackman MR, et al. In this Page. Links to www. View this chapter in Endotext. Related information. PMC PubMed Central citations. Similar articles in PubMed. Pediatric Diabetic Ketoacidosis With Hyperosmolarity: Clinical Characteristics and Outcomes.

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