DIABETIC KETOACIDOSIS AND HYPERGLYCEMIC HYPEROSMOLAR NONKETOTIC SYNDROME

ACUTE COMPLICATIONS OF DIABETES

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DIABETIC KETOACIDOSIS AND HYPERGLYCEMIC HYPEROSMOLAR NONKETOTIC SYNDROME Miriam F. Delaney, MB, BCh, Ariel Zisman, MD, and William M. Kettyle, MD

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic syndrome (HHNS) are life-threatening acute metabolic complications of diabetes mellitus. Although there are some important differences, the pathophysiology, the presenting clinical challenge, and the treatment of these metabolic derangements are similar. Insulin deficiency, either relative or absolute, and elevated levels of stress-responding, counterregulatory hormones (e.g., glucagon, catecholamines, growth hormone, and cortisol) are the hallmarks of these conditions. Each of these complications can be seen in type 1 and type 2 diabetes, although DKA is usually seen in patients with type 1 diabetes and HHNS in patients with type 2 disease. The clinical management of these syndromes involves careful evaluation and correction of the metabolic and volume status of the patient, identification and treatment of precipitating and comorbid conditions, a smooth transition to a long-term treatment regimen, and a plan to prevent recurrence.

From the Endocrinology-Hypertension Division, Brigham and Women’s Hospital (MFD): Section on Molecular and Cellular Physiology, J o s h Diabetes Center (AZ),Boston; and the MlT Medical Department, Massachusetts Institute of Technology, Cambridge (WMK),Massachusetts

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MORTALITY AND EPIDEMIOLOGY

Patients with DKA or HHNS usually do not die as a result of hypertonicity or acidosis but succumb to a concurrent disorder that may have precipitated (e.g., myocardial infarction, sepsis, pancreatitis) or developed during the treatment of the metabolic and volume abnormalities of DKA and HHNS. Some deaths occur as a clear complication of therapy.

Diabetic Ketoacidosis

The annual incidence of DKA in the United States, as reported by the National Diabetes Data Group in 1995, was 4.6 to 8 episodes per It is estimated that 2% to 8% of all diabetic 1000 diabetic s~bjects.2~ hospital admissions are for the treatment of DKA.27,29, 65 Until the discovery of insulin in 1922, the mortality rate for DKA was virtually 100%. By 1932, the mortality rate decreased to approximately 30% and reached single digits by the 1 9 6 0 ~ . ' ~ In, ~developed countries, the current overall mortality rate for DKA ranges from 2% to lo%, a rate that has shown little decline over the last 3 decades.'%23, 5o The mortality rate in patients aged more than 65 years exceeds 20% , compared with a rate of 2% to 4% in younger adults.l2,~ 3 45,

Hyperglycemic Hyperosmolar Nonketotic Syndrome

Hyperglycemic hyperosmolar nonketotic syndrome occurs at a frequency of 17.5 cases per 100,000 person-years and accounts for 1in 1000 admissions to the hospital.55There has been no sigruficant decrease in the incidence of HHNS or in its associated morbidity and mortality over the last 15 to 20 years. In one series, the mean age of presentation ranged from 57 to 69 years, 70% of patients were females, 39% had an acute infection, 28% were nursing home residents, and 18% had dementia.87 Although most patients have a previous diagnosis of type 2 diabetes, as many as 40% in some series may have no previous diagnosis of diabetes mellitus. Rarely is HHNS seen in childhood or in patients with type 1 diabetes.", 25 Mortality rates as high as 12% to 46% have been recorded. Wachtel and c o - ~ o r k e r found s ~ ~ an increasing mortality associated with increasing age. The mortality rate was 10% with age less than 75 years, 19% with age from 75 to 84 years, and 35% with age greater than 85 years. The mortality rate increases with higher levels of serum osmolality. A mortality rate of 7% was found when the serum osmolality was less than 350 mOsm/L, 14% when 350 to 374 mOsm/L, 32% when 375 to 399 mOsm/L, and 37% when greater than 400 mOsm/L.

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PATHOPHYSIOLOGY

Insulin deficiency, either relative or absolute, leads to increased hepatic glucose production and decreased peripheral use of glucose. In DKA and HHNS (Figs. 1 and 2), the degree of hyperglycemia results in levels of glucose in the glomerular filtrate that exceed the reabsorption maximum, and a volume- and electrolyte-depleting diuresis ensues. For those patients who progress to DKA, the insulin deficiency also leads to lipolysis, the formation of ketoacids, and the development of acidosis. Patients with HHNS do not typically have significant ketosis or acidosis but have a greater degree of volume depletion with the development of prerenal azotemia, which further impairs glucose disposal and leads to extreme hyperglycemia and hyperosmolality. In established type 1 diabetic patients who omit their insulin or in newly diagnosed type 1 diabetic patients who present with DKA, circulating insulin levels are low or undetectable, suggesting that the lack of insulin is primarily responsible for the decompensated metabolic state. Nevertheless, a large number of insulin-dependent patients with DKA who have maintained or even increased their insulin doses have been found to have circulating insulin levels that are high.l0*59 Similarly newly diagnosed obese type 2 diabetic patients who present in ketoacidosis retain some insulin secretory c a p a ~ i t y .Among ~ , ~ ~ these type 2 diabetic

fGlucagon and counter-regulatory

iGlucwse uptake

Hyperglycemia

t Glumnecgenesis

I

deDletion

/

Figure 1. Pathogenesis of diabetic ketoacidosis. 'Absolute or relative.

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$Insulin'

tGlucagon and

cwnter-regulatory

Hyperglycemia Hyperosmolalii 4

Dehydration JThIrst

Figure 2. Pathogenesis of hyperglycemic hyperosmolar nonketotic syndrome. "Relative or absolute.

patients, insulin levels, although measurable, are not high enough to prevent DKA, and many of these patients achieve near-normoglycemic remission with diet, oral hypoglycemic agents, or both after initial insulin treatment. In HHNS, basal insulin secretion is maintained as shown by elevated peripheral C-peptide levels. Insulin levels are adequate to prevent peripheral lipolysis in adipose tissue but are not sufficient to allow adequate peripheral uptake of glucose or to prevent hepatic overproduction of glucose.4' HypergIycemia

In DKA and HHNS, hepatic glucose overproduction is associated with an increase in the ratio of glucagon to insulin in the portal venous blood?l, 59 In the presence of insulin deficiency or resistance, elevated glucagon levels lead to increased glycogenolysis and gluconeogenesis with decreased glycolysis and fatty acid synthesis. Stress-responsive, counterregulatory hormones have an important role in glucose overproduction in DKA and HHNS. Elevated cortisol levels stimulate protein catabolism with a consequent increase in circulating levels of amino acids, providing gluconeogenic precursors to the

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liver. In addition, glucagon and catecholamines induce the activation of glycogen phosphorylase, which leads to hepatic glycogen breakdown. Hyperglycemia is further worsened by reduced glucose uptake in peripheral tissues. Elevated catecholamine, growth hormone, cortisol, plasma free fatty acid, and amino acid concentrations, electrolyte depletion, and acidosis interfere with insulin action in peripheral target tissues.=,59 In patients with HHNS, Malchoff and c o - ~ o r k e r have s ~ ~ shown that glucagon levels correlate with the degree of hyperglycemia. Insulin is the major factor suppressing hepatic ketogenesis, yet the levels of insulin are not adequate to prevent glucagon-induced hepatic gluc0neogenesis.5~ Ketosis and Acidosis Diabetic Ketoacidosis

In DKA, the development of ketosis requires enhanced mobilization of long-chain fatty acids from stored triglycerides and a shift in hepatic lipid metabolism so that incoming fatty acids are preferentially oxidized to form ketone bodies rather than re-esterified into triacylglycerols and secreted in the form of very low-density lipoproteins. Insulin is a powerful suppressor of lipolysis. Minimal increases in insulin concentration (in the order of 5 yU/mL) can effectively suppress triacylglycerol breakdown in adipose tissue,38an effect mediated by the inhibition of hormone-sensitive lipase. Insulin deficiency or resistance and elevated circulating counterregulatory hormone levels promote lipolysis and inhibit triglyceride synthesis, with net efflux of fatty acids from the adipocyte into the circulation. Once in the hepatocyte, the fate of the fatty acids is largely determined by the cytosolic levels of malonyl-c0A.2~Lipid oxidation occurs in the mitochondrial matrix, and the primary regulatory step for fatty acid oxidation in the liver is the transport of CoA esters into mitochondria. The enzyme carnitine palmitoyltransferase I (CPT I), located on the outer mitochondrial membrane, catalyzes the transesterification of acyl-CoA with carnitine so that fatty acids can enter the poxidative pathway. Malonyl-CoA, the first committed intermediate in fatty acid synthesis, is a potent inhibitor of CPT I and of fatty acid oxidation. In DKA, the high ratio of glucagon-to-insulin in portal blood induces a sharp fall in the levels of malonyl-CoA that results in disinhibition of CPT I, favoring the oxidation of fatty acids and ketogenesis. By blocking glycolysis, glucagon decreases the availability of metabolic intermediates (e.g., oxaloacetate, and citrate) required for the synthesis of malonyl-CoA. A fall in the concentration of malonyl-CoA promotes fatty acid oxidation to form acetyl-CoA and the synthesis of the ketones, acetoacetic acid, and P-hydroxybutyrate. In addition, there is decreased peripheral use of ketone bodies, further aggravating the hyperketonemia and metabolic acidosis.” 67.72 n,82 Acidosis also causes important physiologic alterations. Acetoacetate

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and P-hydroxybutyrate are relatively strong acids (pKs of 4.8 and 4.7, respectively), and protons from the ketoacids titrate bicarbonate and other buffers while the ketone anions (nonvolatile acids) accumulate in plasma, resulting in an increase in unmeasured anions and accounting for an elevated plasma anion gap? Hyperglycemic Hyperosmolar Nonketotic Syndrome

Patients with HHNS have higher portal vein insulin levels than are seen in patients with DKA, allowing the liver to metabolize free fatty acids in a nonketogenic marmenu Hyperosmolality and dehydration also inhibit lipolysis, resulting in fewer free fatty acids being delivered to the liver.6 Volume and Electrolyte Depletion

Hyperglycemia leads to a significant osmotic diuresis accompanied by a major urinary loss of electrolytes. In DKA and HHNS, hyperglycemia raises extracellular fluid osmolality and causes the shift of water from the intracellular to the extracellular compartment, leading to cellular dehydration and, early in the process, to mild expansion of the extracellular space with the consequent modest dilution of serum sodium concentration. The movement of water is accompanied by a shift of potassium and phosphorus out of the cell. With more prolonged and severe hyperosmolality and dehydration, serum sodium concentration may normalize or even become elevated. There is a significant totalbody water deficit, usually on the order of 5 to 7 L in DKA and up to 8 to 10 L in HHNS. Diabetic Ketoacidosis

Ketone bodies exert an additional significant urinary osmolar effect. It is estimated that they account for one-third to one-half of the osmotic diuresis in patients with DKA.= In addition, urinary ketoacids promote additional excretion of positively charged ions (e.g., sodium, potassium, calcium, and magnesium) to maintain electrical neutrality. Renal excretion of glucose prevents the blood glucose concentration from rising above 500 to 600 mg/dL as long as renal function is preserved. Hyperglycemic Hyperosmolar Nonketotic Syndrome An intact thirst mechanism and access to free water should lead to increased fluid intake in patients with significant glucose-induced os+ motic d i ~ r e s i sMcKenna .~~ and co-workers65have shown that patients surviving HHNS, when water-deprived, have a subnormal osmoregulated thirst and fluid intake. As hyperglycemia worsens, hyperosmolality develops, and alterations in mental status occur. A depressed level of

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consciousness leads to a decrease in fluid intake, worsening hyperglycemia, and hyperosmolality, with eventual development of lethargy or coma. In HHNS, the degree of mental status change is associated with the degree of hyperosmolality and dehydration. Hyperglycemia and hyperosmolality lead to insulin resistance, which intensifies the hyperglycemia and hyperosmolality. CLINICAL PRESENTATION Diabetic Ketoacidosis

The clinical presentation of patients with DKA often includes vomiting, thirst, polyuria, an altered sensorium, weakness, fatigue, abdominal discomfort, and air hunger.' The duration of symptoms is usually relatively short, ranging from hours to a day or two, probably owing to the toxic effects of ketosis and acidosis. Kussmaul respirations and evidence of ileus and volume depletion are often found on examination. Blood glucose levels at presentation in patients with DKA are variable. Approximately 15% of patients have glucose values less than 350 mg/dL at presentation. This observation has been referred to as euglycemic DKA, which may be seen when gluconeogenesis is impaired (e.g., in liver disease, acute alcohol ingestion, prolonged fasting/ food deprivation) or when insulin-independent glucose use is high (e.g., in pregnancy).42,65. 69 Defined arterial pH criteria for DKA range from as high as less than 7.35 to as low as less than 7.20, and plasma bicarbonate concentration from less than 19 to 10 mEq/L or less. An increased anion gap (AG = Na' - HCO, - C1-) >16 mEq/L is common. Plasma osmolality is usually increased but does not often exceed 320 mOsm/ kg. Ketones, usually measured by the semiquantitative nitropmsside reaction, are usually strongly positive in the urine and are detected in variable concentrations in the serum. Laboratory criteria for DKA are summarized in Table 1. Table 1. LABORATORY CRITERIA OF DKA AND HHNS Laboratorv Criteria Glucose (serum), mg/dL Arterial pH HCO, (serum), mEq/L BUN (serum), mg/dL Osmolality, mOsm/ kg Ketones* Urine Serum BUN = blood urea nitrogen. *Nitroprusside reaction.

DKA

HHNS

>250 <7.3 <15 <25 <320

>600 >7.3 >20 >30 >330

>+3 at >1:2 dilution

-

+

-

or small or small

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Hyperglycemic Hyperosmolar Nonketotic Syndrome

In contrast to DKA, the onset of HHNS is usually insidious. Several days of deteriorating glycemic control, polyuria, and polydipsia are followed by increasing lethargy.l8 Alterations in mental status range from mild confusion to lethargy, stupor, generalized or partial complex seizures, myoclonic jerks, chorea, aphasia, cerebrovascular accident, or coma. Because most patients are unable to provide a detailed history at presentation, a collateral history obtained from family or friends with information outlining previous medical history and medications, is vital. Hypotension, tachycardia, tachypnea, fever, dehydration, and shock with peripheral hypoperfusion with varying degrees of altered mental status may be present on initial evaluation. Central nervous system changes in HHNS may mimic a focal neurologic event such as a cerebrovascular accident and may resolve with correction of the underlying metabolic condition. Diagnostic criteria for HHNS include a blood glucose level of greater than 600 mg/dL (>33 mmol/L), osmolality of greater than 330 mOsm/ kg, prerenal azotemia, pH greater than 7.3, and serum bicarbonate greater than 20 mEq/L (Table 1).Although some patients will have detectable urine ketones, most patients do not have a metabolic acidosis. Lactic acidosis may develop from an underlying infection or other cause, and measurement of ketoacids and lactate levels is essential if the pH is less than 7.3. A mixed syndrome of DKA and HHNS should be suspected if the pH is less than 7.3, ketones are present in the serum, and osmolarity is greater than 320 mOsm/L. Despite large fluid losses, the serum sodium concentration may be artificially normal or even low owing to severe hyperglycemia causing a dilutional hyponatremia and hypertriglyceridemia resulting in some degree of pseudohyponatremia.

PRECIPITATING FACTORS

Diabetic Ketoacidosis

Several epidemiologic studies have shown that omission of insulin in established type 1 diabetic patients, infection, and new-onset diabetes are among the most common precipitating events that lead to DKA (Table 2).” 51, The infectious precipitants are frequently urinary tract infections and pneumonia. Even infections otherwise considered trivial can precipitate DKA in susceptible diabetic individuals. In an early series of 101 patients using continuous subcutaneous insulin infusion (CSII) therapy and followed up for 3 years, there were 36 episodes of acute severe loss of glycemic control in 20 patients. Most of these cases were caused by inadvertent interruption of insulin (42%) or infection, leading to DKA.= Although improvements in delivery techniques and patient education have reduced this problem signifi-

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Table 2. PRECIPITATING FACTORS IN DKA AND HHNS Precipitating Factors

Diabetes

Acute illness

Medications

Substance abuse GI1

=

ExampledComments

New onset Poorly controlled Cessation of therapy Omission of insulin/ medication CSII (pump) failure Infection Myocardial infarction Acute pancreatitis Abdominal catastrophe Cerebrovascular accident Severe burns Renal failure Thiazides Beta-blockers Phenytoin Glucocorticoids Didanosine Cisplatinum, L-asparaginase Somatostatin Hyperalimentation Alcohol Cocaine

continuous subcutaneous insulin infusion.

cantly a recent study reported that the cause of DKA in 61% of patients using CSII therapy was a pump or catheter defect or an incorrect insulin preparati~n.'~, 74, 91 The accelerated pharmacokinetics of insulin lispro may lead to the onset of DKA more rapidly in the event that doses are omitted or a pump-related failure occurs.s9 Fear of hypoglycemia or a poor understanding of diabetes and insulin kinetics may be accompanied by omission or a significant reduction of an insulin dose at the onset of a medical illness, leading to the development of DKA. Other important precipitating factors include myocardial infarction (which may be symptomatically silent in patients with long-standing diabetes), stroke, pulmonary embolism, acute pancreatitis, gastrointestinal bleeding, trauma, glucocorticoid use, and severe emotional stress. In some patients with known diabetes, DKA develops without a clear 48, 75, 94 precipitating c0ndition.2~, Hyperglycemic Hyperosmolar Nonketotic Syndrome

The progression from poor glucose control to overt HHNS requires profound hyperglycemia for a significant period of time (2 days to 2 weeks), which allows an extreme state of hyperosmolality and dehydration to develop. Patients who do not monitor their blood sugar may be at increased risk for HHNS. In as many as 42% of previously diagnosed

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diabetic patients, HHNS is commonly preceded by poor c o m ~ l i a n c e . ~ ~ As is true for DKA, an acute illness is a common precursor of HHNS (Table 2). The most common infectious causes involve the urinary and respiratory tracts.26As shown in Table 2, some medications can contribute to the onset of uncontrolled hyperglycemia and precipitate HHNS.1, 14, 26, 50, 70, 76, 70, 06, 94 Stopping oral hypoglycemic agents or insulin or inadequate doses of these medications may lead to HHNS in patients with type 2 diabetes. Substance abuse, in particular the use of alcohol and cocaine, are potential contributors to noncompliance in patients with type 2 diabetes. In one series, alcohol and cocaine use were associated with HHNS in 44% and 9% of an urban population, re~pectively.~~ CLINICAL EVALUATION

The initial evaluation should include a brief but focused history and physical examination. Evaluation of volume and hydration status should proceed immediately, and laboratory studies should be initiated. Treatment with fluids and insulin can begin before the results of laboratory studies have been obtained. Most patients with DKA and HHNS require treatment in an intensive care setting because close monitoring is essential.97Blood glucose, electrolytes (e.g., sodium, potassium, carbon dioxide, and chloride), blood urea nitrogen (BUN), and creatinine should be determined and the anion gap calculated as seen in the following box:

Useful Formulas for the Evaluation and Treatment of DKA and HHNS 1. Calculation of the anion gap (AG): AG = “a+] - [CIHC0,-] 2. Calculation of the effective serum osmolality: Effective P, = measured Po,, - (BUN/28) Effective Po,, = 2 X (“a+] [K’]) (glucose in mg/dU18) 3. Correction of serum sodium: ([glucose in mg/dL] - 100) Corrected “a+] = “a+] 1.6 X 100

+

+

+

+

Osmolality should be calculated but can also be directly measured with correction for the level of urea. Diabetic Ketoacidosis An initial set of arterial blood gases should be obtained to asses, acid-base status. Creatinine levels may be falsely elevated as ketone

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Measured,by , nitroprussidereaction

I1 0

0

Not measured by , nitroprussidereaction

n

-

2

6

8

10

Hours after Initiation of Therapy

Figure 3. Ketone bodies. A, The chemical structures of acetoacetate, acetone, and P-OHbutyrate. The solid box indicates those measured by the nitroprusside reaction. B, The course of ketone body concentrations during treatment of DKA. (B, Modified from Schade DS, Eaton RP: Metabolic and clinical significance of ketosis. Special Topics in Endocrinology and Metabolism 4:l-27,1982; with permission.)

bodies, acetoacetate in particular, interfere with automated creatinine meas~rements.~~ Serum ketones can be measured using different methods. Semiquantitative methods based on the sodium nitroprusside reaction are usually sufficient but have the limitation of detecting acetoacetate and acetone (with tenfold-less sensitivity) but not p-hydroxybutyrate (Fig. 3). In the typical patient with DKA in whom a 3:l ratio of p-hydroxybutyrate to acetoacetate is present, this limitation does not represent a problem; however, when this ratio is altered in favor of p-hydroxybutyrate, such as in the patient who has lactic acidosis or alcohol excess, this method may underestimate the degree of ketonemia. Direct measurements of phydroxybutyrate may be warranted in these situations. In all other cases, there is no clear advantage of quantitative measurements of ketone bodiesx, 92 because the severity of acidosis is best judged by the blood pH and the anion gap. Hyperglycemic Hyperosmolar Nonketotic Syndrome

To assess and follow volume status carefully central venous monitoring may be necessary. When blood glucose values are greater than 400

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to 450 mg/dL, laboratory determinations and not fingerstick, bedside measurements are needed for accurate assessment of the response of glucose to therapy. In DKA and HHNS, altered mental status and neuropathy may mask the signs and symptoms of an acute, severe, comorbid rocess. A sigruficant infectious process or infarction may be present in ! lt e absence of history, fever, or impressive physical findings. After a basic evaluation is completed and volume and insulin therapy have started, a more thorough history and physical examination should be obtained. A complete blood count and differential should be determined. Chest radiographs, electrocardiograms, cultures of blood, urine, and sputum, cardiac enzymes, liver function tests, and amylase should be routinely obtained. Other evaluations should be ordered as indicated by clinical suspicion. MANAGEMENT The management of DKA and HHNS can be divided into six categories, the first four of which should be carried out simultaneously: 1. Replacement of fluid losses 2. Correction of hyperglycemia and, in patients with DKA, of metabolic acidosis 3. Replacement of electrolyte losses 4. Detection and treatment of precipitating causes and complications 5. Conversion to a durable diabetes management regimen following the correction of DKA or HHNS 6. Prevention of recurrence Successful treatment of DKA and HHNS requires frequent monitoring of the patient's condition and response to interventions. A flow sheet that charts the volume status and metabolic progress of the patient should be generated at the outset and maintained diligently during the management of DKA and HHNS. Replacement of Fluid Losses Patients with DKA and HHNS are invariably dehydrated and sodium depleted. Expansion of the extracellular fluid volume with intravenous fluids (crystalloids or colloids) improves cardiac output and renal function and facilitates the excretion of glucose. In addition, fluid therapy reduces the serum concentration of counterregulatory hormones with consequent improvement in insulin sensitivity. Hydration alone in the absence of exogenous insulinadministration may result in sigruficant improvement.35,59,90The previously listed formulas (see Box) are helpful in estimating the severity of hyperosmolarity and the degree of sodium depletion. Although they do not provide an exact prescription for re-

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placement therapy, they are helpful in forming an approach to replacement therapy. Diabetic Ketoacidosis Few controlled studies are available to guide fluid therapy. Initially, the goal is to correct the circulatory volume deficit, followed by correction of the whole-body water deficit over the ensuing 24 to 48 hours. The preferred initial solution is normal saline (0.9% NaCl), which has the advantage of rapidly expanding the extracellular fluid volume without causing an abrupt fall in plasma osmolality that could promote a rapid shift of water into cells. After correction of the volume deficit, correction of the water deficit can be accomplished by switching to hypotonic solutions such as 0.45% saline. The decision to switch to a hypotonic solution will also depend on the serum sodium concentration, the rate of decrease in osmolality, and the emergence of hyperchloremic metabolic acidosis. Some clinicians suggest using 0.45% saline solutions initially in cases when the corrected serum sodium exceeds 150 mEq/L5I or when the calculated effective plasma osmolality is greater than 320 mOsm/ kg.” Theoretically, a slow correction of the volume deficit may prolong the altered metabolic state as a result of continued catecholamine release, whereas rapid correction may enhance the urinary loss of ketones (bicarbonate precursors), leading to hyperchloremic metabolic acidosis. Additionally, rapid fluid administration has been implicated in the pathogenesis of symptomatic brain swelling and pulmonary edema.19,24 In a prospective study, Adrogue and co-workers3 observed that, in patients without significant circulatory compromise, a slower fluid replacement rate (normal saline at 500 mL/hour for the first 4 hours, followed by 250 mL/hour for the next 4 hours) was associated with more effective correction of acidosis than saline replacement at twice those rates. Hyperglycemic Hyperosmolar Nonketotic Syndrome Vigorous fluid replacement is essential early in the treatment of HHNS to prevent mortality associated with hypovolemia. Losses of water exceed those of sodium, resulting in hypertonic dehydration, and correction requires administration of hypotonic Hypotensive patients should be treated with isotonic intravenous fluids until stable, followed by hypotonic fluids. Severely hyperosmolar patients (>330 mOsm/ L) should receive half normal strength intravenous fluids initially. Patients with less severe hypertonicity can be treated with isotonic fluids. Fluid replacement should be at a rate of 1 to 2 L / hour in the first 1 to 2 hours, followed by 1 L/hour for 3 to 4 hours depending on the response to therapy, blood pressure, and urine output. Once these parameters are stable, 0.4570 saline is infused to replace half of the water deficit over the first 12 hours and the remainder in the next 24 hours.

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Correction of Hyperglycemia and Acidosis Diabetic Ketoacidosis

Insulin therapy should be started shortly after the diagnosis of DKA is confirmed and adequate hydration has begun. Insulin lowers the plasma glucagon level, counteracts the effect of glucagon on hepatic ketone production, inhibits the efflux of fatty acids and amino acids from adipose tissue and skeletal muscle, respectively, and enhances glucose uptake and use by these tissues. Regular crystalline insulin should be given intravenously as a continuous infusion.% The controversy surrounding the issue of high-dose (25-150 U/hour) versus lowdose (5-10 U/hour) insulin regimens has been essentially resolved in favor of low-dose insulin administration.l% 51, 79, 93 Several studies have shown that modest doses of insulin are effective in correcting the metabolic acidosis, restore euglycemia at a rate that limits rapid changes in plasma osmolality, cause a gradual mobilization of potassium and phosphorus to the intracellular space, and prevent the occurrence of hypogl cemia and hypokalemia that are often seen with higher doses. T e resulting circulating insulin concentrations are usually sufficient to inhibit completely lipolysis and the hepatic production of ketoacids.” 23, 38, 49 A loading dose of regular insulin given as an intravenous bolus of 0.1 to 0.2 U/kg is followed by a continuous infusion of insulin at a rate of 5 to 10 U/hour. During the first 4 to 8 hours of therapy, blood glucose should be monitored hourly. The goal is to achieve a rate of decline in plasma glucose of approximately 75 to 90 mg/dL/hour. If the blood glucose is not falling at the desired rate, the rate of insulin infusion should be adjusted accordingly. When continuous infusion of insulin is not feasible (e.g., lack of infusion pumps, inadequate monitoring), a safe alternative is the administration of low-dose intermittent intramuscular injections. A loading dose of 10 to 20 U (a third of which could be given as an intravenous bolus) is usually followed by 5 U/hour.” Because hyperglycemia is almost invariably resolved before ketosis is controlled, glucose (usually in the form of 5% dextrose) should be added to the intravenous fluids when the plasma glucose concentration reaches 250 to 300 mg/dL.64This step prevents an excessive decline in plasma osmolality that could lead to cerebral edema4 and avoids hypoglycemia. Insulin infusion should continue until significant correcA common mistake is discontinuing tion of ketonemia is achieved.23,B,95 the insulin infusion prematurely before adequate clearance of ketoacids from the serum or without provision for conversion to a longer-acting form of insulin, placing the patient at risk for rebound acidosis. The use of bicarbonate in the treatment of DKA has been controversial. Although severe acidemia has been associated with vascular refractoriness to adrenergic action and impaired myocardial contractility, several retrospective studiesm,71 and two prospective studies have failed to show any objective benefit of alkali therapy in patients with DKA.7*17,s*56

K

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In fact, bicarbonate therapy has been implicated in worsening hypokalemia, causing paradoxical central nervous system acidosis and delaying ketone body clearance.m,48, 53, 71 Okuda and co-workers71have shown that alkali infusion augments ketone body production and promotes accumulation of acetoacetate in body fluids. The available data suggest that bicarbonate therapy should not be given to ketoacidotic patients unless their arterial pH is below 6.9, or other indications are present (e.g., severe hyperkalemia, shock). If needed, one or two ampules of sodium bicarbonate (44-88 mEq NaHC03) should be diluted in 0.45% saline and given intravenously over 1 to 2 hours. Although helpful diagnostically at the time of presentation, serum or plasma ketone levels as measured by the nitroprusside reaction are not helpful in the management of DKA. The nitroprusside reaction does not measure the principal ketone body present in DKA, p-hydroxybutyrate (Fig. 3). Because p-hydroxybutyrate is oxidized to acetoacetate during correction of DKA, measurement of serum ketones by the nitroprusside reaction may lead to the impression that ketosis is not improving or even worsening when, in fact, the total ketone body concentration is decreasing.8oUrine ketone measurements do not accurately reflect the course of care and may remain positive long after significant metabolic improvement has occurred. Hyperglycemic Hyperosmolar Nonketotic Syndrome

Because insulin leads to the intracellular transport of glucose with resultant fluid shift from the intravascular to intracellular space, hypotension may occur if adequate hydration does not precede insulin therWith adequate hydration alone, the glucose concentration may drop by 80 to 200 m g / d L / h o ~ r After . ~ ~ the initiation of hydration, an insulin regimen consisting of a 10-Unit intravenous bolus of short-acting insulin followed by an infusion of 0.1 to 0.15 Units of insulin/kg/hour should be started with an expected fall in blood glucose concentration at a rate of 80 to 100 mg/dL/hour. A rapid fall in serum glucose to less than 250 mg/dL within the first 24 hours seems to increase the risk for cerebral edema. Once the blood glucose approaches 250 to 300 mg/dL, 5% dextrose should be added to the intravenous fluids and the rate of insulin infusion reduced. Carroll and Matz19found that low-dose insulin regimens reduced the mortality rate to 3% in younger patients and 21% in the elderly when accompanied by adequate rehydration. Replacement of Electrolyte Losses Potassium

Despite severe whole-body potassium deficits, 3 to 5 mEq/ kg in DKA and 5 to 10 mEq/kg in HHNS, patients frequently have elevated plasma potassium concentrations.13,45, 63 Patients presenting with normo-

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kalemia or hypokalemia may have even greater potassium deficits. Vomiting or nasogastric suction and pre-event diuretic use may further decrease total-body potassium levels. Hypertonicity, insulin deficiency, and acidosis, when present, cause a shift of potassium from the intracellular to the extracellular space, which, in the presence of an osmotic diuresis, results in sigruficant urinary potassium loss. During the treatment of these syndromes, the plasma potassium concentration will invariably fall owing to the combined effects of hydration, improvement in aad-base status, and insulin-mediated entry of potassium into the Hypokalemia is a potential life-threatening complication of the treatment of DKA and HHNS. In some patients, the presence of hyporeninemic hypoaldosteronism or tissue catabolism with the release of potassium, such as in rhabdomyolysis, may complicate the evaluation and treatment of the potassium balance. The amount and rate of potassium replacement are guided by the serum potassium concentration and the level of renal function. Because the quality of renal function may not be clear at the time of presentation, potassium should not be added to the initial intravenous fluids unless the potassium concentration is less than 4 mEq/L. Once adequate urine output is established, 20 to 40 mEq of potassium should be added to each liter of intravenous fluid. The goal is to maintain serum potassium in the normal range of 4 to 5 mEq/L. Potassium added to intravenous solutions should be well mixed before administration, and electrocardiography monitoring may be helpful in the management of some patients. Some patients require aggressive potassium replacement. Patients who have oliguria still require potassium replacement, albeit at a sigruficantly reduced rate.63 Phosphate In a manner analogous to potassium, total-body deficits of phosphate exist in patients with DKA and HHNS despite normal or increased serum levels." Early studies indicated beneficial effects and improved outcome in ketoacidotic patients given phosphorus replacemenP2;however, these effects have not been confirmed in more recent controlled studies,30,46 making it difficult to recommend routine phosphorus repletion in the treatment of DKA. In a series of patients treated for hyperglycemia without phosphate replacement, no patients experienced severe hypophosphatemia.3Or %, 96 If serum levels are low, it is reasonable to administer potassium phosphate when potassium is also needed to avoid hypophosphatemia. Careful monitoring of serum calcium concentration is necessary because tetany can occur with phosphate administration.16, 98 Detection and Treatment of PrecipitatingCauses and Complications

Any identifiable source of infection should be evaluated appropriately and treated aggressively with antibiotic therapy. Although not

,

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proven to reduce the mortality and morbidity in DKA or HHNS,33* 54 if no source of infection is identified, empiric antibiotic therapy should be considered because of the high incidence of infection and infectionrelated deaths. Serial cardiac enzymes and electrocardiographictracings should be obtained and reviewed for the possible presence of ischemia and infarction, even in patients without cardiac symptoms. The recovery of mental status may lag behind the correction of hyperglycemia and hyperosmolality owing to ongoing renal losses of free water as renal function recovers or overly rapid correction of serum hyperosmolality and resultant hyp~natremia.~ The major complications related to the treatment of DKA and HHNS include hypoglycemia, hypokalemia, and, rarely, cerebral edema. The use of low-dose insulin regimens, potassium replacement early in management, the addition of glucose to intravenous solutions, and attentive monitoring of therapeutic response should significantly reduce these complications. Hyperchloremic metabolic acidosis and rebound ketoacidosis owing to premature cessation of insulin therapy are complications specific to DKA. During the treatment of DKA, the serum bicarbonate concentration increases with therapy but often is not restored to normal because of urinary loss of ketone bodies. The loss of ketone bodies results in substrate deficiency for the generation of bicarbonate with the development of hyperchloremia. This form of metabolic acidosis is usually transient and has no clinical consequence. Cerebral edema is a dreaded but fortunately rare complication of the treatment of DKA and HHNS. It is more commonly seen in children with DKA, in whom it represents an important cause of ketoacidosisrelated death. It is manifested by headache, progressive drowsiness, and lethargy in a patient with otherwise adequate resolution of hyperglycemia and The most frequently proposed explanation is the development of an osmotic disequilibrium during correction of the hyperosmolar state. The central nervous system adapts to intracellular dehydration by generation of idiogenic osmols, possibly including myoinositol, taurine, and betaine. If the correction of extracellular tonicity occurs faster than the dissipation of these intracellular osmols, an osmotic gradient will promote brain cell swelling. Insulin treatment, per se, may have a role in its development?, 26 In these patients, cerebral edema is associated with a rapid correction of plasma glucose to below 250 to 300 mg/dL within the first 24 hours of therapy. Acute renal failure may develop in patients with DKA and HHNS and is more likely in patients with extremely elevated blood sugars.52 Subclinical rhabdomyolysis, possibly owing to shrinkage of muscle cells and impaired glucose use, is a common finding in patients with HHNS (as many as 50%), but secondary acute renal failure is extremely rare.52 Many patients do not have myoglobinuria; thus, monitoring serum creatine phosphokinase levels is the most sensitive way to screen for this potentially serious complicati~n.~~ Hyperosmolality and hypernatremia have been shown to alter factor VIII, contributing to a hypercoagulable

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~tate.3~ It has been suggested that thrombotic complications may be prevented if adequate correction of hypovolemia occurs at the onset of treatment. Prophylactic anticoagulant therapy should also be considered." Conversion to a Realistic Durable Diabetes Management Regimen

In patients with DKA or HHNS, conversion to a regimen of diabetes care that is appropriate for their individual situation should be considered and designed carefully. For patients in DKA who were on a reasonable regimen before the development of DKA, a return to their previous regimen is usually adequate. When DKA is the initial manifestation of type 1 diabetes, an insulin regimen based on the number of units needed to control glycemia and ketosis should be designed, usually incorporating at least two doses of insulin per day. DKA quickly returns on cessation of intravenous insulin infusion unless a subcutaneous insulin preparation is administered. An hour after the administration of subcutaneous insulin, the insulin infusion can be discontinued. For patients with HHNK, insulin therapy should be changed to the subcutaneous route after significant improvement in hyperglycemia and hydration. Blood sugar is controlled more easily once the acute state of HHNS is controlled and underlying precipitating comorbid conditions are treated. Some patients can be easily controlled on small doses of insulin. Because type 2 diabetes mellitus is commonly controlled with oral agents, most of these patients are tried on an oral hypoglycemic agent at a later date. Prevention

Patient and clinician education should be the foundation of an approach to prevent the acute complications of diabetes. For patients with type 1 diabetes, careful monitoring of glucose and ketone levels and adherence to sick-day rules should decrease the incidence and severity of DKA. Monitoring ketone levels when glucose concentrations are elevated or when an illness develops should alert patients and clinicians to the need for more insulin and for a search for a precipitating illness or condition. Although not yet studied, measurement of P-hydroxybutyrate using fingerstick techniques has the potential to identify DKA early in its development, leading to a prompt increase in insulin dose and hydration. Monitoring glucose levels and ensuring adequate hydration should decrease the risk for HHNS. Screening programs directed at identifying type 2 diabetes in the community will help identify patients at risk for HHNS. Avoiding the use of medications that interfere with the secretion or effectiveness of insulin and carefully monitoring glucose levels when

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such medications are essential should also decrease the risk for HHNS. Beta-blockers may exacerbate insulin-induced hypoglycemia but may also cause hyperglycemia, as may calcium channel blockers. Diuretics can aggravate glucose intolerance, increase insulin resistance, and cause hyperglycemia. Angiotensin-converting enzyme inhibitors, central agonists, a-blockers, and vasodilators have neutral effects on glucose hom e o ~ t a s i s .Other ~ ~ medications known to alter glycemic control (see Table 2), especially glucocorticoids, should be used with caution in patients with diabetes. The following list summarizes key points and concepts in the evaluation and management of patients with DKA and HHNS: Insulin deficiency, either absolute or relative, and counterregulatory hormone excess cause DKA and HHNS. An electrolyte- and volume-depleting diuresis leads to the development of DKA and HHNS. Acidosis with a wide anion gap and the presence of ketone bodies, especially P-hydroxybutyrate, are the hallmarks of DKA. Severe volume depletion, hyperosmolarity, and prerenal azotemia characterize HHNS. Management of DKA and HHNS should involve the following: Creation of a flow chart to document and monitor care Volume and electrolyte replacement Insulin Evaluation and treatment of comorbid precipitating or complicating conditions Complications to be avoided include the following: Hypokalemia Hypoglycemia Sudden large volume shifts Inadequate volume replacement Premature discontinuance of insulin therapy Creation and transfer to a durable regimen of diabetes care is vital. Prevention is an important aspect of management. References 1. Abraham MR, Kharduri R Hyperglycemic hyperosmolar nonketotic syndrome as initial presentation of type 2 diabetes in a young cocaine abuser. Diabetes Care 22: 1380-1381, 1999 2. Adrogue HJ, Wilson H, Boyd AE, et al: Plasma acid-base patterns in diabetic ketoacidosis. N Engl J Med 307: 1603-1610,1982 3. Adrogue HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoaadosis: Use in patients without extreme volume deficit. JAMA 262:2108-2113,1989 4. Arieff AI, Kleeman CR Cerebral edema in diabetic comas. 11. Effects of hyperosmolality, hyperglycemia and insulin in diabetic rabbits. J Clin Endocrinol Metab 3830571067, 1974 5. Arieff AI, Kleeman CR Studies on mechanisms of cerebral edema in diabetic comas:

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Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. J Clin Invest 52571-583, 1973 6. Arieff AI, Carroll HR: Nonketotic hyperosmolar coma with hyperglycemia: Clinical features, pathophysiology renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine 51:73-94, 1972 7. Assal JP, Aoki lT, Manzano FM, et al: Metabolic effects of sodium bicarbonate in management of diabetic ketoacidosis. Diabetes 23:405-411, 1974 8. Balasse EO, Fery F Ketone body production and disposal: Effects of fasting diabetes, and exercise. Diabetes Metab Rev 5247-270,1989 9. Banerji MA, Chaiken RL, Huey H, et al: GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4 Flatbush diabetes. Diabetes 43:741-745, 1994 10. Barrett EJ, DeFronzo RA, Bevilacqua S, et al: Insulin resistance in diabetic ketoacidosis. Diabetes 31:923-928, 1982 11. Basso A, Dalla Paola L, Erle G, et al: Hyperosmolar nonketotic coma at the onset of type I diabetes in a child. J Endocrinol Invest 20237-239, 1997 12. Basu A, Close CF, Jenkins D, et al: Persisting mortality in diabetic ketoacidosis. Diabet Med 10282-284, 1993 13. Beigelman P M Severe diabetic ketoacidosis (diabetic "coma"): 482 Episodes in 257 patients. Experience of three years. Diabetes 2 0 490-500,1971 14. Berger W, Keller U Treatment of diabetic ketoaadosis and nonketotic hyperosmolar diabetic coma. Baillieres Clin Endocrinol Metab 6 1-22, 1992 15. Bode BW, Steed RD, Davidson PC Reduction in severe hypoglycemia with longterm continuous subcutaneous insulin infusion in type I diabetes. Diabetes Care 1 9 326327,1996 16. Bohannon N: Large phosphate shifts with treatment for hyperglycemia. Arch Intern Med 149:1423-1425, 1989 17. Bureau MA, Begin R, Berthiaume Y, et al: Cerebral hypoxia from bicarbonate infusion in diabetic acidosis. J Pediatr 9696S973, 1980 18. Burge MR, Hardy KJ, Schade DS Short-term fasting is a mechanism for the development of euglycemic ketoacidosis during periods of insulin deficiency. J Clin Endocrinol Metab 76: 1192-1198, 1993 19. Carroll P, Matz R Uncontrolled diabetes mellitus in adults Experience in treating diabetic ketoacidosis and hyperosmolar nonketotic coma with low-dose insulin and a uniform treatment regimen. Diabetes Care 6579-585, 1983 20. Chang MH, Li JY, Lee SR, et al: Nonketotic hyperglycaemic chorea: A SPECT study. J Neurol Neurosurg Psychiatry 60: 428-430, 1996 21. DeFronzo RA, Felig P, Ferrannini E, et al: Effect of graded doses of insulin on splanchnic and peripheral potassium metabolism in man. Am J Physiol 238: E421427,1980 22. DeFronzo RA, Ferrannini E, Hendler R, et al: Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 3235-45, 1983 23. DeFronzo RA, Matsuda M, Barrett EJ: Diabetic ketoacidosis: A combined metabolicnephrologic approach to therapy. Diabetes Rev 2: 209-238, 1994 24. Duck SC, Weldon W, Pagliara AS, et al: Cerebral edema complicating therapy for diabetic ketoacidosis. Diabetes 2 5 111-115, 1976 25. Eidlitz-Markus T, Varsano I, Kauschansky A Nonketotic hyperosmolar coma in children. Isr J Med Sci 30585-587, 1994 26. Ennis ED, Kreisberg RA: In LeRoith D, Taylor SI, Olefsky JM(eds): Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, Lippincott-Raven, 1996, pp 276-286 27. Faich GA, Fishbein HA, Ellis SE: The epidemiology of diabetic acidosis: A populationbased study. Am J Epidemiol 117:551-558,1983 28. Fein IA, Rachow EC, Sprung CL,et ak Relation of colloid osmotic pressure to arterial hvuoxemia and cerebral edema during wstalloid volume loading of uatients with diabetic ketoacidosis. Ann Intern Med 565?0-575,1982 29. Fishbein H, Palumbo PJ: In Harris MI, et al (eds): Diabetes in America (National Diabetes Data Group). Washington, DC,National Institutes of Health, 1995, pp 283-291 '

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30. Fisher JN, Kitabchi AE: A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab 57177-180, 1983 31. Foster DW, McGarry JD: The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 309 159-169, 1983 32. Franks M, Berris RF, Kaplan NO, et al: Metabolic studies in diabetic acidosis. 11. The effect of the administration of sodium phosphate. Arch Intem Med 81: 42-55, 1948 33. Fulop M: The treatment of severely uncontrolled diabetes mellitus. Adv Intern Med 29: 327-356, 1984 34. Fulop M, Hoberman HD, Rusuff JH, et al: Lactic acidosis in diabetic patients. Arch Intern Med 136:987-990, 1976 35. Fulop M, Murthy V, Michilli A, et al: Serum beta-hydroxybutyrate measurement in patients with uncontrolled diabetes mellitus. Arch Intem Med 159:381-384, 1999 36. Genuth S Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic syndrome in adults. In Lebovitz H (ed): Therapy for Diabetes Mellitus and Related Disorders, ed 3, vol 1. Alexandria, VA, American Diabetes Association, 1998, pp 83-96 37. Grant PJ, Tate GM, Hughes JR, et al: Does hypematremia promote thrombosis? Thromb Res 4 0 393-399,1985 38. Groop LC, Bonadonna RC, DelPrato S, et a1 Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus: Evidence for multiple sites of insulin resistance. J Clin Invest 8 4 205-213, 1989 39. Gupta S, Prabhu MR, Gupta MS, et al: Severe nonketotic hyperosmolar coma-intensive care management. Eur J Anaesthesiol 15: 603-606, 1998 40. Hale PJ, Crase J, Nattrass M: Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. BMJ (Clin Res Ed) 289: 1035-1038, 1984 41. Hamblin PS, Topliss DJ, Chosich N, et al: Deaths associated with diabetic ketoacidosis and hyperosmolar coma, 1973-1988. Med J Aust 151: 439,441442,444, 1989 42. Jenkins D, Close CF, Krentz AJ, et al: Euglycaemic diabetic ketoacidosis: Does it exist? Acta Diabetol 30251-253, 1993 43. Joffe BI, Seftel HC, Goldberg R, et al: Factors in the pathogenesis of experimental nonketotic and ketoacidotic diabetic stupor. Diabetes 22: 653-657, 1975 44. Kebler R, McDonald FD, Cadnapaphomchai F:Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med 79: 571-576, 1985 45. Keller U, Berger W, Ritz R, et al: Course and prognosis of 86 episodes of diabetic coma: A five year experience with a uniform schedule of treatment. Diabetologia 11: 93-100, 1975 46. Keller U, Berger W Prevention of hypophosphatemia by phosphate infusion during treatment of diabetic ketoacidosis and hyperosmolar coma. Diabetes 29: 87-95, 1980 47. Kitabchi AE, Murphy MB: Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma. Med Clin North Am 7 2 15451563,1988 48. Kitabchi AE, Wall BM Diabetic ketoacidosis. Med Clin North Am 79: 9-37,1995 49. Kitabchi AE: Low-dose insulin therapy in diabetic ketoacidosis: Fact or fiction? Diabetes Metab Rev 5: 337-363, 1989 50. Laffel L: Ketone bodies: A review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Rev 15:412426, 1999 51. Lebovitz HE: Diabetic ketoacidosis. Lancet 345: 767-772, 1995 52. Leung CB, Li PK, Lui SF, et al: Acute renal failure (ARF) caused by rhabdomyolysis due to diabetic hyperosmolar nonketotic coma: A case report and literature review. Renal Failure 1481435, 1992 53. Lever E, Jaspan JB: Sodium bicarbonate therapy in severe diabetic ketoacidosis. Am J Med 75263-268, 1983 54. Levine SN, Sanson TH: Treatment of hyperglycaemic hyperosmolar nonketotic syndrome. Drugs 38: 462472, 1989 55. Lorber D: Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 79:3952, 1995 56. Lutterman JA, Adriaansen AA, van 't Laar A Treatment of severe diabetic ketoaadosis: A comparative study of two methods. Diabetologia 1717-21, 1979 57. Luzi L, Barrett EJ, Groop LC, et al: Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis. Diabetes 371470-1477, 1988

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58. Maioli M, Arca GM, Ganau A, et al: A case of hyperglycemic hyperosmolar nonketotic coma during anesthesia: A possible cause of failed re-awakening. Diabetes Res 1 8 4 5 48, 1991 59. Malchoff CD, Pohl SL, Kaiser DL, et al: Determinants of glucose and ketoacid concentrations in acutely hyperglycemic diabetic patients. Am J Med 77275285, 1984 60. Malone ML, Gennis V, Goodwin JS: Characteristics of diabetic ketoacidosis in older versus younger adults. J Am Geriatr SOC4O:llOO-1104, 1992 61. Marliss EB, Ohman JL Jr, Aoki lT,et al: Altered redox state obscuring ketoacidosis in diabetic patients with lactic acidosis. N Engl J Med 283:978-980, 1970 62. Martin HE, Smith K, Wilson M The fluid and electrolyte therapy of severe diabetic acidosis and ketosis. Am J Med 24:376-389, 1958 63. Matz R Management of the hyperosmolar hyperglycemic syndrome. Am Fam Physician 60:1468-1476, 1999 64. McGarry JD,Foster DW Regulation of ketogenesis and clinical aspects of the ketotic state. Metabolism 21:471489, 1972 65. McKenna K, Morris AD, Azam H, et al: Exaggerated vasopressin secretion and attenuated osmoregulated thirst in human survivors of hyperosmolar coma. Diabetologia 42:534-538, 1999 66. Microvascular and acute complications in IDDM patients: The EURODIAB IDDM Complications Study. Diabetologia 37278-285, 1994 67. Miles JM, Gerich JE: Glucose and ketone body kinetics in diabetic ketoacidosis. Clin Endocrinol Metab 12303-319, 1983 68. Morris LR, Murphy MB, Kitabchi AE: Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med 105:836-840, 1986 69. Munro JF,Campbell IW,McCuish AC, et al: Euglycaemic diabetic ketoacidosis. BMJ 2:578-580, 1973 70. Munshi MN, Martin RE, Fonseca VA: Hyperosmolar nonketotic diabetic syndrome following treatment of human immunodeficiency virus with didanosine. Diabetes Care 17316-317, 1994 71. Okuda Y, Adrogue HJ, Field JB, et al: Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. J Clin Endocrinol Metab 81:314-320, 1996 72. Owen OE, Block BS, Pate1 M, et al: Human splanchnic metabolism during diabetic ketoacidiosis. Metabolism 26381-398, 1977 73. Owen OE, Licht JH, Sapir DG: Renal function and effects of partial rehydration during diabetic ketoacidosis. Diabetes 30:510-518, 1981 74. Peden NR, Braaten JT, McKendry JB: Diabetic ketoacidosis during long-term treatment with continuous subcutaneous insulin infusion. Diabetes Care 71-5, 1984 75. Reichel A, Rietzsch H, Kohler HJ, et al: Cessation of insulin infusion at night-time during CSII-therapy: Comparison of regular human insulin and insulin lispro. Exp Clin Endocrinol Diabetes 106168-172, 1998 76. Rowe PA, Mather HG: Hyperosmolar nonketotic diabetes mellitus associated with metolazone. BMJ (Clin Res Ed) 291:25-26, 1985 77. Ruderman NB, Goodman MN: Inhibition of muscle acetoacetate utilization during diabetic ketoacidosis. Am J Physiol226136-143, 1974 78. Sakakura C, Hagiwara A, Kin S, et al: A case of hyperosmolar nonketotic coma occurring during chemotherapy using cisplatin for gallbladder cancer. Hepatogastroenterology 46:2801-2803, 1999 79. Schade DS, Eaton RP: Dose response to insulin in man: Differential effects on glucose and ketone body regulation. J Clin Endocrinol Metab 44:1038-1053,1977 80. Schade DS, Eaton RP: Metabolic and clinical significance of ketosis. Special Topics in Endocrinology and Metabolism 4:l-27, 1982 81. Scott RS, Brown LJ, Clifford P: Use of health services by diabetic persons. 11. Hospital admissions. Diabetes Care 843-47, 1985 82. Sherwin RS, Hendler RG, Felig P: Effect of diabetes mellitus and insulin on the turnover and metabolic response to ketones in man. Diabetes 25:776-784, 1976 83. Siperstein MD:Diabetic ketoacidosis and hyperosmolar coma. Endocrinol Metab Clin North Am 2k415-432, 1992 84. Thiebaud D, Jacot E, DeFronzo RA, et al: The effect of graded doses of insulin on total

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