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Home , Diabetes, Diabetic ketoacidosis, Hyperosmolar syndrome

In Brief

Diabetic (DKA) and hyperosmolar hyperglycemic syndrome (HHS) are two acute complications of that can result in increased morbidity and mortality if not efficiently and effectively treated. Mortality rates are 2–5% for DKA and 15% for HHS, and mortality is usually a conse- quence of the underlying precipitating (s) rather than a result of the metabolic changes of . Effective standardized treatment proto- cols, as well as prompt identification and treatment of the precipitating cause, are important factors affecting outcome.

Diabetic Ketoacidosis and Hyperglycemic

The two most common life-threaten- having because 29% ing complications of diabetes mellitus of patients were obese, had measur- include (DKA) able secretion, and had a low Guillermo E. Umpierrez, MD, FACP; and hyperglycemic hyperosmolar syn- prevalence of autoimmune markers of Mary Beth Murphy, RN, MS, CDE, drome (HHS). Although there are -cell destruction.4 MBA; and Abbas E. Kitabchi, PhD, important differences in their patho- Treatment of patients with DKA MD, FACP, FACE genesis, the basic underlying mecha- and HHS utilizes significant health nism for both disorders is a reduction care resources. Recently, it was esti- in the net effective concentration of mated that treatment of DKA episodes circulating insulin coupled with a accounts for more than one of every concomitant elevation of counterreg- four dollars spent on direct ulatory (, cate- medical care for adults with type 1 cholamines, cortisol, and growth hor- diabetes, and for one of every two dol- mone). lars for those patients experiencing These hyperglycemic emergencies multiple episodes of DKA.5 continue to be important causes of Despite major advances in their morbidity and mortality among management, recent series have patients with diabetes. DKA is report- reported a of 2–5% for ed to be responsible for more than DKA, and ~15% for HHS.1,2 DKA is 100,000 hospital admissions per year the most common cause of in in the United States1 and accounts for children and adolescents with type 1 4–9% of all hospital discharge sum- diabetes and accounts for half of all maries among patients with diabetes.1 in diabetic patients <24 years The incidence of HHS is lower than of age.6 DKA and accounts for <1% of all pri- The cause of death in patients with mary diabetic admissions.1 DKA and HHS rarely results from the Most patients with DKA have type metabolic complications of hyper- 1 diabetes; however, patients with glycemia or metabolic but type 2 diabetes are also at risk during rather relates to the underlying med- the catabolic of acute illness.2 ical illness that precipitated the meta- Contrary to popular belief, DKA is bolic decompensation. Thus, success- more common in adults than in chil- ful treatment requires a prompt and dren.1 In community-based studies, careful search for the precipitating more than 40% of African-American cause(s). patients with DKA were >40 years of This review discusses the pathogen- age and more than 20% were >55 esis, clinical presentation, complica- years of age.3 Many of these adult tions, and recommendations for treat- patients with DKA were classified as ment of DKA and HHS. 28 Diabetes Spectrum Volume 15, Number 1, 2002 PATHOGENESIS synthesis. Malonyl CoA inhibits carni- reported that psychological problems Acute Care of Patients With Diabetes / From Research to Practice DKA is characterized by hyper- tine palmitoyl-transferase I (CPT I), complicated by eating disorders were glycemia, , and the rate-limiting enzyme for transester- a contributing factor in 20% of recur- increased circulating total body ification of fatty acyl CoA to fatty acyl rent ketoacidosis in young women. concentration. Ketoacidosis , allowing oxidation of fatty More recently, it was reported that up results from the lack of, or ineffective- acids to . CPT I is to one-third of young women with ness of, insulin with concomitant ele- required for movement of FFA into the have eating distur- vation of counterregulatory hormones mitochondria where oxida- bances,18 which affect the manage- (glucagon, catecholamines, cortisol, tion takes place. The increased activity ment of diabetes and increase the risk and growth ).7,8 The associa- of fatty acyl CoA and CPT I in DKA of microvascular complications. tion of insulin deficiency and leads to accelerated ketogenesis.8 Factors that may lead to insulin omis- increased counterregulatory hormones Studies in animals and humans sion in young subjects included fear of leads to altered production with diabetes have shown that lower gaining weight with good metabolic and disposal and to increased insulin levels are needed for antilipoly- control, fear of , rebel- and production of ketone bodies. sis than for peripheral glucose lion from authority, and diabetes- Hyperglycemia results from increased uptake.10,11 HHS is characterized by a related stress. Noncompliance with hepatic and renal glucose production relative deficiency of insulin concen- therapy has also been reported to be a ( and ) tration to maintain normoglycemia major precipitating cause for DKA in and impaired glucose utilization in but adequate levels to prevent lipolysis urban black and medically indigent peripheral tissues.7 Increased gluco- and ketogenesis.11 To date, very few patients. A recent study reported that neogenesis results from the high avail- studies have been performed compar- in urban black patients, poor compli- ability of noncarbohydrate substrates ing differences in counterregulatory ance with insulin accounted for more (alanine, lactate, and glycerol in the response in DKA versus HHS. than 50% of DKA cases admitted to a and glutamine in the )9 Patients with HHS have been reported major urban hospital.3 and from the increased activity of glu- to have higher insulin concentration Most patients with HHS have type coneogenic enzymes (phosphoenol (demonstrated by basal and stimulat- 2 diabetes. HHS is the initial manifes- pyruvate carboxykinase [PEPCK], ed C-peptide levels),12 and reduced tation of diabetes in 7–17% of fructose-1,6-bisphosphatase, and concentrations of FFA, cortisol, patients.1,3 is the major pre- pyruvate carboxylase). From a quanti- , and glucagon com- cipitating factor, occurring in tative standpoint, increased hepatic pared to patients with DKA.12–14 30–60% of patients, with urinary glucose production represents the However, one study reported similar tract and being major pathogenic disturbance respon- levels of FFA in patients with DKA the most common infections.19 In sible for hyperglycemia in patients and HHS,12 indicating that further many instances, an acute illness, such with DKA.7 In addition, both hyper- studies are needed to characterize as cerebrovascular accident or glycemia and high ketone levels cause metabolic responses in such patients. myocardial , provokes the osmotic that leads to hypo- release of counterregulatory hor- volemia and decreased glomerular fil- PRECIPITATING CAUSES mones, resulting in hyperglycemia. tration rate. The latter further aggra- DKA is the initial manifestation of dia- Furthermore, in many cases, the vates hyperglycemia. betes in 20% of adult patients1 and patient or caregiver is unaware of the The mechanisms that underlie the 30–40% of children15,16 with type 1 of decompensat- increased production of have diabetes. In patients with established ed diabetes, or the patient is unable to recently been reviewed.8 The combina- diabetes, precipitating factors for DKA treat the progressive . tion of insulin deficiency and increased include infections, intercurrent illness- Certain that cause DKA concentration of counterregulatory es, psychological stress, and poor com- may also precipitate the development hormones causes the activation of hor- pliance with therapy. Infection is the of HHS, including , mone-sensitive in . most common precipitating factor for , dilantin, and - The increased activity of tissue lipase DKA, occurring in 30–50% of cases. blockers. causes breakdown of triglyceride into and pneumonia glycerol and free fatty acids (FFA). account for the majority of infections. DIAGNOSIS While glycerol becomes an important Other acute conditions that may pre- Symptoms and Signs substrate for gluconeogenesis in the cipitate DKA include cerebrovascular The clinical presentation of DKA usu- liver, the massive release of FFA accident, alcohol/drug abuse, pancre- ally develops rapidly, over a period of assumes pathophysiological predomi- atitis, pulmonary , myocar- <24 hours. Polyuria, polydipsia, and nance, as they are the hepatic precur- dial infarction, and trauma. Drugs that may be present for several sors of the ketoacids. In the liver, FFA affect , such days before the development of are oxidized to ketone bodies, a as , , sympath- ketoacidosis, and and process predominantly stimulated by omimetic agents, and , abdominal are frequently the glucagon. Increased concentration of may also precipitate the development presenting symptoms. Abdominal glucagon lowers the hepatic levels of of DKA. pain, sometimes mimicking an acute malonyl coenzyme A (CoA) by block- Recent studies have emphasized the abdomen, is reported in 40–75% of ing the conversion of pyruvate to importance of noncompliance and cases of DKA.20 In our institution, we acetyl CoA through inhibition of psychological factors in the incidence have observed that the presence of acetyl CoA carboxylase, the first rate- of DKA. In a survey of 341 female is associated with a limiting enzyme in de novo fatty acid patients with type 1 diabetes,17 it was more severe metabolic acidosis and

29 Diabetes Spectrum Volume 15, Number 1, 2002 with a history of alcohol or glycemia, hyperketonemia, and meta- reaction provides a semiquantitative abuse, but not with the severity of bolic acidosis. estimation of acetoacetate and hyperglycemia or dehydration. In the past, the most widely used levels but does not recognize the pres- Although the potential of an acute diagnostic criteria for DKA included a ence of -hydroxybutyrate, which is abdominal problem requiring surgical glucose level >250 mg/dl, a the main ketoacid in DKA. Therefore, intervention should not be over- moderate degree of ketonemia, serum this test may underestimate the level of looked, in the majority of patients, the <15 mEq/l, arterial pH ketosis. Direct measurement of - abdominal pain spontaneously <7.3, and an increased anion gap hydroxybutyrate is now available by resolves after correction of the meta- metabolic acidosis. Although these method, which is a more bolic disturbance. criteria served well for research pur- accurate indicator of ketoacidosis. reveals signs poses, they have significant limitations of dehydration, including loss of skin in clinical practice because the majori- Common Laboratory Pitfalls turgor, dry mucous membranes, ty of patients with DKA present with Patients with DKA frequently present , and . Mental mild metabolic acidosis despite elevat- with leukocytosis in the absence of status can vary from full alertness to ed serum glucose and -hydroxybu- infection. However, a leukocyte count profound lethargy; however, <20% of tyrate concentrations. Thus, the bio- >25,000 mm3 or the presence of patients are hospitalized with loss of chemical criteria for diagnosis were >10% neutrophil bands is seldom consciousness.2,21 Most patients are recently modified.2 Table 1 summa- seen in the absence of bacterial infec- normothermic or even hypothermic at rizes the biochemical criteria for the tion.22 The admission serum is presentation. Acetone on breath and diagnosis and empirical subclassifica- usually low because of the osmotic labored Kussmaul respiration may tion of DKA and HHS. flux of water from the intracellular to also be present on admission, particu- The diagnostic criteria for HHS the extracellular space in the presence larly in patients with severe metabolic include a plasma glucose concentra- of hyperglycemia. To assess the severi- acidosis. tion >600 mg/dl, a serum osmolality ty of sodium and water deficit, serum Typical patients with HHS have >320 mOsm/kg of water, and the sodium may be corrected by adding undiagnosed diabetes, are between 55 absence of significant ketoacidosis. 1.6 mg/dl to the measured serum sodi- and 70 years of age, and frequently Although by definition patients with um for each 100 mg/dl of glucose are nursing home residents. Most HHS have a serum pH >7.3, a serum above 100 mg/dl. An increase in patients who develop HHS do so over bicarbonate >18 mEq/l, and negative serum sodium concentration in the days to weeks during which they ketone bodies in and plasma, presence of hyperglycemia indicates a experience , , and mild ketonemia may be present. rather profound degree of water loss. progressive decline in the level of con- Approximately 50% of patients with Extreme , which sciousness. The most common clinical HHS have an increased may be present during DKA due to presentation for patients with HHS is metabolic acidosis as the result of con- impaired lipoprotein lipase activity, altered sensorium.19 comitant ketoacidosis and/or an may cause lipemic serum with spuri- Physical examination reveals signs increase in serum lactate levels.2 ous lowering of serum glucose of volume depletion. Fever due to The assessment of ketonemia, the (pseudonormoglycemia)23 and serum underlying infection is common, and key diagnostic feature of ketoacidosis, sodium (pseudohyponatremia)24 in signs of acidosis (Kussmaul respira- is usually performed by the nitroprus- laboratories still using volumetric test- tion, acetone breath) are usually side reaction. However, clinicians ing or dilution of samples with ion- absent. Gastrointestinal manifesta- should be aware that the nitroprusside specific electrodes. tions (abdominal pain, vomiting) fre- quently reported in patients with DKA are not typically present in Table 1. Diagnostic Criteria for DKA and HHS HHS. Thus, the presence of abdomi- nal pain in patients without signifi- Diagnostic Criteria and Classification cant metabolic acidosis needs to be DKA HHS investigated. In some patients, focal Mild Moderate Severe neurological signs (, hemi- anopsia) and (partial motor Plasma glucose (mg/dl) >250 >250 >250 >600 seizures more common than general- Arterial pH 7.25–7.30 7.00–<7.24 <7.00 >7.30 ized) may be the dominant clinical features, resulting in a common misdi- Serum bicarbonate (mEq/L) 15–18 10–<15 <10 >15 agnosis of .21 Despite the focal Urine ketone* Positive Positive Positive Small nature of neurological findings, these manifestations often reverse complete- Serum ketone* Positive Positive Positive Small ly after correction of the metabolic Effective serum osmolality** Variable Variable Variable >320 mOsm/kg disorder. Anion gap*** >10 >12 >12 <12 Laboratory Findings Alteration in sensorium A A/D S/C S/C Although the diagnoses of DKA and or mental obtundation HHS can be suspected on clinical *Nitroprusside reaction method **Calculation: Effective serum osmolality: 2[measured Na (mEq/L)] glucose (mg/dl)/18 grounds, confirmation is based on ***Calculation: Anion gap: (Na ) (Cl HCO3 ) (mEq/L). See text for details. laboratory tests. The syndrome of A, alert; D, drowsy; S, stuporous, C, comatose. DKA consists of the triad of hyper- 30 Diabetes Spectrum Volume 15, Number 1, 2002 The admission serum ketoacidosis have DKA. Patients with serum bicarbonate concentration <18 Acute Care of Patients With Diabetes / From Research to Practice concentration is usually elevated in chronic ethanol abuse with a recent mEq/l. patients with DKA. In a recent series,3 binge culminating in , vomit- the mean serum potassium in patients ing, and acute may present TREATMENT with DKA and those with HHS was with . The key Figures 1 and 2 show the recommend- 5.6 and 5.7 mEq/l, respectively. These diagnostic feature that differentiates ed algorithm suggested by the recent high levels occur because of a shift of diabetic and alcohol-induced ketoaci- American Diabetes Association posi- potassium from the intracellular to dosis is the concentration of blood tion statement on treatment of DKA the extracellular space due to glucose.26 While DKA is characterized and HHS.27 In general, treatment of acidemia, insulin deficiency, and by severe hyperglycemia, the presence DKA and HHS requires frequent hypertonicity. Similarly, the admission of ketoacidosis without hyperglycemia of patients, correction of serum phosphate level may be normal in an alcoholic patient is virtually hypovolemia and hyperglycemia, or elevated because of metabolic aci- diagnostic of alcoholic ketoacidosis. replacement of electrolyte losses, and dosis. Dehydration also can lead to In addition, some patients with careful search for the precipitating increases in total serum protein, albu- decreased intake (<500 kcal/day) cause(s). A flow sheet is invaluable for min, , and creatine phospho- for several days may present with recording vital signs, volume and rate kinase concentration in patients with starvation . However, a healthy of fluid administration, insulin acute diabetic decompensation. subject is able to adapt to prolonged dosage, and urine output and to assess Finally, serum , which is fasting by increasing ketone clearance the efficacy of medical therapy. In measured by a colorimetric method, by peripheral tissue (brain and mus- addition, frequent laboratory moni- may be falsely elevated as a result of cle) and by enhancing the kidney’s toring is important to assess response interference by blood acetoacetate lev- ability to excrete ammonia to com- to treatment and to document resolu- els.25 pensate for the increased acid produc- tion of hyperglycemia and/or metabol- Clinicians should remember that tion. Therefore, a patient with starva- ic acidosis. Serial laboratory measure- not all patients who present with tion ketosis rarely presents with a ments include glucose and electrolytes

Figure 1. Protocol for Management of Adult Patients with Diabetic Ketoacidosis *Serum Na+ should be corrected for hyperglycemia (for each 100 mg/dl glucose above 100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value). **Upper limits for serum potassium may vary by laboratory. Adapted with permission from reference 27. 31 Diabetes Spectrum Volume 15, Number 1, 2002 and, in patients with DKA, venous 0.45% (250–500 mL/h) management is insulin therapy. pH, bicarbonate, and anion gap val- depending on the serum sodium con- Prospective randomized studies have ues until resolution of hyperglycemia centration and state of hydration. The clearly established the superiority of and metabolic acidosis. goal is to replace half of the estimated low-dose insulin therapy in that small- water deficit over a period of 12–24 er doses of insulin result in less hypo- Fluid Therapy h. See Table 2 for typical total body glycemia and .29,30 Insulin Patients with DKA and HHS are deficits of water and electrolytes in increases peripheral glucose utilization invariably volume depleted, with an DKA and HHS. and decreases hepatic glucose produc- estimated water deficit of ~100 ml/kg Once the plasma glucose reaches tion, thereby lowering blood glucose of body weight.28 The initial fluid 250 mg/dl in DKA and 300 mg/dl in concentration. In addition, insulin therapy is directed toward expansion HHS, replacement fluids should con- therapy inhibits the release of FFAs of intravascular volume and restora- tain 5–10% dextrose to allow contin- from adipose tissue and decreases tion of renal perfusion. Isotonic ued insulin administration until ketogenesis, both of which lead to the saline (0.9% NaCl) infused at a rate ketonemia is controlled while avoid- reversal of ketogenesis. of 500–1,000 mL/h during the first 2 ing hypoglycemia.2 An additional In critically ill and mentally h is usually adequate, but in patients important aspect of fluid management obtunded patients, with hypovolemic , a third or in hyperglycemic states is to replace given intravenously by continuous fourth liter of isotonic saline may be the volume of urinary losses. Failure infusion is the treatment of choice. needed to restore normal blood pres- to adjust fluid replacement for urinary Such patients should be admitted to sure and tissue perfusion. losses may delay correction of elec- an or to a step After intravascular volume deple- trolytes and water deficit. down unit where adequate nursing tion has been corrected, the rate of care and quick turnaround of labora- normal saline infusion should be Insulin Therapy tory tests results are available. An ini- reduced to 250 mL/h or changed to The cornerstone of DKA and HHS tial intravenous of regular

Figure 2. Management of Adult Patients with Hyperosmolar Hyperglycemic Syndrome *This protocol is for patients admitted with mental status change or severe dehydration who require admission to an ICU. **Effective serum osmolality calculation: 2[measured Na (mEq/l)] glucose (mg/dl)/18 ***Serum Na+ should be corrected for hyperglycemia (for each 100 mg/dl glucose above 100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value). †Upper limits for serum potassium may vary by laboratory. Adapted with permission from reference 27. 32 Diabetes Spectrum Volume 15, Number 1, 2002 Table 2. Typical Total Body Deficits of Water and Electrolytes Bicarbonate Acute Care of Patients With Diabetes / From Research to Practice 28 Bicarbonate administration in patients Seen in DKA and HHS with DKA remains controversial. Severe metabolic acidosis can lead to Typical Deficit impaired myocardial contractility, DKA HHS cerebral vasodilatation and , and Total water (L) 6 9 several gastrointestinal complications. However, rapid alkalinization may Water (ml/kg)* 100 100–200 result in hypokalemia, paradoxical Na (mEq/kg)* 7–10 5–13 central acidosis, and Cl (mEq/kg)* 3–5 5–15 worsened intracellular acidosis (as a result of increased K (mEq/kg)* 3–5 4–6 production) with resultant . PO4 (mEq/kg)* 5–7 3–7 Controlled studies have failed to show Mg (mEq/kg)* 1–2 1–2 any benefit from bicarbonate therapy in patients with DKA with an arterial Ca (mEq/kg)* 1–2 1–2 pH between 6.9 and 7.1.35 However, *Per kg of body weight most experts in the field recommend bicarbonate replacement in patients insulin of 0.15 unit/kg of body intramuscular injection (Figures 1 and with a pH <7.0. In patients with DKA weight, followed by a continuous 2). The effectiveness of intramuscular with arterial pH ≥7.0, or in patients infusion of regular insulin at a dose of or subcutaneous administration has with HHS, bicarbonate therapy is not 0.1 unit/kg/h (5–10 unit/h) should be been shown to be similar; however, recommended.2 See Figures 1 and 2 administered. This will result in a fair- subcutaneous injections are easier and for dosing guidelines. ly predictable decrease in plasma glu- less painful. cose concentration at a rate of 65–125 Phosphate mg/h.31 Potassium Total body phosphate deficiency is When plasma glucose levels reach Despite a total body potassium deficit universally present in patients with 250 mg/dl in DKA or 300 mg/dl in of ~3–5 mEq/kg of body weight, most DKA, but its clinical relevance and HHS, the insulin infusion rate is patients with DKA have a serum benefits of replacement therapy remain reduced to 0.05 unit/kg/h (3–5 potassium level at or above the upper uncertain. Several studies have failed units/h), and dextrose (5–10%) limits of normal.2 These high levels to show any beneficial effect of phos- should be added to intravenous fluids. occur because of a shift of potassium phate replacement on clinical out- Thereafter, the rate of insulin adminis- from the intracellular to the extracellu- come.36 Furthermore, aggressive phos- tration may need to be adjusted to lar space due to acidemia, insulin defi- phate therapy is potentially hazardous, maintain the above glucose values ciency, and hypertonicity. Both insulin as indicated in case reports of children until ketoacidosis or mental obtunda- therapy and correction of acidosis with DKA who developed hypocal- tion and hyperosmolality are resolved. decrease serum potassium levels by cemia and tetany secondary to intra- During therapy, capillary blood glu- stimulating cellular potassium uptake venous phosphate administration.37 cose should be determined every 1–2 in peripheral tissues. Therefore, to pre- Theoretical advantages of phosphate hours at the bedside using a glucose vent hypokalemia, most patients therapy include prevention of respira- oxidase reagent strip. Blood should be require intravenous potassium during tory and generation of ery- drawn every 2–4 h for determination the course of DKA therapy. Replace- throcyte 2,3-diphosphoglycerate. of serum electrolytes, glucose, blood ment with intravenous potassium Because of these potential benefits, nitrogen, creatinine, , (two-thirds as potassium chloride careful phosphate replacement may be phosphorus, and venous pH. [KCl] and one-third as potassium indicated in patients with cardiac dys- A conscious patient with mild DKA phosphate [KPO4]) should be initiated function, anemia, respiratory depres- could be admitted to a general hospi- as soon as the serum potassium con- sion, and in those with serum phos- tal ward. In such patients, the admin- centration is below 5.0 mEq/L. The phate concentration lower than istration of regular insulin every 1–2 h treatment goal is to maintain serum 1.0–1.5 mg/dl. If phosphate replace- by subcutaneous or intramuscular potassium levels within the normal ment is needed, it should be adminis- route has been shown to be as effec- range of 4–5 mEq/L. tered as a potassium salt, by giving tive in lowering blood glucose and In some hyperglycemic patients half as KPO4 and half as KCl. In such ketone bodies concentration as giving with severe potassium deficiency, patients, because of the risk of the entire insulin dose by intravenous insulin administration may precipitate hypocalcemia, serum and infusion.32,33 Furthermore, it has been profound hypokalemia,34 which can phosphate levels must be monitored shown that the addition of albumin in induce life-threatening during phosphate infusion. the infusate was not necessary to pre- and respiratory . vent adsorption of insulin to the IV Thus, if the initial serum potassium is TRANSITION TO tubing or bag.33 Such patients should lower than 3.3 mEq/L, potassium SUBCUTANEOUS INSULIN receive the recommended hydrating replacement should begin immediately Patients with moderate to severe DKA solution and an initial “priming” dose by an infusion of KCl at a rate of 40 should be treated with continuous of regular insulin of 0.4 unit/kg of mEq/h, and insulin therapy should be intravenous insulin until ketoacidosis body weight, given half as intravenous delayed until serum potassium is ≥3.3 is resolved. Criteria for resolution of bolus and half as a subcutaneous or mEq/L (Figure 1). ketoacidosis include a blood glucose 33 Diabetes Spectrum Volume 15, Number 1, 2002 <200 mg/dl, a serum bicarbonate level perception of warning symptoms of associated with increased risk for cere- ≥18 mEq/L, a venous pH >7.3, and a developing hypoglycemia), which may bral edema. Hyperglycemia superim- calculated anion gap ≤12 mEq/L. The complicate after posed on an ischemic insult increases criteria for resolution of HHS include resolution of hyperglycemic crises. the extent of neurological damage, improvement of mental status, blood Hypoglycemia is not frequently blood-brain barrier dysfunction, and glucose <300 mg/dL, and a serum observed in patients with HHS. Blood edema formation. osmolality of <320 mOsm/kg. glucose values <60 mg/dl have been In addition, it has been shown that When these levels are reached, sub- reported in <5% of HHS patients dur- a lower serum sodium concentration cutaneous insulin therapy can be ing intravenous insulin therapy.3 that does not resolve during therapy started. If patients are able to eat, Although the admission serum may be associated with increased risk split-dose therapy with both regular potassium concentration is commonly of .42,43 The more fre- (short-acting) and intermediate-acting elevated in patients with DKA and quent occurrence of cerebral edema in insulin may be given. It is easier to HHS, during treatment, plasma con- children than in adults may be make this transition in the morning centration of potassium will invariably explained in part by the fact that chil- before breakfast or at dinnertime. decrease. Both insulin therapy and cor- dren’s brains have higher oxygen Patients with known diabetes may rection of acidosis decrease serum requirements than those of adults and be given insulin at the dosage they potassium levels by stimulating cellular are thus more susceptible to ischemia. were receiving before the onset of potassium uptake in peripheral tissues. Measures that may decrease the DKA. In patients with newly diag- Thus, to prevent hypokalemia, replace- risk of cerebral edema in high-risk nosed diabetes, an initial insulin dose ment with intravenous potassium as patients are gradual replacement of of 0.6 unit/kg/day is usually sufficient soon as the serum potassium concen- sodium and water deficits in patients to achieve and maintain metabolic tration is ≤5.0 mEq/L is indicated with high serum osmolality (maximal control. Two-thirds of this total daily (upper limits may vary by laboratory). reduction in osmolality 3 mOsm/kg/h) dose should be given in the morning In patients admitted with normal and the addition of dextrose to the and one-third in the evening as a split- or reduced serum potassium, insulin hydrating solutions once blood glu- mixed dose. If patients are not able to administration may precipitate pro- cose reaches 250 mg/dl in DKA and eat, intravenous insulin should be found hypokalemia.34 Thus, if the ini- 300 mg/dl in HHS.2 continued while an infusion of 5% tial serum potassium is <3.3 mEq/L, Patients with cerebral edema dextrose in half-normal saline is given intravenous potassium replacement should be transferred to an intensive at a rate of 100–200 mL/h. should begin immediately, and insulin care unit setting. If signs of increased A critical element to avoid recur- therapy should be held until serum or brain hernia- rence of hyperglycemia or ketoacido- potassium is ≥3.3 mEq/L (see Figures tion are present, only 7–14% of sis during the transition period to sub- 1 and 2). patients recover without permanent cutaneous insulin is to allow a 1- or 2- Cerebral edema is a rare but seri- significant neurological . h overlap of intravenous insulin infu- ous of DKA. It occurs in Treatment includes the immediate sion during the initiation of subcuta- ~1% of episodes of DKA in chil- use of intravenous ,40 reduc- neous regular insulin to ensure ade- dren38,39 and is associated with a mor- tion of fluid administration rate, and quate plasma insulin levels. tality rate of 40–90%.40 Clinically, possible mechanical ventilation to help cerebral edema is characterized by a reduce brain swelling.44 COMPLICATIONS decreasing level of consciousness and and therapy have no proven Hypoglycemia is the most common , followed by seizures, benefit over the immediate use of complication during insulin infusion. sphincter incontinence, pupillary intravenous mannitol.40 Despite the use of low-dose insulin changes, papilledema, bradycardia, protocols, hypoglycemia is still report- and respiratory arrest. PREVENTION ed in 10–25% of patients with DKA.3 It has been hypothesized that cere- The financial burden of DKA and The failure to reduce insulin infusion bral edema in children with DKA may HHS is estimated to exceed $1 billion rate and/or to use dextrose-containing be caused by the rapid shift in extra- per year. The most common precipi- solutions when blood glucose levels cellular and intracellular fluids and tating causes of DKA and HHS reach 250 mg/dl is the most important changes in osmolality due to accumu- include infection, intercurrent illness, associated with hypo- lation of osmolytes in brain cells psychological stress, and noncompli- glycemia during insulin infusion. exposed to hyperosmolar conditions.41 ance with therapy. Many episodes Frequent A rapid decrease in extracellular could be prevented through better and (every 1–2 h) is mandatory to recog- osmolality during treatment would novel approaches to patient education nize hypoglycemia and serious compli- then result in osmotically mediated and effective outpatient treatment cations. Many patients with hyper- swelling of the brain. Although programs. glycemic crises who experience hypo- osmotic factors and other mechanisms Paramount in this effort is glycemia during treatment do not expe- may a part in the development of improved education regarding sick- rience adrenergic manifestations of cerebral edema, recent data suggest day management. Education on sick- sweating, nervousness, , hunger, that cerebral edema in children with day management should review: and tachycardia despite low blood glu- DKA is related to brain ischemia.42 In • the importance of early contact cose levels (GEU, unpublished observa- children with DKA, both hypocapnia with the health care provider tions). Clinicians should be aware that (which causes cerebral vasoconstric- • the importance of insulin during an recurrent episodes of hypoglycemia tion) and extreme dehydration (as illness and the reasons never to dis- might be associated with a state of determined by a high initial serum continue insulin without contacting hypoglycemia unawareness (loss of urea nitrogen concentration) were the health care team 34 Diabetes Spectrum Volume 15, Number 1, 2002 • blood glucose goals and the use of nize or cannot treat the symptoms of and metabolic characteristics of hyperosmolar Acute Care of Patients With Diabetes / From Research to Practice supplemental short- or rapid-acting diabetes and dehydration or, in many nonketotic coma. Diabetes 20:228–238, 1971 insulin cases, who have caregivers who are 14Lindsey CA, Falooma GR, Unger RH: Plasma • availability of medications to sup- not knowledgeable about the signs glucagon in nonketotic hyperosmolar coma. press a fever and treat an infection and symptoms of diabetes and the JAMA 229:1771–1773, 1974 • initiation of an easily digestible li- conditions, procedures, and medica- 15Kaufman FR, Halvorson M: The treatment and quid containing carbohydrates tions that can lead to decompensa- prevention of diabetic ketoacidosis in children and salt when nauseated tion. Therefore, additional education and adolescents with type 1 diabetes mellitus. • information for family members on as well as the use of glucose and Pediatr Ann 28:576–582, 1999 sick-day management and record ketone monitoring may decrease the 16Kauffman FR, Halvorson M: Strategies to pre- keeping, including assessing and incidence and severity of HHS in this vent diabetic ketoacidosis in children with known type 1 diabetes. Clin Diabetes documenting temperature, respira- susceptible group. 15:236–239, 1997 tion and pulse, blood glucose and 17 urine/blood ketones, insulin taken, Polonsky WH, Anderson BJ, Lohrer PA, Aponte JE, Jacobson AM, Cole CF: Insulin omis- oral intake, and weight References sion in women with IDDM. Diabetes Care • information for 1 17:1178–1185, 1994 providers and school personnel on Graves EJ, Gillium BS: Detailed diagnosis and procedures: National Discharge Survey, 1995. 18Rydall AC, Rodin GM, Olmsted MP, Devenyi the signs and symptoms of new- National Center for Health Statistics. Vital RG, Daneman D: Disordered eating behavior onset and decompensated diabetes. Health Stat 13 (no. 133), 1997 and microvascular complications in young women with insulin-dependent diabetes mellitus. Approximately 50% of DKA 2Kitabchi AE, Umpierrez GE, Murphy MB, N Engl J Med 336:1849–1854, 1997 admissions may be preventable with Barrett EJ, Kreisberg RA, Malone JI, Wall BM: improved outpatient treatment pro- Management of hyperglycemic crises in patients 19Wachtel TJ, Tetu-Mouradjain LM, Goldman grams and better to self- with diabetes. Diabetes Care 24:31–53, 2001 DL, Ellis SE, O’Sullivan PS: Hyperosmolality and acidosis in diabetes mellitus: a three-year experi- care. Outpatient management is more 3Umpierrez GE, Kelly JP, Navarrete JE, Casals ence in Rhode Island. J Gen Int Med 6:495–502, cost effective and can minimize missed MMC, Kitabchi AE: Hyperglycemic crises in 1991 days of school or work for patients urban Blacks. Arch Int Med 157:669–675, 1997 20Campbell IW, Duncan LJ, Innes JA, MacCuish with diabetes and their family mem- 4Umpierrez GE, Woo W, Hagopian WA: AC, Munro JF: Abdominal pain in diabetic bers.45 The frequency of hospitaliza- Immunogenetic analysis suggests different patho- metabolic decompensation: clinical significance. genesis for obese and lean African-Americans tions for DKA have been reduced fol- JAMA 233:166–168, 1975 lowing diabetes education programs, with diabetic ketoacidosis. Diabetes Care 22:1517–1523, 1999 21 improved follow-up care, and access Guisado R, Arieff AI: Neurologic manifesta- tions of diabetic : correlation with bio- 15,45,46 5Javor KA, Kotsanos JG, McDonald RC, Baron to medical advice. chemical alterations in the brain. Metabolism AD, Kesterson JG, Tierney WM: Diabetic Additionally, an alarming rise in 24:665–669, 1975 ketoacidosis charges relative to medical charges insulin discontinuation because of of adult patients with type I diabetes. Diabetes 22Slovis CM, Mark VG, Slovis RJ, Bain RP: economic reasons as the precipitating Care 20:349–354, 1997 Diabetic ketoacidosis and infection: leukocyte cause for DKA in urban African count and differential as early predictors of infec- 6Basu A, Close CF, Jenkins D, Krentz AJ, tion. Am J Emerg Med 5:1–5, 1987 Americans illustrates the need for Nattrass M, Wright AD: Persisting mortality in health care legislation guaranteeing diabetic ketoacidosis. Diabet Med 10:282–289, 23Rumbak MJ, Hughes TA, Kitabchi AE: reimbursement for medications to 1992 Pseudonormoglycaemia in diabetic ketoacidosis with elevated triglycerides. Am J Emerg Med treat diabetes. 7Gerich JE, Lorenzi M, Bier DM, Tsalikian E, 9:61–63, 1991 Novel approaches to patient educa- Schneider V, Karam JH, Forsham PH: Effects of tion incorporating a variety of health physiologic levels of glucagon and growth hor- 24Kaminska ES, Pourmatabbed G: Spurious labo- care beliefs and socioeconomic issues mone on human carbohydrate and lipid metabo- ratory values in diabetic ketoacidosis and hyper- lism: studies involving administration of exoge- lipidemia. Am J Emerg Med 11:77–80, 1993 are critical to an effective prevention nous hormone during suppression of endogenous program. hormone secretion with somatostatin. J Clin 25Assadi FK, John EG, Formell L, Rosenthal IM: Home blood ketone monitoring Invest 57:875–884, 1976 Falsely elevated serum creatinine concentration in ketoacidosis. J Pediatr 107:562–564, 1985 systems, which measure -hydroxybu- 8McGarry JD: Regulation of ketogenesis and the tyrate levels on a fingerstick blood renaissance of carnitine palmitoyltransferase. 26Umpierrez GE, DiGirolamo M, Tuvlin JA, specimen, are now commercially Diabetes Metab Rev 5:271–284, 1989 Issacs SD, Bhoolasm SM, Kokko JP: Differences 47 in metabolic and hormonal milieu in diabetic- available. These systems measure - 9 Felig P, Wahren J: Influence of endogenous and alcohol-induced ketoacidosis. J Crit Care hydroxybutyrate levels in 30 seconds insulin secretion on splanchnic glucose and 15:52–59, 2000 with a detection range of 0–6 mmol/L. amino acid metabolism in man. J Clin Invest 27 Clinical studies have shown that ele- 50:1702–1711, 1971 American Diabetes Association: Hyperglycemic crises in patients with diabetes mellitus (Position vations of -hydroxybutyrate levels 10Yu SS, Kitabchi AE: Biological activity of Statement). Diabetes Care 24:1988–1996, 2001 are extremely common in patients and related polypeptides in the tis- 28 with poorly controlled diabetes, even sue. J Biol Chem 248:3753–3761, 1973 Ennis ED, Stahl EJVB, Kreisburg RA: The hyperosmolar hyperglycemic syndrome. Diabetes in the absence of positive urinary 11Shade DS, Eaton RP: Dose response to insulin Rev 2:115–126, 1994 ketones.48 The use of home glucose- in man: differential effects on glucose and ketone 29 ketone meters may allow early recog- body regulation. J Clin Endocrinol Metab Kitabchi AE, Fisher JN, Murphy MB, Rumbak 44:1038–1053, 1977 MJ: Diabetic ketoacidosis and the hyperglycemic nition of impending ketoacidosis, hyperosmolar nonketotic state. In Joslin’s which may help to guide insulin thera- 12Chupin M, Charbonnel B, Chupin F: C-peptide Diabetes Mellitus 13th ed. Kahn CR, Weir GC, py at home and may possibly prevent blood levels in ketoacidosis and in hyperosmolar Eds. Philadelphia, Pa., Lea & Febiger, 1994, p. hospitalization for DKA. non-ketotic . Acta Diabet 738–770 18:123–128, 1981 HHS occurs frequently in elderly or 30Kitabchi AE, Ayyagari V, Guerra SMO, debilitated patients who do not recog- 13Gerich JE, Martin MM, Recant LL: Clinical Medical House Staff: The efficacy of low dose 35 Diabetes Spectrum Volume 15, Number 1, 2002 versus conventional therapy of insulin for treat- phate in diabetic ketoacidosis. Diabetes Care Anderson BJ: Changing the process of diabetes ment of diabetic ketoacidosis. Ann Int Med 2:265–268, 1979 care improves metabolic outcomes and reduces 84:633–638, 1976 hospitalizations. Qual Manag Health Care 38 Bello FA, Sotos JF: Cerebral oedema in diabetic 6:53–62, 1998 31Morris LR, Kitabchi AE: Efficacy of low-dose ketoacidosis in children. Lancet 336:64, 1990 insulin therapy for severely obtunded patients in 46Runyan JW: The Memphis chronic pro- 39 diabetic ketoacidosis. Diabetes Care 3:53–56, Duck SC, Wyatt DT: Factors associated with gram: comparisons in outcome and the nurse’s 1980 brain herniation in the treatment of diabetic extended role. JAMA 231:264–267, 1975 32 ketoacidosis. J Pediatr 113:10–14, 1988 Fisher JN, Shahshahani MN, Kitabchi AE: 47Byrne HA, Tieszen KL, Hollis S, Dornan TL, 40 Diabetic ketoacidosis: low-dose insulin therapy Rosenbloom AL: Intracerebral crises during New JP: Evaluation of an electrochemical sensor by various routes. N Engl J Med 297:238–241, treatment of diabetic ketoacidosis. Diabetes Care for measuring blood ketones. Diabetes Care 1977 13:22–33, 1990 23:500–503, 2000 33 41 Sacks HS, Shahshahani M, Kitabchi AE, Fisher Finberg L: Why do patients with diabetic 48MacGillivray MH, Li PK, Lee JT, Mills BJ, JN, Young RT: Similar responsiveness of diabetic ketoacidosis have cerebral swelling, and why Vourhess ML, Putnam TI, Schaeffer PA: ketoacidosis to low-dose insulin by intramuscu- does treatment sometimes make it worse? Arch Elevated plasma beta-hydroxybutyrate concen- lar injection and albumin-preinfusion. Ann Int Pediatr Adolesc Med 150:785–786, 1996 trations without in healthy insulin- Med 90:36–42, 1979 42Glaser N, Barnett P, McCaslin I, Nelson D, dependent diabetic patients. J Clin Endocrinol 34Abramson E, Arky R: Diabetic acidosis with Trainor J, Louie J, Kaufman F, Quayle K, Metab 54:665–668, 1982 initial hypokalemia: therapeutic implications. Roback M: Risk factors for cerebral edema in JAMA 196:401–403, 1966 children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Guillermo E. Umpierrez, MD, FACP, 35Morris LR, Murphy MB, Kitabchi AE: Committee of the American Academy of Bicarbonate therapy in severe diabetic ketoacido- is an associate professor of medicine, Pediatrics. N Engl J Med 344:264–269, 2001 sis. Ann Intern Med 105:836–840, 1986 Mary Beth Murphy, RN, MS, CDE, 43Silver SM, Clark EC, Schroeder BM, Sterns MBA, is research nurse director, and 36Fisher JN, Kitabchi AE: A randomized study of RH: Pathogenesis of cerebral edema after treat- phosphate therapy in the treatment of diabetic Abbas E. Kitabchi, PhD, MD, FACP, ment of diabetic ketoacidosis. Kidney Int ketoacidosis. J Clin Endocrinol Metab FACE, is a professor of medicine and 51:1237–1244, 1997 57:177–180, 1983 director of the Division of 44White NH: Diabetic ketoacidosis in children. 37Zipf MB, Bacon GE, Spencer ML, Kelch RP, , Diabetes, and Endocrinol Metab Clin North Am 29:657–682, Hopwood NJ, Hawker CD: Hypocalcemia, Metabolism at the University of 2000 hypomagnesemia, and transient hypoparathy- Tennessee Health Science Center in roidism during therapy with potassium phos- 45Laffel LM, Brachett J, Kaufman F, Ho J, Memphis.

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