Hyperglycemic Crises in Patients with Diabetes Mellitus

POSITION STATEMENT

Hyperglycemic Crises in Patients With Diabetes Mellitus

AMERICAN DIABETES ASSOCIATION and sympathomimetic agents (e.g., do- butamine and terbutaline), may precipi- tate the development of HHS or DKA. In young patients with type 1 diabetes, psy- etoacidosis and hyperosmolar hy- lation from adipose tissue (lipolysis) and chological problems complicated by eat- perglycemia are the two most seri- to unrestrained hepatic fatty acid oxida- ing disorders may be a contributing factor K ous acute metabolic complications tion to ketone bodies (␤-hydroxybutyrate in 20% of recurrent ketoacidosis. Factors of diabetes, even if managed properly. [␤-OHB] and acetoacetate), with result- that may lead to insulin omission in These disorders can occur in both type 1 ing ketonemia and metabolic acidosis. On younger patients include fear of weight and type 2 diabetes. The mortality rate in the other hand, HHS may be caused by gain with improved metabolic control, patients with diabetic ketoacidosis (DKA) plasma insulin concentrations that are in- fear of hypoglycemia, rebellion from au- is Ͻ5% in experienced centers, whereas adequate to facilitate glucose utilization thority, and stress of chronic disease (13). the mortality rate of patients with hyper- by insulin-sensitive tissues but adequate osmolar hyperglycemic state (HHS) still (as determined by residual C-peptide) to DIAGNOSIS remains high at ϳ15%. The prognosis of prevent lipolysis and subsequent keto- both conditions is substantially worsened genesis, although the evidence for this is History and physical examination at the extremes of age and in the presence weak (14). Both DKA and HHS are asso- The process of HHS usually evolves over of coma and hypotension (1–10). ciated with glycosuria, leading to osmotic several days to weeks, whereas the evolu- This position statement will outline diuresis, with loss of water, sodium, po- tion of the acute DKA episode in type 1 precipitating factors and recommenda- tassium, and other electrolytes (3,15–20). diabetes or even in type 2 diabetes tends tions for the diagnosis, treatment, and The laboratory and clinical characteristics to be much shorter. Although the symp- prevention of DKA and HHS. It is based of DKA and HHS are summarized in Ta- toms of poorly controlled diabetes may be on a previous technical review (11), bles 1 and 2. As can be seen, DKA and present for several days, the metabolic al- which should be consulted for further in- HHS differ in magnitude of dehydration terations typical of ketoacidosis usually formation. and degree of ketosis (and acidosis). evolve within a short time frame (typically Ͻ24 h). Occasionally, the entire symp- PATHOGENESIS — Although the PRECIPITATING tomatic presentation may evolve or de- pathogenesis of DKA is better understood FACTORS — The most common pre- velop more acutely, and the patient may than that of HHS, the basic underlying cipitating factor in the development of present in DKA with no prior clues or mechanism for both disorders is a reduc- DKA or HHS is infection. Other precipi- symptoms. For both DKA and HHS, the tion in the net effective action of circulat- tating factors include cerebrovascular ac- classical clinical picture includes a history ing insulin coupled with a concomitant cident, alcohol abuse, pancreatitis, of polyuria, polydipsia, polyphagia, elevation of counterregulatory hormones, myocardial infarction, trauma, and drugs. weight loss, vomiting, abdominal pain such as glucagon, catecholamines, corti- In addition, new-onset type 1 diabetes or (only in DKA), dehydration, weakness, sol, and growth hormone. These hor- discontinuation of or inadequate insulin clouding of sensoria, and finally coma. monal alterations in DKA and HHS lead in established type 1 diabetes commonly Physical findings may include poor skin to increased hepatic and renal glucose leads to the development of DKA. Elderly turgor, Kussmaul respirations (in DKA), production and impaired glucose utiliza- individuals with new-onset diabetes (par- tachycardia, hypotension, alteration in tion in peripheral tissues, which result ticularly residents of chronic care facili- mental status, shock, and ultimately coma in hyperglycemia and parallel changes ties) or individuals with known diabetes (more frequent in HHS). Up to 25% of in osmolality of the extracellular space who become hyperglycemic and are un- DKA patients have emesis, which may be (12,13). The combination of insulin de- aware of it or are unable to take fluids coffee-ground in appearance and guaiac ficiency and increased counterregula- when necessary are at risk for HHS (6). positive. Endoscopy has related this find- tory hormones in DKA also leads to the Drugs that affect carbohydrate metab- ing to the presence of hemorrhagic gastri- release of free fatty acids into the circu- olism, such as corticosteroids, thiazides, tis. Mental status can vary from full ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● alertness to profound lethargy or coma, with the latter more frequent in HHS. Al- The recommendations in this paper are based on the evidence reviewed in the following publication: Management of hyperglycemic crises in patients with diabetes (Technical Review). Diabetes Care 24:131– though infection is a common precipitat- 153, 2001. ing factor for both DKA and HHS, The initial draft of this position statement was prepared by Abbas E. Kitabchi, PhD, MD; Guillermo E. patients can be normothermic or even Umpierrez, MD; Mary Beth Murphy, RN, MS, CDE, MBA; Eugene J. Barrett, MD, PhD; Robert A. Kreisberg, hypothermic primarily because of pe- MD; John I. Malone, MD; and Barry M. Wall, MD. The paper was peer-reviewed, modified, and approved by the Professional Practice Committee and the Executive Committee, October 2000. Revised 2001. ripheral vasodilation. Hypothermia, if Abbreviations: ␤-OHB, ␤-hydroxybutyric acid; AKA, alcoholic ketoacidosis; DKA, diabetic ketoacidosis; present, is a poor prognostic sign (21). HHS, hyperosmolar hyperglycemic state. Caution needs to be taken with patients

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Table 1—Diagnostic criteria for DKA and HHS is usually not lower than 18 mEq/l. DKA must also be distinguished from other DKA causes of high–anion gap metabolic aci- dosis, including lactic acidosis, ingestion Mild Moderate Severe HHS of drugs such as salicylate, methanol, eth- Plasma glucose (mg/dl) Ͼ250 Ͼ250 Ͼ250 Ͼ600 ylene glycol, and paraldehyde, and Arterial pH 7.25–7.30 7.00–7.24 Ͻ7.00 Ͼ7.30 chronic renal failure (which is more typi- Serum bicarbonate (mEq/l) 15–18 10 to Ͻ15 Ͻ10 Ͼ15 cally hyperchloremic acidosis rather than Urine ketones* Positive Positive Positive Small high–anion gap acidosis). Clinical history Serum ketones* Positive Positive Positive Small of previous drug intoxications or met- Effective serum osmolality Variable Variable Variable Ͼ320 formin use should be sought. Measure- (mOsm/kg)† ment of blood lactate, serum salicylate, Anion gap‡ Ͼ10 Ͼ12 Ͼ12 Ͻ12 and blood methanol level can be helpful Alteration in sensoria or mental Alert Alert/drowsy Stupor/coma Stupor/coma in these situations. Ethylene glycol (anti- obtundation freeze) is suggested by the presence of cal- cium oxalate and hippurate crystals in the *Nitroprusside reaction method; †calculation: 2[measured Na (mEq/l)] ϩ glucose (mg/dl)/18; ‡calculation: ϩ Ϫ Ϫ ϩ Ϫ urine. (Na ) (Cl HCO3 ) (mEq/l). See text for details. Paraldehyde ingestion is indicated by its characteristic strong odor on the who complain of abdominal pain on pre- triglyceridemia. Serum potassium con- breath. Because these intoxicants are low– sentation, because the symptoms could centration may be elevated because of an molecular weight organic compounds, be either a result or an indication of a pre- extracellular shift of potassium caused by they can produce an osmolar gap in addi- cipitating cause (particularly in younger insulin deficiency, hypertonicity, and aci- tion to the anion gap acidosis (14–16). patients) of DKA. Further evaluation is demia. Patients with low-normal or low necessary if this complaint does not re- serum potassium concentration on ad- TREATMENT — Successful treatment solve with resolution of dehydration and mission have severe total-body potassium of DKA and HHS requires correction of metabolic acidosis. deficiency and require very careful car- dehydration, hyperglycemia, and electro- diac monitoring and more vigorous po- lyte imbalances; identification of comor- Laboratory findings tassium replacement, because treatment bid precipitating events; and above all, The initial laboratory evaluation of pa- lowers potassium further and can pro- frequent patient monitoring. Guidelines tients with suspected DKA or HHS should voke cardiac dysrhythmia. The occur- for the management of patients with DKA include determination of plasma glucose, rence of stupor or coma in diabetic and HHS follow and are summarized in blood urea nitrogen/creatinine, serum ke- patients in the absence of definitive eleva- Figs. 1, 2, and 3. Table 3 includes a sum- tones, electrolytes (with calculated anion tion of effective osmolality (>320 mOsm/ mary of major recommendations and ev- gap), osmolality, urinalysis, urine ketones kg) demands immediate consideration of idence gradings. by dipstick, as well as initial arterial blood other causes of mental status change. Ef- gases, complete blood count with differ- fective osmolality may be calculated by Fluid therapy ential, and electrocardiogram. Bacterial the following formula: 2[measured Na Adult patients. Initial fluid therapy is di- cultures of urine, blood, and throat, etc., (mEq/l)] ϩ glucose (mg/dl)/18. Amylase rected toward expansion of the intravas- should be obtained and appropriate anti- levels are elevated in the majority of pa- cular and extravascular volume and biotics given if infection is suspected. tients with DKA, but this may be due to restoration of renal perfusion. In the ab- HbA1c may be useful in determining nonpancreatic sources, such as the pa- sence of cardiac compromise, isotonic sa- whether this acute episode is the culmi- rotid gland. A serum lipase determination line (0.9% NaCl) is infused at a rate of nation of an evolutionary process in pre- may be beneficial in the differential diag- 15–20 ml kg–1 body wt h–1 or greater viously undiagnosed or poorly controlled nosis of pancreatitis. However, lipase during the 1st hour (ϳ1–1.5 l in the av- diabetes or a truly acute episode in an oth- could also be elevated in DKA. Abdomi- erwise well-controlled patient. A chest X- nal pain and elevation of serum amylase ray should also be obtained if indicated. and liver enzymes are noted more com- Table 2—Typical total body deficits of water Tables 1 and 2 depict typical laboratory monly in DKA than in HHS. and electrolytes in DKA and HHS* findings in patients with DKA or HHS. The majority of patients with hyper- Differential diagnosis Total water (l) 6 9 glycemic emergencies present with leuko- Not all patients with ketoacidosis have Water (ml/kg)† 100 100–200 cytosis proportional to blood ketone body DKA. Starvation ketosis and alcoholic ke- Naϩ (mEq/kg) 7–10 5–13 concentration. Serum sodium concentra- toacidosis (AKA) are distinguished by ClϪ (mEq/kg) 3–55–15 tion is usually decreased because of the clinical history and by plasma glucose Kϩ (mEq/kg) 3–54–6 osmotic flux of water from the intracel- concentrations that range from mildly el- PO4 (mmol/kg) 5–73–7 lular to the extracellular space in the evated (rarely Ͼ250 mg/dl) to hypoglyce- Mgϩϩ (mEq/kg) 1–21–2 presence of hyperglycemia, and less mia. In addition, although AKA can result Caϩϩ (mEq/kg) 1–21–2 commonly, serum sodium concentration in profound acidosis, the serum bicar- *Data are from Ennis et al. (15) and Kreisberg (8); may be falsely lowered by severe hyper- bonate concentration in starvation ketosis †Per kilogram of body weight.

DIABETES CARE, VOLUME 25, SUPPLEMENT 1, JANUARY 2002 S101 Position Statement

Figure 1—Protocol for the management of adult patients with DKA. *DKA diagnostic criteria: blood glucose Ͼ250 mg/dl, arterial pH Ͻ7.3, bicarbonate Ͻ15 mEq/l, and moderate ketonuria or ketonemia. †After history and physical examination, obtain arterial blood gases, complete blood count with differential, urinalysis, blood glucose, blood urea nitrogen (BUN), electrolytes, chemistry profile, and creatinine levels STAT as well as an electrocardiogram. Obtain chest X-ray and cultures as needed. ‡Serum Na should be corrected for hyperglycemia (for each 100 mg/dl glucose Ͼ100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value). IM, intramuscular; IV, intravenous; SC subcutaneous.

–1 erage adult). Subsequent choice for fluid should not exceed 3 mOsm kg H2O pansion should not exceed 50 ml/kg over replacement depends on the state of hy- h–1 (14–20,22). In patients with renal or the first4hoftherapy. Continued fluid dration, serum electrolyte levels, and uri- cardiac compromise, monitoring of se- therapy is calculated to replace the fluid nary output. In general, 0.45% NaCl rum osmolality and frequent assessment deficit evenly over 48 h. In general, 0.45– infused at 4–14 ml kg–1 h–1 is appro- of cardiac, renal, and mental status must 0.9% NaCl (depending on serum sodium priate if the corrected serum sodium is be performed during fluid resuscitation levels) infused at a rate of 1.5 times the normal or elevated; 0.9% NaCl at a similar to avoid iatrogenic fluid overload (14– 24-h maintenance requirements (ϳ5ml rate is appropriate if corrected serum so- 20,22). kg–1 h–1) will accomplish a smooth re- dium is low. Once renal function is as- Pediatric patients (<20 years of age). hydration, with a decrease in osmolality –1 –1 sured, the infusion should include 20–30 Initial fluid therapy is directed toward ex- not exceeding 3 mOsm kg H2O h . mEq/l potassium (2/3 KCl and 1/3 KPO4) pansion of the intravascular and extravas- Once renal function is assured and serum until the patient is stable and can tolerate cular volume and restoration of renal potassium is known, the infusion should oral supplementation. Successful prog- profusion. The need for vascular volume include 20–40 mEq/l potassium (2/3 KCl ress with fluid replacement is judged by expansion must be offset by the risk of or potassium-acetate and 1/3 KPO4). hemodynamic monitoring (improvement cerebral edema associated with rapid Once serum glucose reaches 250 mg/dl, in blood pressure), measurement of fluid fluid administration. The 1st hour of flu- fluid should be changed to 5% dextrose input/output, and clinical examination. ids should be isotonic saline (0.9% NaCl) and 0.45–0.75% NaCl, with potassium as Fluid replacement should correct esti- at the rate of 10–20 ml kg–1 h–1.Ina described above. Therapy should include mated deficits within the first 24 h. The severely dehydrated patient, this may monitoring mental status to rapidly iden- induced change in serum osmolality need to be repeated, but the initial reex- tify changes that might indicate iatrogenic

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Figure 2—Protocol for the management of adult patients with HHS. *Diagnostic criteria: blood glucose Ͼ600 mg/dl, arterial pH Ͼ7.3, bicarbonate Ͼ Ͼ 15 mEq/l, mild ketonuria or ketonemia, and effective serum osmolality 320 mOsm/kg H2O. This protocol is for patients admitted with mental status change or severe dehydration who require admission to an intensive care unit. For less severe cases, see text for management guidelines. Effective serum osmolality calculation: 2[measured Na (mEq/l)] ϩ glucose (mg/dl)/18. †After history and physical examination, obtain arterial blood gases, complete blood count with differential, urinalysis, plasma glucose, blood urea nitrogen (BUN), electrolytes, chemistry profile, and creatinine levels STAT as well as an electrocardiogram. Obtain chest X-ray and cultures as needed. ‡Serum Na should be corrected for hyperglycemia (for each 100 mg/dl glucose Ͼ100 mg/dl, add 1.6 mEq to sodium value for corrected serum value). IV, intravenous; SC subcutaneous.

fluid overload, which can lead to symp- a continuous insulin infusion of regular it may be possible to decrease the insulin tomatic cerebral edema (23–25). insulin at a dose of 0.1 unit kg–1 h–1 infusion rate to 0.05–0.1 unit kg–1 h–1 may be started in these patients. This low (3–6 units/h), and dextrose (5–10%) may Insulin therapy dose of insulin usually decreases plasma be added to the intravenous fluids. There- Unless the episode of DKA is mild (Table glucose concentration at a rate of 50–75 after, the rate of insulin administration or 1), regular insulin by continuous intrave- mg dl–1 h–1, similar to a higher-dose the concentration of dextrose may need to nous infusion is the treatment of choice. insulin regimen (26). If plasma glucose be adjusted to maintain the above glucose ϩ In adult patients, once hypokalemia (K does not fall by 50 mg/dl from the initial values until acidosis in DKA or mental Ͻ3.3 mEq/l) is excluded, an intravenous value in the 1st hour, check hydration sta- obtundation and hyperosmolarity in HHS bolus of regular insulin at 0.15 units/kg tus; if acceptable, the insulin infusion may are resolved. body wt, followed by a continuous infu- be doubled every hour until a steady glu- Ketonemia typically takes longer to sion of regular insulin at a dose of 0.1 unit cose decline between 50 and 75 mg/h is clear than hyperglycemia. Direct mea- kg–1 h–1 (5–7 units/h in adults), should achieved. surement of ␤-OHB in the blood is the be administered. An initial insulin bolus When the plasma glucose reaches preferred method for monitoring DKA. is not recommended in pediatric patients; 250 mg/dl in DKA or 300 mg/dl in HHS, The nitroprusside method only measures

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Figure 3—Protocol for the management of pediatric patients (Ͻ20 years) with DKA or HHS. *DKA diagnostic criteria: blood glucose Ͼ250 mg/dl, venous pH Ͻ7.3, bicarbonate Ͻ15 mEq/l, moderate ketonuria or ketonemia.†HHS diagnostic criteria: blood glucose Ͼ600 mg/dl, venous pH Ͼ7.3, bicarbonate Ͼ15 mEq/l, and altered mental status or severe dehydration. ‡After the initial history and physical examination, obtain blood glucose, venous blood gases, electrolytes, blood urea nitrogen (BUN), creatinine, calcium, phosphorous, and urine analysis STAT. §Usually 1.5 times the 24 h maintenance requirements (ϳ5ml kgϪ1 hϪ1) will accomplish a smooth rehydration; do not exceed two times the maintenance requirement. ʈThe potassium in solution should be 1/3 KPO4 and 2/3 KCl or Kacetate. IM, intramuscular; IV, intravenous; SC subcutaneous. acetoacetic acid and acetone. However, lution of acidosis. With mild DKA, subcutaneous regular insulin as needed ␤-OHB, the strongest and most prevalent regular insulin given either subcutane- every 4 h. In adult patients, this can be acid in DKA, is not measured by the ni- ously or intramuscularly every hour is as given in 5-unit increments for every 50 troprusside method. During therapy, effective as intravenous administration in mg/dl increase in blood glucose above ␤-OHB is converted to acetoacetic acid, lowering blood glucose and ketone bod- 150 mg/dl for up to 20 units for blood which may lead the clinician to believe ies (27). Patients with mild DKA should glucose of Ն300 mg/dl. When the patient that ketosis has worsened. Therefore, as- first receive a “priming” dose of regular is able to eat, a multiple-dose schedule sessments of urinary or serum ketone lev- insulin of 0.4–0.6 units/kg body wt, half should be started that uses a combination els by the nitroprusside method should as an intravenous bolus and half as a sub- of short- or rapid-acting and intermedi- not be used as an indicator of response to cutaneous or intramuscular injection ate- or long-acting insulin as needed to therapy. During therapy for DKA or HHS, (22). Thereafter, 0.1 unit kg–1 h–1 of control plasma glucose. Continue intra- blood should be drawn every 2–4 h for regular insulin should be given subcuta- venous insulin infusion for 1–2 h after the determination of serum electrolytes, glu- neously or intramuscularly. split-mixed regimen is begun to ensure cose, blood urea nitrogen, creatinine, os- Criteria for resolution of DKA in- adequate plasma insulin levels. An abrupt molality, and venous pH (for DKA). cludes a glucose Ͻ200 mg/dl, serum bi- discontinuation of intravenous insulin Generally, repeat arterial blood gases are carbonate Ն18 mEq/l, and a venous pH of coupled with a delayed onset of a subcu- unnecessary; venous pH (which is usually Ͼ7.3. Once DKA is resolved, if the patient taneous insulin regimen may lead to 0.03 units lower than arterial pH) and an- is NPO, continue intravenous insulin and worsened control; therefore, some over- ion gap can be followed to monitor reso- fluid replacement and supplement with lap should occur in intravenous insulin

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Table 3—Summary of major recommendations bicarbonate be added to 400 ml sterile water and given at a rate of 200 ml/h. In Recommendations Grading patients with a pH of 6.9–7.0, 50 mmol sodium bicarbonate is diluted in 200 ml ● Initiate insulin therapy according to recommendations in position statement. A sterile water and infused at a rate of 200 ● Unless the episode of DKA is mild, regular insulin by continuous B ml/h. No bicarbonate is necessary if pH is intravenous infusion is preferred. Ͼ7.0. ● Assess need for bicarbonate therapy and, if necessary, follow treatment C Insulin, as well as bicarbonate ther- recommendations in position statement: bicarbonate may be beneficial in apy, lowers serum potassium; therefore, patients with a pH Ͻ6.9; not necessary if pH is Ͼ7.0 potassium supplementation should be ● Studies have failed to show any beneficial effect of phosphate replacement A maintained in intravenous fluid as de- on the clinical outcome in DKA. However, to avoid cardiac and skeletal scribed above and carefully monitored. muscle weakness and respiratory depression due to hypophosphatemia, (See Fig. 1 for guidelines.) Thereafter, ve- careful phosphate replacement may sometimes be indicated in patients nous pH should be assessed every2hun- with cardiac dysfunction, anemia, or respiratory depression and in those til the pH rises to 7.0, and treatment with serum phosphate concentration Ͻ1.0 mg/dl. should be repeated every2hifnecessary. ● Studies of cerebral edema in DKA are limited in number. Therefore, to avoid C (See Kitabchi et al. [11] for a complete the occurrence of cerebral edema, follow the recommendations in the description of studies done to date on the position statement regarding a gradual correction of glucose and use of bicarbonate in DKA.) osmolality as well as the judicious use of isotonic or hypotonic saline, In the pediatric patient, there are no depending on serum sodium and the hemodynamic status of the patient. randomized studies in patients with pH ● Initiate fluid replacement therapy based on recommendations in position A Ͻ6.9. If the pH remains Ͻ7.0 after the statement. initial hour of hydration, it seems prudent Scientific evidence was ranked based on the American Diabetes Association’s grading system. The highest to administer 1–2 mEq/kg sodium bicar- ranking (A) is assigned when there is supportive evidence from well-conducted, generalizable, randomized bonate over the course of 1 h. This so- controlled trials that are adequately powered, including evidence from a meta-analysis that incorporated dium bicarbonate can be added to NaCl, quality ratings in the analysis. An intermediate ranking (B) is given to supportive evidence from well- conducted cohort studies, registries, or case-control studies. A lower rank (C) is assigned to evidence from with any required potassium, to produce uncontrolled or poorly controlled studies or when there is conflicting evidence with the weight of the a solution that does not exceed 155 mEq/l evidence supporting the recommendation. Expert consensus (E) is indicated, as appropriate. For a more sodium. No bicarbonate therapy is re- detailed description of this grading system, refer to Diabetes Care 24 (Suppl. 1): S1–S2, 2001. quired if pH is Ն7.0 (30,31). therapy and initiation of the subcutane- tain a serum potassium concentration Phosphate ous insulin regimen. Patients with known within the normal range of 4–5 mEq/l. Despite whole-body phosphate deficits in diabetes may be given insulin at the dose Rarely, DKA patients may present with DKA that average ϳ1.0 mmol/kg body they were receiving before the onset of significant hypokalemia. In such cases, wt, serum phosphate is often normal or DKA or HHS and further adjusted as potassium replacement should begin with increased at presentation. Phosphate con- needed for control. In patients with newly fluid therapy, and insulin treatment centration decreases with insulin therapy. diagnosed diabetes, the initial total insu- should be delayed until potassium con- Prospective randomized studies have Ϫ lin dose should be ϳ0.5–1.0 units kg 1 centration is restored to Ͼ3.3 mEq/l to failed to show any beneficial effect of Ϫ day 1, divided into at least two doses in avoid arrhythmias or cardiac arrest and phosphate replacement on the clinical a regimen including short- and long- respiratory muscle weakness. outcome in DKA (32), and overzealous acting insulin until an optimal dose is es- phosphate therapy can cause severe hy- tablished. Finally, some type 2 diabetes pocalcemia with no evidence of tetany patients may be discharged on oral anti- Bicarbonate (17,32). However, to avoid cardiac and hyperglycemic agents and dietary ther- Bicarbonate use in DKA remains contro- skeletal muscle weakness and respiratory apy. versial (28). At a pH Ͼ7.0, reestablishing depression due to hypophosphatemia, insulin activity blocks lipolysis and re- careful phosphate replacement may Potassium solves ketoacidosis without any added sometimes be indicated in patients with Despite total-body potassium depletion, bicarbonate. Prospective randomized cardiac dysfunction, anemia, or respira- mild to moderate hyperkalemia is not un- studies have failed to show either benefi- tory depression and in those with serum common in patients with hyperglycemic cial or deleterious changes in morbidity or phosphate concentration Ͻ1.0 mg/dl. crises. Insulin therapy, correction of aci- mortality with bicarbonate therapy in When needed, 20–30 mEq/l potassium dosis, and volume expansion decrease se- DKA patients with pH between 6.9 and phosphate can be added to replacement rum potassium concentration. To prevent 7.1 (29). No prospective randomized fluids. No studies are available on the hypokalemia, potassium replacement is studies concerning the use of bicarbonate use of phosphate in the treatment of initiated after serum levels fall below 5.5 in DKA with pH values Ͻ6.9 have been HHS. mEq/l, assuming the presence of adequate reported. Given that severe acidosis may Continuous monitoring using a flow- urine output. Generally, 20–30 mEq po- lead to a myriad of adverse vascular ef- sheet (Fig. 4) aids in the organization of tassium (2/3 KCl and 1/3 KPO4) in each fects, it seems prudent that for adult pa- recovery parameters and treatment inter- liter of infusion fluid is sufficient to main- tients with a pH Ͻ6.9, 100 mmol sodium ventions.

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progress as brain stem herniation occurs. The progression may be so rapid that pap- illedema is not found. Once the clinical symptoms other than lethargy and behav- ioral changes occur, mortality is high (Ͼ70%), with only 7–14% of patients re- covering without permanent morbidity. Although the mechanism of cerebral edema is not known, it likely results from osmotically driven movement of water into the central nervous system when plasma osmolality declines too rapidly with the treatment of DKA or HHS. There is a lack of information on the morbidity associated with cerebral edema in adult patients; therefore, any recommendations for adult patients are clinical judgements, rather than scientific evidence. Preven- tion measures that might decrease the risk of cerebral edema in high-risk patients are gradual replacement of sodium and water deficits in patients who are hyperosmo- lar (maximal reduction in osmolality 3 –1 –1 mOsm kg H2O h ) and the addition of dextrose to the hydrating solution once blood glucose reaches 250 mg/dl. In HHS, a glucose level of 250–300 mg/dl should be maintained until hyperosmo- larity and mental status improves and the patient becomes clinically stable (34). Hypoxemia and, rarely, noncardio- genic pulmonary edema may complicate the treatment of DKA. Hypoxemia is at- tributed to a reduction in colloid osmotic pressure that results in increased lung water content and decreased lung compli- ance. Patients with DKA who have a wid- ened alveolo-arteriolar oxygen gradient Figure 4—DKA/HHS flowsheet for the documentation of clinical parameters, fluid and electro- lytes, laboratory values, insulin therapy, and urinary output. From Kitabchi et al. (14). noted on initial blood gas measurement or with pulmonary rales on physical ex- amination appear to be at higher risk for COMPLICATIONS — The most are not clinically significant except in the development of pulmonary edema. common complications of DKA and HHS cases of acute renal failure or extreme ol- include hypoglycemia due to overzealous iguria. PREVENTION treatment with insulin, hypokalemia due Cerebral edema is a rare but fre- Many cases of DKA and HHS can be pre- to insulin administration and treatment quently fatal complication of DKA, occur- vented by better access to medical care, of acidosis with bicarbonate, and hyper- ring in 0.7–1.0% of children with DKA. It proper education, and effective commu- glycemia secondary to interruption/ is most common in children with newly nication with a health care provider during discontinuance of intravenous insulin diagnosed diabetes, but it has been re- an intercurrent illness. The observation therapy after recovery without subse- ported in children with known diabetes that stopping insulin for economic rea- quent coverage with subcutaneous insu- and in young people in their twenties sons is a common precipitant of DKA in lin. Commonly, patients recovering from (25,33). Fatal cases of cerebral edema urban African-Americans (35,36) is dis- DKA develop hyperchloremia caused by have also been reported with HHS. Clin- turbing and underscores the need for our the use of excessive saline for fluid and ically, cerebral edema is characterized by health care delivery systems to address electrolyte replacement and transient a deterioration in the level of conscious- this problem, which is costly and clini- non–anion gap metabolic acidosis as ness, with lethargy, decrease in arousal, cally serious. chloride from intravenous fluids replaces and headache. Neurological deterioration Sick-day management should be re- ketoanions lost as sodium and potassium may be rapid, with seizures, inconti- viewed periodically with all patients. It salts during osmotic diuresis. These bio- nence, pupillary changes, bradycardia, should include specific information on chemical abnormalities are transient and and respiratory arrest. These symptoms 1) when to contact the health care pro-

S106 DIABETES CARE, VOLUME 25, SUPPLEMENT 1, JANUARY 2002 Position Statement vider, 2) blood glucose goals and the use school personnel so that they can identify Care 17:1178–1185, 1994 of supplemental short-acting insulin dur- signs and symptoms of uncontrolled dia- 14. Kitabchi AE, Fisher JN, Murphy MB, ing illness, 3) means to suppress fever and betes and new-onset diabetes can be diag- Rumbak MJ: Diabetic ketoacidosis and treat infection, and 4) initiation of an eas- nosed at an earlier time. This has been the hyperglycemic hyperosmolar nonke- ily digestible liquid diet containing carbo- shown to decrease the incidence of DKA totic state. In Joslin’s Diabetes Mellitus. 13th ed. Kahn CR, Weir GC, Eds. Phila- hydrates and salt. Most importantly, the at the onset of diabetes (30,38). delphia, Lea & Febiger, 1994, p. 738– patient should be advised to never dis- 770 continue insulin and to seek professional 15. Ennis ED, Stahl EJVB, Kreisberg RA: The advice early in the course of the illness. References hyperosmolar hyperglycemic syndrome. Successful sick-day management de- 1. McGarry JD, Woeltje KF, Kuwajima M, Diabetes Rev 2:115–126, 1994 pends on involvement by the patient Foster DW: Regulation of ketogenesis and 16. Marshall SM, Walker M, Alberti KGMM: and/or a family member. The patient/ the renaissance of carnitine palmitoyl Diabetic ketoacidosis and hyperglycae- family member must be able to accurately transferase. Diabetes Metab Rev 5:271– mic non-ketotic coma. In International measure and record blood glucose, urine 284, 1989 Textbook of Diabetes Mellitus. 2nd ed. Al- or blood ketone determination when 2. DeFronzo RA, Matsuda M, Barrett E: berti KGMM, Zimmet P, DeFronzo RA, Ͼ Diabetic ketoacidosis: a combined meta- Eds. New York, John Wiley, p. 1215– blood glucose is 300 mg/dl, insulin ad- bolic-nephrologic approach to therapy. 1229, 1997 ministered, temperature, respiratory and Diabetes Rev 2:209–238, 1994 17. Carroll P, Matz R: Uncontrolled diabetes pulse rate, and body weight and must be 3. Atchley DW, Loeb RF, Richards DW, mellitus in adults: experience in treating able to communicate this to a health care Benedict EM, Driscoll ME: A detailed diabetic ketoacidosis and hyperosmolar professional. Adequate supervision and study of electrolyte balances following coma with low-dose insulin and uniform help from staff or family may prevent withdrawal and reestablishment of insulin treatment regimen. Diabetes Care 6:579– many of the admissions for HHS due to therapy. J Clin Invest 12:297–326, 1933 585, 1983 dehydration among elderly individuals 4. Halperin ML, Cheema-Dhadli S: Renal 18. Ennis ED, Stahl EJ, Kreisberg RA: Diabetic who are unable to recognize or treat this and hepatic aspects of ketoacidosis: a ketoacidosis. In Diabetes Mellitus: Theory evolving condition. Better education of quantitative analysis based on energy turn- and Practice. 5th ed. Porte D Jr, Sherwin over. Diabetes Metab Rev 5:321–336, 1989 RS, Eds. Amsterdam, Elsevier, 1997, p. care givers as well as patients regarding 5. Malone ML, Gennis V, Goodwin JS: Char- 827–844 signs and symptoms of new-onset diabe- acteristics of diabetic ketoacidosis in older 19. Hillman K: Fluid resuscitation in diabetic tes; conditions, procedures, and medica- versus younger adults. J Am Geriatr Soc emergencies: a reappraisal. Intensive Care tions that worsen diabetes control; and 40:1100–1104, 1992 Med 13:4–8, 1987 the use of glucose monitoring could po- 6. Matz R: Hyperosmolar nonacidotic diabe- 20. Fein IA, Rackow EC, Sprung CL, Grod- tentially decrease the incidence and sever- tes (HNAD). In Diabetes Mellitus: Theory man R: Relation of colloid osmotic pres- ity of HHS. and Practice. 5th ed. Porte D Jr, Sherwin sure to arterial hypoxemia and cerebral The annual incidence rate for DKA RS, Eds. Amsterdam, Elsevier, 1997, p. edema during crystalloid volume loading from population-based studies ranges 845–860 of patients with diabetic ketoacidosis. Ann from 4.6 to 8 episodes per 1,000 patients 7. Morris LE, Kitabchi AE: Coma in the Intern Med 96:570–575, 1982 diabetic. In Diabetes Mellitus: Problems in 21. Matz R: Hypothermia in diabetic acidosis. with diabetes, with a trend toward an in- Management. Schnatz JD, Ed. Menlo Park, Hormones 3:36–41, 1972 creased hospitalization rate in the past CA, Addison-Wesley, 1982, p. 234–251 22. Kitabchi AE, Sacks HS, Young RT, Morris two decades (37). The incidence of HHS 8. Kreisberg RA: Diabetic ketoacidosis: new L: Diabetic ketoacidosis: reappraisal of accounts for Ͻ1% of all primary diabetic concepts and trends in pathogenesis and therapeutic approach. Ann Rev Med 30: admissions. Significant resources are treatment. Ann Int Med 88:681–695, 1978 339–357, 1979 spent on the cost of hospitalization. Based 9. Klekamp J, Churchwell KB: Diabetic ke- 23. Mahoney CP, Vleck BW, DelAguila M: on an annual average of ϳ100,000 hospi- toacidosis in children: initial clinical as- Risk factors for developing brain hernia- talizations for DKA in the U.S., with an sessment and treatment. Pediatric Annals tion during diabetic ketoacidosis. Pediatr average cost of $13,000 per patient, the 25:387–393, 1996 Neurology 21:721–727, 1999 annual hospital cost for patients with 10. Glaser NS, Kupperman N, Yee CK, 24. Finberg L: Why do patients with diabetic Schwartz DL, Styne DM: Variation in the ketoacidosis have cerebral swelling, and DKA may exceed $1 billion per year. management of pediatric diabetic ketoac- why does treatment sometimes make it Many of these hospitalizations could be idosis by specialty training. Arch Pediatr worse? Pediatr Adolescent Med 150:785– avoided by devoting adequate resources Adolescent Med 151:1125–1132, 1997 786, 1996 to apply the measures described above. 11. Kitabchi AE, Umpierrez GE, Murphy MB, 25. Duck SC, Wyatt DT: Factors associated Because repeated admissions for DKA Barrett EJ, Kreisberg RA, Malone JI, Wall with brain herniation in the treatment of are estimated to drain approximately one BM: Management of hyperglycemic crises diabetic ketoacidosis. J Pediatr 113:10– of every two health care dollars spent on in patients with diabetes mellitus (Tech- 14, 1988 adult patients with type 1 diabetes, re- nical Review). Diabetes Care 24:131–153, 26. Kitabchi AE, Ayyagari V, Guerra SMO, sources need to be redirected toward pre- 2001 Medical House Staff: The efficacy of low vention by funding better access to care 12. Beigelman PM: Severe diabetic ketoacido- dose versus conventional therapy of insu- sis (diabetic coma): 482 episodes in 257 lin for treatment of diabetic ketoacidosis. and educational programs tailored to in- patients: experience of three years. Diabe- Ann Int Med 84:633–638, 1976 dividual needs, including ethnic and per- tes 20:490–500, 1971 27. Fisher JN, Shahshahani MN, Kitabchi AE: sonal health care beliefs. In addition, 13. Polonsky WH, Anderson BJ, Lohrer PA, Diabetic ketoacidosis: low dose insulin resources should be directed toward the Aponte JE, Jacobson AM, Cole CF: Insulin therapy by various routes. N Engl J Med education of primary care providers and omission in women with IDDM. Diabetes 297:238–247, 1977

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28. Barnes HV, Cohen RD, Kitabchi AE, Mur- of severe diabetic ketoacidosis? Critical cause of diabetic ketoacidosis. Diabetes phy MB: When is bicarbonate appropriate Care Medicine 27: December1999 Care 18:483–489, 1995 in treating metabolic acidosis including 32. Fisher JN, Kitabchi AE: A randomized 36. Umpierrez GE, Kelly JP, Navarrete JE, diabetic ketoacidosis? In Debates in Medi- study of phosphate therapy in the treat- Casals MMC, Kitabchi AE: Hyperglyce- cine. Gitnick G, Barnes HV, Duffy TP, et ment of diabetic ketoacidosis. J Clin Endo- mic crises in urban blacks. Arch Int Med al., Eds. Chicago, Yearbook, 1990, p. 172 crinol Metab 57:177–180, 1983 157:669–675, 1997 29. Morris LR, Murphy MB, Kitabchi AE: Bi- 33. Rosenbloom AL: Intracerebral crises dur- 37. Fishbein HA, Palumbo PJ: Acute meta- carbonate therapy in severe diabetic keto- ing treatment of diabetic ketoacidosis. Di- bolic complications in diabetes. In Diabe- acidosis. Ann Int Med 105:836–840, 1986 abetes Care 13:22–33, 1990 tes in America. National Diabetes Data 30. Vanelli M, Chiari G, Ghizzoni L, Costi G, 34. Holsclaw DS Jr, Torcato B: Acute pulmo- Group, Ed. Bethesda, MD, National Insti- Giacalone T, Chiarelli F: Effectiveness of a nary edema in juvenile diabetic ketoaci- tutes of Health, 1995, p. 283–291 (NIH prevention program for diabetic ketoaci- dosis. Pediatr Pulmonology 24:438–443, publ. no. 95-1468) dosis in children. Diabetes Care 22:7–9, 1997 38. Kaufman FR, Halvorsen M: The treatment 1999 35. Musey VC, Lee JK, Crawford R, Klatka and prevention of diabetic ketoacidosis 31. Viallon A, Zeni F, Lafond P, Venet C, MA, McAdams D, Phillips LS: Diabetes in in children and adolescents with type 1 Tardy B, Page Y, Bertrand JC: Does bicar- urban African-Americans. I. Cessation of diabetes mellitus. Pediatr Annals 28:576– bonate therapy improve the management insulin therapy is the major precipitating 582, 1999

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