endocriniología - hyperglicemic crisis in adult patients with diabetes

Hyperglycemic Crises in Adult PatientsWith DiabetesA consensus statement from the American Diabetes Association

ABBAS E. KITABCHI, PHD, MD1

GUILLERMO E. UMPIERREZ, MD2

MARY BETH MURPHY, RN, MS, CDE, MBA1

ROBERT A. KREISBERG, MD3

D iabetic ketoacidosis (DKA) and hy-perosmolar hyperglycemic state(HHS) are the two most serious

acute metabolic complications of diabe-tes. Most patients with DKA have autoim-mune type 1 diabetes; however, patientswith type 2 diabetes are also at risk duringthe catabolic stress of acute illness such astrauma, surgery, or infection. Table 1 out-lines the diagnostic criteria and electro-lyte and fluid deficits for both disorders.The mortality rate in patients with DKA is�5% in experienced centers, whereas themortality rate of patients with HHS stillremains high at �11% (1–8). Death inthese conditions is rarely due to the met-abolic complications of hyperglycemia orketoacidosis but rather relates to the un-derlying precipitating illness. The prog-nosis of both conditions is substantiallyworsened at the extremes of age and in thepresence of coma and hypotension (7,9–11)

This consensus statement will outlineprecipitating factors and recommenda-tions for the diagnosis, treatment, andprevention of DKA and HHS in adult sub-jects. It is based on a previous technicalreview and more recently published peer-reviewed articles since 2001, which shouldbe consulted for further information.

PATHOGENESIS — Although thepathogenesis of DKA is better understoodthan that of HHS, the basic underlyingmechanism for both disorders is a reduc-tion in the net effective action of circulat-ing insulin coupled with a concomitantelevation of counterregulatory hormones,such as glucagon, catecholamines, corti-sol, and growth hormone (1,3,4,8–13).DKA and HHS can fall anywhere alongthe disease continuum of diabetic meta-bolic derangements. At one extreme, pureDKA without significant hyperosmolaritytypically indicates the total or relative ab-sence of insulin (seen in type 1 diabetes).At the other extreme, HHS without keto-acidosis typically occurs with lesser de-grees of insulin deficiency, as seen in type2 diabetes. However, in most circum-stances, a mixed presentation occurs de-pending on the duration of symptoms,coexisting medical illnesses, or underly-ing precipitating cause. In one study (14),123 DKA laboratory admission profileswere reviewed, and 37% demonstrated anelevated total osmolality.

Hormonal alterations in DKA andHHS lead to increased gluconeogenesisand hepatic and renal glucose productionand impaired glucose utilization in pe-ripheral tissues, which results in hyper-

glycemia and hyperosmolality of the ex-tracellular space (1,3,10–17). The com-bination of insulin deficiency andincreased counterregulatory hormones inDKA also leads to the release of free fattyacids into the circulation from adipose tis-sue (lipolysis) and to unrestrained hepaticfatty acid oxidation to ketone bodies (�-hydroxybutyrate ([�-OHB] and acetoace-tate), with resulting ketonemia andmetabolic acidosis (18). On the otherhand, HHS may be caused by plasma in-sulin concentrations that are inadequateto facilitate glucose utilization by insulin-sensitive tissues but adequate (as deter-mined by residual C-peptide) to preventlipolysis and subsequent ketogenesis(15). Both DKA and HHS are associatedwith glycosuria, leading to osmotic diure-sis, with loss of water, sodium, potassium,and other electrolytes (6,15–17). Thepathogenic pathways of DKA and HHSare depicted in Fig. 1. The diagnostic cri-teria and typical total deficits of water andelectrolytes in DKA and HHS are summa-rized in Table 1. As can be seen, DKA andHHS differ in the magnitude of dehydra-tion, ketosis, and acidosis.

DKA is a proinflammatory state pro-ducing reactive oxygen species that areindicative of oxidative stress. A recentstudy (19) has shown elevated levels ofproinflammatory cytokines and lipid per-oxidation markers, as well as cardiovas-cular risk factors (plasminogen activatorinhibitor-1) and C-reactive protein,which return to normal levels with insulintherapy and remission of hyperglycemia.

PRECIPITATING FACTORS —The two most common precipitating fac-tors in the development of DKA or HHSare inadequate or inappropriate insulintherapy or infection (1,4,8–12). Otherprecipitating factors include pancreatitis,myocardial infarction, cerebrovascularaccident, and drugs. In addition, new-onset type 1 diabetes or discontinuationof insulin in established type 1 diabetescommonly leads to the development ofDKA. Underlying medical illness such asstroke or myocardial infarction that pro-vokes the release of counterregulatory

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

From the 1Division of Endocrinology, Diabetes, and Metabolism, University of Tennessee Health ScienceCenter, Memphis, Tennessee; the 2Clinical Research Center and Diabetes Unit, Grady Memorial Hospital/Emory University School of Medicine; and the 3Teaching Faculty, University of South Alabama, BaptistHealth System, Birmingham, Alabama.

Address correspondence and reprint requests to Dr. Abbas E. Kitabchi, Director, Division of Endocrinol-ogy, Diabetes and Metabolism, University of Tennessee Health Science Center, 956 Court Ave., Suite D334,Memphis, Tennessee 38163. E-mail: [email protected].

The initial draft of this position statement was prepared by the authors as listed above. The manuscript wasthen peer-reviewed, modified, and approved by the Professional Practice Committee and the ExecutiveCommittee, March 2006.

Abbreviations: �-OHB, �-hydroxybutyrate; DKA, diabetic ketoacidosis; HHS, hyperosmolar hypergly-cemic state.

The recommendations in this article are based on the evidence reviewed in the following publication:Management of hyperglycemic crises in patients with diabetes (Technical Review). Diabetes Care 24:131–153, 2001, as well as subsequent peer-reviewed publications since 2001.

A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversionfactors for many substances.

DOI: 10.2337/dc06-9916© 2006 by the American Diabetes Association.

R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t sC O N S E N S U S S T A T E M E N T

DIABETES CARE, VOLUME 29, NUMBER 12, DECEMBER 2006 2739

hormones and/or compromises the accessto water is likely to result in severe dehy-dration and HHS. In most patients, re-stricted water intake is due to the patientbeing bedridden or restrained and is ex-acerbated by the altered thirst response ofthe elderly. Because 20% of these patientshave no history of diabetes, delayed rec-ognition of hyperglycemic symptomsmay have led to severe dehydration. El-

derly individuals with new-onset diabetes(particularly residents of chronic care fa-cilities) or individuals with known diabe-tes who become hyperglycemic and areunaware of it or are unable to take fluidswhen necessary are at risk for HHS(8,11,12). Drugs that affect carbohydratemetabolism, such as corticosteroids, thia-zides, and sympathomimetic agents (e.g.,dobutamine and terbutaline) (10) and

second-generation antipsychotics agents(20) may precipitate the development ofHHS or DKA. In young patients with type1 diabetes, psychological problems com-plicated by eating disorders may be a con-tributing factor in 20% of recurrentketoacidosis (21). Factors that may leadto insulin omission in younger patientsinclude fear of weight gain with improvedmetabolic control, fear of hypoglycemia,rebellion from authority, and the stress ofchronic disease. Before 1993, the use ofcontinuous subcutaneous insulin infu-sion devices had also been associated withan increased frequency of DKA (22), butwith improvement in technology and bet-ter education of patients, the incidence ofDKA appears to have reduced in pumpusers. However, additional prospectivestudies are needed to document reduc-tion of DKA incidence with the use of con-tinuous subcutaneous insulin infusiondevices (23).

During the past decade, an increasingnumber of DKA cases without precipitat-ing cause have been reported in children,adolescents, and adult subjects with type2 diabetes. Observational and prospectivestudies indicate that over half of newlydiagnosed adult African-American andHispanic subjects with unprovoked DKAhave type 2 diabetes (24–27). In such pa-tients, clinical and metabolic features oftype 2 diabetes include a high rate of obe-sity, a strong family history of diabetes, a

Table 1—Diagnostic criteria and typical total body deficits of water and electrolytes in DKA and HHS

DKA

HHSMild Moderate Severe

Diagnostic criteria and classificationPlasma glucose (mg/dl) �250 mg/dl �250 mg/dl �250 mg/dl �600 mg/dlArterial pH 7.25–7.30 7.00 to �7.25 �7.00 �7.30Serum bicarbonate (mEq/l) 15–18 10 to �15 �10 �15Urine ketone* Positive Positive Positive SmallSerum ketone* Positive Positive Positive SmallEffective serum osmolality† Variable Variable Variable �320 mOsm/kgAnion gap‡ �10 �12 �12 �12Mental status Alert Alert/drowsy Stupor/coma Stupor/coma

Typical deficitsTotal water (l) 6 9Water (ml/kg)§ 100 100–200Na� (mEq/kg) 7–10 5–13Cl� (mEq/kg) 3–5 5–15K� (mEq/kg) 3–5 4–6PO4 (mmol/kg) 5–7 3–7Mg�� (mEq/kg) 1–2 1–2Ca�� (mEq/kg) 1–2 1–2

*Nitroprusside reaction method. †Calculation of effective serum osmolality: 2�measured Na� (mEq/l)� � �glucose (mg/dl)�/18. ‡Calculation of anion gap: (Na�) ��Cl� � HC03

� (mEq/l)�. §Per kg body wt. Data adapted from refs. 1, 4, and 7.

Figure 1— Pathogenesis of DKA and HHS, stress, infection, and/or insufficient insulin. ��Ac-celerated pathway (ref. 10).

Hyperglycemic crises in diabetic adults

2740 DIABETES CARE, VOLUME 29, NUMBER 12, DECEMBER 2006

measurable pancreatic insulin reserve,low prevalence of autoimmune markersof �-cell destruction, and the ability todiscontinue insulin therapy during fol-low-up (28,29). This variant of type 2 di-abetes has been referred to in theliterature as idiopathic type 1 diabetes,atypical diabetes, Flatbush diabetes, type1.5 diabetes, and more recently as keto-sis-prone type 2 diabetes (24,30). At pre-sentation, they have markedly impairedinsulin secretion and insulin action(25,26,29), but aggressive managementwith insulin significantly improves �-cellfunction, allowing discontinuation of in-sulin therapy within a few months of fol-low-up (25–27). Recently, it was reportedthat the near-normoglycemic remission isassociated with a greater recovery of basaland stimulated insulin secretion and that10 years after diabetes onset, 40% of pa-tients with ketosis-prone type 2 diabetesare still non–insulin dependent (24–27).

Furthermore, a novel genetic mecha-nism related to the high prevalence of glu-cose-6-phosphate dehydrogenasedeficiency has been linked with ketosis-prone diabetes (31).

DIAGNOSIS

History and physical examinationThe process of HHS usually evolves overseveral days to weeks, whereas the evolu-tion of the acute DKA episode in type 1diabetes or even in type 2 diabetes tendsto be much shorter. Although the symp-toms of poorly controlled diabetes may bepresent for several days, the metabolic al-terations typical of ketoacidosis usuallyevolve within a short time frame (typically�24 h). The classic clinical picture of pa-tients with DKA includes a history ofpolyuria, polydipsia, weight loss, vomit-ing, abdominal pain, dehydration, weak-ness, mental status change, and coma.Physical findings may include poor skinturgor, Kussmaul respirations, tachycar-dia, hypotension, alteration in mental sta-tus, shock, and ultimately coma. Up to25% of DKA patients have emesis, whichmay be coffee-ground in appearance andguaiac positive. Mental status can varyfrom full alertness to profound lethargy orcoma, with the latter more frequent inHHS. Although infection is a commonprecipitating factor for both DKA andHHS, patients can be normothermic oreven hypothermic primarily because ofperipheral vasodilation (32). Severe hy-pothermia, if present, is a poor prognosticsign. Abdominal pain, sometimes mim-

icking an acute abdomen, is present in50–75% of DKA cases (33,34). The ab-dominal pain usually resolves with cor-rection of hyperglycemia and metabolicacidosis. The most common clinical pre-sentation in patients with HHS is alteredsensorium (4,8,11,12). Physical examina-tion reveals signs of dehydration with lossof skin turgor, weakness, tachycardia,and hypotension. Fever due to underly-ing infection is common, and signs of ac-idosis (Kussmaul breathing, acetonebreath) are usually absent. In some pa-tients, focal neurologic signs (hemipare-sis, hemianopsia) and seizures (partialmotor seizures more common than gen-eralized) may be the dominant clinicalfeatures (1,4,6,8).

Laboratory findingsThe initial laboratory evaluation of pa-tients with suspected DKA or HHS shouldinclude determination of plasma glucose,blood urea nitrogen, creatinine, serumketones, electrolytes (with calculated an-ion gap), osmolality, urinalysis, urine ke-tones by dipstick, as well as initial arterialblood gases and complete blood countwith differential. An electrocardiogram,chest X-ray, and urine, sputum, or bloodcultures should also be obtained, if clini-cally indicated. HbA1c may be useful indetermining whether this acute episode isthe culmination of an evolutionary pro-cess in previously undiagnosed or poorlycontrolled diabetes or a truly acute epi-sode in an otherwise well-controlled pa-tient. The diagnostic criteria for DKA andHHS are shown in Table 1.

DKA consists of the biochemical triadof hyperglycemia, ketonemia, and meta-bolic acidosis. Accumulation of ketoacidsresults in an increased anion gap meta-bolic acidosis. The anion gap is calculatedby subtracting the sum of chloride andbicarbonate concentration from the so-dium concentration [Na� � (Cl� �HCO3

�)]. The normal anion gap has beenhistorically reported to be �12 2mEq/l. Most laboratories, however, cur-rently measure sodium and chloride con-centrations using ion-specific electrodes,which measure plasma chloride concen-tration 2–6 mEq/l higher than with priormethods (35). Thus, the normal aniongap using the current methodology is be-tween 7 and 9 mEq/l, and an anion gap�10–12 mEq/l indicates the presence ofincreased anion gap acidosis. The severityof DKA is classified as mild, moderate, orsevere based on the severity of metabolicacidosis (blood pH, bicarbonate, ketones)

and the presence of altered mental status(1). Significant overlap between DKA andHHS has been reported in more than one-third of patients (1,2,14). Although mostpatients with HHS have an admission pH�7.30, a bicarbonate level �20 mEq/l,mild ketonemia may be present.

The majority of patients with hyper-glycemic emergencies present with leuko-cytosis proportional to blood ketone bodyconcentration (2,10). However, leukocy-tosis �25,000 may designate infectionand require further evaluation (36). Theadmission serum sodium is usually lowbecause of the osmotic flux of water fromthe intracellular to the extracellular spacein the presence of hyperglycemia. An in-crease in serum sodium concentration inthe presence of hyperglycemia indicates arather profound degree of water loss. Un-less the plasma is cleared of chylomi-crons, pseudonormoglycemia andpseudohyponatremia may occur in DKA(37,38). Serum potassium concentrationmay be elevated because of an extracellu-lar shift of potassium caused by insulindeficiency, hypertonicity, and acidemia(3,10,39).

Patients with low normal or low se-rum potassium concentration on admis-sion have severe total-body potassiumdeficiency and require very careful car-diac monitoring and more vigorous po-tassium replacement, because treatmentlowers potassium further and can pro-voke cardiac dysrhythmia. The classicwork of Atchley et al. (40) established thatthe total body deficit of sodium and po-tassium might be as high as 500 –700mEq (39,40).

Studies on serum osmolality andmental alteration have established a posi-tive linear relationship between osmolal-ity and mental obtundation (14). Theoccurrence of stupor or coma in diabeticpatients in the absence of definitive eleva-tion of effective osmolality (320 mOsm/kg) demands immediate consideration ofother causes of mental status change. Inthe calculation of effective osmolality{2[measured Na (mEq/l)] � [glucose(mg/dl)]/18}, the urea concentration isnot taken into account because it is freelypermeable and its accumulation does notinduce major changes in intracellular vol-ume or osmotic gradient across the cellmembrane (4).

Amylase levels are elevated in the ma-jority of patients with DKA, but this maybe due to nonpancreatic sources, such asthe parotid gland (41). A serum lipase de-termination may be beneficial in the dif-

Kitabchi and Asssociates


ferential diagnosis of pancreatitis;however, lipase could also be elevated inDKA. Finally, abnormal acetoacetate lev-els may falsely elevate serum creatinine ifthe clinical laboratory uses a colorometricmethod for the creatinine assay (42).

Differential diagnosisNot all patients with ketoacidosis haveDKA. Starvation ketosis and alcoholic ke-toacidosis are distinguished by clinicalhistory and by plasma glucose concentra-tions that range from mildly elevated(rarely �200 mg/dl) to hypoglycemia. Inaddition, although alcoholic ketoacidosiscan result in profound acidosis, the serumbicarbonate concentration in starvationketosis is usually not �18 mEq/l. DKAmust also be distinguished from othercauses of high anion gap metabolic acido-sis, including lactic acidosis; ingestion ofdrugs such as salicylate, methanol, ethyl-ene glycol, and paraldehyde; and chronicrenal failure.

A clinical history of previous drugabuse or metformin use should be sought.Measurement of blood lactate, serum sa-licylate, and blood methanol level can behelpful in these situations. Ethylene gly-col (antifreeze) is suggested by the pres-ence of calcium oxalate and hippuratecrystals in the urine. Paraldehyde inges-tion is indicated by its characteristicstrong odor on the breath. Because theseintoxicants are low–molecular-weight or-ganic compounds, they can produce anosmolar gap in addition to the anion gapacidosis (10,43). A recent report (44) sug-gested a relationship between low carbo-hydrate dietary intake and metabolicacidosis.

Finally, four case reports have shownthat patients with undiagnosed acromeg-aly may present with DKA as the primarymanifestation of their disease (45–48).

TREATMENT — Successful treatmentof DKA and HHS requires correction ofdehydration, hyperglycemia, and electro-lyte imbalances; identification of comor-bid precipitating events; and above all,frequent patient monitoring. Protocolsfor the management of patients with DKAand HHS are summarized in Figs. 2 and 3.

Fluid therapyInitial fluid therapy is directed toward ex-pansion of the intravascular and extra vas-cular volume and restoration of renalperfusion. In the absence of cardiac com-promise, isotonic saline (0.9% NaCl) isinfused at a rate of 15–20 ml � kg�1 body

wt � h�1 or 1–1.5 l during the first hour.The subsequent choice for fluid replace-ment depends on the state of hydration,serum electrolyte levels, and urinary out-put. In general, 0.45% NaCl infused at4–14 ml � kg�1 body wt � h�1 is appro-priate if the corrected serum sodium isnormal or elevated; 0.9% NaCl at a similarrate is appropriate if corrected serum so-dium is low (Fig. 2). Successful progresswith fluid replacement is judged by he-modynamic monitoring (improvement inblood pressure), measurement of fluid in-put and output, laboratory values, andclinical examination. Fluid replacementshould correct estimated deficits withinthe first 24 h. In patients with renal orcardiac compromise, monitoring of se-rum osmolality and frequent assessmentof cardiac, renal, and mental status mustbe performed during fluid resuscitation toavo id i a t rogen i c flu id ove r load(1,3,4,10,12,16,17). Adequate rehydra-tion with subsequent correction of the hy-perosmolar state has been shown to resultin a more robust response to low-dose in-sulin therapy (49).

Insulin therapyUnless the episode of DKA is uncompli-cated and mild/moderate (Table 1), regu-lar insulin by continuous intravenousinfusion is the treatment of choice. Inadult patients, once hypokalemia (K� �3.3 mEq/l) is excluded, an intravenousbolus of regular insulin at 0.1 unit/kgbody wt, followed by a continuous infu-sion of regular insulin at a dose of 0.1 unit� kg�1 � h�1 should be administered. Thislow dose of insulin usually decreasesplasma glucose concentration at a rate of50–75 mg � dl�1 � h�1, similar to a higher-dose insulin regimen (50,51). If plasmaglucose does not decrease by 50–75 mgfrom the initial value in the first hour, theinsulin infusion may be doubled everyhour until a steady glucose decline isachieved. When the plasma glucosereaches 200 mg/dl in DKA or 300 mg/dlin HHS, it may be possible to decrease theinsulin infusion rate to 0.05–0.1 unit �kg�1 � h�1, at which time dextrose may beadded to the intravenous fluids (1,4,10).Thereafter, the rate of insulin administra-tion or the concentration of dextrose mayneed to be adjusted to maintain theabove-glucose values until acidosis inDKA or mental obtundation and hyperos-molality in HHS are resolved.

Prospective and randomized studieshave reported on the efficacy and cost ef-fectiveness of subcutaneous rapid-acting

insulin analogs in the management of pa-tients with uncomplicated DKA. Patientstreated with subcutaneous rapid-actinginsulin received an initial injection of 0.2units/kg followed by 0.1 unit/kg everyhour or an initial dose of 0.3 units/kg fol-lowed by 0.2 units/kg every 2 h untilblood glucose was �250 mg/dl, then theinsulin dose was decreased by half to 0.05or 0.1 unit/kg, respectively, and adminis-tered every 1 or 2 h until resolution ofDKA (52,53). There were no differencesin length of hospital stay, total amount ofinsulin administration until resolution ofhyperglycemia or ketoacidosis, or num-ber of hypoglycemic events among treat-ment groups. In addition, the use ofinsulin analogs allowed treatment of DKAin general wards or in the emergency de-partment, avoiding admission to an inten-sive care unit. By avoiding intensive careadmissions, these investigators reported areduction of 30% in the cost of hospital-ization (51–54).

Ketonemia typically takes longer toclear than hyperglycemia. Direct mea-surement of �-OHB in the blood is thepreferred method for monitoring DKAand has become more convenient withthe recent development of bedside meterscapable of measuring whole-blood�-OHB (55). The nitroprusside method,which is used in clinical chemistry labo-ratories, measures acetoacetic acid andacetone; however, �-OHB, the strongestand most prevalent acid in DKA, is notmeasured by the nitroprusside method.During therapy, �-OHB is converted toacetoacetic acid, which may lead the cli-nician to believe that ketosis has wors-ened (42). Therefore, assessments ofurinary or serum ketone levels by the ni-troprusside method should not be used asan indicator of response to therapy. Dur-ing therapy for DKA or HHS, bloodshould be drawn every 2–4 h for deter-mination of serum electrolytes, glucose,blood urea nitrogen, creatinine, osmolal-ity, and venous pH (for DKA). Generally,repeat arterial blood gases are unneces-sary during the treatment of DKA in he-modynamically stable patients. Sincevenous pH is only 0.02–0.03 units lowerthan arterial pH (56), it is adequate to as-sess venous pH response to therapy, thusavoiding the pain and potential complica-tions associated with repeated arterialpunctures.

Criteria for resolution of DKA includeglucose �200 mg/dl, serum bicarbonate�18 mEq/l, and venous pH �7.3. Whenthe patient is able to eat, a multiple-dose



Figu

re2

—Protocolfor

them

anagementofadultpatients

with

DK

A.*D

KA

diagnosticcriteria:serum

glucose�

250m

g/dl,arterialpH�

7.3,serumbicarbonate

�18

mE

q/l,and

moderate

ketonuriaor

ketonemia.N

ormallaboratory

valuesvary;check

locallabnorm

alrangesfor

allelectrolytes.†After

historyand

physicalexam,obtain

capillaryglucose

andserum

orurine

ketones(nitroprusside

method).B

egin1

literof0.9%

NaC

lover1

hand

drawarterialblood

gases,complete

bloodcountw

ithdifferential,urinalysis,

serumglucose,B

UN

,electrolytes,chemistry

profile,andcreatinine

levelsSTA

T.O

btainelectrocardiogram

,chestX-ray,and

specimensfor

bacterialcultures,asneeded.*SerumN

a�

shouldbe

correctedfor

hyperglycemia

(foreach

100m

g/dlglucose�

100m

g/dl,add1.6

mE

qto

sodiumvalue

forcorrected

serumsodium

value).Adapted

fromref.1.



insulin schedule should be started thatuses a combination of short- or rapid-acting and intermediate- or long-actinginsulin as needed to control plasma glu-cose. Intravenous insulin infusion shouldbe continued for 1–2 h after the subcuta-neous insulin is given to ensure adequateplasma insulin levels. An abrupt discon-tinuation of intravenous insulin coupledwith a delayed onset of a subcutaneousinsulin regimen may lead to hyperglyce-mia or recurrence of ketoacidosis. If thepatient is to remain n.p.o., it is preferableto continue the intravenous insulin infu-sion and fluid replacement. Patients withknown diabetes may be given insulin atthe dose they were receiving before theonset of DKA or HHS. In insulin-naıvepatients, a multidose insulin regimen

should be started at a dose of 0.5–0.8units � kg�1 � day�1, including regular orrapid-acting and basal insulin until an op-timal dose is established. However, goodclinical judgment and frequent glucoseassessment are vital in initiating a new in-sulin regimen in insulin-naıve patients.

PotassiumDespite total-body potassium depletion(40,57), mild to moderate hyperkalemiais not uncommon in patients with hyper-glycemic crises. Insulin therapy, correc-tion of acidosis, and volume expansiondecrease serum potassium concentration.To prevent hypokalemia, potassium re-placement is initiated after serum levelsdecrease to �5.3 mEq/l, assuming thepresence of adequate urine output at 50

ml/h). Generally, 20–30 mEq potassiumin each liter of infusion fluid is sufficientto maintain a serum potassium concentra-tion within the normal range of 4 –5mEq/l. Rarely, DKA patients may presentwith significant hypokalemia. In suchcases, potassium replacement should be-gin with fluid therapy, and insulin treat-ment should be delayed until potassiumconcentration is restored to �3.3 mEq/lto avoid arrhythmias or cardiac arrest andrespiratory muscle weakness (57–58).

BicarbonateBicarbonate use in DKA remains contro-versial (58). At a pH �7.0, administrationof insulin blocks lipolysis and resolves ke-toacidosis without any added bicarbonate(3,18,40). However, the administration

Figure 3— Protocol for the management of adult patients with HHS. HHS diagnostic criteria: serum glucose �600 mg/dl, arterial pH �7.3, serumbicarbonate �15 mEq/l, and minimal ketonuria and ketonemia. Normal laboratory values vary; check local lab normal ranges for all electrolytes.†After history and physical exam, obtain capillary glucose and serum or urine ketones (nitroprusside method). Begin 1 liter of 0.9% NaCl over 1 hand draw arterial blood gases, complete blood count with differential, urinalysis, serum glucose, BUN, electrolytes, chemistry profile and creatininelevels STAT. Obtain electrocardiogram, chest X-ray, and specimens for bacterial cultures, as needed. Adapted from ref. 1. *Serum Na� should becorrected for hyperglycemia (for each 100 mg/dl glucose �100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value).



of bicarbonate may be associated withseveral deleterious effects including an in-creased risk of hypokalemia (59), de-creased tissue oxygen uptake, andcerebral edema (60,61). A prospectiverandomized study in 21 patients failed toshow either beneficial or deleteriouschanges in morbidity or mortality withbicarbonate therapy in DKA patients withan admission arterial pH between 6.9 and7.1 (62). This study was small and limitedto those patients with an admission arte-rial pH of �6.9. The average pH in thebicarbonate group was 7.03 0.1 and forthe nonbicarbonate group was 7.0 0.02. Therefore, if the pH is 6.9–7.0, itseems prudent to administer 50 mmol bi-carbonate in 200 ml of sterile water with10 mEq KCL over 1 h until the pH is�7.0. No prospective randomized stud-ies concerning the use of bicarbonate inDKA with pH values �6.9 have been re-ported. Given that severe acidosis maylead to a myriad of adverse vascular ef-fects, adult patients with a pH �6.9should receive 100 mmol sodium bicar-bonate (two ampules) in 400 ml sterilewater (an isotonic solution) with 20 mEqKCl administered at a rate of 200 ml/h for2 h until the venous pH is �7.0. Bicar-bonate as well as insulin therapy lowersserum potassium; therefore, potassiumsupplementation should be maintained inthe intravenous fluid as described aboveand carefully monitored. (See Fig. 2 forguidelines.) Thereafter, venous pHshould be assessed every 2 h until the pHrises to 7.0, and treatment should be re-peated every 2 h if necessary. See refer-ence 1 for further review.

PhosphateDespite whole-body phosphate deficits inDKA that average 1.0 mmol � kg�1 � bodywt�1, serum phosphate is often normal orincreased at presentation. Phosphate con-centration decreases with insulin therapy.Prospective randomized studies (63,64)have failed to show any beneficial effect ofphosphate replacement on the clinicaloutcome in DKA, and overzealous phos-phate therapy can cause severe hypocal-cemia (63,65). Therefore, the routine useof phosphate in the treatment of DKA orHHS has resulted in no clinical benefit tothe patient (63). However, to avoid car-diac and skeletal muscle weakness andrespiratory depression due to hypophos-phatemia, careful phosphate replacementmay sometimes be indicated in patientswith cardiac dysfunction, anemia, or re-spiratory depression and in those with a

serum phosphate concentration �1.0mg/dl (66,67). When needed, 20 –30mEq/l potassium phosphate can be addedto replacement fluids.

COMPLICATIONS — The mostcommon complications of DKA and HHSinclude hypoglycemia and hypokalemiadue to overzealous treatment with insulin.Low potassium may also occur as a result oftreatment of acidosis with bicarbonate. Hy-perglycemia may occur secondary to inter-ruption/discontinuance of intravenousinsulin therapy after recovery from DKA butwithout subsequent coverage with subcuta-neous insulin. Commonly, patients recov-ering from DKA develop a transienthyperchloremic non–anion gap acidosis(68–70). The hyperchloremic acidosis iscaused by the loss of large quantities of ke-toanions that occur during the develop-ment of DKA. Because ketoanions aremetabolized with regeneration of bicarbon-ate, the prior loss of ketoacid anions in theurine hinders regeneration of bicarbonateduring treatment (71). Other mechanismsinclude the administration of intravenousfluids containing chloride that exceeds theplasma chloride concentration and the in-tracellular shifts of NaHCO3 during correc-tion of DKA (70).

Cerebral edema is a rare but fre-quently fatal complication of DKA, occur-ring in 0.7–1.0% of children with DKA. Itis most common in children with newlydiagnosed diabetes, but it has been re-ported in children with known diabetesand in young people in their twenties(72–74). Fatal cases of cerebral edemahave also been reported with HHS. Clin-ically, cerebral edema is characterized bydeterioration in the level of conscious-ness, lethargy, decreased arousal, andheadache. Neurological deteriorationmay be rapid, with seizures, inconti-nence, pupillary changes, bradycardia,and respiratory arrest. These symptomsprogress as brain stem herniation occurs.The progression may be so rapid that pap-illedema is not found. Once the clinicalsymptoms other than lethargy and behav-ioral changes occur, mortality is high(�70%), with only 7–14% of patients re-covering without permanent morbidity.Although the mechanism of cerebraledema is not known, it may result fromosmotically driven movement of waterinto the central nervous system whenplasma osmolality declines too rapidlywith the treatment of DKA or HHS (72–74). However, a recent study (75) usingmagnetic resonance imaging to assess ce-

rebral water diffusion and cerebral vascu-lar perfusion during the treatment of 14children with DKA found that the cere-bral edema was not a function of cerebraltissue edema but rather a function of in-creased cerebral perfusion. There is a lackof information on the morbidity associ-ated with cerebral edema in adult pa-tients; therefore, any recommendationsfor adult patients are based on clinicaljudgment rather than scientific evidence.Preventive measures that might decreasethe risk of cerebral edema in high-risk pa-tients are gradual replacement of sodiumand water deficits in patients who are hy-perosmolar and the addition of dextroseto the hydrating solution once blood glu-cose reaches 200 mg/dl in DKA and 300mg/dl in HHS. In HHS, a glucose level of250 –300 mg/dl should be maintaineduntil hyperosmolarity and mental statusimproves and the patient becomes clini-cally stable. Hypoxemia and, rarely, non-cardiogenic pulmonary edema maycomplicate the treatment of DKA. Hypox-emia is attributed to a reduction in colloidosmotic pressure that results in increasedlung water content and decreased lungcompliance (10). Patients with DKA whohave a widened alveolo-arteriolar oxygengradient noted on initial blood gas mea-surement or with pulmonary rales onphysical examination appear to be athigher risk for the development of pulmo-nary edema.

PREVENTION — Many cases of DKAand HHS can be prevented by better ac-cess to medical care, proper education,and effective communication with a healthcare provider during an intercurrent illness.The observation that stopping insulin foreconomic reasons is a common precipi-tant of DKA in urban African Americansand Hispanics (2,76,77) underscores theneed for our health care delivery systemsto address this problem, which is costlyand clinically serious (78). Sick-day man-agement should be reviewed periodicallywith all patients. It should include spe-cific information on 1) when to contactthe health care provider, 2) blood glucosegoals and the use of supplemental short-or rapid-acting insulin during illness, 3)means to suppress fever and treat infec-tion, and 4) initiation of an easily digest-ible liquid diet containing carbohydratesand salt. Most importantly, the patientshould be advised to never discontinueinsulin and to seek professional adviceearly in the course of the illness. Success-ful sick-day management depends on in-



volvement by the patient and/or a familymember. The patient/family membermust be able to accurately measure andrecord blood glucose, urine, or blood ke-tone determination when blood glucose is�300 mg/dl; insulin administered; tem-perature; respiratory and pulse rates; andbody weight, and must be able to commu-nicate all of this to a health care profes-sional. Adequate supervision and helpfrom staff or family may prevent many ofthe admissions for HHS due to dehydra-tion among elderly individuals who areunable to recognize or treat this evolvingcondition. Better education of caregiversas well as patients regarding signs andsymptoms of new-onset diabetes; condi-tions, procedures, and medications thatworsen diabetes control; and the use ofglucose monitoring could potentially de-crease the incidence and severity of HHS.

The annual incidence rate for DKAfrom population-based studies rangesfrom 4.6 to 8 episodes per 1,000 patientswith diabetes, with a trend toward an in-creased hospitalization rate in the past 2decades. The incidence of HHS accountsfor �1% of all primary diabetic admis-sions. Significant resources are spent onthe cost of hospitalization. DKA episodesrepresent more than $1 of every $4 spenton direct medical care for adult patientswith type 1 diabetes and $1 of every $2 inthose patients experiencing multiple epi-sodes. Based on an annual average of100,000 hospitalizations for DKA in theU.S., with an average cost of $13,000 perpatient (79), the annual hospital cost forpatients with DKA may exceed $1 billionper year. Many of these hospitalizationscould be avoided by devoting adequateresources to apply the measures de-scribed above. Because repeated admis-sions for DKA are estimated to drainapproximately one of every two healthcare dollars spent on adult patients withtype 1 diabetes, resources need to be re-directed toward prevention by fundingbetter access to care and educational pro-grams tailored to individual needs, in-cluding ethnic and personal health carebeliefs. In addition, resources should bedirected toward the education of primarycare providers and school personnel sothat they can identify signs and symptomsof uncontrolled diabetes and new-onsetdiabetes can be diagnosed earlier. This hasbeen shown to decrease the incidence ofDKA at the onset of diabetes (80).

NOTE ADDED IN PROOF — Arecent study from a city hospital reports

that active cocaine use is an independentrisk factor for recurrent DKA (81).

Acknowledgments— Studies cited by the au-thors were supported in part by USPHS grantsRR00211 (to the General Clinical ResearchCenter) and AM 21099, training grant AM07088 of the National Institutes of Health, andgrants from Novo-Nordisk, Eli Lilly, theAmerican Diabetes Association, and the AbeGoodman Fund.

References1. Kitabchi AE, Umpierrez GE, Murphy MB,

Barrett EJ, Kreisberg RA, Malone JI, WallBM: Management of hyperglycemic crisesin patients with diabetes (Technical Re-view). Diabetes Care 24:131–153, 2001

2. Umpierrez GE, Kelly JP, Navarrete JE,Casals MM, Kitabchi AE: Hyperglycemiccrises in urban blacks. Arch Intern Med157:669–675, 1997

3. DeFronzo RA, Matzuda M, Barret E: Dia-betic ketoacidosis: a combined metabolic-nephrologic approach to therapy. DiabetesRev 2:209–238, 1994

4. Ennis ED, Stahl EJVB, Kreisberg RA: Thehyperosmolar hyperglycemic syndrome.Diabetes Rev 2:115–126, 1994

5. Fishbein HA, Fishbein HA, Palumbo PJ:Acute metabolic complications in diabe-tes. In Diabetes in America. National Dia-betes Data Group, National Institute ofHealth, 1995, p. 283–291 (NIH publ. no.95-1468).

6. Lorber D: Nonketotic hypertonicity in di-abetes mellitus. Med Clin North Am 79:39–52, 1995

7. Kreisberg RA: Diabetic ketoacidosis: anupdate. Crit Care Clin 3:817–834, 1987

8. Wachtel TJ, Tctu-Mouradjian LM, Gold-man DL, Ellis SA, O’Sullivan PS: Hyper-osmolarity and acidosis in diabetesmobility. J Gen Int Met 6:495–502, 1991

9. Malone ML, Gennis V, Goodwin JS: Char-acteristics of diabetic ketoacidosis in olderversus younger adults. J Am Geriatr Soc40:1100–1104, 1992

10. Kitabchi AE, Umpierrez GE, Murphy MB:Diabetic ketoacidosis and hyperglycemichyperosmolar state. In International Text-book of Diabetes Mellitus. 3rd ed. De-Fronzo RA, Ferrannini E, Keen H andZimmet P, Eds. John Wiley & Sons,Chichester, U.K., 2004, p. 1101–1119

11. Wachtel TJ, Silliman RA, Lamberton P:Prognostic factors in the diabetic hyper-osmolar state. J Am Geriatr Soc 35:737–741, 1978

12. Wachtel TJ: The diabetic hyperosmolarstate. Clin Geriatr Med 6:797–806, 1990

13. Gerich JE, Martin MM, Recant L: Clinicaland metabolic characteristics of hyperos-molar nonketotic coma. Diabetes 20:228–238, 1971

14. Kitabchi AE, Fisher JN: Insulin therapy of

diabetic ketoacidosis: physiologic versuspharmacologic doses of insulin and theirroutes of administration. In Handbook ofDiabetes Mellitus. Brownlee M, Ed. NewYork, Garland ATPM, 1981, p. 95–149

15. Chupin M. Charbonnel B, Chupin F: C-peptide blood levels in ketoacidosis andin hyperosmolar non-ketotic diabeticcoma. ACTA Diabetol 18:123–128, 1981

16. Hillman K: Fluid resuscitation in diabeticemergencies: a reappraisal. Intensive CareMed 13:4–8, 1987

17. Delaney MF, Zisman A, Kettyle WM: dia-betic ketoacidosis and hyperglycemichyperosmolar nonketotic syndrome. Endo-crinol Metab Clin North Am 29:683–705,2000

18. McGarry JD, Woeltje KF, Kuwajima M,Foster DW: Regulation of ketogenesis andthe renaissance of carnitine palmitoyl-transferase. Diabete Metab Rev 5:271–284,1989

19. Stentz FB, Umpierrez GE, Cuervo R,Kitabchi AE: Proinflammatory cytokines,markers of cardiovascular risks, oxidativestress, and lipid peroxidation in patientswith hyperglycemic crises. Diabetes53:2079–2086, 2004

20. Newcomer JW: Second generation (atyp-ical) antipsycotics and metabolic effects: acomprehensive literature review. CNSDrugs 19 (Suppl. 1):1–93, 2005

21. Polonsky WH, Anderson BJ, Lohrer PA,Aponte JE, Jacobson AM, Cole CF: Insulinomission in women with IDDM. DiabetesCare 17:1178–1185, 1994

22. Peden NR, Broatan JT, McKenry JB: Dia-betic ketoacidosis during long-term treat-ment with continuous subcutaneousinsulin infusion. Diabetes Care 7:1–5,1984

23. Weissberg-Benchell J, Antisdel-LomaglioJ, Seshadri, R: Insulin pump therapy: ameta-analysis. Diabetes Care 26:1079–1087, 2003

24. Umpierrez GE, Smiley D, Kitabchi AE:Ketosis-prone type 2 diabetes mellitus.Annals Int Med 144:350–357, 2006

25. Maldonado M, Hampe CS, Gaur LK,D’Amico S, Iyer D, Hammerle LP, BolgianoD, Rodriguez L, Rajan A, Lernmark A, Bala-subramanyam A: Ketosis-prone diabetes:dissection of a heterogeneous syndrome us-ing an immunogenetic and beta-cell func-tional classification, prospective analysis,and clinical outcomes. J Clin EndocrinolMetab 88:5090–5098, 2003

26. Mauvais-Jarvis F, Sobngwi E, Porcher R,Riveline JP, Kevorkian JP, Vaisse C, Char-pentier G, Guillausseau PJ, Vexiau P,Gautier JF: Ketosis-prone type 2 diabetesin patients of sub-Saharan African origin:clinical pathophysiology and natural his-tory of beta-cell dysfunction and insulinresistance. Diabetes 53:645–653, 2004

27. Umpierrez GE, Casals MM, Gebhart SP,Mixon PS, Clark WS, Phillips LS: Diabeticketoacidosis in obese African-Americans.



Diabetes 44:790–795, 199528. Banerji MA, Chaiken RL, Huey H, Tuomi

T, Norin AJ, Mackay IR, Rowley MJ, Zim-met PZ, Lebovitz HE: GAD antibody neg-ative NIDDM in adult black subjects withdiabetic ketoacidosis and increased fre-quency of human leukocyte antigen DR3and DR4: Flatbush diabetes. Diabetes 43:741–745, 1994

29. Umpierrez GE, Woo W, Hagopian WA,Isaacs SD, Palmer JP, Gaur LK, NepomGT, Clark WS, Mixon PS, Kitabchi AE: Im-munogenetic analysis suggests differentpathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Dia-betes Care 22:1517–1523, 1999

30. Kitabchi AE: Editorial: Ketosis-prone dia-betes: a new subgroup of patients withatypical type 1 an type 2 diabetes? J ClinEndocrinol Metab 88:5087–5089, 2003

31. Sobngwi E, Gautier JF, Kevorkian JP, Vil-lette JM, Riveline JP, Zhang S, Vezian P,Led, SM, Vaisse C, Mauvis-Jarris F: Highprevalence of glucose 6-phosphate dehy-drogenase deficiency without gene muta-tion suggests a novel genetic mechanismpredisposed to ketosis-prone diabetesJ Clin End Metab 90:4446–4451, 2005

32. Matz R: Hypothermia in diabetic acidosis.Hormones 3:36–41, 1972

33. Umpierrez G, Freire AX: Abdominal painin patients with hyperglycemic crises. JCrit Care 17:63–67, 2002

34. Campbell IW, Duncan LJ, Innes JA, Mac-Cuish AC, Munro JF: Abdominal pain indiabetic metabolic decompensation: clin-ical significance. JAMA 233:166–168,1975

35. Winter SD, Pearson JR, Gabow PA,Schultz AL, Lepoff RB The fall of the se-rum anion gap. Arch Intern Med 150: 311–313

36. Slovis CM, Mark VG, Slovis RJ, Bain RP:Diabetic ketoacidosis & infection leuko-cyte count and differential as early predic-tors of infection. Am J Emeg Med 5:1–5,1987

37. Kaminska ES, Pourmoabbed G: Spuriouslaboratory values in diabetic ketoacidosisand hyperlipidaemia. Am J Emerg Med 11:77–80, 1993

38. Rumbak MJ, Hughes TA, Kitabchi AE:Pseudonormoglycaemia in diabetic keto-acidosis with elevated triglycerides. Am JEmerg Med 9:61–63, 1991

39. Adrogue HJ, Lederer ED, Suki WN,Eknoyan G: Determinants of plasma po-tassium levels in diabetic ketoacidosis.Medicine 65:163–171, 1986

40. Atchley DW, Loeb RF, Richards DW,Benedict EM, Driscoll ME: A detailedstudy of electrolyte balance followingwithdrawal and reestablishment of insu-lin therapy. J Clin Invest 12:297–321,1933

41. Vinicor F, Lehrner LM, Karn RC, MerrittAD: Hyperamylasemia in diabetic ketoac-idosis: sources and significance. Ann In-

tern Med 91:200–204, 197942. Gerard SK, Rhayam-Bashi H: Character-

ization of creatinine error in ketotic pa-tients: a prospective comparison ofalkaline picrate methods with an enzy-matic method. Am J Clin Pathol 84:659–661, 1985

43. Kitabchi AE, Fisher JN, Murphy MB,Rumbak MJ: Diabetic ketoacidosis andthe hyperglycemic hyperosmolar non-ke-totic state. In Joslin’s Diabetes Mellitus.13th ed. Kahn CR, Weir GC, Eds. Phila-delphia, Lea & Febiger, 1994, p. 738–770

44. Shah P, Isley WL: Ketoacidosis during alow carbohydrate diet. N Engl J Med 354:97–98, 2006

45. Soveid M, Ranjbar-Omrani G: Ketoacido-sis as the primary manifestation of acro-megaly. Arch Iranian Med 8:326–328,2005

46. Katz JR, Edwards R, Kahn M, Conway GS:Acromegaly presenting with diabetic ke-toacidosis. Postgrad Med J 72:682–683,1996

47. Vidal-Cortada J, Conget-Donlo JI, Na-varro-Tellex MP, Halperin Rabinovic I,Vilardell Latorre E: Diabetic ketoacidosisas the first manifestation of acromegaly.An Med Interna 12:76–78, 1995

48. Szeto CC, Li KY, Ko GT, Szeto CC, Li KY,Ko GT, Chow CC, Yeung VT, Chan JC,Cockram CS: Acromegaly presenting in awoman with diabetic ketoacidosis and in-sulin resistance. Int J Clin Pract 51:476–477, 1997

49. Bratusch-Marrain PR, Komajati M, Wald-hausal W: The effect of hyperosmolarityon glucose metabolism. Pract Cardiol 11:153–163, 1985

50. Kitabchi AE, Ayyagari V, Guerra SM: Theefficacy of low-dose versus conventionaltherapy of insulin for treatment of dia-betic ketoacidosis. Ann Intern Med 84:633–638, 1976

51. Kitabchi AE: Low dose insulin therapy indiabetic ketoacidosis: fact or fiction. Dia-bete Metab Rev 5:337–363, 1989

52. Umpierrez GE, Latif K, Stoever J, CuervoR, Park L, Freire AX, A EK: Efficacy ofsubcutaneous insulin lispro versus con-tinuous intravenous regular insulin forthe treatment of patients with diabetic ke-toacidosis. Am J Med 117:291–296, 2004

53. Umpierrez GE, Cuervo R, Karabell A, La-tif K, Freire AX, Kitabchi AE: Treatment ofdiabetic ketoacidosis with subcutaneousinsulin aspart. Diabetes Care 27:1873–1878, 2004

54. Della Manna T, Steinmetz L, Campos PR,Farhat SC, Schvartsman C, Kuperman H,Setian N, Damiani D: Subcutaneous use ofa fast-acting insulin analog: an alternativetreatment for pediatric patients with dia-betic ketoacidosis. Diabetes Care 28:1856–1861, 2005

55. Guerci B, Benichou M, Floriot M, BohmeP, Fougnot S, Franck P, Drouin P: Ac-

curacy of an electrochemical sensor formeasuring capillary blood ketones by fin-gerstick samples during metabolic deteri-oration after continuous subcutaneousinsulin infusion interruption in type 1 di-abetic patients. Diabetes Care 26:1137–1141, 2003

56. Kelly AM: The case for venuous ratherthan arterial blood gages in diabetic keto-acidosis. Emerg Med Australia 18:64–67,2006

57. Beigelman PM: Potassium in severe dia-betic ketoacidosis (Editorial). Am J Med54:419–420, 1973

58. Abramson E, Arky R: Diabetic acidosiswith initial hypokalemia: therapeutic im-plications. JAMA 196:401–403, 1966

59. Viallon A, Zeni F, Lafond P, Venet C,Tardy B, Page Y, Bertrand JC: Does bicar-bonate therapy improve the managementof severe diabetic ketoacidosis? Crit CareMed 27:2690–2693, 1999

60. Glaser NS, Wooten-Gorges SL, Marcin JP,Buonocore MH, Dicarlo J, Neely EK, Bar-nes P, Bottomly J, Kuppermann N: Mech-anism of cerebral edema in children withdiabetic ketoacidosis. J Pediar 145:149–150, 2004

61. Glaser NS, Wooten-Gorges SL, Buono-core MH, Marcin JP, Rewers A, Strain J,Dicarlo J, Neely EK, Barnes P, Kupper-mann N: Frequency of subclinical cere-bral edema in children with diabeticketoacidosis. Pediatr Diabetes 7:75–80,2006

62. Morris LR, Murphy MB, Kitabchi AE: Bi-carbonate therapy in severe diabetic keto-acidosis. Ann Intern Med 105:836–840,1986

63. Fisher JN, Kitabchi AE: A randomizedstudy of phosphate therapy in the treat-ment of diabetic ketoacidosis. J Clin Endo-crinol Metab 57:177–180, 1983

64. Barsotti MM: Potassium phosphate andpotassium chloride in the treatment of di-abetic ketoacidosis. Diabetes Care 3:569,1980

65. Winter RJ, Harris CJ, Phillips LS, GreenOC: Diabetic ketoacidosis: induction ofhypocalcemia and hypomagnesemia byphosphate therapy. Am J Med 67:897–900, 1979

66. Keller V, Berger W: Prevention of hy-pophosphalemia by phosphate infusionduring treatment of diabetic ketoacidosisand hyperosmolar coma. Diabetes 29:87–95, 1980

67. Kreisberg RA: Phosphorus deficiency andhypophosphatemia. Hosp Pract 12:121–128, 1977

68. Adrogue HJ, Wilson H, Boyd AE 3rd, SukiWN, Eknoyan G: Plasma acid-base pat-terns in diabetic ketoacidosis. N EnglJ Med 307:1603–1610, 1982

69. Oh MS, Carroll HJ, Goldstein DA, FeinIA: Hyperchloremic acidosis during therecovery phase of diabetic ketosis. Ann In-tern Med 89:925–927, 1978



70. Oh MS, Carroll HJ, Uribarri J: Mechanismof normochloremic and hyperchloremicacidosis in diabetic ketoacidosis. Nephron54:1–6, 1990

71. Fleckman AM: Diabetic ketoacidosis. En-docrinol Metabol Clin North Am 22:181–207, 1993

72. Duck SC, Wyatt DT: Factors associatedwith brain herniation in the treatment ofdiabetic ketoacidosis. J Pediatr 113:10–14, 1988

73. Glaser N, Barnett P, McCaslin I, Nelson D,Trainor J, Louie J, Kaufman F, Quayle K,Roback M, Malley R, Kuppermann N:Risk factors for cerebral edema in childrenwith diabetic ketoacidosis: the PediatricEmergency Medicine Collaborative Re-search Committee of the American Acad-emy of Pediatrics. N Engl J Med 344:264–269, 2001

74. Silver SM, Clark EC, Schroeder BM,

Sterns RH: Pathogenesis of cerebraledema after treatment of diabetic ketoac-idosis. Kidney Int 51:1237–1244, 1997

75. Glaser NS, Wootton-Gorges SL, MarcinJP, Buonocore MH, DiCarlo J, Neely K,Barnes P, Bottomly J, Kuppermann N:Mecahanism of cerebral edema in chil-dren with diabetic ketoacidosis. J Pediatr145:164–171, 2004

76. Musey VC, Lee JK, Crawford R, KlatkaMA, McAdams D, Phillips LS: Diabetes inurban African-Americans. I. Cessation ofinsulin therapy is the major precipitatingcause of diabetic ketoacidosis. DiabetesCare 18:483–489, 1995

77. Maldonado MR, Chong ER, Oehl MA,Balasubramanyam A: Economic impact ofdiabetic ketoacidosis in a multiethnic in-digent population: analysis of costs basedon the precipitating cause. Diabetes Care26:1265–1269, 2003

78. Kitabchi AE: Hyperglycemic crises: im-proving prevention and management.Fam Physician 71:1659–1660, 2005

79. Javor KA, Kotsanos JG, McDonald RC,Baron AD, Kesterson JG, Tierney WM: Di-abetic ketoacidosis charges relative tomedical charges of adult patients withtype 1 diabetes. Diabetes Care 20:349–354, 1997

80. Vanelli M, Chiari G, Ghizzoni L, Costi G,Giacalone T, Chiarelli F: Effectiveness of aprevention program for diabetic ketoaci-dosis in children: an 8-year study inschools and private practices. DiabetesCare 22:7–9, 1999

81. Nyenwe E, Loganathan R, Blum S, EzutehD, Erani D, Wan J, Palace M, Kitabchi A:Active use of cocaine: an independent riskfactor for recurrent diabetic ketoacidosisin a city hospital. Endocrine Practice. Inpress



endocriniología - hyperglicemic crisis in adult patients with diabetes

Documents