Journal of Critical Care, Vol 17, No 1 (March), 2002: pp 63-67 63

Background: The aim of the study was to evaluate the

incidence and prognosis of abdominal pain in patients

with diabetic ketoacidosis (DKA) and hyperglycemic

hyperosmolar nonketotic state (HHS). Abdominal

pain, sometimes mimicking an acute abdomen, is a

frequent manifestation in patients with DKA. The

prevalence and clinical significance of gastrointestinal

symptoms including abdominal pain in HHS have not

been prospectively evaluated.

Materials and Methods: This is a prospectively col-

lected evaluation of 200 consecutive patients with hy-

perglycemic crises admitted to a large inner-city teach-

ing hospital in Atlanta, GA.We analyzed the admission

clinical characteristics, laboratory studies, and hospi-

tal course of 189 consecutive episodes of DKA and 11

cases of HHS during a 13-month period starting in

October 1995.

Results: Abdominal pain occurred in 86 of 189 pa-

tients with DKA (46%). In 30 patients, the cause of ab-

dominal pain was considered to be secondary to the

precipitating cause of metabolic decompensation.

Five of them required surgical intervention including

1 patient with Fournier’s necrotizing fasciitis, 1 with

cholecystitis, 1 with acute appendicitis, and 2 patients

with perineal abscess.The presence of abdominal pain

was not related to the severity of hyperglycemia or

dehydration; however, a strong association was ob-

served between abdominal pain and metabolic aci-

dosis. In DKA patients with abdominal pain, the mean

serum bicarbonate (9 � 1 mmol/L) and blood pH

(7.12 � 0.02) were lower than in patients without pain

(15 � 1 mmol/L and 7.24 � 0.09, respectively, both

P � .001). Abdominal pain was present in 86% of pa-

tients with serum bicarbonate less than 5 mmol/L, in

66% of patients with levels of 5 to less than 10

mmol/L, in 36% of patients with levels 10 to less than

15 mmol/L, and in 13% of patients with bicarbonate

levels 15 to 18 mmol/L. Patients with DKA and ab-

dominal pain had a more frequent history of alcohol

(51%) and cocaine abuse (13%) than those without ab-

dominal pain (24% and 2%, respectively, both P �

.001). One patient with HHS reported nausea and vom-

iting on admission, but abdominal pain was not re-

ported in any patient with HHS.

Conclusions: Gastrointestinal manifestations includ-

ing abdominal pain are common in patients with DKA

and are associated with severe metabolic acidosis and

with a history of alcohol or cocaine abuse, but not

with the severity of hyperglycemia or dehydration. Our

study indicates that investigation of the etiology of

abdominal pain in DKA should be reserved for patients

without severe metabolic acidosis or if the pain per-

sists after the resolution of ketoacidosis.

Copyright 2002, Elsevier Science (USA). All rights

reserved.

Abdominal Pain in Patients With Hyperglycemic Crises

Guillermo Umpierrez and Amado X. Freire

DIABETIC KETOACIDOSIS (DKA) and hy-perglycemic hyperosmolar nonketotic state

(HHS) are the most common hyperglycemic emer-gencies in patients with diabetes. It is estimated thatDKA and HHS account for up to one fourth of alldiabetes-related hospital admissions,1-4 and recentepidemiologic studies in the United States indicatethat hospitalizations for DKA and HHS are in-creasing.1 Despite advances in their treatment, DKAand HHS remain serious events with mortality ratesas high as 5% to 10%.2,5 The cause of death in pa-tients with DKA and HHS rarely results from themetabolic complications of hyperglycemia or meta-bolic acidosis but relates to the underlying medicalillness that precipitated the ketoacidosis. Thus, suc-cessful treatment requires a prompt and carefulsearch for the precipitating cause.

The clinical presentation of DKA usually devel-ops rapidly, over a time span of less than 24 hours.Polyuria, polydipsia, and weight loss may be pre-sent for several days before the development of ke-toacidosis, whereas nausea, vomiting, and abdom-inal pain are frequently the presenting symptoms.Abdominal pain, sometimes mimicking an acute

abdomen, is especially common in children.6,7

These abdominal manifestations occur in 40% to75% of cases of DKA.8-11 The abdominal pain usu-ally resolves with correction of hyperglycemia,metabolic acidosis, and electrolyte disturbances.However, in the face of such severe illness and be-cause of fear of missing an intra-abdominal med-ical or surgical process that may have precipitatedthe development of ketoacidosis, extensive labora-tory and radiologic studies may be ordered. In someinstances, exploratory laparotomy is performedwithout positive results, increasing the cost of med-ical care, and the morbidity and mortality risk inpatients with DKA.12-14

From the Department of Medicine and Preventive Medicine,University of Tennessee Health Science Center, Memphis, TN.

Address reprint requests to Guillermo E. Umpierrez, MD, As-sociate Professor of Medicine, Department of Medicine, Uni-versity of Tennessee Health Science Center, 951 Court Ave, Rm340M, Memphis, TN 38163.

Copyright 2002, Elsevier Science (USA). All rights reserved.0883-9441/02/1701-0009$35.00/0doi:10.1053/jcrc.2002.33030

Most patients who develop HHS do so over daysto weeks, during which they have experiencedpolyuria, polydipsia, and progressive decline in thelevel of consciousness. The most common reasonfor seeking medical attention is unresponsive-ness.4,15 In patients with HHS, the prevalence ofgastrointestinal symptoms including abdominalpain has not been reported.

The aim of this study was to determine the preva-lence and clinical significance of abdominal painin patients with hyperglycemic crises.

MATERIALS AND METHODS

This was a prospective evaluation of 200 consecutive patientswith hyperglycemic crises admitted to Grady Memorial Hos-pital in Atlanta during a 13-month period starting in October1995. Of the 200 patients, 189 patients (95%) met the diag-nostic criteria for DKA (111 men and 82 women) and 11 pa-tients were admitted with HHS (4 men and 7 women). The di-agnosis of DKA was established in the emergency departmentby a plasma glucose level greater than 13.8 mmol/L (250mg/dL), a serum bicarbonate level lower than 15 mmol/L, ablood pH less than 7.3, a calculated anion gap greater than 14mmol/L, a positive serum ketone level at a dilution equal to orgreater than 1:4 by the nitroprusside reaction. Diagnostic crite-ria for HHS included a plasma glucose level greater than600 mg/dL (33.3 mmol/L), a total serum osmolality greater than320 mmol/kg, a blood pH greater than 7.3, a serum bicarbon-ate level greater than 15 mmol/L, and a serum ketone level equalto or less than 1:2 dilutions. Total serum osmolality was calcu-lated as follows:

[2 � sodium ion (mmol/L)] � [glucose (mg/dL)/18]� [blood urea nitrogen (mg/dL)/2.8],

with normal values being 290 � 5 mmol/kg of water.The presence or absence of abdominal pain, nausea, and vom-

iting was recorded on admission. The evidence of abdominalguarding and rebound tenderness was sought on physical ex-amination. In addition, patient information was collected re-garding demographic characteristics, precipitating cause formetabolic decompensation, substance abuse (alcohol or co-caine), renal disease, previous history of DKA or HHS, glucoseand acid-base status, concurrent medical diagnoses, and hospi-tal outcome including mortality.

Statistical AnalysisComparisons of demographics and continuous clinical char-

acteristics between groups were performed by using unpairedt test. For categoric variables, �2 analysis was used when ap-plicable. Association between metabolic acidosis and severityof abdominal pain was assessed by Mantel-Hanzel �2 analysisfor trend in the 189 DKA patients. A P value of .05 was con-sidered significant. StatView version 5.0 (SAS Institute, Cary,NC) was the statistical software used for the analysis.

RESULTS

The study population included 189 patients withDKA and 11 patients with HHS. Their clinical char-acteristics are shown in Table 1. Abdominal painwas reported in 86 of 189 patients with DKA(46%). Patients with DKA and abdominal painwere younger (37 �; 1 yr, standard error of mean)than patients without abdominal pain (41 � 2 yr,P � .03). The mean duration of diabetes and num-ber of patients with newly diagnosed diabetes weresimilar between DKA patients with and without ab-dominal pain. Pain was associated with abdominaltenderness in all patients, and rebound tendernesswas present in 12% of patients. Nausea and vom-iting were reported in 66% of DKA patients withabdominal pain and in 35% of patients without ab-dominal pain (P � .001). No patient with HHScomplained of abdominal pain on admission andonly 1 patient with HHS who had a known historyof gastroparesis reported nausea and vomitingbefore admission.

In 30 of the 86 DKA patients with abdominalpain (35%), the etiology of the pain was consid-ered to be secondary to the precipitating cause ofmetabolic decompensation. Four patients presentedwith acute pancreatitis and 4 with acute exacerba-tion of chronic alcoholic pancreatitis. Three pa-tients were diagnosed with acute alcoholic hepati-

64 UMPIERREZ AND FREIRE

Table 1. Clinical Characteristics on Admission

DKA With DKA WithoutAbdominal Pain Abdominal Pain

Number of patients 86 103Age (yrs) 37 � 13 41 � 21Sex (men/women) 47/43 64/39Duration of diabetes (yr) 7 � 1 9 � 1New-onset diabetes 16 (18) 18 (17)History of alcohol use 44 (51)† 25 (24)History of cocaine use 11(13)‡ 2 (2)Blood glucose (mg/dL) 596 � 246 586 � 245Bicarbonate (mmol/L) †9 � 1† 15 � 15PH 7.12 � .02† 7.24 � .092Sodium (mmol/L) 133 � 133 133 � 133Potassium (mmol/L) 5.4 � 1‡. 5.0 � .10Serum osmolality (mmol/L) 307 � 207 307 � 207BUN (mg/dL) 24 � 24 24 � 22Creatinine (mg/dL) 1.8 � .21 1.6 � .81

Data are means � SEM or n (%).*P � .05.†P � .0001.‡P � .01.

tis, 2 with gastritis, 1 with peptic ulcer disease, and1 with viral hepatitis. Six patients had pyelonephri-tis, 2 had gastroenteritis, and 2 were considered tohave pelvic inflammatory disease. Only 5 patientsadmitted with DKA and abdominal pain requiredsurgical intervention including 1 patient withFournier’s necrotizing fasciitis, 1 with cholecysti-tis, 1 with acute appendicitis, and 2 with perinealabscess.

We found no association between the presenceof abdominal pain and the initial blood glucoselevel and/or severity of dehydration as indicated bythe admission serum osmolality and urea nitrogenconcentration (Table 1). In contrast, we observed astrong correlation between the severity of meta-bolic acidosis and the presence of abdominal pain(P � .001). Patients with DKA and abdominal painhad a mean serum bicarbonate (9 � 1 mmol/L) andblood pH level (7.12 � 0.02) significantly lowerthan in patients with DKA without abdominal pain(15 � 1 mmol/L and 7.24 � 0.09, respectively, bothP � .0001). The association between abdominalpain and severity of metabolic acidosis was con-firmed by �2 analysis of trend (P � .0001). The re-lationship between admission levels of bicarbonate,glucose, and osmolality and the presence of ab-dominal pain is shown in Table 2. Pain was present

in 25 of the 29 (86%) patients with bicarbonate lev-els less than 5 mmol/L, in 66% of patients with lev-els between 5 and less than 10 mmol/L, in 36%with levels 10 and less than 15 mmol/L, and in 13%of those with bicarbonate between 15 and 18mmol/L. The admission pH level also correlatedwith the presence of abdominal pain. A total of 86%of patients with pH less than 7.0 complained of ab-dominal pain, a value higher than that reported inpatients with pH between 7 and less than 7.25 andpH 7.25 to 7.30 in whom pain was 47% and 25%,respectively, both P � .01.

Noncompliance with medical therapy or discon-tinuation of insulin was the leading cause of DKAand accounted for 57% of patients with abdominalpain and 43% of patients without abdominal pain.Substance abuse including alcohol and cocaineabuse played an important role in decreased com-pliance and perhaps in the pathogenesis of ab-dominal pain. Patients with DKA and abdominalpain had a greater history of alcohol (51%) and co-caine abuse (13%) compared with those withoutabdominal pain (24% and 2%, respectively, bothP � .001).

In all patients without an identifiable cause ofabdominal pain, the pain spontaneously resolvedafter resolution of metabolic acidosis. In such pa-tients, the mean duration of insulin therapy untilresolution of ketoacidosis was 12 � 2 hours. Twopatients died during the study period, 1 patient withDKA admitted with Fournier’s necrotizing fasciitis,and 1 patient in the HHS group who was admittedwith urosepsis and bladder malignancy.

DISCUSSION

The evaluation of abdominal pain in patientswith DKA may be difficult and frequently chal-lenges the physicians’ clinical acumen. Faced witha seriously ill patient, the clinician must judgewhether the abdominal pain is a consequence of themetabolic decompensation or if the pain signals aserious underlying intra-abdominal process thatmay have precipitated the development of ketoaci-dosis. Because of the fear of missing an intra-abdominal medical or surgical process, extensivelaboratory and radiologic studies may be ordered.However, in the majority of such patients, the ab-dominal pain is likely to resolve with correctionof ketoacidosis. In some instances, exploratory la-parotomy is performed without positive results,

ABDOMINAL PAIN IN DKA 65

Table 2. Admission Serum Bicarbonate, Glucose,

and Osmolality Levels in Patients With DKA

and Abdominal Pain

No. PatientsTotal No. (%) With

DKA Patients Abdominal Pain

Bicarbonate (mmol/L)�5 29 25 (86)5 to �10 47 31 (66)10 to �15 66 24 (36)15-18 47 26 (13)

Glucose (mg/dL)�400 55 20 (36)400-600 60 29 (48)600 74 37 (50)

Calculated osmolality (mmol/kg)�300 63 30 (48)300-320 89 36 (40)320 37 20 (54)

NOTE. Total serum osmolality was calculated as follows:[2 � sodium ion (mEq/L)] � [glucose (mg/dL)/18] � [bloodurea nitrogen (mg/dL)/2.8], with normal values being 290 � 5mmol/kg of water. To convert glucose values to mmol/L,divide glucose (mg/dL) by 18.

increasing the cost of medical care, and themorbidity and mortality risk in patients withDKA.12-14 Until now, the prevalence and clinicalsignificance of gastrointestinal symptoms, includ-ing abdominal pain in patients with HHS, have notbeen prospectively evaluated.

Abdominal manifestations including nausea,vomiting, and abdominal pain are frequently re-ported in patients with DKA. In agreement withprevious reports,7,8,12,16 the cause of the abdomi-nal pain in most patients could not be identified byclinical and radiologic studies, but the pain spon-taneously resolved after resolution of ketoacidosis.In one third of patients with DKA, the abdominalpain was considered to be secondary to the pre-cipitating cause of metabolic decompensation;however, surgical intervention was required in only5 of 86 (6%) patients with DKA and abdominalpain.

Our study indicates that the abdominal pain inDKA is associated with a more severe metabolicacidosis compared with those without abdominalpain. Based on the recent classification of severityof DKA,1 75% of the patients with severe DKApresented with pain, but only 13% with mild DKAexperienced abdominal pain. In contrast, we ob-served no association between the presence of ab-dominal pain and the initial blood glucose leveland/or severity of dehydration. The admission bloodglucose and serum osmolality were similar betweenDKA patients with and without abdominal pain.Moreover, none of the patients with HHS presentedwith abdominal pain despite the fact that they wereadmitted with a mean blood glucose concentrationgreater than 1,000 mg/dL and a mean serum osmo-lality greater than 350 mOsm/L. Although the num-ber of patients with HHS in this study is too smallto reach a definitive conclusion on the lack of asso-ciation between abdominal pain and HHS, our re-sults indicate that in patients with mild DKA or inthe absence of significant metabolic acidosis, it maybe dangerous to attribute abdominal pain to themetabolic decompensation.

The pathogenesis of reversible gastrointestinalsymptoms in patients with DKA has not been rig-orously defined, and may be multifactorial, in-volving metabolic, humoral, and neural processes.Nausea and vomiting have been attributed to eithera central neurogenic response to increased ketonebodies and acidosis or to gastric atony and gen-eralized ileus.7 Acute hyperglycemia has been

shown to impair gastrointestinal motility in dia-betic patients and in normal subjects.17-21 Althoughdelayed gastric emptying may be related to neuro-pathic changes,19-21 acute hyperglycemia has beenshown to produce gastroparesis by a direct effect.21

Similarly, acute hyperglycemia has adverse ef-fects on esophageal motility and gallbladder con-tractility.22-24 It is also possible that increased cir-culating levels of glucagon and catecholaminesin DKA may delay gastrointestinal motility.7 Inaddition, the abdominal pain in DKA has beenattributed to rapid expansion of the hepatic cap-sule, presumably secondary to fatty liver,7,8 orto bowel ischemia secondary to severe volumedepletion and metabolic acidosis9 or mesentericinsufficiency.25,26

In agreement with recent publications,2,27,28 ourstudy indicates that omission of insulin and poorcompliance with medical therapy is a major pre-cipitating cause of DKA in urban patients. Severalstudies have indicated that patients with diabetesand substance abuse are twice as likely to fail totake their insulin in the 24 hours before hospital-ization.27-29 In addition to its role in decreased com-pliance, a history of alcohol and cocaine abuse mayplay a role in the pathogenesis of abdominal painand metabolic decompensation. Alcohol excessmay be complicated with alcoholic pancreatitis andketoacidosis,30 and cocaine may precipitate mesen-teric ischemia.31,32 In addition, animal and humanstudies,33-35 have shown that cocaine increases theconcentration of counterregulatory hormones, in-cluding epinephrine, norepinephrine, corticotropin,and cortisol, which might act as a precipitating fac-tor for DKA.

In summary, our study indicates that gastroin-testinal manifestations including nausea, vomiting,and abdominal pain are common in patients withDKA. The presence of abdominal pain was asso-ciated with a more severe metabolic acidosis andwith a history of alcohol or cocaine abuse, but notwith the severity of hyperglycemia or dehydration.Although a potential acute abdominal problemprompting surgical intervention should not be over-looked, in the majority of patients, the abdominalpain spontaneously resolves after correction of themetabolic disturbance. In the absence of an overtcause for abdominal pain, allowing several hoursto treat the underlying acidosis constitutes the bestdiagnostic tool to elucidate the cause of abdominalpain in ketoacidosis.

66 UMPIERREZ AND FREIRE

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ABDOMINAL PAIN IN DKA 67

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