Diabetic Ketoacidosis

Diabetic KetoacidosisDiabetic Ketoacidosis

Gary David Goulin, MDGary David Goulin, MD

Goals & ObjectivesGoals & Objectives

• Understand the action of insulin on the Understand the action of insulin on the metabolism of carbohydrates, protein, and fatmetabolism of carbohydrates, protein, and fat

• Understand the pathophysiology of IDDM Understand the pathophysiology of IDDM and DKAand DKA

• Understand the management approach to the Understand the management approach to the patient with DKApatient with DKA

• Appreciate the complications that can occur Appreciate the complications that can occur during treatment of DKAduring treatment of DKA

IntroductionIntroduction

• Diabetes mellitus is a syndrome of Diabetes mellitus is a syndrome of disturbed energy homeostasis caused by a disturbed energy homeostasis caused by a deficiency of insulin or of its action deficiency of insulin or of its action resulting in abnormal metabolism of resulting in abnormal metabolism of carbohydrate, protein, and fatcarbohydrate, protein, and fat

• Diabetes mellitus is the most common Diabetes mellitus is the most common endocrine-metabolic disorder of childhood endocrine-metabolic disorder of childhood and adolescenceand adolescence


• Individuals affected by insulin-dependent Individuals affected by insulin-dependent diabetes confront serious burdens that diabetes confront serious burdens that include an absolute daily requirement for include an absolute daily requirement for exogenous insulin, the need to monitor their exogenous insulin, the need to monitor their own metabolic control, and the need to pay own metabolic control, and the need to pay constant attention to dietary intakeconstant attention to dietary intake


• Morbidity and mortality stem from Morbidity and mortality stem from metabolic derangements and from long-metabolic derangements and from long-term complications that affect small and term complications that affect small and large vessels and result in retinopathy, large vessels and result in retinopathy, nephropathy, neuropathy, ischemic heart nephropathy, neuropathy, ischemic heart disease, and arterial obstruction with disease, and arterial obstruction with gangrene of the extremitiesgangrene of the extremities

ClassificationClassification

• Type I Diabetes (Type I Diabetes (insulin-dependent diabetes insulin-dependent diabetes mellitusmellitus, IDDM), IDDM)– characterized by severe insulinopenia and characterized by severe insulinopenia and

dependence on exogenous insulin to prevent dependence on exogenous insulin to prevent ketosis and to preserve lifeketosis and to preserve life

– onset occurs predominantly in childhoodonset occurs predominantly in childhood– probably has some genetic predisposition and is probably has some genetic predisposition and is

likely autoimmune-mediatedlikely autoimmune-mediated


• Type II Diabetes (Type II Diabetes (non-insulin-dependent non-insulin-dependent diabetes mellitusdiabetes mellitus, NIDDM), NIDDM)– patients are not insulin dependent and rarely develop ketosispatients are not insulin dependent and rarely develop ketosis

– generally occurs after age 40, and there is a high incidence of generally occurs after age 40, and there is a high incidence of associated obesityassociated obesity

– As the prevalence of childhood obesity increases, more As the prevalence of childhood obesity increases, more adolescents are presenting with NIDDMadolescents are presenting with NIDDM

– insulin secretion is generally adequate; insulin resistance is presentinsulin secretion is generally adequate; insulin resistance is present

– no associated genetic predispositionno associated genetic predisposition


• Secondary DiabetesSecondary Diabetes– occurs in response to other disease processes:occurs in response to other disease processes:

• exocrine pancreatic disease (cystic fibrosis)exocrine pancreatic disease (cystic fibrosis)

• Cushing syndromeCushing syndrome

• poison ingestion (rodenticides)poison ingestion (rodenticides)

Type I Diabetes Mellitus: Type I Diabetes Mellitus: EpidemiologyEpidemiology

• Prevalence of IDDM among school-age Prevalence of IDDM among school-age children in the US is 1.9 per 1000children in the US is 1.9 per 1000

• The annual incidence in the US is about 12 - The annual incidence in the US is about 12 - 15 new cases per 100,00015 new cases per 100,000

• Male to female ratio is equalMale to female ratio is equal

• Among African-Americans, the occurrence Among African-Americans, the occurrence of IDDM is about 20 - 30% of that seen in of IDDM is about 20 - 30% of that seen in Caucasian-AmericansCaucasian-Americans

Type I Diabetes Mellitus: Type I Diabetes Mellitus: EpidemiologyEpidemiology

• Peaks of presentation occur at 5 - 7 years of Peaks of presentation occur at 5 - 7 years of age and at adolescenceage and at adolescence

• Newly recognized cases appear with greater Newly recognized cases appear with greater frequency in the autumn and winterfrequency in the autumn and winter

• Definite increased incidence of IDDM in Definite increased incidence of IDDM in children with congenital rubella syndromechildren with congenital rubella syndrome

Type I Diabetes Mellitus: Type I Diabetes Mellitus: Etiology and PathogenesisEtiology and Pathogenesis

• Basic cause of clinical findings is sharply Basic cause of clinical findings is sharply diminished secretion of insulindiminished secretion of insulin

• The mechanisms that lead to failure of The mechanisms that lead to failure of pancreatic pancreatic -cell function are likely -cell function are likely autoimmune destruction of pancreatic isletsautoimmune destruction of pancreatic islets

• IDDM is more prevalent in persons with IDDM is more prevalent in persons with Addison’s disease, Hashimoto’s thyroiditis, Addison’s disease, Hashimoto’s thyroiditis, and pernicious anemiaand pernicious anemia

Type I Diabetes Mellitus: Type I Diabetes Mellitus: Etiology and PathogenesisEtiology and Pathogenesis

• 80 - 90% of newly diagnosed patients with 80 - 90% of newly diagnosed patients with IDDM have anti-islet cell antibodiesIDDM have anti-islet cell antibodies

Type I Diabetes Mellitus: Type I Diabetes Mellitus: PathophysiologyPathophysiology

High Plasma Insulin Low Plasma Insulin(Postprandial State) (Fasted State)

Liver: Glucose uptake Glucose productionGlycogen synthesis GlycogenolysisAbsence of gluconeogenesis GluconeogenesisLipogenesis Absence of lipogenesisAbsence of ketogenesis Ketogenesis

Muscle: Glucose uptake Absence of glucose intakeGlucose oxidation Fatty acid and ketone oxidationGlycogen synthesis GlycogenolyssProtein synthesis Proteolysis and amino acid release

Adipose tissue: Glucose uptake Absence of glucose uptakeLipid synthesis Lipolysis and fatty acid releaseTriglyceride uptake Absence of triglyceride uptake


• Progressive destruction of Progressive destruction of -cells leads to a -cells leads to a progressive deficiency of insulinprogressive deficiency of insulin

• As IDDM evolves, it becomes a permanent As IDDM evolves, it becomes a permanent low-insulin catabolic state which feeding low-insulin catabolic state which feeding does not reversedoes not reverse

• Secondary changes involving stress Secondary changes involving stress hormones accelerate the metabolic hormones accelerate the metabolic decompensationdecompensation


• With progressive insulin deficiency, excessive With progressive insulin deficiency, excessive glucose production and impairment of utilization glucose production and impairment of utilization result in hyperglycemia, with glucosuria result in hyperglycemia, with glucosuria developing when the renal threshold of ~ 180 developing when the renal threshold of ~ 180 mg/dL is exceededmg/dL is exceeded

• The resultant osmotic diuresis produces polyuria, The resultant osmotic diuresis produces polyuria, urinary losses of electrolytes, dehydration, and urinary losses of electrolytes, dehydration, and

compensatory polydipsiacompensatory polydipsia


• Hyperosmolality as a result of progressive Hyperosmolality as a result of progressive hyperglycemia contributes to cerebral hyperglycemia contributes to cerebral obtundation in DKAobtundation in DKA

• Serum osmolality:Serum osmolality:– {Serum Na{Serum Na++ + K + K++} x 2 + } x 2 + glucoseglucose + + BUNBUN

18 3


• DKA results in altered lipid metabolismDKA results in altered lipid metabolism– increased concentrations of total lipids, increased concentrations of total lipids,

cholesterol, triglycerides, and free fatty acidscholesterol, triglycerides, and free fatty acids– free fatty acids are shunted into ketone body free fatty acids are shunted into ketone body

formation due to lack of insulin; the rate of formation due to lack of insulin; the rate of formation exceeds the capacity for their formation exceeds the capacity for their peripheral utilization and renal excretion peripheral utilization and renal excretion leading to accumulation of ketoacids, and leading to accumulation of ketoacids, and therefore metabolic acidosistherefore metabolic acidosis


• With progressive dehydration, acidosis, With progressive dehydration, acidosis, hyperosmolality, and diminished cerebral hyperosmolality, and diminished cerebral oxygen utilization, consciousness becomes oxygen utilization, consciousness becomes impaired, and the patient ultimately impaired, and the patient ultimately becomes comatosebecomes comatose

Type I Diabetes Mellitus: Type I Diabetes Mellitus: Clinical ManifestationsClinical Manifestations

• Classic presentation of diabetes in children Classic presentation of diabetes in children is a history of polyuria, polydipsia, is a history of polyuria, polydipsia, polyphagia, and weight loss, usually for up polyphagia, and weight loss, usually for up to one monthto one month

• Laboratory findings include glucosuria, Laboratory findings include glucosuria, ketonuria, hyperglycemia, ketonemia, and ketonuria, hyperglycemia, ketonemia, and metabolic acidosis. Serum amylase may be metabolic acidosis. Serum amylase may be elevated. Leukocytosis is commonelevated. Leukocytosis is common

Type I Diabetes Mellitus: Type I Diabetes Mellitus: Clinical ManifestationsClinical Manifestations

• Keotacidosis is responsible for the initial Keotacidosis is responsible for the initial presentation of IDDM in up to 25% of presentation of IDDM in up to 25% of childrenchildren– early manifestations are mild and include vomiting, early manifestations are mild and include vomiting,

polyuria, and dehydration polyuria, and dehydration

– More severe cases include Kussmaul respirations, odor of More severe cases include Kussmaul respirations, odor of acetone on the breathacetone on the breath

– abdominal pain or rigidity may be present and mimic abdominal pain or rigidity may be present and mimic acute appendicitis or pancreatitisacute appendicitis or pancreatitis

– cerebral obtundation and coma ultimately ensuecerebral obtundation and coma ultimately ensue

Type I Diabetes Mellitus: Type I Diabetes Mellitus: DiagnosisDiagnosis

• Diagnosis of IDDM is dependent on the Diagnosis of IDDM is dependent on the demonstration of hyperglycemia in demonstration of hyperglycemia in association with glucosuria with or without association with glucosuria with or without ketonuriaketonuria

• DKA must be differentiated from acidosis and DKA must be differentiated from acidosis and coma due to other causes:coma due to other causes:– hypoglycemia, uremia, gastroenteritis with hypoglycemia, uremia, gastroenteritis with

metabolic acidosis, lactic acidosis, salicylate metabolic acidosis, lactic acidosis, salicylate intoxication, encephalitisintoxication, encephalitis

Type I Diabetes Mellitus: Type I Diabetes Mellitus: DiagnosisDiagnosis

• DKA exists when there is hyperglycemia (> DKA exists when there is hyperglycemia (> 300 mg/dL), ketonemia, acidosis, 300 mg/dL), ketonemia, acidosis, glucosuria, and ketonuriaglucosuria, and ketonuria

Type I Diabetes Mellitus: Type I Diabetes Mellitus: TreatmentTreatment

• Treatment is divided into 3 phasesTreatment is divided into 3 phases– treatment of ketoacidosistreatment of ketoacidosis– transition periodtransition period– continuing phase and guidancecontinuing phase and guidance


• Goals of treatment of DKAGoals of treatment of DKA– intravascular volume expansionintravascular volume expansion– correction of deficits in fluids, electrolytes, and correction of deficits in fluids, electrolytes, and

acid-base statusacid-base status– initiation of insulin therapy to correct initiation of insulin therapy to correct

catabolism, acidosiscatabolism, acidosis


• Intravascular volume expansionIntravascular volume expansion– dehydration is most commonly in the order of 10%dehydration is most commonly in the order of 10%

– initial hydrating fluid should be isotonic salineinitial hydrating fluid should be isotonic saline

• this alone will often slightly lower the blood glucosethis alone will often slightly lower the blood glucose

• rarely is more than 20 cc/kg fluid required to restore rarely is more than 20 cc/kg fluid required to restore hemodynamicshemodynamics

• Treatment of electrolyte abnormalitiesTreatment of electrolyte abnormalities

– serum Kserum K++ is often elevated, though total body K is often elevated, though total body K++ is depleted is depleted

– KK++ is started early as resolution of acidosis and the administration is started early as resolution of acidosis and the administration of insulin will cause a decrease in serum Kof insulin will cause a decrease in serum K++


• Phosphate is depleted as well. Phosphate may be added as Phosphate is depleted as well. Phosphate may be added as KPOKPO44 especially if serum chloride becomes elevated especially if serum chloride becomes elevated

• ““Pseudohyponatremia” is often presentPseudohyponatremia” is often present

– Expect that the NaExpect that the Na++ level will rise during treatment level will rise during treatment

– Corrected NaCorrected Na++ = Measured Na = Measured Na++ + 0.016(measured + 0.016(measured glucose - 100)glucose - 100)

– If NaIf Na++ does does notnot rise, true hyponatremia may be present rise, true hyponatremia may be present (possibly increasing cerebral edema risk) and should be (possibly increasing cerebral edema risk) and should be treatedtreated


• BICARBONATE IS ALMOST NEVER BICARBONATE IS ALMOST NEVER ADMINISTEREDADMINISTERED– bicarbonate administration leads to increased bicarbonate administration leads to increased

cerebral acidosiscerebral acidosis• HCOHCO33

-- combines with H combines with H++ and dissociated to CO and dissociated to CO22 and and

HH22O. Whereas bicarbonate passes the blood-brain O. Whereas bicarbonate passes the blood-brain

barrier slowly, CObarrier slowly, CO22 diffuses freely, thereby diffuses freely, thereby

exacerbating cerebral acidosis and cerebral exacerbating cerebral acidosis and cerebral depressiondepression


• Indications for bicarbonate administration Indications for bicarbonate administration include include severesevere acidosis leading to acidosis leading to cardiorespiratory compromisecardiorespiratory compromise

• Increasing evidence suggests that Increasing evidence suggests that subclinical cerebral edema occurs in the subclinical cerebral edema occurs in the majority of patients treated with fluids and majority of patients treated with fluids and insulin for DKAinsulin for DKA


• Cerebral edema is the major life-threatening Cerebral edema is the major life-threatening complication seen in the treatment of complication seen in the treatment of children with DKAchildren with DKA– clinically apparent cerebral edema occurs in clinically apparent cerebral edema occurs in

~1% of episodes of DKA~1% of episodes of DKA– mortality is 40 - 90%mortality is 40 - 90%– cerebral edema is responsible for 50 - 60% of cerebral edema is responsible for 50 - 60% of

diabetes deaths in childrendiabetes deaths in children


– Cerebral edema usually develops several hours Cerebral edema usually develops several hours after the institution of therapyafter the institution of therapy

– manifestations include headache, alteration in manifestations include headache, alteration in level of consciousness, bradycardia, emesis, level of consciousness, bradycardia, emesis, diminished responsiveness to painful stimuli, diminished responsiveness to painful stimuli, and unequal or fixed, dilated pupilsand unequal or fixed, dilated pupils


• Excessive use of fluids, large doses of insulin, and Excessive use of fluids, large doses of insulin, and especially the use of bicarbonate have been linked to the especially the use of bicarbonate have been linked to the increased formation of cerebral edemaincreased formation of cerebral edema

– fluids are generally limited to ~ 3 L/mfluids are generally limited to ~ 3 L/m22/24 hours/24 hours

• Children who present with elevated BUN, PChildren who present with elevated BUN, PaaCOCO22 < 15 torr, < 15 torr,

or who demonstrate a lack of an increase in serum Naor who demonstrate a lack of an increase in serum Na++ during therapy have an increased probability of cerebral during therapy have an increased probability of cerebral edemaedema

• Therapy of cerebral edema may include treatment with Therapy of cerebral edema may include treatment with mannitol, hypertonic saline and hyperventilationmannitol, hypertonic saline and hyperventilation


• Insulin TherapyInsulin Therapy– continuous infusion of low-dose insulin IV (~ continuous infusion of low-dose insulin IV (~

0.1 U/kg/hr) is effective, simple, and 0.1 U/kg/hr) is effective, simple, and physiologically soundphysiologically sound

– goal is togoal is to slowlyslowly decrease serum glucose ( decrease serum glucose (<< 100 100 mg/dL/hrmg/dL/hr

– frequent laboratory and blood gas analyses are frequent laboratory and blood gas analyses are obtained to ensure ongoing resolution of obtained to ensure ongoing resolution of metabolic acidosismetabolic acidosis


• ““Maintenance” IV fluid at a rate of 2000 - Maintenance” IV fluid at a rate of 2000 - 2400 cc/m2400 cc/m22/day consists of 2/3 NS (0.66%) /day consists of 2/3 NS (0.66%) or NSor NS– 5% Dextrose is added to IVF when blood 5% Dextrose is added to IVF when blood

glucose is ~ 300 mg/dLglucose is ~ 300 mg/dL– 10% Dextrose is added when blood glucose is ~ 10% Dextrose is added when blood glucose is ~

200 mg/dL200 mg/dL


• Insulin is used to treat Insulin is used to treat acidosisacidosis, not , not hyperglycemiahyperglycemia

– insulin should insulin should nevernever be stopped if ongoing acidosis be stopped if ongoing acidosis persistspersists

• When the acidosis is corrected, the continuous insulin When the acidosis is corrected, the continuous insulin infusion may be discontinued and subcutaneous insulin infusion may be discontinued and subcutaneous insulin initiatedinitiated

• With this regimen, DKA usually is usually fully corrected With this regimen, DKA usually is usually fully corrected in 36 to 48 hoursin 36 to 48 hours


• Hypoglycemic Reactions (Insulin Shock)Hypoglycemic Reactions (Insulin Shock)– symptoms and signs include pallor, sweating, symptoms and signs include pallor, sweating,

apprehension, trembling, tachycardia, hunger, apprehension, trembling, tachycardia, hunger, drowsiness, mental confusion, seizures and comadrowsiness, mental confusion, seizures and coma

– management includes administration (if conscious) of management includes administration (if conscious) of carbohydrate-containing snack or drinkcarbohydrate-containing snack or drink

– glucagon 0.5 mg is administered to an unconscious or glucagon 0.5 mg is administered to an unconscious or vomiting childvomiting child

Suggested ReadingSuggested Reading

• Glaser N, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. NEJM 355;4:264-269.

• Menon RK, Sperling MA. Diabetic Ketoacidosis. In: Fuhrman BP, Zimmerman JJ, ed. Pediatric Critical Care. Second Edition. St. Louis: Mosby-Year Book, Inc., 1998:844-52.

• Kohane DS, Tobin JR, Kohane IS. Endocrine, Mineral, and Metabolic Disease in Pediatric Intensive Care. In: Rogers, ed. Textbook of Pediatric Intensive Care. Third Edition. Baltimore: Williams & Wilkins, 1996:1261-72.

• Magee MF, Bhatt BA. Management of Decompensated Diabetes: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome. In: Zaloga GP, Marik P, ed. Critical Care Clinics: Endocrine and Metabolic Dysfunction Syndromes in the Critically Ill. Volume 17:1. Philadelphia: W.B. Saunders Company, 2001: 75-106.

Case Scenario #1Case Scenario #1

• A 10 y/o male (~30 kg) presents to the ED with a A 10 y/o male (~30 kg) presents to the ED with a one-day history of emesis and lethargy.one-day history of emesis and lethargy.

• Vitals show T 37C, HR 110, RR 25 BP 99/65. Vitals show T 37C, HR 110, RR 25 BP 99/65. Patient is lethargic, but oriented x 3. Exam reveals Patient is lethargic, but oriented x 3. Exam reveals the odor of acetone on the breath, dry lips, but the odor of acetone on the breath, dry lips, but otherwise unremarkableotherwise unremarkable

• Labs: pH 7.05 PaCOLabs: pH 7.05 PaCO22 20, PaO 20, PaO22 100, BE -20, Na 100, BE -20, Na++

133, K 133, K ++ 5.2, Cl 96 CO 5.2, Cl 96 CO22 8. Urine shows 4+ 8. Urine shows 4+

glucose and large ketonesglucose and large ketones


• How much fluid would you administer as a How much fluid would you administer as a bolus?bolus?

• Would you administer bicarbonate?Would you administer bicarbonate?

• What is the “true” serum sodium?What is the “true” serum sodium?

• How much insulin would you administer?How much insulin would you administer?

• What IVF would you start? At what rate?What IVF would you start? At what rate?


• A 4 y/o female in the PICU is undergoing A 4 y/o female in the PICU is undergoing treatment for new onset IDDM and DKA. She is treatment for new onset IDDM and DKA. She is on an insulin infusion at 0.1 u/kg/hr, and fluids are on an insulin infusion at 0.1 u/kg/hr, and fluids are running at 2400 cc/m2/day.running at 2400 cc/m2/day.

• Over the last hour, she has been complaining Over the last hour, she has been complaining about increasing headache. She is now found to about increasing headache. She is now found to be unresponsive with bilateral fixed and dilated be unresponsive with bilateral fixed and dilated pupils, HR is 50 with BP 150/100. pupils, HR is 50 with BP 150/100.

• What is your next step in management?What is your next step in management?

Documents

Diabetic Ketoacidosis