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DIABETIC KETOACIDOSISTulsi Ram Shrestha
Diabetic KetoacidosisBiochemical triad of ketonaemia, hyperglycaemia and acidaemia.A medical emergency and remains a serious cause of morbidity, principally in people with type 1 diabetesHowever, an increasing number of patients presenting with DKA have underlying type 2 diabetes. Lack of a diabetic history does not exclude the diagnosis
Epidemiology4.6 to 8 episodes per 1000 patients with diabetes in USA. (Johnson 1980, Faich 1983)More than 11% of people with Type 1 diabetes had an episode of DKA in England between 2004 and 2009. (National Diabetes Audit 20082009)Remains a significant clinical problem in spite of improvements in diabetes care (Fishbein 1995, Umpierrez 19997).
MortalityMortality rates have fallen significantly in the last 20 years from 7.96% to 0.67% (Lin 2005).Still high in developing countries and among non hospitalized patients (Otieno 2005)Children and adolescentsCerebral oedemaAdultsHypokalaemiaAcute respiratory distress syndromeComorbidities: MI, sepsis or pneumonia (Hamblin 1989)
Precipitating factors/ CausesInfectionPneumonia, sepsis, UTILack of insulinInsulin pump failureNonadherence to insulin treatment plansOther physiologic stressorsArterial thrombosis, cerebrovascular accident, Cushing disease, hemochromatosis, myocardial infarction, pancreatitis, pregnancy, psychological stress, shock/hypovolemia, traumaDrugsAntipsychotic agents: clozapine, olanzapine, risperidoneOthers: corticosteroids, glucagon, interferon
DiagnosisCardinal biochemical features Hyperketonaemia ( 3 mmol/L) and ketonuria (>2+ on standard urine sticks) Hyperglycaemia (blood glucose 11 mmol/L (~200 mg/dL)) Metabolic acidosis (venous bicarbonate 250> 250> 250Arterial pH7.25-7.307.00-7.24< 7.00Sodium Bicarbonate (mEq/L)15 1810 - 15< 10Urine KetonesPositivePositivePositiveSerum KetonesPositivePositivePositiveSerum Osmolality (mOsm/kg)VariableVariableVariableAnion Gap (mmol/L)> 10> 12> 12Mental StatusAlertAlert/DrowsyStupor/Coma
Clinical featuresSymptomsPolyuria, thirstWeight lossWeaknessNausea, vomitingLeg crampsBlurred visionAbdominal painSignsDehydrationHypotension (postural or supine)Cold extremities/peripheral cyanosisTachycardiaAir hunger (Kussmaul breathing)Smell of acetoneHypothermiaConfusion, drowsiness, coma (10%)
Differential diagnosisGastroenteritisHyperosmolar hyperglycemic stateMyocardial infarctionPancreatitisStarvation ketosis
High anion gap metabolic acidosis:Alcoholic ketoacidosisEthylene glycol intoxicationLactic acidosisMethanol intoxicationParaldehyde ingestionRhabdomyolysisSalicylate intoxicationUremia
InvestigationsVenous bloodUrea Na+/ K+ GlucoseBicarbonateKetonesUrineKetonesLeucocyte esterase
ECGPossible MIInfection screenFull blood countBlood and urine cultureC-reactive proteinChest X-rayAmylase/ lipaseRule out Pancreatitis
New principlesMeasurement of blood ketones, venous pH and bicarbonate and their use as treatment markersMonitoring of ketones and glucose using bedside metersReplacing sliding scale insulin with weight-based fixed rate IV insulin infusion Use of venous blood rather than arterial blood in blood gas analysersMonitoring of electrolytes on the blood gas analyser with intermittent laboratory confirmationContinuation of long acting insulin analogues as normalInvolvement diabetes specialist team as soon as possible
ManagementHour 1: Immediate management upon diagnosis: 0 to 60 minutes.AimsCommence IV 0.9% sodium chloride solutionFixed rate IVII but only after fluid therapy has been commencedEstablish monitoring regime appropriate to patient: hourly blood glucose and ketone measurementat least 2 hourly serum K+ for the first 6 hoursClinical / biochemical assessment of the patientInvolvement of diabetes specialist team ASAP
Action 1 - Intravenous access and initial investigationsRapid ABC (Airway, Breathing, Circulation)Large bore iv cannula and iv fluid replacementClinical assessmentRR; Temp, BP, PR, SpO2Glasgow Coma Scale (A drowsy patient in the context of DKA is serious and the patient requires critical care input. Consider NG tube with airway protection to prevent aspiration.)Full clinical examination
Initial investigationsContinuous cardiac monitoringContinuous pulse oximetryConsider precipitating causes and treat appropriatelyEstablish usual medication for diabetes
Action 2 Restoration of circulating volume
Average loss of fluid and electrolytes in adult DKA of moderate severityWater 6LNa+ 500 mmolCl- 400 mmolK+ 350 mmol
Commence crystalloid (NS)If systolic BP < 90 mmHgGive 500 mL over 1015 minsRepeat if SBP< 90mmHgIf systolic BP 90 mmHg (for a previously well 70kg adult)1L over 1st hour1L over next 2 hours1L over next 2 hours1L over next 4 hours1L over next 4 hours1L over next 6 hours
Exercise caution in the following patientsYoung people aged 18-25 yearsElderlyPregnantHeart or kidney failureOther serious co-morbidities
Action 3 - Commence a fixed rate intravenous insulin infusion50 U human soluble insulin in 50 mL 0.9% sodium chloride IV infusion at 0.1 U/kg/hr (i.e. 7ml/hr if weight is 70kg)Targets blood ketone by 0.5 mmol/L/hour bicarbonate by 3 mmol/L/hour glucose by 3 mmol/L/hourK+ 4.0 - 5.0 mmol/L
Action 4 - Potassium replacementSerum potassium is often high on admission but falls precipitously upon treatment with insulin. Potassium replacementPlasma K+ > 5.5 mmol/L Nil3.54.5 mmol/L 20 mmol/L< 3.5 mmol/L40 mmol/LIf K+ < 3.5 mmol/L, K+ replacement before insulin
B. 60 minutes to 6 hoursAimsClear the blood of ketones and suppress ketogenesisAchieve the targets Fall of ketones of at least 0.5 mmol/L/hrRise of bicarbonate by 3 mmol/L/hrFall of blood glucose by 3 mmol/L/hrMaintain serum K+ in normal rangeAvoid hypoglycaemia
Action 1 Re-assess patient, monitor vital signsUrinary catheterization if incontinent or anuric (not passed by 60 min)NG tube if patient obtunded or if persistently vomitingAccurate fluid balance chart, minimum urine output 0.5ml/kg/hrContinuous cardiac monitoring in severe DKA
Action 2 Review metabolic parametersMeasure blood ketones and capillary glucose hourly Review patients response to fixed rate IVII hourly by calculating rate of change of ketone level fall (or rise in bicarbonate or fall in glucose).
Assess resolution of ketoacidosisIf blood ketones not falling by at least 0.5 mmol/L/hr increase insulin infusion rate by 1 unit/hr increments hourly until ketones falling at target ratesIf bicarbonate not rising by at least 3 mmol/L/hr increase insulin infusion rate by 1 unit/hr increments hourly If glucose is not falling by at least 3 mmol/L/hr increase insulin infusion rate by 1 unit/hr increments hourly Always check the insulin infusion pump if its working and connected and that the correct insulin residual volume is present
Measure venous blood gas for pH, bicarbonate and K+ at 60 minutes and 2 hours and 2 hourly thereafter.If K+ is outside the reference range, assess the appropriateness of K+ replacement and check it hourly. Continue insulin until ketones < 0.3 mmol/L, venous pH > 7.3 and/or venous bicarbonate >18 mmol/L. If glucose falls below 14 mmol/L (~250 mg/dl) add 10% glucose at 125mls/hour with NS.Monitor and replace potassium as it may fall rapidly.
Action 3 Identify and treat precipitating factorsInfectionInadequate insulin treatment or noncomplianceInfarcts
C. 6 to 12 hours.AimsEnsure that clinical/ biochemical parameters are improvingContinue IV fluid replacementContinue insulin administrationAssess for complications of treatment Continue to treat precipitating factors as necessaryAvoid hypoglycaemia
Action 1 Re-assess patient, monitor vital signsIf patient not improving seek senior adviceEnsure referral has been made to diabetes team
Action 2 Review biochemical and metabolic parametersAt 6 hours check pH, bicarbonate, potassium, blood ketones and glucoseResolution is defined as ketones less than 0.3mmol/L, venous pH over 7.3
D. 12 to 24 HOURSExpectation: By 24 hours ketonaemia and acidosis should have resolvedAimsEnsure clinical/ biochemical parameters improving/ have normalisedContinue IV fluids if not eating and drinking.Continue to treat precipitating factors as necessarySubcutaneous insulin if patient is eating and drinking normally
Action 1 Re-assess patient, monitor vital signsAction 2 Review biochemical and metabolic parametersAt 12 hours check pH, bicarbonate, K+, blood ketones and glucoseResolution is defined as ketones 7.3
E. Conversion to subcutaneous insulin.When biochemically stable Glucose 7.3and the patient is ready and able to eat
Overlap between the insulin infusion and first injection of fast acting insulin of 1- 2 hoursAbrupt discontinuation may lead to acute fall in insulin, recurrence of hyperglycemia and/ or ketoacidosis.If unable to take oral nutrition, continue IVIIIn insulin-nave patients, a multi- dose insulin at a dose 0.5- 0.8 U/ kg including a bolus
complicationsCerebral oedemaMore common in children than in adultsOccurs within a few hours of initiation of treatmentRecent studies: cerebral hypoperfusion with subsequent reperfusion (Glaser 2001, Glaser 2008, Yuen 2008).Risk factors (Wolfsdorf 2009, Carlotti 2010)Younger ageNew-onset diabetesLonger duration of symptomsSevere acidosisLow initial bicarbonate levelLow sodium levelHigh glucose level at presentationRapid hydration
Signs of cerebral edema that require immediate evaluation HeadachePersistent vomitingHypertensionBradycardiaLethargyTreatmentMannitol (20% 0.5-1 g/kg over 10-15 minutes) or Hypertonic saline (3% 2.5-5 ml/kg over 10-15 minutes)
Acute circulatory failureDue to hypovolemiaMay cause acute renal failureCorrected by NSMay need ionotropes in severe hypotensionSepsis treated by antibiotics
Acute gastric dilatationVomiting and abdominal distensionAuscultation: Succusion splashAbdominal Xray: ground glass appearanceTreated with NG aspiration
Pulmonary oedema Occurs within a few hours of initiationDue to rapid infusion of crystalloids over a short period of time (Dixon 2006)Elderly patients and those with impaired cardiac function are at particular riskMonitoring of cvp should be considered.
Hypokalaemia and hyperkalaemiaHypoglycemiaAcute renal failureShock
Controversies1. Arterial or venous measurements?Venous vs arterial pH is 0.02-0.15 pH units and arterial vs venous bicarbonate is 1.88 mmol/L (Kelly 2006, Gokel 2000). Not necessary to use arterial blood to measure acid base status (Ma 2003)Arterial line insertion: only if its use will influence management i.e. for frequent arterial oxygen level measurements or monitoring blood pressure in the critically ill patient
2. Blood ketone measurement?Frequent repeated measurement of blood ketone has become a practical option due to availability of bedside meters Resolution of DKA depends upon the suppression of ketonaemiaMeasurement of blood ketones now represents best practice in monitoring the response to treatment.
3. Colloid versus crystalloid?Many guidelines suggest that in hypotensive patients initial fluid resuscitation should be with colloid.However, the hypotension results from a loss of electrolyte solution and it is more physiological to replace with crystalloid. A recent Cochrane review did not support the use of colloid in preference to crystalloid fluid (Perel 2007).
4. Rate of fluid replacement?Rapid fluid replacement may lead to cerebral oedema in children and young adults. Paediatric guidelines recommend cautious fluid replacement over 48 hours.
5. 0.9% saline or Hartmanns solution for resuscitation?Advantages of NSDecades of clinical experienceReadily available in clinical areas Commercially available ready mixed with K+ at required concentrations, 20mmol/L (0.15%) or 40mmol/L (0.3%)Supports safe practice with injectable potassium (NPSA compliant (NPSA alert 2002)
6. Continuation of long-acting insulin analogues?Continuation of SC analogues during the initial management of DKA provides background insulin when the IV insulin is discontinued. Avoids rebound hyperglycaemia when IV insulin is stopped and should avoid excess length of stay
7. Fixed-rate intravenous insulin infusion versus variable rate?Fixed dose(s) per kg body weight enable rapid blood ketone clearanceFixed rate may need to be adjusted in insulin resistant states if the ketone concentration is not falling fast enough, and/or the bicarbonate level is not rising fast enough.
8. Initiating treatment with a bolus of insulin?Bolus doesnt decrease time to normalization of glucose, pH, bicarbonate level (Goyal et all 2008)A bolus dose is not necessary provided that the insulin infusion is started promptly at a dose of at least 0.1 unit/kg/hour (Kitabchi et all 2008)
9. Intravenous bicarbonate?Adequate fluid and insulin therapy will resolve the acidosis in DKA and the use of bicarbonate is not indicated (Morris 1986, Hale 1984). Excessive bicarbonate may increase CO2 partial pressure in CSF and may lead to a paradoxical increase in CSF acidosis (Ohman 1971). Some evidence suggest bicarbonate treatment leading to development of cerebral oedema in children and young adults (Glaser 2001)
10. Use of intravenous phosphate?Phosphate deficits in DKA: 1 mmol/kg of body weightNo evidence of benefit of phosphate replacement (Wilson 1982)However, in the presence of respiratory and skeletal muscle weakness, phosphate measurement and replacement should be considered (Liu 2004).
Strategies to prevent DKA
Diabetic educationBlood glucose monitoringIdentification of precipitating factorsHome monitoring of ketonesSupplemental short-acting insulin regimensEasily digestible liquid diets when sickReducing (not eliminating) insulin when patients are not eatingGuidelines for when patients should seek medical attentionCase monitoring of high-risk patientsSpecial education for patients on pump management
ReferencesDavidsons Principles and Practice of Medicine 22nd EditionJoint British Diabetes Societies Inpatient Care Group guidelines for The Management of Diabetic Ketoacidosis in Adults British Society for Paediatric Endocrinology and Diabetes guidelines for the management of DKAAmerican diabetic association guidelinesTHANK YOU