DIABETIC DIABETIC KETOACIDOSISKETOACIDOSIS

DISHAN LOWEDISHAN LOWEConsultant EndocrinologistConsultant Endocrinologist

General HospitalGeneral HospitalKandyKandy

Diabetic Ketoacidosis Diabetic Ketoacidosis

Metabolic acidosis from the accumulation Metabolic acidosis from the accumulation of ketones due to severely depressed of ketones due to severely depressed insulin levelsinsulin levels

Typically characterized by;Typically characterized by; Hyperglycemia (blood glucoseHyperglycemia (blood glucose>25>250 mg/dL)0 mg/dL) Low bicarbonate (<15 mEq/L)Low bicarbonate (<15 mEq/L) Acidosis (pH <7.30) Acidosis (pH <7.30) Ketonemia and ketonuriaKetonemia and ketonuria

In the US:In the US: DKA seen primarily in type 1 DMDKA seen primarily in type 1 DM Incidence is roughly 2/100 patient years of Incidence is roughly 2/100 patient years of

diabetes, with about 3% of type 1 diabetic diabetes, with about 3% of type 1 diabetic patients initially presenting with DKApatients initially presenting with DKA

Mortality <5% in experienced centers . Mortality <5% in experienced centers .

Before the discovery of insulin in 1922, Before the discovery of insulin in 1922, mortality rate was 100%mortality rate was 100%

Mortality in HHS still remains high at 15%Mortality in HHS still remains high at 15%

DKA tends to occur in individuals younger DKA tends to occur in individuals younger than 19 years, the more brittle type 1 than 19 years, the more brittle type 1 diabetic patientsdiabetic patients

May occur in type 1 and type 2 diabetic May occur in type 1 and type 2 diabetic patients of any agepatients of any age

Most serious acute metabolic Most serious acute metabolic complications of diabetes mellituscomplications of diabetes mellitus

Copyright ©2003 CMA Media Inc. or its licensors

Chiasson, J.-L. et al. CMAJ 2003;168:859-866

Schematic of the pathogenesis of diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS)

Diabetic ketoacidosis (DKA) and the Diabetic ketoacidosis (DKA) and the Hyperglycemic Hyperosmolar State (HHS) Hyperglycemic Hyperosmolar State (HHS) appear as 2 extremes in the spectrum of appear as 2 extremes in the spectrum of Diabetic DecompensationDiabetic Decompensation

Overlap of DKA/HHSOverlap of DKA/HHS

Findings in 612 patients admitted with hyperglycemia

0

20

40

60

DKA HHS Mixed

Wachtel et al. J Gen Int Med 6:495, 1991

%

Copyright ©2003 CMA Media Inc. or its licensors

Chiasson, J.-L. et al. CMAJ 2003;168:859-866

Pathophysiology of DKAPathophysiology of DKA

Relative/absolute insulin deficiency Relative/absolute insulin deficiency

Elevations of insulin counterregulatory Elevations of insulin counterregulatory hormones (ICRH)hormones (ICRH)

GlucagonGlucagonCatecholamines (epinephrine, norepinephrine)Catecholamines (epinephrine, norepinephrine)

CortisolCortisol

Growth hormoneGrowth hormone

Pathogenesis of DKAPathogenesis of DKA

What causes hyperglycemia?What causes hyperglycemia?

What causes ketogenesis?What causes ketogenesis?

InsulinInsulinAnabolic actionsAnabolic actions

Promotes glucose uptake in muscle and fatPromotes glucose uptake in muscle and fatStimulates glucose oxidationStimulates glucose oxidationRegulates rates of hepatic glucose productionRegulates rates of hepatic glucose productionStimulates glycogen formationStimulates glycogen formationStimulates protein synthesis and lipogenesis Stimulates protein synthesis and lipogenesis Increases lipoprotein lipase activityIncreases lipoprotein lipase activity

Inhibits catabolic processesInhibits catabolic processesInhibits glycogen breakdownInhibits glycogen breakdownInhibits gluconeogenesisInhibits gluconeogenesisInhibits protein breakdownInhibits protein breakdownInhibits lipolysisInhibits lipolysisInhibits ketogenesisInhibits ketogenesis

GlucagonGlucagon

Inhibits insulin mediated glucose Inhibits insulin mediated glucose uptakeuptake

Stimulates gluconeogenesisStimulates gluconeogenesis Stimulates glycogenolysisStimulates glycogenolysis Inhibits lipogenesisInhibits lipogenesis Stimulates ketone formationStimulates ketone formation

Epi Increase EGP Norepi Activates lipolysis

Inhibits insulin release

Decrease glucose uptake Cortisol Increased EGP

Increase protein breakdownIncrease lipolysis

Growth Decrease glucose uptakeHormone

Other Counterregulatory Hormones

Insulin deficiency

glucose uptake (muscle/fat)

Glucagon excess

Proteolysis Alanine

Lipolysis glycerol GNG

Hyperglycemia

Stimulates ketogenesis

Insulin deficiency Insulin deficiency

glucose uptake (muscle/fat)

Proteolysis Alanine

Lipolysis glycerol

Insulin deficiency

Pathogenesis of DKAPathogenesis of DKA

What causes acidosis?What causes acidosis?

Lipid and ketone metabolismLipid and ketone metabolism

Triglyceride

Activation of HSL

GlycerolMassive release of FFA

Insulin deficiency Increase ICRH

Glucagon

Substrate for GNGIncrease production of ketone bodies by

the liver

Glucagon+

Glucagon effect on ketoacid productionGlucagon effect on ketoacid production

Acetyl CoA Malonyl CoA FFAAcetyl CoA Malonyl CoA FFA

acetyl CoA carboxylaseacetyl CoA carboxylase

Low levels of malonyl CoA Increased CPT1Low levels of malonyl CoA Increased CPT1

Increase in CPT1 facilitates entry of FFA into the Increase in CPT1 facilitates entry of FFA into the mitochondria for oxidationmitochondria for oxidation

__

Outer Membrane

Inner Membrane

Mitochondrial matrix

Fatty Acyl CoA

CoASH

Carnitine Acyl carnitine

CPT1

CPT2

CoASH

Acetyl CoA

Fatty acid

β oxidation

Acyl CoA

Cytosol

Triglyceride synthesis Malonyl CoA

Ketone bodies

Keto-acidsKeto-acidsBeta-hydroxybutyrate and acetoacetatic acidBeta-hydroxybutyrate and acetoacetatic acid

Weak acids that dissociate at Weak acids that dissociate at physiologic pHphysiologic pH

HH++ + HCO3- H2O and CO2 + HCO3- H2O and CO2 Decrease in serum HCO3- Decrease in serum HCO3- Increase in Anion Gap approximately Increase in Anion Gap approximately

equal to the decline in bicarbonate equal to the decline in bicarbonate levelslevels

Keto-acidsKeto-acidsBeta-hydroxybutyrate and acetoacetatic acidBeta-hydroxybutyrate and acetoacetatic acid

Nitroprusside RXN:Nitroprusside RXN:

Acetest Test mainly for Acetest Test mainly for Ketostix acetoacetateKetostix acetoacetate

Chemstrips UGKChemstrips UGK

Measuring Measuring urine and serum ketonesurine and serum ketones Absence of a nitroprusside reaction does not Absence of a nitroprusside reaction does not

eliminate the possibility of DKAeliminate the possibility of DKA Even a positive test can grossly underestimate Even a positive test can grossly underestimate

the severity of the DKAthe severity of the DKA Conversely, the persistence of or an increase in Conversely, the persistence of or an increase in

ketones during therapy is not necessarily a ketones during therapy is not necessarily a manifestation of deteriorating clinical status, and manifestation of deteriorating clinical status, and may in fact be a sign of improvementmay in fact be a sign of improvement

Renal threshold for glucose ~ 180-200 Renal threshold for glucose ~ 180-200 mg/dlmg/dl

Renal threshold for ketones is very lowRenal threshold for ketones is very low

Differential diagnosisDifferential diagnosis

Starvation ketosis Starvation ketosis Alcoholic ketoacidosis (AKA)Alcoholic ketoacidosis (AKA) Other causes of high-anion gap metabolic Other causes of high-anion gap metabolic

acidosis;acidosis; lactic acidosislactic acidosis ingestion of drugs such as salicylate, ingestion of drugs such as salicylate,

methanol, ethylene glycol, and paraldehyde methanol, ethylene glycol, and paraldehyde chronic renal failure chronic renal failure

Precipitating factors for Precipitating factors for DKA/HHSDKA/HHS

New onset DM (8%)New onset DM (8%)

Omission of or Omission of or inadequate dose of inadequate dose of insulin (21%)insulin (21%)

Any acute illnessAny acute illness

MI (5%)MI (5%)

Pancreatitis (5%)Pancreatitis (5%)

Infection (37%)Infection (37%)

Drugs/alcohol (10%)Drugs/alcohol (10%)

Insulin pump Insulin pump malfunctionmalfunction

Luteal phase decrease Luteal phase decrease in insulin sensitivityin insulin sensitivity

HypovolemiaHypovolemia

Unknown (14%)Unknown (14%)

Clinical presentation

Ketoacidosis usually evolve in <24 hrs Ketoacidosis usually evolve in <24 hrs May evolve or develop more acutelyMay evolve or develop more acutely May present in DKA with no prior clues or May present in DKA with no prior clues or

symptoms symptoms

For both DKA and HHS, the classical For both DKA and HHS, the classical clinical picture includesclinical picture includes; ; a history of polyuria, polydipsia, polyphagia, a history of polyuria, polydipsia, polyphagia, weight loss, weight loss, vomiting, vomiting, abdominal pain (only in DKA), abdominal pain (only in DKA), dehydration, dehydration, weakness, weakness, clouding of sensoria, and finally coma clouding of sensoria, and finally coma

Physical findings may include poor skin turgor, Physical findings may include poor skin turgor, Kussmaul respirations (in DKA), tachycardia, Kussmaul respirations (in DKA), tachycardia, hypotension, alteration in mental status, shock, hypotension, alteration in mental status, shock, and ultimately coma (more frequent in HHS). and ultimately coma (more frequent in HHS).

A normal or elevated temperature may indicate A normal or elevated temperature may indicate underlying infection underlying infection primarily because of primarily because of peripheral vasodilation peripheral vasodilation

Hypothermia, if present, is a poor prognostic Hypothermia, if present, is a poor prognostic sign* sign*

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

Up to 25% of DKA patients have emesis, Up to 25% of DKA patients have emesis, which may be coffee-ground in which may be coffee-ground in appearance. appearance.

Endoscopy has related this finding to the Endoscopy has related this finding to the presence of hemorrhagic gastritispresence of hemorrhagic gastritis

Abdominal Pain Abdominal Pain in Decompensated DMin Decompensated DM

Infrequent with HCO3- > 10 meq/LInfrequent with HCO3- > 10 meq/L

No correlation with degree of No correlation with degree of hyperglycemia or dehydrationhyperglycemia or dehydration

May be related to precipitating eventMay be related to precipitating event

Campbell et al. JAMA 233:66, 1975Campbell et al. JAMA 233:66, 1975

Level of consciousness is related to the Level of consciousness is related to the severity of the serum osmolarity in severity of the serum osmolarity in DKA/HHSDKA/HHS

250

300

350

400

1 2 3 4

Fulop et al. Lancet 2:635, 1973

Glasgow Coma scale

Occurrence of coma in diabetic patients in the Occurrence of coma in diabetic patients in the absence of definitive elevation of effective absence of definitive elevation of effective osmolality ≥320 mOsm/kg demands osmolality ≥320 mOsm/kg demands immediate consideration of other causes of immediate consideration of other causes of such change.such change.

Effective osmolality may be calculated by the Effective osmolality may be calculated by the

following formula:following formula:2[measured Na (mEq/l)] + glucose (mg/dl)/182[measured Na (mEq/l)] + glucose (mg/dl)/18

Initial laboratory evaluation of patients with Initial laboratory evaluation of patients with suspected DKA or HHS should include suspected DKA or HHS should include plasma glucoseplasma glucose blood urea/creatinineblood urea/creatinine serum ketonesserum ketones electrolytes (with electrolytes (with

calculated anion gap)calculated anion gap) osmolalityosmolality

UrinalysisUrinalysis urine ketones by urine ketones by

dipstickdipstick arterial blood gasesarterial blood gases complete blood count complete blood count

with differentialwith differential electrocardiogram.electrocardiogram.

Bacterial culturesBacterial cultures of urine, blood, and throat, of urine, blood, and throat, etc., should be obtained and appropriate etc., should be obtained and appropriate antibiotics given if infection is suspected. antibiotics given if infection is suspected.

CXRCXR should also be obtained if indicated. should also be obtained if indicated. HbA1cHbA1c may be useful in determining may be useful in determining

◊◊culmination of an evolutionary process in culmination of an evolutionary process in previously undiagnosed or poorly controlled previously undiagnosed or poorly controlled

diabetes diabetes ◊◊truly acute episode in an otherwise truly acute episode in an otherwise well-well-

controlled patientcontrolled patient

FINDINGFINDING CAUSE/SCAUSE/S

Leukocytosis Leukocytosis Proportional to blood ketone body Proportional to blood ketone body concentration, Infection concentration, Infection

Hyponatraemia*Hyponatraemia* Osmotic flux of water from the Osmotic flux of water from the intracellular to the extracellular space, intracellular to the extracellular space, Severe hypertriglyceridemia Severe hypertriglyceridemia

HypokalaemiaHypokalaemia Extracellular shift of potassium caused by Extracellular shift of potassium caused by insulin deficiency, hypertonicity, and insulin deficiency, hypertonicity, and acidemiaacidemia

Elevated Amylase Elevated Amylase Non-pancreatic sources, such as the Non-pancreatic sources, such as the parotid gland parotid gland

* Serum Na should be corrected for hyperglycemia (for each 100 mg/dl glucose >100 mg/dl, add 1.6 mEq to sodium value for corrected Na value)

Treatment Treatment

The success of treatment of DKA and The success of treatment of DKA and HHS depends on; HHS depends on; Adequate correction of Adequate correction of dehydrationdehydration, ,

hyperglycemiahyperglycemia, , ketoacidosisketoacidosis and and electrolyte electrolyte deficits deficits

Identification & treatment of any Identification & treatment of any comorbidcomorbid precipitating eventsprecipitating events

Frequent patient Frequent patient monitoringmonitoring

Fluid therapyFluid therapy

Objective is to expand extracellular Objective is to expand extracellular volume and restore renal perfusionvolume and restore renal perfusion

Start with infusion of isotonic saline Start with infusion of isotonic saline (0.9% NaCl) at a rate of 15–20 mL/kg per hour (0.9% NaCl) at a rate of 15–20 mL/kg per hour

during the first hour (1–1.5 L in the average during the first hour (1–1.5 L in the average adult) adult)

Subsequent choice of fluid replacement Subsequent choice of fluid replacement depends on the state of hydration, depends on the state of hydration, electrolyte levels and urinary output.electrolyte levels and urinary output.

Infuse Infuse 0.45% Nacl0.45% Nacl at a rate of 4–14 mL/kg at a rate of 4–14 mL/kg

per hour if the per hour if the correctedcorrected serum Na is serum Na is normal or elevatednormal or elevated . .

0.9% NaCl0.9% NaCl at a similar rate is appropriate at a similar rate is appropriate if corrected if corrected serum Na is lowserum Na is low

Successful progress with fluid Successful progress with fluid replacement is judged by; replacement is judged by; hemodynamic monitoring (improve BP)hemodynamic monitoring (improve BP) measurement of fluid input/outputmeasurement of fluid input/output clinical examinationclinical examination

Fluid replacement should correct Fluid replacement should correct estimated deficits within the first 24 h. estimated deficits within the first 24 h.

Induced change in s osmolality should not Induced change in s osmolality should not exceed 3 mOsm · kg-1 H2O · h-1exceed 3 mOsm · kg-1 H2O · h-1

When the plasma glucose level reaches When the plasma glucose level reaches 250mg/dl, change to 250mg/dl, change to 5% dextrose5% dextrose with with 0.45% Nacl infused at 150-250 ml/hr 0.45% Nacl infused at 150-250 ml/hr

Paediatric patients (<20 yrs of age)Paediatric patients (<20 yrs of age)

The 1st hr of fluids should be isotonic The 1st hr of fluids should be isotonic saline at 10–20 ml · kg-1 · h-1. saline at 10–20 ml · kg-1 · h-1.

Initial reexpansion should not exceed 50 Initial reexpansion should not exceed 50 ml/kg over the first 4 h of therapy. ml/kg over the first 4 h of therapy.

Replace fluid deficit evenly over 48 hReplace fluid deficit evenly over 48 h In general, 0.45–0.9% NaCl (depending In general, 0.45–0.9% NaCl (depending

on serum Na ) infused at a rate of 1.5 on serum Na ) infused at a rate of 1.5 times the 24-h maintenance times the 24-h maintenance requirements ( 5 ml · kg-1 · h-1) will requirements ( 5 ml · kg-1 · h-1) will accomplish a smooth rehydrationaccomplish a smooth rehydration

Potassium therapy Potassium therapy

The treatment of DKA and HHS with The treatment of DKA and HHS with rehydration and insulin is typically rehydration and insulin is typically associated with a rapid decline in the associated with a rapid decline in the plasma K concentration, particularly during plasma K concentration, particularly during the first few hours of therapythe first few hours of therapy

Causes of hypokalaemiaCauses of hypokalaemia

insulin-mediated re-entry of potassium into insulin-mediated re-entry of potassium into the intracellular compartmentthe intracellular compartment

extracellular fluid volume expansionextracellular fluid volume expansion correction of acidosiscorrection of acidosis continued potassium loss owing to continued potassium loss owing to

osmotic diuresis and ketonuria osmotic diuresis and ketonuria

Because treatment will rapidly induce Because treatment will rapidly induce decreased serum K concentrations, K decreased serum K concentrations, K replacement must be initiated as soon as replacement must be initiated as soon as levels fall levels fall below 5.0 mmol/Lbelow 5.0 mmol/L, assuming , assuming urine output is adequate urine output is adequate

It is recommended that It is recommended that 20–30 mmol of K 20–30 mmol of K be added to each litrebe added to each litre of infusion fluid to of infusion fluid to maintain maintain K concentration 4 - 5 mmol/LK concentration 4 - 5 mmol/L

If serum K level is If serum K level is << 3.3 mmol/L 3.3 mmol/L, K , K replacement should be started replacement should be started immediately with fluid therapyimmediately with fluid therapy

Initiation of insulin should be delayed until Initiation of insulin should be delayed until K is restored to K is restored to >>3.3 mmol/L, in order to 3.3 mmol/L, in order to avoid arrhythmia, cardiac arrest and avoid arrhythmia, cardiac arrest and respiratory muscle weakness respiratory muscle weakness

Initially, the serum K level should be Initially, the serum K level should be measured every 1–2 hrs because the most measured every 1–2 hrs because the most rapid change occurs during the first 5 hrs rapid change occurs during the first 5 hrs of treatment. of treatment.

After that, it should be measured every 4–After that, it should be measured every 4–6 hrs as indicated clinically 6 hrs as indicated clinically

Insulin therapyInsulin therapy Consensus is that, in DKA & HHS, regular Consensus is that, in DKA & HHS, regular

insulin should be administered by insulin should be administered by continuous iv infusion in small dosescontinuous iv infusion in small doses through an infusion pumpthrough an infusion pump

Low-dose insulin provides; Low-dose insulin provides; More physiologic insulin concentrationsMore physiologic insulin concentrations More gradual and steady fall in plasma More gradual and steady fall in plasma

glucose levels glucose levels Decreased risk of hypoglycemia and Decreased risk of hypoglycemia and

hypokalemia hypokalemia

As soon as hypokalemia (K < 3.3 mmol/L) As soon as hypokalemia (K < 3.3 mmol/L) excluded, continuous infusion of regular excluded, continuous infusion of regular insulin can be started at a dose of 0.1 insulin can be started at a dose of 0.1 U/kg per hour U/kg per hour

This should produce a gradual decrease This should produce a gradual decrease in the plasma glucose level of 3–4 mmol/L in the plasma glucose level of 3–4 mmol/L per hour per hour

There is evidence that an iv bolus of There is evidence that an iv bolus of insulin is not necessary. However, a bolus insulin is not necessary. However, a bolus may be used at the start of insulin therapy, may be used at the start of insulin therapy, particularly if insulin treatment has been particularly if insulin treatment has been delayed.delayed.

In unusual circumstances where iv In unusual circumstances where iv administration is not possible, the im or sc administration is not possible, the im or sc route has been used effectively. However, route has been used effectively. However, poor perfusion will impair absorption of poor perfusion will impair absorption of insulin.insulin.

If the glucose level does not decline by 3 If the glucose level does not decline by 3 mmol/L in the first hour, the hydration mmol/L in the first hour, the hydration status should be checked; status should be checked;

if it is acceptable, the insulin dose should if it is acceptable, the insulin dose should be be doubled every hourdoubled every hour until a decrease of until a decrease of 3–4 mmol/L per hour3–4 mmol/L per hour in the plasma in the plasma glucose level is observed glucose level is observed

When the plasma glucose level reaches When the plasma glucose level reaches 12–14 mmol/L, the 12–14 mmol/L, the insulin infusion rate insulin infusion rate may be decreased by 50%may be decreased by 50% as 5% as 5% dextrose is addeddextrose is added

Thereafter, the insulin infusion dose must Thereafter, the insulin infusion dose must be adjusted to maintain the plasma be adjusted to maintain the plasma glucose value in the range of 150 – glucose value in the range of 150 – 200mg/dl until the acidosis in DKA (or the 200mg/dl until the acidosis in DKA (or the clouded consciousness and clouded consciousness and hyperosmolality in HHS) have been hyperosmolality in HHS) have been resolvedresolved

It takes longer to correct ketonuria than It takes longer to correct ketonuria than hyperglycemia. hyperglycemia.

Because ß-hydroxybutyric acid is the Because ß-hydroxybutyric acid is the prevalent ketoacid and is gradually prevalent ketoacid and is gradually converted to acetoacetic acid, the converted to acetoacetic acid, the correction of ketonuria is underestimated correction of ketonuria is underestimated when measured by the nitroprusside when measured by the nitroprusside method method

Measurement of Measurement of serum ß-hydroxybutyricserum ß-hydroxybutyric acid levels using a reagent strip and a acid levels using a reagent strip and a reflectance meter has been validatedreflectance meter has been validated

Offers the possibility of bedside diagnosis Offers the possibility of bedside diagnosis with better follow-up parameters of with better follow-up parameters of hyperketonemia during treatmenthyperketonemia during treatment

Once the ketoacidosis in DKA has been Once the ketoacidosis in DKA has been corrected corrected (plasma glucose level < 11.0 (plasma glucose level < 11.0 mmol/L, serum bicarbonate level ≥18 mmol/L, serum bicarbonate level ≥18 mmol/L, venous pH > 7.3 and anion gap < mmol/L, venous pH > 7.3 and anion gap < 12 mmol/L), the clouded consciousness 12 mmol/L), the clouded consciousness and hyperosmolality in HHS have and hyperosmolality in HHS have resolved, and patients are able to take resolved, and patients are able to take fluids orally)fluids orally),, a multidose insulin regimen a multidose insulin regimen may be initiated based on the patient's may be initiated based on the patient's treatment before DKA or HHS developed treatment before DKA or HHS developed

PhosphatePhosphate

Despite whole-body phosphate deficits in Despite whole-body phosphate deficits in DKA , serum phosphate is often normal or DKA , serum phosphate is often normal or increased at presentation. Phosphate increased at presentation. Phosphate concentration decreases with insulin concentration decreases with insulin therapy. therapy.

Prospective randomized studies have Prospective randomized studies have failed to show any beneficial effect of failed to show any beneficial effect of phosphate replacement on the clinical phosphate replacement on the clinical outcome in DKAoutcome in DKA

However, to avoid cardiac and skeletal However, to avoid cardiac and skeletal muscle weakness and respiratory muscle weakness and respiratory depression due to hypophosphatemia, depression due to hypophosphatemia, careful phosphate careful phosphate replacement may replacement may sometimes be indicated in patients with sometimes be indicated in patients with cardiac dysfunction, anemia, or respiratory cardiac dysfunction, anemia, or respiratory depression and in those with serum depression and in those with serum phosphate concentration <1.0 mg/dl.phosphate concentration <1.0 mg/dl.

When needed, 20–30 mEq/l potassium When needed, 20–30 mEq/l potassium phosphate can be added to replacement phosphate can be added to replacement fluids. fluids.

Overzealous phosphate therapy can Overzealous phosphate therapy can cause cause severe hypocalcemiasevere hypocalcemia with no with no evidence of tetany evidence of tetany

BicarbonateBicarbonate Bicarbonate use in DKA remains controversial.Bicarbonate use in DKA remains controversial. At a pH >7.0, reestablishing insulin activity At a pH >7.0, reestablishing insulin activity

blocks lipolysis and resolves ketoacidosis blocks lipolysis and resolves ketoacidosis without any added bicarbonate. without any added bicarbonate. Studies failed to Studies failed to show either beneficial or deleterious changes in show either beneficial or deleterious changes in morbidity or mortality with bicarbonate therapy in morbidity or mortality with bicarbonate therapy in DKA patients with pH between 6.9 - 7.1DKA patients with pH between 6.9 - 7.1

No studies concerning the use of bicarbonate in No studies concerning the use of bicarbonate in DKA with pH values <6.9 have been reported. DKA with pH values <6.9 have been reported.

Severe acidosis may lead to adverse Severe acidosis may lead to adverse vascular effects vascular effects

RECOMMENDATIONS

PH HCO3 Infusion Rate

>7 No HCO3

6.9 - 7 50 mmol in 200ml water 200ml/hr

<6.9 100 mmol in 400ml water 200ml/hr

---

Venous pH should be assessed every 2 h Venous pH should be assessed every 2 h until the pH rises to 7.0, & treatment until the pH rises to 7.0, & treatment should be repeated every 2 h if necessary should be repeated every 2 h if necessary

In the paediatric patient, If pH remains In the paediatric patient, If pH remains <7.0 after the initial hour of hydration, it <7.0 after the initial hour of hydration, it seems prudent to administer 1–2 mEq/kg seems prudent to administer 1–2 mEq/kg HCO3 over the course of 1 h. This HCO3 HCO3 over the course of 1 h. This HCO3 can be added to NaCl, with any required can be added to NaCl, with any required K, to produce a solution that does not K, to produce a solution that does not exceed 155 mEq/l sodium. exceed 155 mEq/l sodium.

COMPLICATIONS OF THERAPY COMPLICATIONS OF THERAPY

HypoglycemiaHypoglycemia - overzealous Rx with insulin - overzealous Rx with insulin HypokalemiaHypokalemia due to insulin & treatment of due to insulin & treatment of

acidosis with bicarbonateacidosis with bicarbonate HyperglycemiaHyperglycemia secondary to secondary to

interruption/discontinuance of iv insulin therapy interruption/discontinuance of iv insulin therapy after recoveryafter recovery

HyperchloremiaHyperchloremia caused by the use of excessive caused by the use of excessive saline saline

Transient non-anion gap metabolic acidosisTransient non-anion gap metabolic acidosis as as ClCl‾‾ from iv fluids replaces ketoanions lost as Na from iv fluids replaces ketoanions lost as Na & K salts during osmotic diuresis& K salts during osmotic diuresis

HypoxemiaHypoxemia noncardiogenic noncardiogenic pulmonary oedemapulmonary oedema Cerebral OedemaCerebral Oedema Hypoxemia is attributed to a reduction in colloid Hypoxemia is attributed to a reduction in colloid

osmotic pressure that results in increased lung osmotic pressure that results in increased lung water content and decreased lung compliance. water content and decreased lung compliance. Patients with DKA who have a widened alveolo-Patients with DKA who have a widened alveolo-arteriolar oxygen gradient noted on initial blood arteriolar oxygen gradient noted on initial blood gas measurement or with pulmonary rales on gas measurement or with pulmonary rales on physical examination appear to be at higher risk physical examination appear to be at higher risk for the development of pulmonary edema for the development of pulmonary edema

COMPLICATIONS OF THERAPYCOMPLICATIONS OF THERAPY

Cerebral edema in DKACerebral edema in DKA

More common in children and young adultsMore common in children and young adults

Incidence ~ 1%Incidence ~ 1%

Accounts for 31% of deaths associated with DKAAccounts for 31% of deaths associated with DKA

Heralded by development of a headache and Heralded by development of a headache and increasing lethargyincreasing lethargy

Develops 4-12 hours after initiation of treatmentDevelops 4-12 hours after initiation of treatment

Proposed risk factors:Proposed risk factors:Low pCOLow pCO22 ( 15 mm Hg) and elevated urea nitrogen ( 15 mm Hg) and elevated urea nitrogen

(>21 mg/dl) at presentation(>21 mg/dl) at presentation

Treatment with bicarbonateTreatment with bicarbonate

Too rapid correction of dehydrationToo rapid correction of dehydration

Once the clinical symptoms other than Once the clinical symptoms other than lethargy and behavioural changes occur, lethargy and behavioural changes occur, mortality is high (>70%)mortality is high (>70%)

Only 7–14% of patients recover without Only 7–14% of patients recover without permanent morbidity permanent morbidity

Cerebral Oedema in DKACerebral Oedema in DKA

Mechanism of Cerebral OedemaMechanism of Cerebral Oedema

Not knownNot known Likely results from osmotically driven Likely results from osmotically driven

movement of water into the central movement of water into the central nervous system when plasma osmolality nervous system when plasma osmolality declines too rapidly with the treatment of declines too rapidly with the treatment of DKA or HHS. DKA or HHS.

There is a lack of information on the There is a lack of information on the morbidity associated with cerebral edema morbidity associated with cerebral edema in adult patients in adult patients

Prevention and treatment of cerebral Prevention and treatment of cerebral edemaedema

PreventionPreventionGradual replacement of Na & HGradual replacement of Na & H22 O deficitsO deficits

Once plasma glucose of 200-250 mg/dl Once plasma glucose of 200-250 mg/dl achieved, maintain at this level with 5% achieved, maintain at this level with 5% dextrosedextrose

TreatmentTreatment IV mannitol 1G/kg over 30 minutes, followed IV mannitol 1G/kg over 30 minutes, followed

by infusion to maintain plasma osmolality by infusion to maintain plasma osmolality and sustain osmotic diuresis of waterand sustain osmotic diuresis of water

Strategies to Prevent Diabetic Ketoacidosis

Diabetic education

Blood glucose monitoring

Sick-day management

Home monitoring of ketones or beta-hydroxybutyrate

Supplemental short-acting insulin regimens

Easily digestible liquid diets when sick

Reducing, rather than eliminating, insulin when patients are not eating

Guidelines for when patients should seek medical attention

Case monitoring of high-risk patients

Special education for patients on pump management