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Diabetic KetoacidosisHyperglycemic Hyperosmolar

State

Dr. Soumar DuttaPG Trainee

Accident and Critical Care Medicine

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Diabetic KetoacidosisDiabetic Ketoacidosis

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IntroductionIntroduction

• Acute life threatening complication of DM

• DKA predominantly seen in type 1 DM

• DKA represents body’s response to cellular starvation due to insulin deficiency & counter regulatory hormone excess

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DKADKA

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ClassificationClassification

Mild DKA Moderate DKA Severe DKA

Plasma glucose > 250 mg/dl > 250 mg/dl > 250 mg/dl

Arterial ph 7.25-7.30 7.0-7.24 < 7.0

Serum bicarbonate 15-18 10-<15 < 10

Urine ketones + + +Anion gap >10 >12 >12

Alteration in sensorium alert alert/drowsy stupor/coma

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Pathophysiology of DKA Pathophysiology of DKA

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• Facilitate uptake of glucose & conversion into glycogen• Inhibits glycogenolysis & gluconeogenesis

• Increase lipogenesis• Inhibit lipolysis

• Uptake of amino acids into muscle cell• Prevents release of amino acids from muscle

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PathophysiologyInsulin Deficiency is the primary defect in patients with DKA

Muscle Hepatocyte Adipose

Glucose

AminoAcids

Glucose-P

Glycogen

Pyruvate, CO2

Glucose

FreefattyacidsKetoacids

Normal Insulin Activity

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Pathophysiology

Insulin

GlucagonEpinephrine

CortisolGrowth Hormone

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Pathophysiology

Decreased Glucose UtilizationLipolysis

Insulin

GlucagonEpinephrine

CortisolGrowth Hormone

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DKA - EarlyDKA - Early

• Relative Insulin Deficiency• Glycogenolysis & gluconeogenesis• Peripheral glucose uptake

Elevates blood glucose

Decreased Utilization post-prandial

and Stress-Induced

hyperglycemia

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Pathophysiology

GluconeogenesisGlycogenolysis

LipolysisKetogenesis

InsulinGlucagon

EpinephrineCortisol

Growth Hormone

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• Insulin Deficiency

GlycogenolysisGluconeogenesisHepatic glucose outputLipolysis: Release FFA -> liver VLDL & ketones Ketonemia and hyper TG

Acidosis , Hyperglycemia & Osmotic diuresis

DKA - LateDKA - Late Increased Production &Decreased Utilization Fasting hyperglycemia

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Islets of Langerhans

-cell destruction Insulin Deficiency

Adipo-cytes

Muscle

Liver

Decreased Glucose Utilization &Increased Production

GlucagonIncreasedProtein

CatabolismIncreasedKetogenesisGlucoaneogenesis,Glycogenolysis

IncreasedLipolysis

HyperglycemiaKetoacidosis

HyperTG

PolyuriaVolume Depletion

Ketonuria

AminoAcids

FattyAcids

StressEpi,Cortisol

GH,Glucagon

Threshold180 mg/dl

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Precipitating factors of DKAPrecipitating factors of DKA

• Omission or reduced daily insulin injection• Infection• Pancreatitis• Myocardial Infarction• Mesentric Ischemia• Renal Insufficeincy• CVA

• Pulmonary embolism• G I hemorrhage• Heat related illness• Parenteral/enteral

alimentation• Rhabdomyolysis• Severe Burns

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Drugs Precipitate DKADrugs Precipitate DKA

• Diuretics• Lithium• Beta Blockers• Mannitol• Chlorpromazine• Cimetidine

• Glucocorticoids• Neuroleptics• Phenytoin• Didanosine• Calcium-channel

blockers• Pentamidine

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Clinical featuresClinical features

Hyperglycemia

Osmotic diuresis and renal loss of Na, K, PO4, Ca and Mg

Hypovolemia,acidosis and hyperventilation

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Clinical featuresClinical features

• Increased PGI2 and PGE2peripheral vasodilation ,nausea, vomiting and abdominal pain.

• Vomiting maladaptive response to counter acidosis exacerbates the potassium losses

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Signs of DKASigns of DKA

• Dehydration• Hyperventilation• Ketotic breath• Tachycardia and hypotension• Disturbed conscious state and shock

• Alteration of consciousness correlate better with elevated serum osmolality (>320 mOsm/L) than with severity of metabolic acidosis

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SymptomsSymptoms

• Polyuria

• Polydipsia

• Nausea and vomiting

• Abdominal Pain

• Breathing difficulty

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Lab InvestigationsLab Investigations

• Serum glucose• Serum electrolytes• Complete blood count• Renal function test• Serum & urine ketones• Blood gas analysis

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Lab InvestigationsLab Investigations

• Blood cultures• Sputum collection • Urine analysis & Culture• Liver function tests & Coagulation profiile• Cardiac enzymes• Thyroid function tests• Toxicological Screening

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RadiologyRadiology

• Chest X ray

• ECG

• USG Abdomen

• CT Head

• Lumbar Puncture

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Corrected SodiumCorrected Sodium

Measured Na + 1.6 (Glucose-100)

100•Na+ depressed 1.6 mEq/L per 100 mg% glucose rise above 100 mg/dl.

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Corrected SodiumCorrected Sodium

Example:Na+ = 123 meq/L and Glucose = 1,250 mg/dl

Measured Na + 1.6 (Glucose-100) 100

= 123 + 1.6 (1250-100) 100Corrected Na+ = 123 + 18 = 141 meq/L

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Serum OsmolaritySerum Osmolarity

2(Na) + Glucose + BUN 18 2.8

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D/D

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Management of DKAManagement of DKA

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Goals of TreatmentGoals of Treatment

• Volume Repletion• Reversal of metabolic consequences of

insulin insufficiency• Correction of acid-base & electrolyte

imbalances• Recognition & Treatment of precipitating

causes• Avoidance of complications

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Management of DKAManagement of DKA

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Approach to therapyApproach to therapy

• Correcting the hyperosmolar state and dehydration is the initial aim of therapy.

• Insulin therapy should be undertaken only after the patient is stable hemodynamically.

Glucose and H2O

H2O lost in urine Loss of ECF, vascular collapse and death

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Fluid ResuscitationFluid Resuscitation

• Single most important step• Fluid deficit around 100ml/kg (5-10L)• Helps in Restore I/V volume• Perfuse vital organs• Increase GFR• Decrease serum Glucose & Ketone levels• To restore normal tonicity

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Fluid balance in diabeticFluid balance in diabetichyperosmolarityhyperosmolarity

ECF = 14 L ICF = 28 L

H2O

ECF ICF

H2O

Osmotic Diuresis

Osmotic Diuresis ECF hyperosmolar from ICF autotransfusion

ECF and ICF both hyperosmolar

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Fluid ResuscitationFluid Resuscitation

• NS most frequently administered fluid• 1 litre in 30 min• 2 litres in 2 hours• 2 litres in 2-6 hours• 2 litres in 6-12 hours

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Fluid ResuscitationFluid Resuscitation

• 2–3 L of 0.9% saline over first 1–3 h (10–15 mL/kg per hour)

• 0.45% saline at 150–300 mL/h; change to 5% glucose and 0.45% saline at 100–200 mL/h when plasma glucose reaches 250 mg/dl.

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Fluid ResuscitationFluid Resuscitation

•CVP guided fluids should be considered for elderly & those with heart disease

•Excess fluid may lead to ARDS & cerebral edema

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Insulin therapyInsulin therapy

Mechanism of Action:

• Inhibit gluconeogenesis, lipolysis, catabolic

hormone secretion, production of ketoacids

• Promote potassium, glucose & phosphate

uptake in tissues

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Insulin therapyInsulin therapy

• Ideal way to administer insulin by continuous infusion of small doses of regular insulin 0.1unit/kg/hr once hypokalemia is excluded.

• I/M or S/C administration of regular insulin should be avoided as insulin absorption may be erratic in volume depleted & vasocostricted patient

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Insulin therapyInsulin therapy

• Goal is to decrease Glucose by 50-75mg/dl/hr.50-75mg/dl/hr.

• Infusion should continue until anion gap normalized

• S/C insulin should bridge for atleast one hour before discontinuation of I/V insulin

• Insulin administration should be W/H if K <3.3 mEq till K is supplemented

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DKA: Switch to S.C. insulinDKA: Switch to S.C. insulin

Can consider switch to SC insulin when:

• AG normalized• BS < 250 mg/dl• Insulin IV requirements < 2U/h• Patient able to eat• Hemodynamically stable

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DKA: Switch to S.C. insulinDKA: Switch to S.C. insulin

• Overlap insulin IV with 1st SC insulin by 2-4h to avoid recurrent ketosis

• T2 DM patients with DKA:• Don’t necessarily have to be continued on

insulin• Once acute stress resolved, many do well on

OHA

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Potassium CorrectionPotassium Correction• K+ defecit: 3-5 mEq/Kg (350 mEq for 70Kg)• Normal to high serum K+

K+ K+H+ H+

Ketoacidosis

Insulin

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Potassium CorrectionPotassium Correction

• Deficiency is due to

• Decreased insulin levels• Metabolic Acidosis• Osmotic Diuresis• Frequent Vomitting

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Goal of K ReplacementGoal of K Replacement

• To maintain a normal extracellular K+ conc during

the acute phase of therapy and to replace intra-

cellular deficits over a period of days

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K SupplementationK Supplementation

Serum Potassium < 3 mEq/L Give 60mEq/l to IVF

3-3.9 mEq/L 40mEq/l to IVF

4-5.4 mEq/L 20 mEq/L to IVF

> 5.5 mEq/L No Replacement necessary

Verify Normal kidney function & Urine output before treatment

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BicarbonateBicarbonate

• Routine use of supplemental bicarbonate in

Rx of DKA is not recommended

• Can be given if PH Is less than 6.9

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ADA RecommendationADA Recommendation

If PH 6.9-7.0 50mEq of NaHCo3+200ml sterile water+10mEq KCl over 1 hour

If Ph <6.9 100mEq of NaHCo3+400ml sterile water+10mEq KCl over 2 hours

Repeat dose of bicarb every 2 hours till PH>7

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Theoretical AdvantagesTheoretical Advantages

• In case of severe acidosis

• Improve myocardial contractility

• Improve catecholamine tissue response

• Decrease work of breathing

• In case of Hyperkalemia

• Elevate ventricular fibrillation threshold

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DisadvantagesDisadvantages

• Severe & worsening hypokalaemia

• Paradoxical CNS acidosis

• Impair oxyhemoglobin dissociation

• Hypertonicity

• Sodium overload

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DisadvantagesDisadvantages

• Delayed recovery from ketosis

• Elevation of lactic levels

• Precipitation of cerebral edema / Pulmonary

edema

• Thrombophlebitis

• Require Central venous cannulation

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HypophosphatemiaHypophosphatemia

• Most severe 24-48 hours after treatment• Treatment If Levels <1.0 mg/dl• C/F

• Hypoxia• Rhabdomyolysis• Hemolysis• Respiratory failure• Cardiac Dysfunction

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HypophosphatemiaHypophosphatemia

• IV (K2PO4 ) : 1ml/hr. (4.4 mEq potassium + 93 mg

phosphate )

• S/E• Hyperphosphatemia• Hypocalcemia• Hypomagnesemia• Metastatic soft tissue calcification• Hypernatremia• Osmotic diuresis

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HypomagnesemiaHypomagnesemia

• Inhibit parathyroid hormone secretion• hypocalcaemia & hyper phosphatemia

• Supplementation if Mg <1.2 mg/dl

• Can give Oral Magnesium oxide or• Parenteral Magnesium sulphate

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Monitoring Monitoring

• Periodical assessment of vital signs

• Level of consciousness

• Hourly urine output

• Serum glucose Q1H

• Serum Potassium Q2H

• Regular assessment of anion gap

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Complications of DKA Complications of DKA

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DKA in PediatricsDKA in Pediatrics

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Criteria for diagnosisCriteria for diagnosis

• Hyperglycemia: CBG > 300mg/dl.

• Metabolic acidosis:pH < 7.25 – 7.30

HCO3- < 15 mEq/L

• Ketonemia

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Clinical featuresClinical features

• Polyuria• Polydipsia• Polyphagia• Abdominal pain• Nausea and vomiting• Rapid weight loss• Fatigue

• Confusion• Visual changes

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SignsSigns

• Dehydration• Tachycardia• Hypotension• Kussmaul respiration (rapid & deep)• Sweet, fruity odour on the breath • LOC/Coma (look for cerebral edema)

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Treatment goalsTreatment goals

• Establish good perfusion status• Reverse the acidosis• Correct electrolyte disturbances• Control hyperglycemia • Ketonemia

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TreatmentTreatment

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Correction of acidosisCorrection of acidosis

Don’t use bicarbonate as• It will increase chances of cerebral edema

by 4 times.• can lead to volume overload,

hypernatremia, paradoxical cerebral acidosis, accelerated K+ loss

Is there any role for bicarbonate in DKA?

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Indication for bicarbonateIndication for bicarbonate

• pH < 7.0• Hemodynamically unstable• Not responding to fluids• Depressed cardiac contractilty• Poor perfusion

Dose: 0.5 – 2 mEq/kg over 1-2 hrs

Stop correction once pH >7.0

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Major complication of DKAMajor complication of DKA

• Cerebral Edema: most dreaded complication• 57-87% of all pediatric DKA-

associated deaths• More in < 5yrs Rare in > 20 yrs.

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Reasons for Cerebral EdemaReasons for Cerebral Edema

• Over aggressive fluid correction• Failure of Na+ to rise with fall of glucose

during treatment• Cerebral ischemia due to severe dehydration

and hypocarbia

Onset : 6-12 hrs. after onset of therapy

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Clinical features Clinical features

• Severe headache• Seizures• Papilledema• Respiratory arrest• Altered mental status

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Hyperglycemia Hyperosmolar State (HHS)

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IntroductionIntroduction

• A metabolic emergency that occurs in diabetic patient usually Type 2 Diabetes Mellitus

• Characterised by uncontrolled hyperglycemia that induces hyperosmolar state and dehydration without significant ketoacidosis.

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Diagnostic featuresDiagnostic features

• Plasma glucose level of 600 mg/dL or greater

• Effective serum osmolality of 320 mOsm/kg or greater

• Profound dehydration (8-12 L) with elevated serum urea nitrogen (BUN)-to-creatinine ratio

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Diagnostic featuresDiagnostic features

• Small ketonuria and absent-to-low ketonemia

• Bicarbonate concentration greater than 15 mEq/L

• Some alteration in consciousness

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DKA Vs. HHSDKA Vs. HHSDKA HHS

Glucose 250-600 >600

Sodium 125-135 135-145

Potassium Normal/inc Normal

Bicarbonate <15meq/l Normal/slightly reduced

Arterial pH <7.3 >7.3

Anion gap Increased Normal/slightly increased

pCO2 20-30 Normal

Osmolality 300-320 >320

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CausesCauses

• Dehydration• Pneumonia and UTI• Counter-regulotary

hormone (e.g cortisol, cathecolamine, glucagon)

• Dialysis• TPN• Non-compliance to OHA

or insulin therapy

Drugs• Diuretics• B-blocker• Histamine(H2)

Blocker• Anti-psychotics

Clozapine, Olanzapine

• Alcohol and cocaine

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PathophysiologyPathophysiologyConcomitant illness

Circulating insulin& of counter-regulatory hormones

renal clearance and peripheral utilization of glucose

Hyperglycemia Osmotic diuresis

Loss of electrocyte and water

Dehydration

Hyperosmolarity Intracellular dehydration

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Clinical features• Occurs only in type 2 DM

• Could be initial presentation of the diabetic state

• Elderly

• Obtundation to coma

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Clinical features• Severe dehydration invariable

• May have associated lactic acidosis due to hypoxia

• Precipitating factors similar to DKA

• Mortality rate is high

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SymptomsSymptoms

Symptoms of hyperglycemia :PolydipsiaPolyuriaLethargic

Others :Weight lossLoss of consciousness

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SymptomsSymptoms

A wide variety of focal and global neurologic changes may be present :

• Drowsiness and lethargy• Delirium• Coma• Focal or generalized seizures• Visual changes or disturbances• Hemiparesis• Sensory deficits

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Physical examination Physical examination

Dehydrated : dry skin, lips, mucous membrane, loss skin turgor

Vital sign : tachycardia (early dehydration), hypotension (later), temperature

Systemic examination to ruled out the cause.

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Differential diagnosisDifferential diagnosis

• Alcoholic ketoacidosis• Delirium (altered mentation)• Dementia• Overdose• Thyrotoxicosis (tachycardia, fever,

dehydration)

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Lab studiesLab studies• Plasma glucose

Hyperglycemia: CBG : > 600 mg/dl• ABG

PH> 7.3HCO3>15 mmol/l

• Serum osmolality>320 mmol/l

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OthersOthers

• Urine-analysis• Exclude UTI• Proteinuria

• Plasma ketone• Plasma electrolyte• Renal function test( Creatinine &BUN)• CBC• Creatine kinase

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Imaging studiesImaging studies

Chest radiograph• Exclude pnuemonia• Cardiomegaly

CT scan of the head• Exclude haemorrhagic stroke, subdural

haematoma• Look for cerebral edema

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ManagementManagement

Treatment Goals:

• Correction of hypovolemia• Identify and treating underlying cause• Correcting electrolyte abnormalities• Gradual correction of hyperglycemia and

osmolarity• Frequent monitoring

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ManagementManagement

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References

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