Management of diabetic ketoacidosis:

from a perspective of nephrologist

제29차 대한당뇨병학회 춘계학술대회

조 장 희 경북대학교병원 신장내과

없 음

본 발표와 관련된 이해관계

대한당뇨병학회 학술위원회

DKA and HHS are Life-Threatening Emergencies

Abbas E et al. Diabetes Care 2009; 32: 1335

Diabetic Ketoacidosis (DKA) Hyperglycemic Hyperosmolar

State (HHS)

Plasma glucose >250 mg/dL

Arterial pH <7.3

Bicarbonate <15 mEq/L

Moderate ketonuria or ketonemia

Anion gap >12 mEq/L

Serum osmolality variable

Plasma glucose >600 mg/dL

Arterial pH >7.3

Bicarbonate >15 mEq/L

Minimal ketonuria and ketonemia

Anion gap variable

Serum osmolality >320 mosm/L

Characteristics of DKA and HHS

Abbas E et al. Diabetes Care 2009; 32: 1335

DKA HHS

Absolute (or near-absolute) insulin

deficiency, resulting in

Severe hyperglycemia

Ketone body production

Systemic acidosis

Develops over hours to 1-2 days

Most common in type 1 diabetes, but

increasingly seen in type 2 diabetes

Severe relative insulin deficiency,

resulting in

Profound hyperglycemia

hyperosmolality

No significant ketosis or acidosis

Develops over days to weeks

Typically presents in type 2 or

previously unrecognized diabetes

Definition of Diabetic Ketoacidosis

Adapted from Kitabchi AE, Fisher JN. Diabetes Mellitus. In: Glew RA, Peters SP, ed. Clinical Studies in Medical Biochemistry. New York, NY: Oxford University Press; 1987:105.

Hyperglycemia

Ketosis

Acidosis

Diabetic Ketoacidosis: Pathophysiology

Unchecked gluconeogenesis Hyperglycemia

Osmotic diuresis Dehydration

Unchecked ketogenesis Ketosis

Dissociation of ketone bodies into hydrogen ion and anions

Anion-gap metabolic acidosis

• Often a precipitating event is identified (infection, lack of insulin administration)

Normal Acid-Base Homeostasis

Chemical buffering: the regulation of PaCO2 by the respiratory system, and the regulation of [HCO3-] by the kidneys, act in concert to maintain a systemic arterial pH between 7.35 and 7.45

Lung : Eliminate CO2

Kidney : Excrete NH4

+

Regenerating HCO3-

Diet

H2CO3

Kidney

CO2

NH4+

H+

HC03-

H+ + HCO3- <-> H2CO3 <-> H2O + CO2

CA: Carbonic Anhydrase

Acid-Base Diagnosis

[H+]

High Normal Low

Mixed disorders if

PaCO2 and HCO3- both low

PaCO2 and HCO3- both high

Plasma anion gap increased Acidemia Alkalemia

HCO3-

Low

HCO3-

High

PaCO2

Low

Metabolic

alkalosis

Respiratory

alkalosis

Respiratory

acidosis

Metabolic

acidosis

PaCO2

High

pH 정상치 : 7.35-7.45

PaCO2 정상치 : 40 mmHg

HCO3- 정상치

: 24 mEq/L

Compensatory response on simple acid-base disturbances

Disorder Prediction of Compensation

Metabolic acidosis PaCO2 = (1.5 HCO3-) + 8

or

PaCO2 will 1.25 mmHg per mmol/L in [HCO3-]

or

PaCO2 = [HCO3-] + 15

Metabolic alkalosis PaCO2 will 0.75 mmHg per mmol/L in [HCO3-]

or

PaCO2 will 6 mmHg per 10-mmol/L in [HCO3-]

or

PaCO2 = [HCO3-] + 15

Respiratory alkalosis

Acute [HCO3-] will 0.2 mmol/L per 1mmHg in PaCO2

Chronic [HCO3-] will 0.4 mmol/L per 1mmHg in PaCO2

Respiratory acidosis

Acute [HCO3-] will 0.1 mmol/L per 1mmHg in PaCO2

Chronic [HCO3-] will 0.4 mmol/L per 1mmHg in PaCO2 9

Serum Anion Gap

AG = [A-] = [Na+] – {[Cl-] + [HCO3-]}

• Normal : 12 ± 2 mmol/L High AG metabolic acidosis

• Acid production (gain)

Normal AG metabolic acidosis • Hyperchloremic metabolic acidosis • Alkail loss

Na+

AG

HCO3-

Cl-

Acid Gain vs. Alkali (HCO3-) Loss

• High anion gap = acid gain • Normal anion gap = hyperchloremia

= = =

Na+

Cl- Cl- Cl-

A-

A-

HCO3-

HCO3-

A-

HCO3-

Normal Acid Gain Alkail loss

A-↑ Cl-↑

Bicarbonate Concentration in DKA

Kamel et al. New Eng J Med 2015

In DKA state,

large deficit of HCO3− in ECF

severe contraction of the volume of ECF

Plasma bicarbonate concentration [HCO3−] only moderately reduced

Bicarbonate deficit becomes evident during re-expansion of the volume

ECF bicarbonate concentration [HCO3−]

= Extracellular Fluid HCO3− content ÷ Extracellular Fluid Volume

Delta-delta (ΔAG/ΔHCO3-) in Metabolic Acidosis

∆AG (pts AG level - 10)/ ∆HCO3- (25 - pts HCO3

-) 1~2: pure high anion gap M.acidosis > 2 : combined with M.alkalosis < 1 : combined with non-gap acidosis

Delta-delta (ΔAG/ΔHCO3-) in DKA

HCO3− deficit = (25 mmol/L x 10L) – (10 mmol/L x 7L) = 180 mmol

Ketoacid anion gain = (15 mmol/L x 7L) - (0 mmol/L x 10L) = 105 mmol

type 1 DM, BW 50kg,

[HCO3−] = 25 mmol/L, Anion gap = 12 mmol/L, ECF 10L

[HCO3−] = 10 mmol/L, Anion gap = 27 mmol/L, ECF 7L

The bicarbonate deficit and the amount of ketoacids retained in

the extracellular fluid are not equal

Indirect loss of Sodium Bicarbonate in DKA

The loss of HCO3− occurs after it reacts with H+ producing carbon

dioxide (CO2) and water (H2O); The loss of Na+ occurs during its

excretion in the urine with β-hydroxybutyrate.

Kamel et al. New Eng J Med 2015

Initial Monitoring

Complete initial evaluation

Check capillary glucose

Check serum/urine ketones

Obtain blood metabolic profile: electrolyte, anion gap, plasma

osmolality

Start IV fluids: 1.0 L of 0.9% NaCl per hour

IV Fluids Therapy

Determine hydration status

Severe Hypovolemia

Mild hypovolemia Cardiogenic shock

Administer 0.9% NaCl (1.0L/hr)

Evaluate corrected serum Na

Hemodynamic monitoring/pressor

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

IV Fluids Therapy

Evaluate corrected serum Na

High Normal

[Na+]=135 meq/L Low

0.45% NaCl (250-500 ml/hr)

0.9% NaCl (250-500 ml/hr)

Serum Glu 200 mg/dL 5% DW + 0.45% NaCl

(150-250 ml/hr)

Insulin Therapy

Serum Glu does not fall by 50-70 mg/dL in first hr double IV or SC insulin bolus Serum Glu 200 mg/dL Reduce insulin to keep Glu 150-200 mg/dL

IV Route Uncomplicated DKA

SC Route

RI insulin 0.1 U/kg as IV bolus

Rapid-actin insulin 0.3 U/kg 0.2 U/kg 1 hr later

Continuous IV 0.1 U/kg/hr

Rapid-actin insulin 0.2 U/kg SC q 2 hrs

Edge al. Diabetologia 2006

Administration of a large volume of fluid over the first 4 hours were associated with an increased risk of cerebral edema

Plasma Osmolality

Urea

- Transported across most cell membranes

- Achieves equal concentrations in ECF and ICF

Total osmolality in plasma

= 2 × [Na+] + [Glucose]/18 + [BUN] /2.8

Effective osmolality in plasma

= 2 × [Na+] + [Glucose]/18

Kamel et al. New Eng J Med 2015

Severity of Acidosis

Bolus Insulin

Large Volume of Fluid

Potassium Replacement

Give 20-30 mEq/L K+

to keep [K+] 4-5 mEq/L

[K+] < 3.3 mEq/L

[K+] = 3.3-5.2 mEq/L

[K+] > 5.2 mEq/L

Hold insulin Give 20-30 mEq/hr

Until [K+] > 3.3 mEq/L

Do not give K+

Check [K+] q 2hrs

Bicarbonate Infusion

pH > 6.9 pH < 6.9

No HCO3- 100 mmol in 400ml H2O

+ 20 mEq KCL for 2 hrs

Repeat q 2 hrs until pH > 7.0 Monitor [K+] q 2 hrs

Severe Acidemia

Decreased cardiac contractility

Diminished responses to catecholamines

Predisposition to cardiac arrhythmias

Hemodynamic instability

Impair the capacity of insulin to slow the rate of ketoacid

production

From 508 potentially relevant articles, 44 were included

Two RCTs demonstrated transient improvement in metabolic

acidosis with bicarbonate treatment within the initial 2 hours.

There was no evidence of improved glycemic control or

clinical efficacy.

Increased risk for cerebral edema and prolonged

hospitalization in children who received bicarbonate

Chua et al. Annals of Intensive Care 2011

Oxidization of Ketoacids

Brain 800 mmol/day

Kidney Oxidization 250 mmol/day Excretion 150 mmol/day

Owen et al. J Clin Invest 1967 & 1969

Infused insulin will slow the rate of ketoacid production

except initial several hours

Bicarbonate Therapy

Considered in the initial treatment of a subgroup

Patients who are expected to have a low rate of ketoacid removal

Marked decrease in their level of consciousness

Preexisting advanced renal dysfunction

Combined with normal anion gap metabolic acidosis

The decision in adult patients with diabetic ketoacidosis should be individualized and not based solely on an arbitrary blood pH value

Kamel et al. New Eng J Med 2015

Delta-delta (ΔAG/ΔHCO3-) in Metabolic Acidosis

∆AG (pts AG level - 10)/ ∆HCO3- (25 - pts HCO3

-) 1~2: pure high anion gap M.acidosis > 2 : combined with M.alkalosis < 1 : combined with non-gap acidosis

Metabolic acidosis – metabolic alkalosis

Key: Only detectable with high-AG acidosis;∆AG>>∆HCO3-

Example: Na+, 140;K+, 3.0;Cl-, 95;HCO3-, 25;AG, 20;PaCo2, 40;PH, 7.42

(uremia with vomiting)

Metabolic acidosis – metabolic acidosis

Key: Mixed high-AG- normal-AG acidosis; ∆HCO3- accounted for by

combined change in ∆AG and ∆ Cl-

Example: Na+, 135;K+, 3.0;Cl=, 110;HCO3-, 10;AG, 15;PaCo2, 25;PH, 7.20

(diarrhea and lactic acidosis, toluene toxicity, treatment of diabetic

ketoacidosis)

Mixed Metabolic Disorders

Examples of Mixed Acid-base Disorders

DKA에서는 혈장 [HCO3-]의 감소와 Anion gap 상승이 동일한 비율로

일어남에도 불구하고 실제로는 HCO3-의 결핍이 훨씬 더 심각할 수가

있다.

소아에서 뇌부종을 줄이기 위해서는 대부분의 뇌부종이 일어나는 초기의 15시간 동안에 Effective Osmolality가 떨어지지 않도록 [Na+]를 지속적으로 모니터링 하면서 free water 투여는 최소한으로 줄여야 한다.

심각한 산혈증이 나타나는 보다 주된 원인은 간에서 생성되는 Ketoacids의 증가보다는 뇌와 신장에서의 Ketoacids 제거가 감소하는 것이다. 따라서 대부분의 DKA에서 HCO3

- 의 투여는 매우 심한 산혈증이나 혈역학적으로 불안정한 경우에만 신중하게 투여해야 한다.

Summary

Thank you for your attention!

Kyungpook national university hospital since 1907

Kyungpook National University Medical Center since 2010