Diagnosis and Management of

Hyperglycemic Crises
(Point of view by AACE guideline)
Diabetic Ketoacidosis
Hyperglycemic Hyperosmolar State

K Heri Nugroho HS

Semarang Endocrine Metabolic Meeting 2018

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HYPERGLYCEMIC CRISES

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TIK :
1. Akhir pembelajaran mahasiswa diharapkan
mampu mengenali keluhan pasien dengan KAD
atau HHS.
2. Akhir pembelajaran mahasiswa diharapkan
mampu mengenali tanda pasien dengan KAD atau
HHS.
3. Akhir pembelajaran mahasiswa diharapkan
mampu mengusulkan beberapa pemeriksaan
penunjang pasien KAD atau HHS
4. Akhir pembelajaran mahasiswa diharapkan
mampu mendiagnosis pasien KAD atau HHS
5. Akhir pembelajaran mahasiswa diharapkan
mampu memahami obat-obat kegawatan serta
memberikan prinsip-prinsip terapi tatalaksana
pasien dengan KAD dan HHS
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 DKA and HHS Are Life-Threatening
Emergencies

Diabetic Ketoacidosis (DKA) Hyperglycemic Hyperosmolar State (HHS)

Plasma glucose >250 mg/dL Plasma glucose >600 mg/dL

Arterial pH <7.3 Arterial pH >7.3

Bicarbonate <15 mEq/L Bicarbonate >15 mEq/L

Moderate ketonuria or ketonemia Minimal ketonuria and ketonemia

Anion gap >12 mEq/L Serum osmolality >320 mosm/L

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 Characteristics of DKA and HHS

Diabetic Ketoacidosis (DKA) Hyperglycemic Hyperosmolar State (HHS)

Absolute (or near-absolute) insulin Severe relative insulin deficiency, resulting

deficiency, resulting in in
• Severe hyperglycemia • Profound hyperglycemia and
• Ketone body production hyperosmolality (from urinary free
• Systemic acidosis water losses)
• No significant ketone production or
acidosis

Develops over hours to 1-2 days Develops over days to weeks

Most common in type 1 diabetes, but Typically presents in type 2 or previously
increasingly seen in type 2 diabetes unrecognized diabetes
Higher mortality rate

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 Definition of Diabetic Ketoacidosis*

Acidosis

*
Ketosis
Hyperglycemia
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.
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 DKA Mortality in the US
Decline in Incidence 1988-2009
3500
1988: 3189 deaths 2009: 2417 deaths
3000

2500
Number

2000

1500

1000

500

CDC. Diabetes data and trends. DKA mortality. Available from:

https://www.cdc.gov/diabetes/statistics/mortalitydka/fnumberofdka.htm.
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Causes of Morbidity and Mortality in DKA

• Shock • Acute renal failure

• Hypokalemia during • Adult respiratory
treatment distress syndrome
• Hypoglycemia during • Vascular thrombosis
treatment • Precipitating illness,
• Cerebral edema including MI, stroke,
during treatment sepsis, pancreatitis,
• Hypophosphatemia pneumonia

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PATHOGENESIS AND
PATHOPHYSIOLOGY
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Diabetic Ketoacidosis: Pathophysiology

Unchecked gluconeogenesis  Hyperglycemia

Osmotic diuresis  Dehydration

Unchecked ketogenesis  Ketosis

Dissociation of ketone bodies into Anion-gap metabolic


hydrogen ion and anions acidosis

Often a precipitating event is identified

(infection, lack of insulin administration)

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 Pathogenesis of Hyperglycemic Crises
DKA HHS

Hyperglycemia Dehydration Lipolysis-

osmotic diuresis
Increased FFA

Increased
glucose
Increased
production
ketogenesis
Insulin Counterregulatory
Deficiency Hormones

Decreased
glucose Metabolic
uptake acidosis
Electrolyte Hypertonicity
abnormalities
Umpierrez G, Korytkowski M. Nat Rev Endocrinol. 2016;12:222-232.
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 Insulin Deficiency

Hyperglycemia

Hyper-
osmolality
Glycosuria

Δ MS
Dehydration

Electrolyte
Renal Failure Losses

Shock CV
Collapse 12
Insulin Deficiency

Lipolysis

FFAs

Ketones

Acidosis

CV
Collapse 13
 Insulin Deficiency

Hyperglycemia Lipolysis

Hyper-
osmolality FFAs
Glycosuria

Δ MS Ketones

Dehydration
Acidosis
Electrolyte
Renal Failure Losses

Shock CV
Collapse 14
 Hyperosmolar Hyperglycemic State:
Pathophysiology

Unchecked gluconeogenesis  Hyperglycemia

Osmotic diuresis  Dehydration

• Presents commonly with renal failure

• Insufficient insulin for prevention of hyperglycemia but
sufficient insulin for suppression of lipolysis and
ketogenesis
• Absence of significant acidosis
• Often identifiable precipitating event (infection, MI)

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 Diabetic Hyperglycemic Crises

overlapping syndromes

Diabetic Ketoacidosis Hyperglycemic Hyperosmolar State

(DKA) (HHS)

Younger, type 1 diabetes Older, type 2 diabetes

No hyperosmolality Hyperosmolality

Volume depletion Volume depletion

Electrolyte disturbances Electrolyte disturbances

Acidosis No acidosis

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FOCUS ON ACIDOSIS

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 Anion Gap Metabolic Acidosis

• The normal anion gap in mEq/L is calculated as:

[Na] - [Cl + HCO3] ; normal gap is <12 mEq/L
• Causes of anion gap acidosis (unmeasured anions)
include:
– Ketoacidosis (diabetic, alcoholic)
– Lactic acidosis (lactate [underperfusion, sepsis])
– Uremia (phosphates, sulfates)
– Poisonings/overdoses (methanol, ethanol, ethylene glycol,
aspirin, paraldehyde)
• In ketoacidosis, the “delta” of the anion gap above 12
mEq/L is composed of anions derived from keto-acids
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 Ketone Bodies in DKA

O O OH O O
CH3 – C – CH2 – C CH3 – C – CH2 – C CH3 – C – CH3
O- H O-

Acetoacetate -Hydroxybutyrate Acetone

• Unless -hydroxybutyrate (-OH B) is specifically ordered, the

ketone bodies are estimated by the nitroprusside reaction in the
lab, which measures only acetone and acetoacetate (AcAc)
• Acetone is not an acid

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 Ketone Body Equilibrium in DKA

AcAc -OH B

NADH + H+ NAD+
• In DKA, the dominant ketoacid is -hydroxybutyric acid (-OH
B), especially in cases of poor tissue perfusion/lactic acidosis
• During recovery, the balance shifts to acetoacetic acid (AcAc)

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PATIENT PRESENTATION

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 Clinical Presentation of
Diabetic Ketoacidosis

History Physical Exam

• Thirst • Kussmaul respirations
• Polyuria • Fruity breath
• Abdominal pain • Relative hypothermia
• Nausea and/or vomiting • Tachycardia
• Profound weakness • Supine hypotension,
orthostatic drop of blood
pressure
Patients with any form of diabetes • Dry mucous membranes
who present with abdominal pain, • Poor skin turgor
nausea, fatigue, and/or dyspnea
should be evaluated for DKA.

Handelsman Y, et al. Endocr Pract. 2016;22:753-762.

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 Lab Findings in DKA

• Hyperglycemia
• Usually >250 mg/dL
• Lower blood glucose values possible, especially under
metabolically stressful conditions (eg, prolonged fasting,
carbohydrate avoidance, extreme sports/physical exertion,
myocardial infarction, stroke, severe infection, surgery)
• Increased blood and urine ketones
• High -hydroxybutyrate
• High anion gap
• Low arterial pH
• Low PCO2 (respiratory compensation)
Handelsman Y, et al. Endocr Pract. 2016;22:753-762.
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 Potassium Balance in DKA

• Potassium is dominantly intracellular

• Urinary losses occur during evolution of DKA (due to
glycosuria)
• Total body potassium stores are greatly reduced in any
patient with DKA
• Potassium moves from inside the cell to the extracellular
space (plasma)
– During insulin deficiency
– In presence of high blood glucose
– As cells buffer hydrogen ions
• Blood levels of potassium prior to treatment are usually
high but may drop precipitously during therapy
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 Clinical Presentation of
Hyperglycemic Hyperosmolar State
• Compared to DKA, in HHS there is greater
severity of:
– Dehydration
– Hyperglycemia
– Hypernatremia, hyperkalemia
– Hyperosmolality
• In HHS, ketogenesis is absent to minimal and is
insufficient to produce significant acidosis

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 Clinical Presentation of
Hyperglycemic Hyperosmolar State

Patient Profile Disease Characteristics

• Older • More insidious development
• More comorbidities than DKA (weeks vs
• History of type 2 diabetes, hours/days)
which may have been • Greater osmolality and mental
unrecognized status changes than DKA
• Dehydration presenting with a
shock-like state

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 Electrolyte and Fluid Deficits in
DKA and HHS
Parameter DKA* HHS*

Water, mL/kg 100 (7 L) 100-200 (10.5 L)

Sodium, mmol/kg 7-10 (490-700) 5-13 (350-910)

Potassium, mmol/kg 3-5 (210-300) 5-15 (350-1050)

Chloride, mmol/kg 3-5 (210-350) 3-7 (210-490)

Phosphate, mmol/kg 1-1.5 (70-105) 1-2 (70-140)

Magnesium, mmol/kg 1-2 (70-140) 1-2 (70-140)

Calcium, mmol/kg 1-2 (70-140) 1-2 (70-140)

* Values (in parentheses) are in mmol unless stated otherwise and refer to the total
body deficit for a 70 kg patient.
Chaisson JL, et al. CMAJ. 2003;168:859-866.
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 Initial Laboratory Evaluation of
Hyperglycemic Emergencies
• Comprehensive metabolic profile
• Serum osmolality
• Serum and urine ketones
• Arterial blood gases
• Lactate (?)
• CBC
• Urinalysis
• ECG
• Blood cultures (?)
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 Laboratory Diagnostic Criteria of
DKA and HHS
Parameter Normal range DKA HHS
Plasma glucose, mg/dL 76-115 ≥250* ≥600
Arterial pH† 7.35-7.45 ≤7.30 >7.30
≥31 (children)
-Hydroxybutyrate, mg/dL 4.2-5.2 ≥40 (adults)
Serum bicarbonate, mmol/L‡ 22-28 ≤18 >15
Effective serum osmolality, mmol/kg 275-295 ≤320 >320
Anion gap,§ mmol/L <10 >10 Variable
Serum ketones¶ Negative Positive None or trace
Urine ketones‡ Negative Moderate to high None or trace

*May occur at lower glucose values, especially under physiologically stressful conditions.
†
If venous pH is used, a correction of 0.03 must be made.
‡
Suggestive but not diagnostic of DKA.
§
Calculation: (Na+) – [Cl- + HCO3- (mEq/L)].
¶
Nitroprusside reaction method.

Chaisson JL, et al. CMAJ. 2003;168:859-866. Handelsman Y, et al. Endocr Pract. 2016;22:753-762. Haw SJ, et al.
In: Managing Diabetes and Hyperglycemia in the Hospital Setting: A Clinician’s Guide. Draznin B, ed. Alexandria,
VA: American Diabetes Association; 2016;284-297.
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 Formulas for Estimating
Serum Osmolality and Effective Osmolality

Osmolality Effective Osmolality

2 x [Na+ mEq/L] 2 x [Na+ mEq/L]

+ [glucose mg/dL] / 18 + [glucose mg/dL] / 18

+ [BUN mg/dL] / 2.8

= Sosm (mosm/Kg H2O) = Sosm (mosm/Kg H2O)

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TREATMENT
RECOMMENDATIONS
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 Management of DKA and HHS

• Replacement of fluids losses

• Correction of hyperglycemia/metabolic acidosis
• Replacement of electrolytes losses
• Detection and treatment of precipitating causes
• Conversion to a maintenance diabetes regimen
(prevention of recurrence)

Kitabchi AE, et al. Diabetes Care. 2009;32:1335-1343.

 Fluid Therapy in DKA

Normal saline, 1-2 L over 1-2 h

Calculate corrected serum sodium

High or normal Low serum sodium

serum sodium

½ NS at 250-500 NS at
mL/h 250-500 mL/h

Glucose < 250 mg/dl

Change to D5% NS or 1/2NS

ADA. Diabetes Care. 2003;26:S109-S117.

 Suggested Initial Rate of Fluid
Replacement*
Hours Volume
1st hour 1000 – 2,000 mL
2nd hour 1000 mL
3rd-5th hours 500 – 1000 mL/hour
6th-12th hours 250 – 500 mL/hour

*Average replacement after initial hemodynamic resuscitation with normal saline when
indicated

Chaithongdi N et al. Hormones (Athens). 2011;10:250-260.

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 Intravenous Insulin Therapy in DKA

IV bolus: 0.1 U/kg body weight

IV drip: 0.1 U/kg/h body weight

Glucose < 250 mg/dl

IV drip: 0.05 – 0.1 U/kg/h

until resolution of ketoacidosis

ADA. Diabetes Care. 2003;26:S109-S117.

 Potassium Replacement

• K+ = > 5.5 mEq/L: no supplemental is required

• K+ = 4 - 5 mEq/L: 20 mEq/L of replacement fluid

• K+ = 3 - 4 mEq/L: 40 mEq/L of replacement fluid

If admission K+ = <3 mEq/L give 10-20 mEq/h until

K+ >3 mEq/L, then add 40 mEq/L to replacement fluid

ADA. Diabetes Care. 2003;26:S109-S117.

 Potassium Repletion in DKA

• K+ >5.2 mEq/L
– Do not give K+ initially, but check serum K+ with basic
metabolic profile every 2 h
– Establish urine output ~50 mL/hr
• K+ <3.3 mEq/L
– Hold insulin and give K+ 20-30 mEq/hr until
K+ >3.3 mEq/L
• K+ = 3.3-5.2 mEq/L
– Give 20-30 mEq K+ in each L of IV fluid to maintain
serum K+ 4-5 mEq/L

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 Phosphorus Repletion in DKA

• A sharp drop of serum phosphorus can also

occur during insulin treatment
• Treatment is usually not required
– Caregiver can give some K+ as K- phos

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 Phosphorus Administration

• Not routinely recommended

• If serum phosphorus < 1 mg/dL:

30-40 mmol K-Phos over 24 h

• Monitor serum calcium level

ADA. Diabetes Care. 2003;26:S109-S117.

 Bicarbonate Administration

• pH > 7.0: no bicarbonate

• pH < 7.0 and bicarbonate < 5 mEq/L:

44.6 mEq in 500 mL 0.45% saline over 1 h until
pH > 7.0

ADA. Diabetes Care. 2003;26:S109-S117.

 Conventional Insulin Guidelines

• Initiate the correction of hypovolemic shock with

fluids, and correct hypokalemia if present, before
starting insulin
• When starting insulin, initially infuse 0.1 to 0.14
units/kg/h
• If plasma glucose does not decrease by 50-75 mg
in the first hour, increase the infusion rate of insulin
• Continue insulin infusion until anion gap closes
• Initiate subcutaneous insulin at least 2 h before
interruption of insulin infusion
Kitabchi AE, et al. Diabetes Care. 2009;32:1335-1343.
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 Subcutaneous Rapid Acting Insulin or
Intravenous Regular Insulin for DKA Treatment

Systematic Review
(N=5 RCTs)

• No substantial difference in time to resolution of DKA

between SC lispro or aspart vs IV regular insulin in
adults
– In single study including children and adolescents, DKA
resolution slower with SC rapid acting analogs than with IV
regular insulin
• Rates of hypoglycemia and duration of hospital stay
comparable between rapid acting insulin analogs and
regular insulin in adults and children

Andrade-Castellanos CA, et al. Cochrane Database Syst Rev. 2016 Jan 21;(1):CD011281.
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 Subcutaneous Insulin Protocols
Rapid Acting Insulin Rapid Acting Insulin Every
Every 1 Hour 2 Hours
• Initial dose • Initial dose
– 0.2 U/kg of body weight, – 0.3 U/kg of body weight,
followed by 0.1 U/kg/h followed by 0.2 U/kg 1 h later,
• When BG <250 mg/dL then
– Change IVF to D5%-0.45% – Rapid acting insulin at 0.2
saline U/kg every 2 h
– Reduce rapid acting insulin to • When BG <250 mg/dL
0.05 unit/kg/h – Change IVF to D5%-0.45%
– Keep glucose ≈ 200 mg/dL saline
until resolution of DKA – Reduce rapid acting insulin to
0.1 U/kg every 2 h
– Keep glucose ≈ 200 mg/dL
Haw SJ, et al. In: Managing Diabetes and Hyperglycemia in the Hospital until resolution of DKA
Setting: A Clinician’s Guide. Draznin B, ed. Alexandria, VA: American
Diabetes Association; 2016;284-297.
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 A Dynamic Insulin Protocol for DKA
Physician orders for DKA: target blood glucose 150-199 mg/dL until recovery

Maintenance
1.0 2.0 3.0 4.0 6.0
rate* (units/h)

BG mg/dL Insulin units/h Insulin units/h Insulin units/h Insulin units/h Insulin units/h

<90 0.1 0.1 0.1 0.1 ←

90-129 0.2 0.3 0.3 0.4 ←
130-149 0.4 0.6 0.8 1.0 ←
150-169 0.6 1.1 1.5 1.8 2.5
170-179 0.8 1.6 2.3 3.0 4.3
180-199 1.0 2.0 3.0 4.0 6.0
200-229 1.1 2.2 3.3 4.4 6.5
230-259 1.3 2.5 3.8 5.0 7.5
260-289 1.4 2.8 4.2 5.6 8.4
290-319 1.5 3.1 4.6 6.2 9.3
320-359 1.7 3.4 5.1 6.8 10.2
360-399 1.8 3.7 5.5 7.4 11.1
≥400 2.0 4.0 6.0 8.0 12.0

*Assigned when the blood glucose is close to 184 mg/dL.

DKA, diabetic ketoacidosis.
Devi R, et al. Diabetes Manage. 2011;1:397-412. Devi R, et al. Diabetes Technol Ther. 2014;16:208-218.
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 A Dynamic Insulin Protocol for HHS
Physician orders for HHS: target blood glucose 200-299 mg/dL until recovery

Maintenance
1.0 2.0 3.0 4.0 6.0
rate* (units/h)
Insulin Insulin Insulin Insulin Insulin
BG mg/dL
units/hr units/hr units/hr units/hr units/hr
<100 0.1 0.1 0.1 0.1 ←
100-149 0.2 0.2 0.3 0.3 ←
150-199 0.3 0.5 0.6 0.7 ←
200-219 0.5 0.8 1.1 1.3 1.7
220-239 0.6 1.1 1.5 1.9 2.6
240-259 0.8 1.5 2.1 2.7 3.9
260-299 1.0 2.0 3.0 4.0 6.0
300-329 1.1 2.1 3.2 4.2 6.3
330-359 1.1 2.3 3.4 4.6 6.9
360-399 1.3 2.5 3.8 5.0 7.5
400-449 1.4 2.8 4.2 5.6 8.3
450-599 1.6 3.3 4.9 6.6 9.9
≥600 2.0 4.0 6.0 8.0 12.0

*Assigned when the blood glucose is close to 271 mg/dL.

HHS, hyperglycemic hyperosmolar state.
Devi R, et al. Diabetes Manage. 2011;1:397-412. Devi R, et al. Diabetes Technol Ther. 2014;16:208-218.
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 Transition to Subcutaneous Insulin After
Resolution of DKA
After Initial IV or SC therapy
(pH>7.3, HCO3 >18, AG < 14)

Give SC basal insulin 2–4 hours before stopping IV insulin

Start multi-dose insulin (basal bolus) regimen

• Insulin analogs are preferred over human insulin
• Basal: glargine or detemir
• Rapid-acting insulin analogs (lispro, aspart, glulisine)
• Analogs result in similar blood glucose control but less
hypoglycemia than human insulin (15% vs 41%)

Use early glargine insulin during treatment of DKA may prevent

rebound hyperglycemia during insulin infusion

Umpierrez G, Korytkowski M. Nat Rev Endocrinol. 2016;12:222-232.

 When to Transition From
IV Insulin Infusion to SC Insulin

DKA HHS
• BG <200 mg/dL and 2 of • Normal osmolality and
the following regaining of normal
– HCO3 ≥15 mEq/L mental status
– Venous pH >7.3 • Allow an overlap of 1-2 h
– Anion gap ≤12 mEq/L between subcutaneous
insulin and
discontinuation of
intravenous insulin

Kitabchi AE, et al. Diabetes Care. 2009;32:1335-1343.

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FINDING THE CAUSE AND
PREVENTING RECURRENCE
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Possible Precipitating Causes or Factors
in DKA: Type 1 Diabetes
• Nonadherence to insulin regimen or psychiatric
issues
• Insulin error or insulin pump malfunction
• Poor “sick-day” management
• Infection (intra-abdominal, pyelonephritis, flu)
• Myocardial infarction
• Pancreatitis
• Other endocrinopathy (rare)
• Steroid therapy, other drugs or substances
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Possible Precipitating Causes or Factors
in DKA: Type 2 Diabetes
• Nonadherence to medication regimen
• Poor “sick-day’ management
• Dehydration
• Renal insufficiency
• Infection (intra-abdominal, pyelonephritis, flu)
• Myocardial infarction, stroke
• Other endocrinopathy (rare)
• Steroid therapy, other drugs or substances

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 Summary

• DKA and HHS are life-threatening emergencies

• Management involves
– Attention to precipitating cause
– Fluid and electrolyte management
– Insulin therapy
– Patient monitoring
– Prevention of metabolic complications during recovery
– Transition to long-term therapy
• Patient education and discharge planning should
aim at prevention of recurrence
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