Hyperglycemic Crisis Crisis - student version.pdfDehydration (Hypovolemia) Blood Glucose is filtered...

Hyperglycemic CrisisDiabetic Ketoacidosis and Hyperosmotic Hyperglycemic Nonketotic State

Daniel J Hellrung DO PhD

[email protected]

May 13, 2015

mailto:[email protected]

Hyperglycemic Crisis

Case Study

Definition of DKA and HHS

Epidemiology

Pathophysiology

Normal Glucose Control

Dysregulation of Glucose in DKA and HHS

Clinical Features

Evaluation and Diagnosis

Treatment Algorithms

Summary

Case Study

35 y.o. male with PMH of type I diabetes mellitus and GERD presents with 2 days of nausea, vomiting, abdominal pain, shortness of breath, cough and fever.

Meds:

20U glargine qHS with 3U Novolog TID AC and Corrective

20mg omeprazole

Allergies: none

FH: Mother - hypothyroid, Father – hyperlipidemia

Soc: non smoker, occ EtOH

Exam: Temp 38C, BP 132/76, HR 103, RR 32, SpO2 98%, Wt 70Kg, Ht 175cm BMI 22.9

Gen: Appears ill, sleepy and confused

HEENT: dry mucus membranes, sunken eyes

Lungs: right upper lobe crackles, tachypneic, Kussmaul pattern

Heart: tachycardic, regular rhythm, normal S1,S2 w/o murmurs. No LE edema. JVP is normal

Abdomen: BS present, mildly tender to palpation diffusely, percussion w/o localizing pain, no organomegaly

Skin: clammy, no jaundice, no abnormal lesions

Neurologic: confused, sleepy, CN II-XII grossly intact, no focal motor or sensory deficits

Case Study

What are your thoughts about this patient

Are there enough clues to give you an idea of what’s happening?

Are you leaning toward DKA or HHS?

What do you think is the underlying etiology of his symptoms?

Stay tuned for the “rest of the story”…

Definitions

DKA – 4 main points

Hyperglycemia usually 350-500 mg/dl (usually <800 mg/dl)

If patient is comatose BG can rise >900 mg/dl

Ketoacidosis (Anion Gap Metabolic Acidosis)

Dehydration (hypovolemia)

Electrolyte disturbances

Occurs rapidly

HHS

Hyperglycemia usually >1000 mg/dl


Plasma osmolality may reach 380 mosmol/kg (normal 275-295)

Typically no metabolic acidosis (if present it is usually mild)


Occurs over days to weeks

Overlap does occur in about 1/3 of patients

Definitions

Image courtesy of ebmedicine.net

Differential Diagnosis

Image courtesy of Annals of Internal Medicine, annals.org

Epidemiology

DKA

Usually associated with DM type I

May occur in DM type II in conditions of

Extreme stress (severe sepsis, septic shock, AMI, trauma)

Ketosis-prone DM type II (e.g. “burned out” DM type II)

Age is usually < 65 years

CDC estimated 140,000 hospital discharges for DKA in 2009 as compared to 80,000 in 1988.

Mortality has declined.

Mortality is usually due to the underlying cause of hyperglycemic crisis

Prognosis is poor for the very young and old. Also when presenting with coma and hypotension

HHS

Associated with DM type II, not seen in DM type I

Age is usually > 65 years

Population data is not available for HHS (per CDC)

Epidemiology

Overall Mortality due to

Hyperglycemic Crisis Number of deaths were stable in

the 1980s

Decreased in the 1990s.

In 2009 (last reported stats by the

CDC)

2,417 deaths

19.8% lower than the 3,012

deaths in 1980.

Image courtesy of cdc.gov

Epidemiology


Mortality Rate of

Hyperglycemic Crisis Declines in the crude and age-

adjusted rates were similar.

The age-adjusted rate decreased

64% from 48.4 per 100,000 diabetic

population in 1980 to 17.3 per

100,000 diabetic population in

2009.

Epidemiology


Mortality Rate by Gender

and Race Black males were

disproportionately affected.

Lowest among white females

In 2009, mortality rate was

42.6 per 100,000 diabetic

population among black

males

19.5 among white males

16.0 among black females

11.7 among white females

Epidemiology – Precipitating factors for DKA

Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients

with diabetes. Diabetes Care 2001; 24:131-53

Pathophysiology

Normal Glucose Regulation

Extracellular glucose is regulated primarily by insulin and glucagon

Blood glucose rises after a meal

Glucose enters the pancreatic beta cell

Beta cells (islet cells) produce insulin which down regulates glucagon from the

alpha cells

Insulin causes the liver to shut down production of glucose by reducing

Glycogenolysis

Gluconeogenesis

Insulin also increases glucose uptake in skeletal muscle cells and adipose tissue

Pathophysiology

DKA

Type I Diabetics: insulin dependent due to autoimmune destruction of

beta cells

Recall the 4 main features of DKA

Hyperglycemia

Ketoacidosis (Anion Gap Metabolic Acidosis)



Let’s go through each one…

Pathophysiology

Pathophysiology

Hyperglycemia

Lack of insulin is akin to lifting the brake from glucagon allowing it

to run amuck.

Glucagon is released from the alpha cells unopposed by

insulin

Glucagon enters the liver cells and stimulates:

Glycogenolysis

Gluconeogenesis

Blood glucose rises fairly precipitously

Pathophysiology

Hyperglycemia Imbalance between insulin and

glucagon

Increase in counter regulatory

hormones including cortisol,

epinephrine, growth hormone

Increase in glycogenolysis and

gluconeogenesis

Blood glucose increases

Common BG

DKA 350-500 mg/dl

HHS >800 mg/dl

Why lower BG in DKA?

Image courtesy dtc.ucsf.edu

PathophysiologyGlycogen

Stored in the liver and muscle

Short term energy supply

Liberated from storage form by

Glycogenolysis

Glucose is produced through

Gluconeogenesis

Image courtesy of bio1151.nicerweb.comImage courtesy of static1.squarespace.com

Pathophysiology

Ketogenesis FFA are liberated from adipose

tissue

Undergo b-oxidation in the liver

Result is 2 ketones and acetone

Acetoacetate

b-Hydroxybutyrate

Acetone is neutral and accounts

for the “fruity” breath.

Ketogenesis results in AGMA

In HHS, No or little acidosis

DMII is insulin resistance

With insulin present,

glucagon is controlled

No FFA for b-oxidation

No acetoacetyl CoA excess

No ketone formation

Image courtesy of pharmqd.com

Pathophysiology

Image courtesy of washington.edu

* Data from Ennis et al (1994) and Kreisberg (1978)

Dehydration (Hypovolemia) Blood Glucose is filtered in the

glomerulus

Reabsorption takes place in the

proximal tubule

SGLT2 transporter carries Na+Glu

into the cell

Glucosuria appears at a blood

glucose level of 200 mg/dl (Tmax

usually 300mg/dl)

Glucosuria causes osmotic

diuresis in distal tubule resulting in

polyuria

Typical free water deficit *

DKA - 6L

HHS - 9L

Why?

Pathophysiology – Osmotic Diuresis

Image courtesy of washington.edu

Water

Water

Pathophysiology

Hyperosmolality High blood glucose (BG)

Increase in ECF by shifting fluid from ICF

Decreases [Na+] by dilutional effects

Osmotic diuresis results in free water loss (with some Na+ and

K+).

Decreased oral intake and losses through emesis

Excretion of ketone anions also contributes to osmotic diuresis

Obligatory losses of urinary cations

Sodium, potassium, and ammonium salts

Hyperosmolality is most prominent in HHS

Higher BG seen in HHS over DKA

Greater degree of osmotic diuresis

The major factor causing mental status changes

Image courtesy of endotext.org

Pathophysiology

Normal is 275-295 mOsm/kg

Pathophysiology

Electrolytes

Disturbances Glucosuria results not

only in water loss but

also electrolytes

In both DKA and HHS

there is a total body

depletion of electrolytes

Most importantly

Na+ and K+

Beware: Patient Labs

may appear to show

normal/high K+… it most

certainly isn’t!

Data from Ennis et al (1994) and Kreisberg (1978)

Pathophysiology

How does the K appear normal then? Remember there is a state of total body K+ depletion and

hyperosmolality

Solvent drag: with hyperosmolality water moves from the ICF to the

ECF and a parallel movement of K+ occurs.

With movement of water out of the cell, the ICF undergoes a

contraction thereby raising IC [K+].

The cell “thinks” the IC [K+] is too high and K+ passively exits the

cell to the ECF

Very minor role in DKA comes from a shift of H+ ions into the cell in

exchange for K+ in an effort to normalize ECF pH

The result can appear to show normal or even elevated K+ on labs

Image modified from courses.lumenlearning.net

Water

Glu

Glu

Glu

Glu

Glu

Glu

Glu

Glu

Glu

Glu

GluGlu

GluGlu

Glu

Summary of Differences

Image courtesy of ebmedicine.net

Back to the Case Study…

35 y.o. male with PMH of type I diabetes mellitus and GERD presents with 2 days of nausea, vomiting, abdominal pain, shortness of breath, cough and fever.

Exam: Temp 38C, BP 132/76, HR 103, RR 32, SpO2 98%, Wt 70Kg, Ht 175cm BMI 22.9

Gen: Appears ill, sleepy and confused

HEENT: dry mucus membranes, sunken eyes

Lungs: right upper lobe crackles, tachypneic, Kussmaul pattern

Heart: tachycardic, regular rhythm, normal S1,S2 w/o murmurs. No LE edema. JVP is normal

Abdomen: BS present, mildly tender to palpation diffusely, percussion w/o localizing pain, no organomegaly

Skin: clammy, no jaundice, no abnormal lesions

Neurologic: confused, sleepy, CN II-XII grossly intact, no focal motor or sensory deficits

Clinical Features - DKA

Image courtesy of healthy-ojas.com

Clinical Features

DKA HHS

Image modified from “DKA versus HHS” by Dr. Kamal Mohd

CO2 + H2O H2CO3 H+ + HCO3

Clinical Features – Respiratory Compensation

Image courtesy of studyblue.com

Clinical Features

Image courtesy of en.wikipedia.org

What does our guy have… DKA or

HHS?

What is the underlying etiology of

his DKA?

Pneumonia

Back to the Case Study…

Typical Lab Findings

Image courtesy of Dharmraj Singh from Perioperative Diabetes mellitus management,

Institute of medical sciences,BHU, Varanasi

Treatment

Image courtesy dearnurses.com

Treatment

Overall Goals - DKA Stabilize hemodynamics

Improve tissue perfusion and correct hypovolemia

Improve cellular response to insulin

Gradual reduction in the serum glucose and plasma osmolality

Cease ketogenesis

Reverse AG metabolic acidosis

Correction of electrolyte imbalance

Prevent complications of overtreatment

Treat the disease process that precipitated the hyperglycemic crisis

Protocol for the management of adult patients with DKA *DKA diagnostic criteria: blood glucose >250 mg/dl, arterial pH <7.3, bicarbonate <15 mEq/l,

and moderate ketonuria or ketonemia.

American Diabetes Association Dia Care 2004;27:s94-s102

Treatment – Allina Protocol for DKA

Developed by the Clinical Decision Support and Endocrinology Expert Group at AllinaHealth

Treatment

Volume Expansion Improve tissue perfusion and correct hypovolemia

Volume repletion resulting in correction of hyperosmolality

Improves sensitivity to low dose insulin therapy

Gradual reduction in the serum glucose, plasma osmolality, AGMA

By increasing GFR improved excretion of BG and ketoacids

In the absence of cardiac compromise, isotonic saline is used

initially for the 1-2 hrs

If in hypovolemic shock, then fluid replacement should be rapid

Otherwise, goal is 15-20 ml/kg lean body weight per hour

Usually 1L in average sized person

Maximum is <50 ml/kg in the first 4 hrs to prevent complications due

to rapidly correcting hyperosmolality

Treatment

Volume Expansion Subsequent choice for fluid replacement depends on the state of

hydration, serum electrolyte levels, and urinary output

0.45% NaCl is appropriate if the corrected serum sodium is

normal or elevated

0.9% NaCl at a similar rate is appropriate if corrected serum

sodium is low (<135 mEq/L)

The addition of dextrose when the BG is 200 mg/dl (DKA) and 250-

300 mg/dl (HHS)

Prevents hypoglycemia

Allow further time for AGMA to resolve (DKA)

Decreases risk of developing cerebral edema

In HHS, maintain BG at this level until resolution of hyperosmolality,

mental status improves and vitals are stable.

Treatment

Volume Expansion Successful progress is determined by

Hemodynamic improvement

Achieving stable goal UOP

Improvement in labs

Signs and symptoms

Fluid replacement should correct the estimated deficits within the

first 24 h

DKA: 6L fluid deficit

HHS: 9L fluid deficit

Recommend monitoring serum osmolality in patients with renal or

cardiac compromise

Monitor for iatrogenic fluid overload and other complications

Treatment

Potassium Total body depletion in both DKA and HHS

Mild to moderate hyperkalemia on labs is common

Serum potassium is decreased by

Insulin, improvement in acidosis, volume expansion

Prevent hypokalemia by replacing potassium serum levels

decrease to <5.3 mEq/l

20–30 mEq potassium/L of IVF should maintain a serum potassium

concentration within the goal range (4 –5 mEq/l)

It may take more potassium replacement though

Rarely, DKA patients may present with significant hypokalemia

To avoid life threatening hypokalemia, start treatment with IVF

containing potassium rather than insulin

Continue infusion until potassium is >3.3 mEq/l

Then start insulin

Treatment

Phosphate Total body depletion in both DKA and HHS

May be normal or increased at presentation

Likely potassium, phosphate decreases with insulin therapy

RCTs have failed to show any clinical benefit to replacing

phosphate

Overcorrection of phosphate may lead to severe hypocalcemia

If serum phosphate concentration <1.0 mg/dl, judicial correction is

recommended to prevent cardiac/skeletal muscle weakness and

respiratory depression

To Be NaHCO3 Or Not To Be?

Bicarbonate Bicarbonate use in DKA remains controversial

If potassium is low on admission, the use of bicarbonate will drive K into the

cells further worsening hypokalemia

At a pH >7.0, insulin blocks lipolysis and resolves ketoacidosis without any

added bicarbonate

A prospective RCT in 21 patients failed to show help or harm in M&M when

the pH was 6.9 - 7.1

However, no prospective randomized studies using bicarbonate in DKA with

pH values <6.9

Given that severe acidosis may lead to a myriad of adverse vascular

effects, adult patients with a pH <6.9 should receive bicarbonate

Treatment

Insulin Therapy Do all patient with DKA need to be treated in the ICU on an insulin

drip?

RCT studies show benefit to treating uncomplicated DKA patients

out of the ICU with subcutaneous rapid-acting insulin. Initial injection of 0.2 units/kg followed by 0.1 unit/kg/hr or an initial

dose of 0.3 units/kg followed by 0.2 units/kg every 2 h until blood

glucose was <250 mg/dl

Then the insulin dose was decreased by half to 0.05 or 0.1 unit/kg,

respectively, and administered every 1 or 2 h until resolution of DKA.

Outcomes: No differences in LOS, total amount of insulin used until

resolution of hyperglycemia or ketoacidosis

No difference in the number of hypoglycemic events among

treatment groups.

The use of insulin analogs allowed treatment of DKA in out of the ICU or

in the emergency department

Avoiding intensive care admissions saved 30% in the cost of

hospitalization

Treatment

Insulin Therapy Unless DKA is uncomplicated and mild/moderate, regular insulin by

infusion is preferred

Bolus with regular insulin at 0.1 U/kg if K is > 3.3 mEq/l

Follow with a continuous infusion at 0.1U/kg/hr

Goal BG decrease of 50-75 mg/dl/hr with low dose insulin.

If BG does not decrease at that rate in the 1st hour, double the insulin

rate every hour until goal is met.

Decrease insulin rate to 0.05-0.1 U/kg/hr when BG reaches

200 mg/dl in DKA

300 mg/dl in HHS

This is the time to add dextrose to IVF to prevent

Hypoglycemia

Allow for acidosis to correct

Correct hyperosmolality

Mental status improvement

Treatment

Insulin - Phase I Initial goal is to stop

ketogenesis to prevent

worsening acidosis

Decrease

counterregulatory

hormone imbalance

Second goal is to correct

hyperglycemia

Goal 50-75 mg/dl/hr

Need to follow closely for

hypokalemia

Monitor AGMA or b-OHB

Follow until BG <250mg/dl,

then go to Phase II

Treatment

Insulin - Phase II Goal is to prevent

hypoglycemia

Correct hyperosmolality

Prevent rebound ketosis

Allow for adequate time

for clinical recovery

Treatment

Monitoring Hourly glucose until stable

Basic metabolic profile (Na, K, acidosis, AG, renal function)

Venous pH in DKA (similar to arterial pH by 0.03 units lower)

AGMA or b-OHB

Volume status, UOP, plasma osmolality

Hemodynamics

Complications of treatment

Clinical improvement (e.g. improved mentation, initiating diet)

Improvement in the underlying condition that caused

hyperglycemic crisis

Treatment

Measuring Ketones Ketonemia typically takes longer to clear than hyperglycemia.

Direct measurement of β-OHB in the blood is the preferred method

Nitroprusside method measures acetoacetic acid and acetone

β-OHB, the strongest and most prevalent acid in DKA

It is not measured by the nitroprusside method

During therapy, β-OHB is converted to acetoacetic acid, which

may lead the clinician to believe that ketosis has worsened

Allina measures β-OHB with an enzymatic assay

Serial measurements give an indication of response to treatment

Many experts recommend simply following the AG on the BMP

Treatment



Treatment

Overall Goals - HHS Stabilize patients hemodynamics

Improve tissue perfusion and correct hypovolemia

Gradual reduction in the serum glucose and plasma osmolarity

Correction of electrolyte imbalance

Prevent complications of overtreatment

Treat the disease process that precipitated the hyperglycemic crisis

Protocol for the management of adult patients with HHS *Diagnostic criteria: blood glucose >600 mg/dl, arterial pH >7.3, bicarbonate >15 mEq/l,

mild ketonuria or ketonemia, and effective serum osmolality >320 mOsm/kg H2O.

American Diabetes Association Dia Care 2004;27:s94-s102

Treatment – Allina Protocol for HHS

Treatment

Treatment

Insulin - Phase I Notice that potassium

replacement in the IVF

is up to the discretion

of the physician based

on labs.

This is similar to the

DKA protocol but

there is less guidance

on the HHS protocol

for KCL dosing based

on labs.

Begin Phase II when

BG reaches 250-300

mg/dl

Treatment

Treatment

Endpoints Criteria for resolution of DKA is glucose <200 mg/dl and 2 of the following (ADA

guidelines)

Serum bicarbonate ≥15 mEq/l

AG correction (usually <12 mEq/l)

Venous pH >7.3

When the patient is able to eat

Combination of subcutaneously administered short- or rapid-acting and

intermediate- or long-acting insulin should be started

Intravenous insulin infusion should be continued for 1–2 h after the

subcutaneous.

Hyperglycemia or recurrence of ketoacidosis may occur if insulin infusion is

discontinued too soon after giving subcutaneous insulin

Endpoints for HHS include

Improved mentation

Volume repletion

Taking PO diet

Complications

Hypoglycemia

Over aggressive insulin therapy

Hyperglycemia

Insufficient overlap of insulin infusion and subcutaneous insulin

Hypokalemia

Insufficient repletion or use of bicarbonate

Non-anion gap metabolic acidosis (hyperchloremic acidosis)

Not a true complication

Results from urinary excretion of keto anions and loss of

bicarb equivalent in exchange for retention of chloride

Also excessive chloride in IVF during volume expansion Pulmonary edema from aggressive IVF repletion

Complications

Cerebral Edema Both DKA and HHS patients are at risk

More common in children (has been reported in 20 y.o.’s)

Rare but mostly fatal

Signs and Symptoms include

Deterioration in the level of consciousness, lethargy, decreased

arousal, and headache

Seizures, incontinence, pupillary changes, bradycardia, and

respiratory arrest.

Deterioration may be rapid and symptoms progress as brain stem

herniates.

Mortality reaches 70% once the clinical symptoms (excluding lethargy

and behavioral changes)

Only 7–14% of patients recovering without permanent morbidity

Complications

Cerebral Edema May result from osmotically driven movement of water into the CNS when the

plasma osmolality decreases too rapidly.

One study in children with DKA used MRI to assess cerebral water diffusion and

cerebral vascular perfusion during treatment.

Cerebral edema was not a function of cerebral tissue edema but rather a

function of increased cerebral perfusion.

No data in adults and cannot clearly extrapolate from children

Preventive measures include (no matter if hyperosmolar or not),

Gradual replacement of sodium and water deficits by adding dextrose to

IVF when BG reaches 200 mg/dl in DKA and 300 mg/dl in HHS.

In HHS, a BG of 250–300 mg/dl should be maintained until hyperosmolarity

and mental status improves and the patient becomes clinically stable.

Max reduction in plasma osmolality of 3 mosmol/kg/hr (theoretical)

Summary

DKA and HHS are life threatening disorders of diabetes

Both present with profound hypovolemia from free water loss

DKA is associated with AGMA, but HHS is not

Both may have significant total body electrolyte depletion Initial goals of treatment

Stabilization of hemodynamics

Correction of life threatening electrolyte disorders

Volume repletion

Cessation of ketogenesis and correction AGMA (DKA)

Correction of BG

Avoidance of complications

Treat underlying precipitating factors for hyperglycemic crisis Education on prevention of hyperglycemic crisis

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