Transcript DIABETES 911: Diagnosing and Managing Diabetic Ketoacidosis

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Educational Objectives
At the conclusion of this activity, participants should be able
to demonstrate the ability to:
• Apply diagnostic criteria and recent clinical experience to
improve the recognition of hyperglycemic emergencies,
specifically DKA and HHS
• Evaluate the impact of the results from recent randomized
control trials on the prevalence, risk factors, and consequences
of antidiabetic therapy-induced hypoglycemia for the care of
T2DM patients
• Utilize guidelines and expert recommendations to manage
patients with diabetes who present with hypoglycemic and
hyperglycemic complication
Polling Question
Baseline Survey
Please rate your confidence in managing T2DM in patients
who present with a hypoglycemic emergency:
A. Expert
B. Very confident
C. Confident
D. Slightly confident
E. Not confident
Polling Question
Baseline Survey
Please rate your confidence in recognizing and managing a
hyperglycemic emergency such as DKA in your T2DM
patients:
A. Expert
B. Very confident
C. Confident
D. Slightly confident
E. Not confident
Polling Question
Baseline Survey
An 82-year-old man with a 33-year history of T2DM presents to the emergency
department with increasing agitation and slurred speech, which began about 2 hours
ago. He also says he has had a stomach virus for about a week. Medications include
metformin, along with meal-time and a once-daily insulin to manage his T2DM, and
an antihypertensive. The patient states he is compliant with his medications.
What do you consider?
A. TIA or stroke, quickly test for confirmation, and initiate tissue plasminogen
activator immediately since still within window for neurologic correction
B. Hypoglycemia since the patient’s oral intake has been greatly reduced, but the
patient continues to take antihyperglycemic medications as prescribed; measure
the patient’s glucose level
C. HHS due to dehydration from ongoing vomiting
D. Acute pancreatitis
Polling Question
Baseline Survey
A 56-year-old overweight woman presents with sudden-onset severe lethargy. Other
symptoms include nausea and vomiting and complaints of pain on urination. She was
diagnosed with pneumonia 2 weeks prior. The patient is also an alcoholic, but says
she has not had a drink in the past week. Medications include an SGLT-2 inhibitor,
beta-blocker and statin therapy, and aspirin. Her most recent HbA1c level was 7.4%,
blood pressure 135/78 mm/Hg. and cholesterol 188 mg/dL.
What do you consider?
A. Her breath smells sweet; measure the patient’s blood-alcohol level
B. Test for DKA because of the patient’s symptoms, infection status, and medical
history
C. Hydrate the patient and prescribe antibiotics for a UTI prior to discharge
D. Work-up the patient for an MI due to her medical history
Hyperglycemic Emergencies:
DKA and Hyperglycemic
Hyperosmolar
Hyperglycemic Crises
• DKA
– Most common hyperglycemic emergency in patients with type 1 and
type 2 diabetes
– DKA accounts for 4%-9% of all hospital discharge summaries among
patients with diabetes
– Annual average of ~135,000 hospitalizations for DKA in the United
States
– Most common mortality rate <2%
• HHS
– Hospitalization rate lower than DKA, approximately <1% of all primary
diabetic admissions
– Mortality rates ~15%
Kitabchi AE et al. Diabetes Care 2009;32:1335-1343.
DKA Incidence from NHDS
Number (in Thousands)
Growth in incidence since 1980 (primary diagnosis)
Year
2006 Incidence: 134,663 episodes
CDC/NCHS, National Hospital Discharge Survey (NHDS). www.cdc.gov/nchs/about/major/hdasd/nhds.htm. Accessed: 12/2011.
Type 1 Diabetes Accounts for the Majority of
Primary* DKA Episodes
Primary DKA Episodes
• 34% of episodes are T2D
~46,000 cases
134,633 (2006
T1D - Children
18%
T1D - Adults
48%
T2D
34%
66%
• Longer hospital stays with T2D
4.2 days with T2D vs average
of 3.5 days with T1D
34%
T2D accounts for 34% of primary DKA cases and
more than 50% of secondary causes
*Primary DKA: DKA with no known precipitating cause vs secondary DKA: DKA caused by a precipitating cause
(infection, heart attack, etc.)
National Hospital Discharge Survey (NHDS); 2006.
DKA-related Mortality Rates Have Been in
Decline Since the 90s
Mortality due to DKA (per annum)
DKA Death Rates per 100,000 pop
Crude
Overall 2006 mortality rate for DKA: 0.41%
Centers for Disease Control and Prevention. www.cdc.gov/diabetes/statistics/complications_national.htm.
Age Adjusted
Pathogenesis of Hyperglycemic Crises
Hyperglycemia
osmotic diuresis
Dehydration
LipolysisIncreased FFA
Increased
glucose
production
Insulin
Deficiency
Counterregulatory
Hormones
Decreased
glucose
uptake
Increased
ketogenesis
Metabolic
acidosis
Electrolyte
abnormalities
Hypertonicity
Pasquel FJ, Umpierrez GE. DKA & HHS Pathogenesis; In: DeGroot Endocrinology Textbook. 2014.
Diagnostic Criteria for DKA and HHS
DKA
Plasma glucose (mg/dl)
pH
Bicarbonate (mEq/l)
Urine ketones*
Serum ketones*
Effective serum Osmol
(mOsm/kg)†
Alteration in sensoria
or mental obtundation
Mild
Moderate
Severe
HHS
>250
7.25-7.3
15-18
positive
positive
variable
>250
7.0-<7.24
10- <15
positive
positive
variable
>250
<7.0
<10
positive
positive
variable
> 600
>7.30
> 15
small
small
>320
alert
alert/
drowsy
stupor/
coma
stupor/
coma
* Nitroprusside reaction method
† Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18
Kitabchi AE et al. Diabetes Care. 2001;24:131-153.
Useful Formulas for the Evaluation of DKA
1. Calculation of anion gap (AG):
AG = [Na+] – [Cl- + HCO3-] (normal <12 mEq/L)
2. Total and effective serum osmolality:
Total = 2[Na+] + glucose (mg/dL) + BUN (mg/dL)
18
2.8
(normal 275-295 mmol/L)
Effective = 2[Na+] + glucose (mg/dL)
18
Case Study
18-year-old African American male admitted with a 3 week hx. of polyuria,
polydipsia, and 20-lb weight loss. One day prior to admission, developed
nausea, vomiting, and diffuse abdominal pain.
Physical exam: 100/80 mmHg, HR: 112/min, RR: 24/min
Weight: 160 lb, BMI: 22 kg/m2
Lethargic with Kussmaul breathing; otherwise, PE was WNL; no endorgan complications of DM
14.4
12.4
315k
44%
130 92 22
636
5.4 12 1.1
Venous pH: 7.18
B-OH-B: 8.7 MM
U/A: + ketones
HbA1c: 13.2%
Precipitating Causes for DKA and HHS
Umpierrez GE et al. Arch Intern Med. 1997;157:669-675.
Euglycemic Diabetic Ketoacidosis
A Potential Complication of Treatment with
Sodium-Glucose Co-transporter 2 Inhibition
Peters AL et al. Diabetes Care. 2015;38:1687-1693.
SGLT2-I and Risk of Ketoacidosis in T1D
Potential Mechanisms
Taylor SI et al. J Clin Endocrinol Metab. 2015;100:2849-2852.
Polling Question
Baseline Survey
Which of the following is not a sign/symptom of DKA?
A. Nausea and/or vomiting
B. Decreased urine output
C. Tachycardia
D. Acetone breath
Clinical Presentation of DKA
Symptoms
Signs
• Polydipsia
• Hypothermia
• Polyuria
• Tachycardia
• Weakness
• Tachypnea
• Weight loss
• Kussmaul breathing
• Nausea
• Ileus
• Vomiting
• Acetone breath
• Abdominal pain
• Altered sensorium
The onset of DKA is usually relative short,
ranging from hours to a day or two.
Mental Status at Presentation in DKA
Mental Status and Osmolality
Serum Osmolality (mOsm/L)
Level of Consciousness
Alert: <300 mOsm/L
Stupor or coma: ≥320 mOsm/L
Umpierrez GE et al. Arch Intern Med. 1997;157:669-675.
Polling Question
Baseline Survey
Laboratory studies to confirm a diagnosis of DKA include:
A. CMP, urinalysis, serum ketones
B. Venous or arterial pH
C. MRI in patients with altered mental status
D. A and B
E. A and C
CMP = comprehensive metabolic panel
Initial Laboratory Studies
• Immediate determination of blood glucose by finger stick and
serum ketones (B-OH-B) or urinary ketones
• Laboratory studies:
– Venous or arterial pH (ABG’ss)
– CBC with differential
– CMP (glucose, electrolytes, bicarbonate, PO4, Mg, BUN, creatinine)
– Serum ketones
– Urinalysis
– Bacterial cultures*
– Cardiac enzymes*
* If clinically indicated
Kitabchi AE et al. Diabetes Care. 2009;32:1335-1343.
Blood -OHB Levels in
DKA Detection and Treatment
• -OHB concentrations >0.5 mmol/L are considered
“abnormal”
• Patients presenting with DKA can range between 3-12
mmol/L -OHB
– -OHB ≤1.0 mmol/L — treat blood glucose level appropriately
– -OHB 1.1 to 3.0 mmol/L — insulin and fluids; retest in 1 hour
and, if no improvement, contact physician
– -OHB >3.0 mmol/L — insulin, fluids, urgent medical attention
Wallace TM et al. Q J Med. 2004;97:773-780.
Guerci B et al. Diabetes Metab. 2005;31:401-406.
Managing Hyperglycemic
Emergencies
Management of DKA
• Replacement of fluid losses
• Correction of hyperglycemia/metabolic acidosis
• Replacement of electrolyte 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
Normal or high
serum sodium
Low serum
sodium
½ NS at 250-500
mL/h
NS at
250-500 mL/h
Glucose <250 mg/dL
Change to D5% NS or 1/2NS
Kitabchi AE et al. Diabetes Care. 2009;32:1335-1343.
Intravenous Insulin Therapy in DKA
I.V. Bolus: 0.1 U/kg body Wgt
I.V. drip: 0.1 U/kg/h body Wgt
Glucose <250 mg/dL
IV drip: 0.05 – 0.1 U/kg/h
Until resolution of ketoacidosis
Studies Comparing SC Injections of Lispro vs
Continuous Infusion of Regular insulin in DKA
Vincent M, Nobécourt E. Diabetes Metab. 2013;39:299-305.
Potassium Replacement and Bicarbonate
Therapy in DKA
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
Bicarbonate Therapy
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
Kitabchi AE et al. Diabetes Care. 2009;32:1335-1343.
Management after Resolution of DKA
• Patients with DKA should be treated with IV insulin or
rapid-acting SC insulin until ketoacidosis is resolved
• Criteria for resolution of DKA
– BG ≤250 mg/dL
– Serum bicarbonate level ≥18 mEq/L
– Venous pH ≥7.3
– (B-OH-B, anion gap)
Transition to Subcutaneous Insulin after
Resolution of DKA
After Initial IV or SQ therapy
(pH >7.3, HCO3 >18, AG < 14)
Give SQ 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 / detemir
• Rapid-acting insulin analogs (lispro, aspart, glulisine)
• Analogs results in similar BG control, but less hypoglycemia
than human insulin (15% vs 41%)
Use of ‘early’ glargine insulin during treatment of DKA may prevent
rebound hyperglycemia during insulin infusion
Draznin et al. JCEM. 2012;97:3132-3137.
Umpierrez GE et al. Diabetes Care. 2009;32:1164-1169.
Summary
• DKA is a common, serious, and expensive complication in
patients with type 1 and type 2 diabetes
• Prevention of metabolic decompensation through patient
education, strict surveillance of glucose homeostasis, and
aggressive diabetes management might reduce the high
morbidity and mortality
• Recent treatment protocols have improved clinical
outcomes in patients with DKA
Hypoglycemic Emergencies:
Hypoglycemia
Definitions: Hypoglycemia
Hypoglycemia: “all episodes of abnormally low plasma
glucose concentration that expose the individual to potential
harm”
1. Severe hypoglycemia: An event requiring assistance of
another person to actively administer carbohydrate, glucagon,
or other resuscitative actions (definitions vary)
2. Documented symptomatic hypoglycemia: An event during
which typical symptoms of hypoglycemia are accompanied by
a low measured BG concentration
International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591.
Definitions: Hypoglycemia (cont)
3. Asymptomatic hypoglycemia: An event not accompanied by
typical symptoms of hypoglycemia, but with a measured low BG
concentration
4. Probable symptomatic hypoglycemia: An event during which
symptoms typical of hypoglycemia are not accompanied by a BG
determination but that are presumed to be caused by a low plasma
glucose concentration
5. Relative (or pseudo-) hypoglycemia: An event during which the
person with diabetes reports any of the typical symptoms of
hypoglycemia and interprets those as indicative of hypoglycemia
with a measured BG concentration that is not low
International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591.
Rates of Hypoglycemia
• 30%-40% of individuals with T1D have 1-3 episodes of
severe hypoglycemia/year
• Rates in insulin-treated T2D ~1/3rd as common
• Rates of mild hypoglycemia ~50 times more common
• Use of SUs, a glinide, or insulin and increased duration of
diabetes increase the risk for hypoglycemia of any kind
International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591.
Hypoglycemia: Impact on Healthcare
Resources
• Analysis of healthcare resource use during severe hypoglycemia
events (requiring external assistance) from 15 trials of T1 and T2DM
using insulin (degludec; degludec/aspart; glargine, biphasic aspart,
detemir)
• 536 severe hypoglycemia events
– 29.3% involved an ambulance/emergency team
– 11.9% led to hospital/emergency room attendance of ≤24 hours
– 6.7% required hospital admission (>24 hours)
• Those receiving basal-oral therapy had greater risk for hospitalization (47.6%)
• Once a severe episode occurred, the tendency to utilize healthcare
resources was higher in T2 vs T1DM
Heller SR et al. Diabet Med. 2015; doi: 10.1111/dme.12844. [Epub ahead of print].
Economic Impact of Severe and Non-severe
Hypoglycemia Episodes
• Review of 14 studies on T1 and T2DM
• Direct cost associated per hypoglycemia episodes requiring
assistance from a healthcare practitioner: $116
Indirect costs associated with:
T1DM
T2DM
severe hypoglycemia requiring
non-medical assistance
$242
$579
severe hypoglycemia requiring
medical assistance
$160
$176
non-severe hypoglycemia
$11
$11
Foos V et al. J Med Econ. 2015;18:420-432.
Case 1: Hypoglycemia
• SV is a 58-year-old female with a 30-year history of type 1
diabetes. She has diabetic retinopathy, but no other
complications.
• She is very physically active working in a preschool.
• She also trains for running 10 Ks and runs 5 days per week.
• Recently she has been having episodes of severe
hypoglycemia, twice overnight when her husband treated her
with glucagon and once while at school when paramedics had
to be called.
• Her target A1c is 6%.
Case 1: Hypoglycemia (cont)
• On questioning, her insulin dosing has not changed.
• However, she no longer senses her lows regularly.
• Currently, she is taking 10 units of long-acting insulin at
bedtime and gives 1 unit for every 20 grams of carbs and a
correction (or sensitivity) factor of 50.
• Her CGM tracing follows.
• What would you recommend and why?
Case 1: Hypoglycemia (cont)
Polling Question
Baseline Survey
Which of the following is true of severe hypoglycemia:
A. It is associated with an increased risk for mortality in
people with type 2 diabetes
B. It is less common in people with type 1 diabetes
C. It is strictly defined as hypoglycemia causing a seizure,
loss of consciousness, or a coma
D. It directly causes an increase in mortality in people with
type 1 diabetes
Intensive Control Increases the Risk of
Severe Hypoglycemia
TABLE – Effects of intensive, compared with conventional, glycemic therapy of type 2
diabetes: meta-analysis of 12 randomized controlled trails (20)
Effect (no. of randomized
controlled trials)
Relative
risk
95% CI (P)
No. of
patients
All-cause mortality
1.02
0.91-1.13 (0.74)
28,359
Cardiovascular mortality (12)
1.11
0.92-1.35 (0.27)
28,359
Microvascular complications (3)
0.88
0.78-0.97 (0.01)
25,600
Severe hypoglycemia (9)
2.39
1.71-3.34 (0.001)
27,844
International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591.
Risk of CV Events and Death in Patients With
vs Without Severe Hypoglycemia: (ADVANCE)
Study inclusion criteria: T2DM + major vascular disease or ≥1 CV risk factor
Macrovascular events
3.45 (2.34-5.08); P<0.001
Death—any cause
3.30 (2.31-4.72); P<0.001
Death—CV cause
3.78 (2.34-6.11); P<0.001
Death—non-CV cause
2.86 (1.67-4.90); P<0.001
Decreased
risk
Adjusted Hazard Ratio
(95% CI)
Increased
risk
Zoungas S et al; ADVANCE Collaborative Group. N Engl J Med. 2010;363:1410-1418.
Summary of ACCORD, ADVANCE, VADT
Severe Hypoglycemia and Mortality Risk
ACCORD
ADVANCE
VADT
Severe Hypo
Intensive
Standard
Intensive
Standard
Intensive
Standard
(%/ year)
3.1%
1.1%
0.7%
0.4%
12.0%
4.0%
Annual mortality
5.0%
4.9%
4.0%
2.8%
3.0%
No hypo
1+ Hypo
2.0%
1.0%
1.3%
1.0%
0.0%
Intensive
Standard
Bonds DE et al. BMJ. 2010;340:b4909.
Polling Question
Baseline Survey
Treatment of hypoglycemia associated autonomic failure
(HAAF) involves:
A. Reducing the total daily insulin dose
B. Hypoglycemia avoidance for 1-2 months
C. Hypoglycemia avoidance for 2-3 weeks
D. Reducing bolus insulin dose
Hypoglycemia Associated Autonomic
Failure (HAAF)
• Defined as attenuation of the sympathoadrenal response to
hypoglycemia that leads to impaired awareness of hypoglycemia,
which increases the risk for severe hypoglycemia
• It is often induced by antecedent hypoglycemia
• The diagnosis is generally made clinically, based on the patient’s
subjective sense of a reduction in symptoms of hypoglycemia
• This impaired awareness is reversible by 2-3 weeks of
hypoglycemia avoidance
• Educational programs exist to help patients restore their sense of
lows
Little SA et al. Diabetes Metab Res Rev. 2014;30:175-190.
Hypoglycemia Associated Autonomic
Failure (HAAF)
Cryer PE. Diabetes. 2005;54:3592-3601.
Management of
Hypoglycemic Emergencies
Recommendations of the International
Hypoglycemia Study Group
People with diabetes treated with a sulfonylurea, a glinide, or
insulin should:
• Be educated about hypoglycemia
• Treat SMPG levels ≤70 mg/dL (3.9 mmol/L) to avoid
progression to clinical iatrogenic hypoglycemia
• Regularly be queried about hypoglycemia, including the
glucose level at which symptoms develop; those developing
symptoms at a glucose level 55 mg/dL (3.0 mmol/L) should be
considered at risk
SMPG = self-monitored plasma glucose
International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591.
Recommendations of the International
Hypoglycemia Study Group (cont)
When hypoglycemia becomes a problem, the diabetes healthcare
provider should:
• Consider each conventional risk factor and those indicative of compromised
glucose counter-regulation
• Avoid sulfonylureas (and glinides) if possible, using insulin analogs when insulin is
required, and consider using CSII, CGM, and CSII + CGM in selected patients
• Provide structured education and, in patients with impaired awareness of
hypoglycemia, prescribe short-term scrupulous avoidance of hypoglycemia
• Seek to achieve the lowest A1c level that does not cause severe hypoglycemia
and preserves awareness of hypoglycemia with an acceptable number of lessthan-severe episodes of hypoglycemia, provided that benefit from glycemic control
can be anticipated
International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591.
Rule of 15 for Treating Hypoglycemia
Guide for Patients
• If BG is 50-70 mg/dL – take 15 grams of simple sugar, such as 4 oz
of juice or 4 glucose tablets.
• Then eat a snack with 15 grams of carbohydrates and a protein. You
can use a carton of yogurt; an apple with cheese; 6 to 7 crackers
with cheese or peanut butter, a KindPlus Bar. You must combine
these additional carbohydrates with a protein. It is important to drink
lots of water when you are low.
• If less than 50 mg/dL – take 30 grams of simple sugar, such as 8 oz
of juice or 8 glucose tablets. Then use the same instructions as
above for your snack. Drink lots of water.
Medline Plus. https://www.nlm.nih.gov/medlineplus/ency/imagepages/19815.htm. Accessed: 12/5/2015.
Rule of 15 for Treating Hypoglycemia
Guide for Patients
• Recheck blood sugar again in 15 minutes. If you are still 70 mg/dL or
less, then repeat the above and recheck in 15 minutes.
• When you are low, your liver also produces glucose. Your glucose
will go up sooner than you will feel better. You must not eat TOO
much when you are treating a low. If you prepare some of these
snacks ahead of time, so they are handy, you will have better control
when you are eating.
• If you eat more than the 30-45 grams of carbohydrates, you will
need to take insulin aspart/insulin lispro/insulin glulisine to cover
these carbs, or your glucose will go very high.
Novolog (insulin aspart), Humalog (insulin lispro), Apidra (insulin glulisine)
Medline Plus. https://www.nlm.nih.gov/medlineplus/ency/imagepages/19815.htm. Accessed: 12/5/2015.
Conclusions
• Hypoglycemia is common in people with diabetes treated
with sulfonylurea agents, glinides, and insulin
• Mild hypoglycemia is much more common than severe
hypoglycemia
• Severe hypoglycemia is associated with an increased risk
of mortality
• HAAF increases the risk for severe hypoglycemia
• Approaches to prevent and treat hypoglycemia need to be
employed
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