HYPERGLYCEMIC

EMERGENCIES

Boston University School of Medicine

July, 2013
Marie McDonnell, MD
marie.mcdonnell@bmc.org
 Outline
• Definitions: DKA , HHS and HK
– Why do they require ICU in most cases? (and when don’t they)

• Relevant Epidemiology

• Simple overview of normal insulin physiology and severe insulin

deficiency
– What is going on?

• Clinical features of acute insulin deficiency

• Hyperglycemic crisis: diagnosis and management

– Big picture: Treat hypovolemia agressively while avoiding
iatrogenic complications of therapy
 Case
• 28 yo man with no prior medical history
• Polyuria, polydipsia for 1 month, severe in last
week
• Subjective fever, flu-like illness for one week
• Drinking fluids to exhaustion – water, juice,
coca cola
• Unable to easily wake patient one morning –
EMS called
 Data
• Awake but lethargic on admission to ER
• BP 92/50, pulse 128, T 99, 90 kg
• Dry membranes Arterial pH= 7.29
• Stat labs: Urine ketones = 2+
Plasma ketones =
132 92 52
1478
Moderate
Phos = 0.9
4.5 14 3.2
Mg = 2.0
• Anion gap = 26
WBC = 10, 000, 80%
lymph
HCT = 44
 Definitions
Cause of Death in Adults: Hypokalemic
• DKA Cardiac Arrest (rare)
– Blood glucose >250 mg/dl
– Metabolic acidosis with ph <7.3 or serum bicarbonate <15mM
• “MILD DKA” is Bicarb 15-18
• “MODERATE DKA” is Bicarb 15 or above with ph >7.0
• “SEVERE DKA” is Bicarb <15 with ph 7.0 or below
• “EARLY DKA” is any Bicarb deficit in the setting of insulin deficiency, a non-official
term
– Ketonemia
• note: most patients with ketonemia have + urine ketones, or ketonuria

• HHS Cause of Death in Adults: Underlying

– Blood glucose >600mg/dl illness (not uncommon)
– arterial ph>7.3
– bicarbonate >15
– effective serum osmolality >320 mOsm/kg H20
– mild ketonuria or ketonemia may be present
 Hyperosmolar Ketoacidosis
• DKA and HHS occur simultaneously
• Worse prognosis
• Implication:
– Much more severe water deficit
– Much more severe insulin deficiency
– Generally more ill overall (underlying illness)
– Requires more aggressive therapies, and hence increased
“iatrogenic” complications
– Identifying this condition is powerful
 Hyperosmolality
• Causes progressive depressed mental function as
osmolality rises.
• If serum total osmolality is <340-350 mOsm/kg,
or effective osmolality <320 (doesn’t include
urea), stupor or coma should suggest another
cause
• Correction yields a very predictable improvement
in mental status. If you don’t see this...?LP, toxic
ingestion, etc.
 Make the correct diagnosis
• EO is the same as tonicity and excludes the
BUN ...
= 2 ( sodium + potassium) + glucose/18,
normal = 280-90

Patient’s effective osm:

= 2 ( 132 + 4.5) + 1478/18 =
273+82 = 355
 Epidemiology
• DKA prevalence is rising
– Since 1996, 50% increase in No. diagnoses in the US
– HHS (when diagnosed properly) is still much less common

• DKA is still the most common cause of death in

children and adolescents with type 1 diabetes
– But death from DKA has declined substantially in last 20-40
years

• Mortality:
– HHS+DKA >> HHS>>>>DKA
• 10-35% >> 5-20% >>>> 1%
• HHS+DKA is often called Hyperosmolar Ketoacidosis (HK)
 Epidemiology
• Initial presentation of type 1 diabetes
– Less and less common. Office diagnoses increasing
• Negrato CA. Temporal changes in the diagnosis of type 1
diabetes by diabetic ketoacidosis in Brazil: A nationwide
survery. Diabet Med 2012 Jan.

• Initial presentation of type 2 diabetes

– Overall represents a larger proportion of presentations
given high prevalence of this disease
– More common in patients of Afro-Caribbean ancestry.
• Mauvis-Jarvis F. Ketosis-prone type 2 diabetes in patients of
Sub-Saharan African origin. Diabetes 2004) (Balasubramanyam
A. New profiles of diabetic ketoacidosis. Type 1 vs. type 2
diabetes and the effect of ethnicity. Arch Intern Med 1999
 Epidemiology: Why?
• Insulin non-adherence: Most likely reason in all studies
– 68% of patients in a large, urban, inner city US location

• Why does insulin non-adherence happen?

– Financial constraint, feeling unwell, being away from insulin
supply and trying to extend the insulin supply. Over 30% of
patients give no reason for discontinuation. However, factors
such as alcohol and substance abuse, younger age at the time of
diagnosis, depression, longer duration of diabetes and
homelessness contribute substantially to cases of recurrent DKA
• Randall L. Recurrent diabetic ketoacidosis in inner city minority patients:
behavioral, socio-economic, and psychosocial factors. Diabetes Care. 2011)

• DKA may be more common in young immigrants, and of

these, girls are 20% more likely to present compared with
boys.
• Fritsch M, Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes.
 HHS
• Mortality 10-30% depending on institution
• Depends on complications:
– In adults, documented major complications include thrombosis, rhabdomyolysis, renal
failure, and irreversible cardiac arrhythmias

• Younger patients have higher mortality in some studies

• Unique syndrome of hyperthermia, rhabdomyolysis and HHS in Young AA

adults reported, >75% mortality, survivors with evidence of CPM

• Yale report 2007, pts aged 10 to 30 yo

– Out of 629 cases with glucose >600, only 10 met criteria for pure HHS (DKA-HHS
excluded)
– 10% mortality
– Deaths limited those with unreversed shock over the first 24 hours of admission and
who received <40 ml/kg of intravenous fluids over the first 6 hours of treatment.
• Children’s hospital: advocating aggressive volume resuscitation
– http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842888/
 Blood glucose
>250 mg/dl

Altered Mental Status

Electrolyte
Marked disturbances
hypovolemia

+/- Acidosis/ Acidemia

Underlying illness:
Infection, MI, Stroke
 Type 1 DM &
DKA Insulin
Production:
Suboptimal
Insulin
Production:
Severely impaired

Insulin Action:
Insulin Action:
Severely impaired
Normal or
suboptimal

Type 2 DM &
HHS
 HHS
DKA
The diabetes landscape is changing

DKA?
HHS?
INSULIN ACTION: Cellular
level
 Overview of Insulin Function
INSULIN

MUSCLE LIVER ADIPOCYTE

Transports Forms
inhibits glucose
glucose, triglycerides
production; allows
amino acids glycogen storage to store fat;
and ions inhibits
lipolysis
(K &phos)
 Insulin: the “fed state” hormone
INSULIN
glucagon Glucose and
amino acids are
actively
transported into
Hormone- cells; normal K
Sensitive Lipase and Phos
transport
Inhibited

Insulin inhibits glycogen

Lipolysis is breakdown
inhibited;
triglycerides are
formed for fat Insulin increases
storage and fatty malonyl coA, inhibiting
acids are not CPT-1, and fatty acids
released are unable to enter
mitochondria for
oxidation
 INSULIN

MUSCLE LIVER ADIPOCYTE

Can’t use More
glucose & Aas glucose is Lipolysis goes
(starvation); made; unchecked, fatty
K & Phos not acids fill the
fatty acids bloodstream…
normally
oxidized for
transported
ATP
Fatty Acid Oxidation Overload

Product: Acetyl CoA, which has to enter TCA

cycle to produce ATP

TCA cycle can only do so much

Enzymes become saturated

What happens to TCA cycle “overflow”?

=Ketone bodies
 Overwhelmed TCA cycle

Acetoacetyl-Coa
So many ketone bodies with
nowhere to go…
…Acidemia impairs the
ability of hemoglobin to
bind oxygen
 GH, EPINEPHRINE,
INSULIN CORTISOL

GLUCAGON
Overwhelming FA
oxidation takes
place…acetyl Coa
Hormone- overwhelms the
Sensitive Lipase TCA cycle & Ketone
Activated Bodies are released
into the blood

LIPOLYSIS GOES
UNCHECKED…
TRIGLYCERIDES
BREAK
DOWN TO FFAs… Increased glucagon/low insulin
decreases malonyl coA, allows
CPT-1 to transport FFAs into
Liver mitochondria for oxidation
How to measure metabolic acidosis?
• Blood pH: measures acidemia

• “Anion Gap”
– Normal extracellular anions =
• Measurable: Cl- and HCO3-
• Unmeasurable: proteins The
– Normal measureable extracellular cation = normal
• Na++ “Gap”

– Electric “balance”
• Anions must =Cations

– Na++ - [Cl- + HCO3-] – (unmeasurable anions) = 0

 “Polyuria” in Hyperglycemic Crisis
• Glycosuria
– Glucose delivery to nephron exceeds ability of kidney to reabsorb glucose
– Excess osmoles of glucose are excreted, along with water and sodium
– The “threshold” probably varies in the population, but is around 220
mg/dl, and with rising glucose excretion increases
Rave K, et al. Nephrol Dial Transplant. 2006

• Renal Concentrating Defect

– Many patients with diabetes have a defective ability to concentrate urine
– This is likely related to glycosuria progressing to “renal wash out” where
the normal electrolyte gradients are lost
– End result: more renal water loss
Spira, et al. Am J Kidney Dis. 1997
PATIENT WITH TYPE 2 DM PATIENT WITH TYPE I DM

SEVERE ILLNESS + LIMITED MILD TO SEVERE ILLNESS

ACCESS TO WATER +/- MISSED INSULIN DOSES

Cortisol,
Cortisol, Epi, Epi,
Norepi... HYPERGLYCEMIA
>220 MG/DL
Norepi, GH
GLUCAGON: INSULIN GLUCAGON: INSULIN

GLUCOSE GLUCOSURIA GLUCOSE

SEVERE DEHYDRATION DEHYDRATION LIPOLYSIS

DEC. PO INTAKE KETOACIDOSIS

HYPEROSMOLALITY &
CONFUSION
1-4 days
2-6 weeks
TO HOSPITAL
Insulin, Potassium and H+ in DKA

H+
K+
 Degree of Dehydration
HHS DKA

Water deficit
Water deficit on on avg. 3-5L
avg. 9L
 Mortality
Q: Which has a higher associated mortality
DKA or HHS?

A: HHS
Recent rates are approximately 15%, whereas
in DKA, it’s <5%
 Diabetic Ketoacidosis:
extreme insulin deficiency
 DKA:
clinical presentation
Polyuria, polydipsia
Fatigue
Nausea, vomiting
Abdominal pain
Increased respiratory rate/dyspnea
Dry membranes
+ ketones on breath (sweet) – unreliable sign
Infection +/- fever
 DKA… and?
• Common complicating factors
– Pancreatitis
– Idiopathic “benign” Amylasemia/Lipasemia
– Toxic Ingestion/Withdrawal
– Renal Dysfunction
– Other severe “stressor”: MI, PE
– A second cause of acidosis (above, + others…)
• Lactic acidosis was seen in 68% of adult pts with DKA (lactate
>2.5 mmol/L) and 40% had lactate >4. It may not be associated
with mortality or other relevant factors (LOS). Correlates with
glucose level, so related to hypoperfusion AND altered glucose
metabolism?
– Journal of Critical Care. BI Deaconess, April 2012
 Suspected DKA –
initial assessment
• Airway, Breathing, Circulation
• IV access:
– Most require central venous line due to severe
hypovolemia, for frequent lab draws, and
multiple drips
– Arterial line not necessary in most cases
– Venous blood gas measurements are reliably
0.03 Ph points higher than arterial..get both at
the same time initially and compare
 Suspected DKA –
initial assessment
Laboratory:
– ABG with stat electrolytes (include phos and Ca)
– Chem 7 for Anion Gap (normal is <10)
– CBC with differential
– Urine analysis, micro, culture
– Ecg, consider troponin
– Serum and urine toxicology screen
– Serum and calculated osmolality
– Serum Acetone
– Lipids
– Amylase/lipase
 DKA:
CLINICAL
MANAGEMENT
DKA pathophysiology

•Treatment is
crystal clear

X
X

•But what is
the best
approach?
 Insulin effect can be slow
• Ketosis causes insulin resistance
– But insulin stops ketosis (so you have to give a LOT at first)
– Need to stop the ketosis before insulin will work well

• You know insulin is working if glucose starts to fall

– Glucose transport is an accurate surrogate marker of insulin
receptor overall function (and the only one we really have)

• When glucose is falling, ketosis is resolving

– At this point, risk of hypoglycemia is high given rapid
improvement in glucose transportation. This likely involves
improved GLUT4 translocation as ketosis resolves
Insulin, Potassium and H+ in DKA

H+
K+
 Insulin, Potassium and H+

NaHCO3 Insulin
(and
other
measures
to correct
acidosis) H+
K+

In HSS or DKA, never give insulin or bicarbonate

until you know the potassium level…always start
fluids first...
Start Fluids First!
 Priority 1: Reperfusion
• BP 92/50, pulse 128
• Renal function: 52/3.2
• Urine output: 50cc in 2 hours
• What is the fluid of choice?

0.9% NORMAL SALINE

RATE: WIDE OPEN to start,
reduce as perfusion improves
 Complete Initial Evaluation. Start 1 Liter of 0.9%
NaCl/hour initially (15-20ml/kg/hr)
IV FLUIDS INSULIN POTASSIUM
Use 0.9% saline 1L/hr in
all cases to restore plasma
volume: 1) urine output at
least 30cc/hour, 2) mental
status improved, 3) blood
pressure and pulse
normalizing
To continue hydration, use
serum Na as a guide:
Na high - 0.45% NaCL
Na normal - 0.45% NaCl
Na low - 0.9% NaCl
When serum glucose
reaches 250, change fluid
to d51/2 NS and continue
with insulin drip, keep
glucose 150-200 mg/dl
until anion gap closed
 Mortality in DKA
• HYPOKALEMIC CARDIAC ARREST

= giving insulin before knowing K

and/or poor monitoring

• Cerebral Edema
• Pulmonary Edema
 Complete Initial Evaluation. Start 1 Liter of 0.9%
NaCl/hour initially (15-20ml/kg/hr)
IV FLUIDS INSULIN POTASSIUM
Use 0.9% saline 1L/hr in
all cases to restore plasma If serum K+ is <3.3 mEq/L
volume: 1) urine output at
least 30cc/hour, 2) mental Hold insulin and give
status improved, 3) blood 40meq K+ until K>3.3
pressure and pulse
normalizing If serum K >5.5, check K
To continue hydration, use q2hours
serum Na as a guide:
If K >3.3,<5.5 give 20-30
Na high - 0.45% NaCL meq in each liter IVF to
Na normal - 0.45% NaCl keep K 4-5

Na low - 0.9% NaCl

Check chem7 q2-4hr until
When serum glucose
stable.
reaches 250, change fluid
to d51/2 NS and continue
with insulin drip, keep
glucose 150-200 mg/dl
until anion gap closed
 Complete Initial Evaluation. Start 1 Liter of 0.9%
NaCl/hour initially (15-20ml/kg/hr)
IV FLUIDS INSULIN POTASSIUM
Use 0.9% saline 1L/hr in
all cases to restore plasma Regular, 0.15u/kg as
IV bolus *** sc/IM if If serum K+ is <3.3 mEq/L
volume: 1) urine output at
least 30cc/hour, 2) mental mild DKA Hold insulin and give
status improved, 3) blood 40meq K+ until K>3.3
pressure and pulse
normalizing 0.1 u/kg/h IV
infusion If serum K >5.5, check K
To continue hydration, use q2hours
serum Na as a guide:
If K >3.3,<5.5 give 20-30
Na high - 0.45% NaCL Check serum glucose meq in each liter IVF to
Na normal - 0.45% NaCl hourly, if doesn’t fall by keep K 4-5
50-70 in first hour, then
Na low - 0.9% NaCl double hourly insulin
dose until glucose falls Check chem7 q2-4hr until
When serum glucose
by 50-70 mg/dl stable.
reaches 250, change fluid
to d51/2 NS and continue
with insulin drip, keep
glucose 150-200 mg/dl
until anion gap closed
Add screen shot
 Coexisting Illness

• Often serious and “masked”

• Patients with Diabetes have more infections and more serious

infections than the general population

• After you start fluids, the search begins for underlying disease…
What about the hyperosmolality?

Correction of hyperosmolality
 Hyperosmolality
• No RCTs on rate of correction

• Expert opinion: avoid lowering Effective

Osmolality by more than 3 mOsm/kg H2O in one
hour
• Epidemiologic data suggests that cerebral edema
during HHS therapy is RARE
– Most patients are elderly, and have more “space up there”
– Hypernatremia from dehydration is protective by
stabilizing the effective osmolality while glucose drops
 Back to case: Day 2-3
• EO = 292
• Serum C02 is 22
• Ph is 7.4 on VBG
• Anion gap is 8
• 1+ Ketones in urine
• Glucose 150-200 on insulin infusion at 2
units/hour
• Wants to eat
 Out of the woods…and the ICUt
• The presence or absence of acetone in the blood or urine
does not indicate how the patient is doing and how
successful your treatment is

• Acetone in the urine can persist for days after acidosis is

resolved, depending on the glomerular filtration rate
(renal function)

The anion gap and serum bicarbonate recovery (often just

partial) are the best ways to decide that the DKA is
resolved
 Out of the woods…and the ICU
• Avoid stopping an insulin infusion without
overlap, or “transition,” subcutaneous
insulin

• Remember that 1 unit/hour is a still

substantial insulin requirement…
 Transition pitfalls

1. Inadequate overlap of subcutaneous insulin with IV

insulin

2. DKA not yet adequately resolved (bicarb >17 and

volume resuscitated)

3. Inadequate dosing of subcutaneous insulin

4. Initial insulin program does not take into account

expected nutritional plan
 Prevention
• Outpatient “coaching” with diabetes nurse
educator
• Sick day guidelines – review on a regular basis
• Inpatient diabetes education
• Early outpatient treatment of infections in patients
with Diabetes
• Know about medications that can impair glucose
control
=
Questions?
Never stop the insulin drip without
moderate or long-acting
subcutaneous insulin “on board”
 Always transition from IV to
subcutaneous insulin
• When: glucose is in goal range and on a stable insulin
rate (+/- 1 unit/ hour), during the past 4-6 hours
• How:
– Step 1: order a diet
– Step 2: Calculate requirement (try 0.8 units/kg/day after
hyperglycemic crisis – works well. If persistent renal
insufficiency, use 0.5-0.6)
– Step 3:Fit into a basal/bolus insulin schedule
– 50% basal/ 50% nutritional, 10% correction dose
– Administer long-acting insulin two hours before stopping the IV
infusion