The document discusses hyperglycemic emergencies, specifically Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS), including definitions, epidemiology, diagnoses, and management strategies. It emphasizes the rising prevalence of DKA and its implications for treatment, highlighting the need for aggressive fluid resuscitation and careful monitoring of potassium levels. The document also outlines the differing mortality rates associated with DKA and HHS, as well as the critical importance of identifying underlying illnesses in affected patients.

1. HYPERGLYCEMIC
EMERGENCIES
Boston University School of Medicine
July, 2013
Marie McDonnell, MD
marie.mcdonnell@bmc.org

2. 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

3. 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

4. • Awake but lethargic on admission to ER
• BP 92/50, pulse 128, T 99, 90 kg
• Dry membranes
• Stat labs:
• Anion gap = 26
Data
132
4.5 14
1478
92 52
3.2
Arterial pH= 7.29
Urine ketones = 2+
Plasma ketones =
Moderate
Phos = 0.9
Mg = 2.0
WBC = 10, 000, 80%
lymph
HCT = 44

5. Definitions
• DKA
– 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
– Blood glucose >600mg/dl
– arterial ph>7.3
– bicarbonate >15
– effective serum osmolality >320 mOsm/kg H20
– mild ketonuria or ketonemia may be present
Cause of Death in Adults: Hypokalemic
Cardiac Arrest (rare)
Cause of Death in Adults: Underlying
illness (not uncommon)

6. 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

7. 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.

8. 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

9. 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)

10. 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

11. 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.
Experience from a large multicenter database. Pediatr Diabetes 2011 June)

12. 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/

13. Blood glucose
>250 mg/dl
Underlying illness:
Infection, MI, Stroke
Marked
hypovolemia
Electrolyte
disturbances
+/- Acidosis/ Acidemia
Altered Mental Status

14. Insulin
Production:
Severely impaired
Insulin Action:
Severely impaired
Insulin Action:
Normal or
suboptimal
Insulin
Production:
Suboptimal
Type 1 DM &
DKA
Type 2 DM &
HHS

15. DKA
HHS

16. The diabetes landscape is changing
DKA?
HHS?

17. INSULIN ACTION: Cellular
level

18. Overview of Insulin Function
Transports
glucose,
amino acids
and ions
(K &phos)
inhibits glucose
production; allows
glycogen storage
Forms
triglycerides
to store fat;
inhibits
lipolysis
INSULIN
MUSCLE LIVER ADIPOCYTE

19. Insulin: the “fed state” hormone
Insulin inhibits glycogen
breakdown
Hormone-
Sensitive Lipase
Inhibited
INSULIN
glucagon
Lipolysis is
inhibited;
triglycerides are
formed for fat
storage and fatty
acids are not
released
Insulin increases
malonyl coA, inhibiting
CPT-1, and fatty acids
are unable to enter
mitochondria for
oxidation
Glucose and
amino acids are
actively
transported into
cells; normal K
and Phos
transport

20. INSULIN
MUSCLE LIVER ADIPOCYTE
Can’t use
glucose & Aas
(starvation);
K & Phos not
normally
transported
Lipolysis goes
unchecked, fatty
acids fill the
bloodstream…
More
glucose is
made;
fatty acids
oxidized for
ATP

21. 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

22. Overwhelmed TCA cycle
Acetoacetyl-Coa

23. So many ketone bodies with
nowhere to go…

24. …Acidemia impairs the
ability of hemoglobin to
bind oxygen

25. Overwhelming FA
oxidation takes
place…acetyl Coa
overwhelms the
TCA cycle & Ketone
Bodies are released
into the blood
Increased glucagon/low insulin
decreases malonyl coA, allows
CPT-1 to transport FFAs into
Liver mitochondria for oxidation
Hormone-
Sensitive Lipase
Activated
INSULIN
GLUCAGON
LIPOLYSIS GOES
UNCHECKED…
TRIGLYCERIDES
BREAK
DOWN TO FFAs…
GH, EPINEPHRINE,
CORTISOL

26. How to measure metabolic acidosis?
• Blood pH: measures acidemia
• “Anion Gap”
– Normal extracellular anions =
• Measurable: Cl- and HCO3-
• Unmeasurable: proteins
– Normal measureable extracellular cation =
• Na++
– Electric “balance”
• Anions must =Cations
– Na++ - [Cl- + HCO3-] – (unmeasurable anions) = 0
The
normal
“Gap”

27. “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

28. PATIENT WITH TYPE 2 DM
SEVERE ILLNESS + LIMITED
ACCESS TO WATER
HYPERGLYCEMIA
>220 MG/DL
GLUCOSURIA
DEHYDRATION
DEC. PO INTAKE
PATIENT WITH TYPE I DM
MILD TO SEVERE ILLNESS
+/- MISSED INSULIN DOSES
TO HOSPITAL
Cortisol, Epi,
Norepi...
2-6 weeks
GLUCAGON: INSULIN
GLUCOSE
SEVERE DEHYDRATION
HYPEROSMOLALITY &
CONFUSION
GLUCAGON: INSULIN
GLUCOSE
LIPOLYSIS
KETOACIDOSIS
1-4 days
Cortisol,
Epi,
Norepi, GH

29. Insulin, Potassium and H+ in DKA
H+
K+

30. Degree of Dehydration
Water deficit on
avg. 9L
Water deficit
on avg. 3-5L
HHS DKA

31. Mortality
Q: Which has a higher associated mortality
DKA or HHS?
A: HHS
Recent rates are approximately 15%, whereas
in DKA, it’s <5%

32. Diabetic Ketoacidosis:
extreme insulin deficiency

33. DKA:
clinical presentation
Polyuria, polydipsia
Fatigue
Nausea, vomiting
Abdominal pain
Increased respiratory rate/dyspnea
Dry membranes
+ ketones on breath (sweet) – unreliable sign
Infection +/- fever

34. 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

35. • 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

36. 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

37. DKA:
CLINICAL
MANAGEMENT

38. DKA pathophysiology
X
X
•Treatment is
crystal clear
•But what is
the best
approach?

39. 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

40. Insulin, Potassium and H+ in DKA
H+
K+

41. Insulin, Potassium and H+
In HSS or DKA, never give insulin or bicarbonate
until you know the potassium level…always start
fluids first...
H+
K+
NaHCO3
(and
other
measures
to correct
acidosis)
Insulin

42. Start Fluids First!

43. 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

44. 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

45. Mortality in DKA
• HYPOKALEMIC CARDIAC ARREST
= giving insulin before knowing K
and/or poor monitoring
• Cerebral Edema
• Pulmonary Edema

46. 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
Check chem7 q2-4hr until
stable.
If K >3.3,<5.5 give 20-30
meq in each liter IVF to
keep K 4-5
If serum K >5.5, check K
q2hours
If serum K+ is <3.3 mEq/L
Hold insulin and give
40meq K+ until K>3.3

47. Complete Initial Evaluation. Start 1 Liter of 0.9%
NaCl/hour initially (15-20ml/kg/hr)
IV FLUIDS INSULIN POTASSIUM
Check serum glucose
hourly, if doesn’t fall by
50-70 in first hour, then
double hourly insulin
dose until glucose falls
by 50-70 mg/dl
0.1 u/kg/h IV
infusion
Regular, 0.15u/kg as
IV bolus *** sc/IM if
mild DKA
Check chem7 q2-4hr until
stable.
If K >3.3,<5.5 give 20-30
meq in each liter IVF to
keep K 4-5
If serum K >5.5, check K
q2hours
If serum K+ is <3.3 mEq/L
Hold insulin and give
40meq K+ until K>3.3
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

48. Add screen shot

50. 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…

51. Correction of hyperosmolality
What about the hyperosmolality?

52. • 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
Hyperosmolality

53. 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

54. 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

55. • Avoid stopping an insulin infusion without
overlap, or “transition,” subcutaneous
insulin
• Remember that 1 unit/hour is a still
substantial insulin requirement…
Out of the woods…and the ICU

56. 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

57. 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

58. =

59. Questions?

61. Never stop the insulin drip without
moderate or long-acting
subcutaneous insulin “on board”

62. • 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
Always transition from IV to
subcutaneous insulin