HYPERGLYCEMIC EMERGENCIES

Boston University School of Medicine

July, 2013Marie 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

• 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

147892 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

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)

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

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

Underlying illness:

Infection, MI, Stroke

Marked

hypovolemia

Electrolyte

disturbances

+/- Acidosis/ Acidemia

Altered Mental Status

Insulin Production:

Severely impaired

Insulin Action:

Severely impaired

Insulin Action:

Normal or suboptimal

Insulin Production:

Suboptimal

Type 1 DM &

DKA

Type 2 DM &

HHS

DKA

HHS

The diabetes landscape is changing

DKA?

HHS?

INSULIN ACTION: Cellular level

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

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

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

Fatty Acid Oxidation Overload

Product: Acetyl CoA, which has to enter TCA cycle to produce ATP

TCA cycle can only do so muchEnzymes 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

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

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”

“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

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

Insulin, Potassium and H+ in DKA

H+K+

Degree of Dehydration

Water deficit on avg. 9L

Water deficit on avg. 3-5L

HHS DKA

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

• 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

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: DKA:

CLINICAL CLINICAL MANAGEMENTMANAGEMENT

DKA pathophysiology

X

X

•Treatment is crystal clear

•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+

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

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 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

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

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…

Correction of hyperosmolality

What about the 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

Hyperosmolality

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

• 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

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”

• 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