1. HYPERGLYCEMIC EMERGENCIES
Boston University School of Medicine
July, 2013
Marie McDonnell, MD

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

5. Definitions
Cause of Death in Adults: Hypokalemic Cardiac Arrest (rare)
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: 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 < 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.
Our patient’s mS normalized over about 30 hours of therapy

8. Make the correct diagnosis
EO is the same as tonicity and excludes the BUN ...
= 2 ( sodium + potassium) + glucose/18, normal =
Patient’s effective osm:
= 2 ( ) /18 =
= 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 years
Mortality:
HHS+DKA >> HHS>>>>DKA
10-35% >> 5-20% >>>> 1%
HHS+DKA is often called Hyperosmolar Ketoacidosis (HK)
DKA and HHS are increasingly common causes for admission to hospital in the U.S. This increase has been noted despite aggressive efforts at preventive strategies. Between 1996 and 2006 there was a 35% increase in the diagnosis of cases of DKA. (Kitabchi Hyperglycemic crisis in adult patients with diabetes.) More recent U.S national hospital discharge data with DKA as the first listed diagnosis showed an increase in DKA diagnosis from 120,000 discharges in 2006 to 140,000 in 2009 which amounts to a further 15 % increase during this time period. Between 1988 and 2009, the age-adjusted hospital discharge rate for DKA per 10,000 population increased by 43.8% (3.2 vs 4.6 per 10,000 population.) (CDC diabetes data and trends accessed at
Traditionally, DKA and HHS diagnoses have been regarded as separate distinct entities however overlap between the two syndromes is well recognized. Hyperglycemic crises, in general, can be thought to constitute a metabolic continuum with pure HHS and pure DKA constituting the extremes of the spectrum. Hyperosmolar ketoacidosis has not been as well studied as pure DKA or HHS, although mortality rates have been consistently reported to be highest in this subgroup of patients. (Ekpebegh CO. Hyperglycaemic crisis in the Eastern Cape province of South Africa. High mortality and association of hyperosmolar ketoacidosis with a new diagnosis of diabetes.) (Wachtel TJ. Hyperosmolarity and acidosis in diabetes mellitus; a three year experience in Rhode Island. J Gen Intern Med 1991)
Ketoacidosis develops in type 2 diabetes when “relative” insulin deficiency is responsible for the inability to maintain adequate cellular insulin action. This is in comparison to the absolute insulin deficiency typical of type 1 diabetes. (MacLsaac RJ, Lee RY, McNeil KJ, et al, 2002 influence of age on the presentation an outcome of acidotic and hyperosmolar diabetic emergencies. intern Med J 32: )(Isotani H, Asaka S, Kameoka K, et al, 1997 Hyperglycemic hyperosmolar syndrome associated with severe ketosis in Japanese woman. Horm Metab Res 29: ) DKA is more common in younger individuals with HHS more commonly being considered a condition of the elderly. However, both DKA and HHS present across the age spectrum and at the extremes of age with HHS being described in children as young as 18 months old. (Gordon EE. The hyperglycemic hyperosmolar syndrome. Am J Med Sci 1976.) As many as 20% of patients with HHS may be under the age of 30. (Wachtel TJ. Hyperosmolarity and acidosis in diabetes mellitus; a three year experience in Rhode Island. J Gen Intern Med 199.1)
Four percent of DKA cases in an epidemiological study in Rhode Island occurred in patients over the age of 85 with a third occurring in patients between the ages of 55 and 85. (Faich GA. The epidemiology of diabetic acidosis: a population based study. Am J Epidemiol. 1983)
DKA is the most common cause of death in children and adolescents with type 1 diabetes (Wolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in infants, children, and adolescents: a consensus statement from the American Diabetes Association. Diabetes Care 2006; 29:1150–2259.) Despite increased prevalence, overall hyperglycemic crisis mortality in the US has declined by over 15% in the last 20 years from a peak of 3189 recorded deaths in 1988 to 2417 deaths in (CDC diabetes data and trends.) Hyperglycemic crisis mortality rates are highest among black males and lowest among white females. Traditionally, mortality has been reported to be highest at the extremes of age. One of the major epidemiological shifts over the past 30 years has been the marked decrease in the mortality rates in patients older than 75 years of age. Death rates in the elderly of almost three times those of people younger than 45 years of age have declined to rates persistently lower than the youngest patients over the past 10 years. (CDC diabetes data and trends)
Type 1 diabetes is often diagnosed as DKA as the initial presentation. While this classic presentation is still common, there is now evidence that type 1 diabetes is more frequently diagnosed by other means including fasting and random blood glucose levels or oral glucose tolerance tests in the community before diagnosis. (Negrato CA. Temporal changes in the diagnosis of type 1 diabetes by diabetic ketoacidosis in Brazil: A nationwide survery. Diabet Med 2012 Jan.) It is important to recognize that Type 2 diabetes presenting with ketoacidosis as the initial manifestation of diabetes is not uncommon, particularly 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)
As would be expected, the degree of metabolic decompensation in terms of DKA severity has remained stable over time. However, newly diagnosed type 1 diabetes cases, presenting initially in DKA, has decreased in the past decade. (De Vries L et al. Decrease in frequency of ketoacidosis at diabetes onset over the past two decades-perspectives of a pediatric tertiary care centre. Diabet Med 2012 Apr.) If born out, this trend may equate to the vast majority of DKA cases being due to recurrence rather than de novo presentation of diabetes.
Psychosocial, economic and behavioral factors play a large role in recurrent DKA admissions with insulin non-adherence the most common reason for recurrent DKA (68% of patients in a large, urban, inner city US location.) Reasons for insulin discontinuation include 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 has been thought to show no specific sex predilection. However, more recent data seems to favor a female predominance. A recent large European cohort of over pediatric patients with type 1 diabetes showed a significant female predilection (20% more common.) In this particular cohort, DKA was also more common in immigrant patients. ( Fritsch M, Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicenter database. Pediatr Diabetes 2011 June)
It is not surprising that most patients have poor metabolic control prior to admission for recurrent DKA with higher A1c values and higher prescribed insulin doses. Hyperglycemic crisis is often preceded by long standing chronic hyperglycemia in most patients whether they are known to have diabetes or not. (Fritsch M, Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicenter database. Pediatr Diabetes 2011 June)
(Weinert LS et al. Precipitating factors of diabetic ketoacidosis at a public hospital in a middle income country. Diabetes Res Clin Pract April)
HHS mortality far exceeds that of DKA with reported mortality rates of 5-20% in comparison to <1% for DKA in adults (Kitabchi Hyperglycemic crisis in adult patients with diabetes.) However, the combination of hyperosmolarity and ketoacidosis carries an even worse prognosis despite occurring in younger individuals than typical HHS patients. A 2010 retrospective review of over 200 admissions for hyperglycemic crisis in a resource poor African region characterized all the HHS patients as being over age 40. However, only 41% of patients with hyperosmolar ketoacidosis were older than 40. Hyperosmolar ketoacidosis is less common than pure DKA or HHS and tend to present with higher levels of altered sensorium and hypernatremia and are more likely to be newly diagnosed with diabetes than patients with classic ketoacidosis or HHS. (Ekpebegh CO. Hyperglycaemic crisis in the Eastern Cape province in South Africa. High mortality and association of hyperosmolar ketoacidosis with a new diagnosis of diabetes.)

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
Decompensated hyperglycemic hyperosmolarity without significant ketoacidosis in the adolescent and young adult population.
Canarie MF, Bogue CW, Banasiak KJ, Weinzimer SA, Tamborlane WV.
Source
Section of Critical Care Medicine, Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
Abstract
AIM:
To identify patients aged years with probable hyperglycemic hyperosmolar syndrome (HHS), to describe demographic and clinical profiles, and to attempt to assess risk factors for poor outcomes.
STUDY DESIGN:
Retrospective cohort study (medical records review).
SETTING:
A 944-bed tertiary care teaching and research hospital and a 425-bed affiliated facility.
PATIENTS:
10-30 year-old patients with a primary or secondary discharge diagnosis of HHS or diabetic ketoacidosis (DKA). Patients with a serum glucose >600 mg/dl in the absence of significant ketoacidosis (possible HHS) were profiled. Further stratification based on measured or calculated serum osmolarity >320 mOsm/kg (probable HHS) was undertaken.
INTERVENTIONS:
Patients received treatment for hyperglycemic crises, consisting primarily of fluids, electrolyte replacement and insulin.
MEASUREMENTS AND MAIN RESULTS:
Of the 629 admissions, 10 with a diagnosis of HHS and 33 with a diagnosis of DKA met the initial study criteria for HHS. 60% were African Americans and 89% were new-onset diabetics. From this group, 20 admissions had serum osmolarity > or =320 mOsm/kg. Fisher's exact test and Pearson coefficients were used to examine associations between risk factor and poor outcomes and correlations between admission data and length of hospital stay, respectively. Serious complications occurred in four patients (including two deaths, 10% mortality) and were limited to 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.
CONCLUSIONS:
HHS was underdiagnosed in this population and occurred disproportionately in African Americans. Serious complications occurred exclusively in those with unreversed shock and inadequate fluid resuscitation.
PMID:
[PubMed - indexed for MEDLINE]
MESH TERMS
MeSH Terms
LINKOUT - MORE RESOURCES
Medical

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

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

15. HHS
DKA

16. The diabetes landscape is changing
BUT AS MANY OF YOU HAVE SEEN, ESPECIALLY WITH THE RISE IN OBESITY IN WESTERN WORLD AMONG ADOLESCENTS, BETTER UNDERSTANDING OF TYPES OF INSULIN RESISTANCE,AND WITH A BETTER IDENTIFICATION OF AUTOIMMUNE TYPE 1 DM IN ADULTS, THE FACES OF THESE TWO CONDITIONS ARE INTERCHANGEABLE…
DKA?
HHS?

17. INSULIN ACTION: Cellular level
Purified in the late 1950s for widespread use

18. Overview of Insulin Function
MUSCLE LIVER ADIPOCYTE
Transports glucose, amino acids and ions
(K &phos)
Forms triglycerides to store fat; inhibits lipolysis
inhibits glucose production; allows glycogen storage
so to measure insulin resistance at 3 levels, they used labeled substrate
A stable isotope labeled fatty acid, typically 13C-palmitate, is continuously infused intravenously in tracer amounts. The rate of appearance of endogenous unlabeled fatty acids into the bloodstream can be determined by calculating the dilution of infused isotope. Upon reaching steady-state, the rate of appearance equals the rate of disappearance or uptake. Therefore, the rate of appearance is equal to the flux or turnover rate of the substrate

19. Insulin: the “fed state” hormone
glucagon
Glucose and amino acids are actively transported into cells; normal K and Phos transport
Hormone-Sensitive Lipase Inhibited
Insulin inhibits glycogen breakdown
Lipolysis is inhibited; triglycerides are formed for fat storage and fatty acids are not released
To make matters worse, without insulin in sufficient quantities, triglycerides are allowed to be transported into the mitochondria, where they are broken down to FFAs and released in huge quantities into the blood stream, where they travel to the liver and form Ketones bodies. During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-CoA are generated. These exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies, or ketogenesis. The ketone bodies are acetoacetate, b-hydroxybutyrate, and acetone. To prevent this part, only a small amount of insulin is required relative to the amount needed to lower blood glucose. This is probably why patients with type-2 or “insulin resistance” predominant diabetes often don’t present with ketosis, but instead the metabolic dissaray that comes with rising glucose
Increased glucagon in DKA reduces hepatic malonyl coa, which normally inhibits carnitine palmitoyl transferase CPT1, which blocks ffas from entering mitochondria for oxidation
Insulin increases malonyl coA, inhibiting CPT-1, and fatty acids are unable to enter mitochondria for oxidation

20. fatty acids oxidized for ATP
INSULIN
MUSCLE LIVER ADIPOCYTE
Can’t use glucose & Aas (starvation); K & Phos not normally transported
More glucose is made;
fatty acids oxidized for ATP
Lipolysis goes unchecked, fatty acids fill the bloodstream…
so to measure insulin resistance at 3 levels, they used labeled substrate
A stable isotope labeled fatty acid, typically 13C-palmitate, is continuously infused intravenously in tracer amounts. The rate of appearance of endogenous unlabeled fatty acids into the bloodstream can be determined by calculating the dilution of infused isotope. Upon reaching steady-state, the rate of appearance equals the rate of disappearance or uptake. Therefore, the rate of appearance is equal to the flux or turnover rate of the substrate

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
Insulin inhibits the adenylate cyclase

22. Overwhelmed TCA cycle
Acetoacetyl-Coa

23. So many ketone bodies with nowhere to go…
The increased production of acetyl-CoA leads to ketone body production that exceeds the ability of peripheral tissues to oxidize them. Ketone bodies are relatively strong acids (pKa around 3.5), and their increase lowers the pH of the blood.

24. …Acidemia impairs the ability of hemoglobin to bind oxygen
This acidification of the blood is dangerous chiefly because it impairs the ability of hemoglobin to bind oxygen.

25. GH, EPINEPHRINE, CORTISOL
INSULIN
GLUCAGON
Overwhelming FA oxidation takes place…acetyl Coa overwhelms the TCA cycle & Ketone Bodies are released into the blood
Hormone-Sensitive Lipase Activated
LIPOLYSIS GOES
UNCHECKED…
TRIGLYCERIDES BREAK
DOWN TO FFAs…
To make matters worse, without insulin in sufficient quantities, triglycerides are allowed to be transported into the mitochondria, where they are broken down to FFAs and released in huge quantities into the blood stream, where they travel to the liver and form Ketones bodies. During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-CoA are generated. These exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies, or ketogenesis. The ketone bodies are acetoacetate, b-hydroxybutyrate, and acetone. To prevent this part, only a small amount of insulin is required relative to the amount needed to lower blood glucose. This is probably why patients with type-2 or “insulin resistance” predominant diabetes often don’t present with ketosis, but instead the metabolic dissaray that comes with rising glucose
Increased glucagon in DKA reduces hepatic malonyl coa, which normally inhibits carnitine palmitoyl transferase CPT1, which blocks ffas from entering mitochondria for oxidation
Increased glucagon/low insulin decreases malonyl coA, allows CPT-1 to transport FFAs into Liver mitochondria for oxidation

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. Cortisol, Epi, Norepi, GH 1-4 days 2-6 weeks TO HOSPITAL
PATIENT WITH TYPE 2 DM
SEVERE ILLNESS + LIMITED ACCESS TO WATER
PATIENT WITH TYPE I DM
MILD TO SEVERE ILLNESS +/- MISSED INSULIN DOSES
GLUCAGON: INSULIN
GLUCOSE
LIPOLYSIS
KETOACIDOSIS
1-4 days
Cortisol, Epi, Norepi, GH
Cortisol, Epi, Norepi...
2-6 weeks
GLUCAGON: INSULIN
GLUCOSE
SEVERE DEHYDRATION
HYPEROSMOLALITY & CONFUSION
HYPERGLYCEMIA
>220 MG/DL
GLUCOSURIA
DEHYDRATION
DEC. PO INTAKE
THIS IS A SUMMARY SLIDE TO GO LATER…
cLINICAL PRESENTATION BASED ON EPIDEMIOLOGIC STUDIES, this is the classic, presentation with variability along the way
hyperosm may actually supress lipolysis to some extent
TO HOSPITAL

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

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

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%
sounds like an ICU-worthy illness...
of note, mortality of both have improved substantially with the increased use of guidelines in DKA, and the translation to HHS. Outcomes in DKA are the same in both community and teaching hospitals

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. 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

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
Osm gap: ethylene glycol, paraldehyde

37. DKA:
CLINICAL MANAGEMENT

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

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
SLUGGISH H+ K+

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

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
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 % NaCL
Na normal % NaCl
Na low - 0.9% NaCl
When serum glucose reaches 250, change fluid to d51/2 NS and continue with insulin drip, keep glucose 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
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 % NaCL
Na normal % NaCl
Na low - 0.9% NaCl
When serum glucose reaches 250, change fluid to d51/2 NS and continue with insulin drip, keep glucose mg/dl until anion gap closed
If serum K+ is <3.3 mEq/L
Hold insulin and give 40meq K+ until K>3.3
If serum K >5.5, check K q2hours
If K >3.3,<5.5 give meq in each liter IVF to keep K 4-5
Check chem7 q2-4hr until stable.

47. Complete Initial Evaluation. Start 1 Liter of 0
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 % NaCL
Na normal % NaCl
Na low - 0.9% NaCl
When serum glucose reaches 250, change fluid to d51/2 NS and continue with insulin drip, keep glucose mg/dl until anion gap closed
Regular, 0.15u/kg as IV bolus *** sc/IM if mild DKA
If serum K+ is <3.3 mEq/L
Hold insulin and give 40meq K+ until K>3.3
0.1 u/kg/h IV infusion
If serum K >5.5, check K q2hours
If K >3.3,<5.5 give meq in each liter IVF to keep K 4-5
Check serum glucose hourly, if doesn’t fall by in first hour, then double hourly insulin dose until glucose falls by mg/dl
Check chem7 q2-4hr until stable.

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…
Aggressive glucose control has a positive effect on mortality and morbidity in inpatients
Insulin drip with optimal control is indicated early, and may be contined if patient not eating reliably

51. Correction of hyperosmolality
What about the hyperosmolality?
Correction of hyperosmolality

52. 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

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 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. 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…

56. Transition pitfalls
Inadequate overlap of subcutaneous insulin with IV insulin
DKA not yet adequately resolved (bicarb >17 and volume resuscitated)
Inadequate dosing of subcutaneous insulin
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. =
Insulins should be standardized in the hospital – home regimens are NOT required, and are often counterproductive, for good control in the hospital

59. Questions?

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

62. 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 )
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
) In order to do this well, the doctor needs 6-8 hours of foresight to plan for the drip to be stopped. The following steps should be followed:
1)     Make sure the patient’s BGs have been within goal range while at a stable insulin rate (+/- 1 unit/ hour), during the past 4-6 hours
2)     Order an appropriate diet (if liquids, NCS; if solid, ADA Kcal + Cardiac NCS)
3)     Calculate the amount of insulin received in the last 6 hours, and multiply by 4 to approximate the 24 hour insulin requirement (this is often an underestimate because patients typically receive low doses of dextrose for nutrition while in the ICU… but this is a safe estimate)
4)     Calculate the sc insulin doses as follows
Total Daily Dose (TDD) = 80% of the 24 hour requirement
Basal Dose (Lantus QHS or NPH split qAM 2/3 dose and qHS 1/3 dose) = 50% of the TDD
Bolus Dose (Humalog or Novolog insulin recommended) = 50% of the TDD, divided among the 3 meals (usually 6-8 units per full meal, and you can write this as a sliding scale for “meals only” to prevent hypoglycemia, holding if BG is <80 premeal)
5)     For hyperglycemia between meals, you can calculate an appropriate dose using a correction factor (CF):
CF = 1700/TDD. The correction dose is the (BG – 100) divided by the CF.The correction dose should be given at least 3 hours after the last dose of rapid acting insulin to prevent “stacking” of insulin action.
6)     Give the sc basal insulin dose (Lantus or NPH) 2 hours before stopping the drip. You can also give the rapid acting insulin at the same time if the patient is about to eat a meal. It is exceedingly important to overlap coverage by giving sc insulin before the IV drip is discontinued, given the very short half-life of IV insulin (4-10 minutes).
For patients who are going to eat, but who are still on >4 units per hour of insulin, keep them on the drip at a basal level and use subcutaneous insulin for their meals. This is a good way to treat the highly insulin resistant patient who is otherwise doing well. First slowly stop all Dextrose-containing IV fluids and adjust the drip as needed. Give a dose of fast-acting insulin with every meal the patient eats while still on the drip. If the patient is small (<60 kg), start with 2 units; if the patient is medium build (60-80kg), start with 4 units; for large and obese patients (>80kg), start with 4-6 units depending on the meal size. This will help you learn about the patient’s nutritional (prandial) insulin needs before they head to the floor.
Remember that insulin requirements are dynamic and can by affected by correction of the insulin resistance from ketoacidosis and glucotoxicity. In type 2 diabetic patients who present with DKA, there might even be recovery of beta cell function to varying degrees (e.g. “Flatbush Diabetes).