1. DKA: Critical Care Lecture Series
PICU Fellows Lecture

2. Objectives Review of the pathophysiology of DKA
Review of Fluid Management
Current DKA Management Guidelines
Review of Common complications
Current Protocols

3. Biochemical criteria Hyperglycemia ~200mg/dL
Venous pH<7.3 or bicarbonate <15
Ketonemia and ketonuria

4. Pathophysiology Steel, S.
Results from an absolute or relative deficiency of circulating insulin
Absolute deficiency occurs in previously undiagnosed type 1 or when patients on treatment do not take their insulin, purposefully or inadvertently
Relative deficiency happens when counter-regulatory hormones increase due to stress:sepsis, trauma, GI illness
Increases-- catecholamines, glucagon, cortisol and growth hormone
Low insulin with high counter-regulatory hormones causes an accelerated catabolic state
Increase glucose production by the liver and the kidney
Via glycogenolysis and gluconeogenesis
Impaired peripheral glucose utilization resulting in hyperosmolarity and hyperglycemia
Increased lipolysis and ketogenesis resulting in metabolic acidosis and ketonemia
Hyperglycemia exceeding the renal threshold and hyperketonemia cause the osmotic diuresis, dehydration and obligatory loss of electrolytes
Aggravated by vomiting
These mechanisms continues to increase the counter-regulatory hormones which worsen the process
Without intervention, life threatening metabolic acidosis and dehydration will occur
Steel, S.

5. 2 1
Declining insulin prdn lowers the insulin:glucagon ratio-->leads to xs gluc prodn via glycogenolysis
Low insulin levels cause hyperglycemia by decreasing peripheral utilization (blocks glut 4)
LOW INSULIN LEVELS STIM FFA RELEASE FROM ADIPOSE TISSUES; the inc in FFA delivery to the liver is necessary but not sufficient for the stimulation of ketone body formation
Modest ketosis occurs during fasting in normal ind but marked ketosis is prevented by ketone stimulation of insulin which limits further release of FFAs from adipose tissue.(leads to dka with inc ketone body production and elevated anion gap) 3

6. 1 2
Acidosis and dehydration eventually stimulates counter-regulatory hormone, cortisol, growth hormone, and catecholamine release.
Cortisol-increase in FFA release from adipose tissue to fuel ketogenesis
Increased epi directly stimulates glycogenolysis and stim glucaneogenic precursosrs from muscle which allows gluconeogeniss to make a more substantial contribution to hyperglycemia
Epi and NE stimulate lypolysis and beta-oxidation of FFAs to form ketone bodies
Catecholamines also stimulate alpha-adrenergic receptors and inhibit insulin release (this may accelerate development of dka in newly diagnosed diabetics-they have some preservation of insulin releasing cells whereas the established diabetics don’t have any insulin producing cells left)
You need a big decline in insulin concentration relative to counter-regulatory hormones is necessary to promote lipolysis and ketogenesis (explains, in part, why type 2 diabetics don’t develop dka)

7. HHS vs DKA Kitabchi, A., Et Al.
The pathogenesis of DKA and HHS are similar, however, in HHS: 1) there is enough insulin to prevent lipolysis and ketogenesis but not adequate to cause glucose utilization (as it takes 1/10 as much insulin to suppress lipolysis as it does to stimulate glucose utilization)(47,48) 2) possible smaller increases in counterregulatory hormones (20,49)
Kitabchi, A., Et Al.

8. Comparing DKA And HHS DKA HHS Hyperglycemia ~200mg/dL
Venous pH<7.3 or bicarbonate <15
Ketonemia and ketonuria
Glucose >600
pH>7.3
Bicarbonate>15
Small ketonuria
Effective serum osmolarity >330mOsom
Stupor or coma
Hyperglycemic hyperosmolar State
Important to recognize the overlap of the two
Especially when hhs has severe dehydration there will be a degree of acidosis
Also if a t1 dm is using high carb beverages to quench thirst their may be extreme hyperglycemia
Careful to take a good hand p
polyuria and polydipsia of HHS may go unrecognized.7 As a result, both dehydration and electrolyte loss are profound in HHS; in adults, fluid losses in HHS have been estimated to be twice those of DKA. Furthermore, obesity and hyperosmolality can make the clinical assessment of dehydration unreliable.9, 10, 11, 12, 13, 14 It has been suggested on the basis of information from small case series that intake of copious quantities of carbonated sugar-enriched drinks before presentation may be a common feature of patients presenting with severe hyperglycemia. Because these case series lack control data, however, it is unclear whether this finding is specific to these patients
Despite severe electrolyte losses and total body volume depletion, hypertonicity leads to preservation of intravascular volume, and signs of dehydration may be less evident (Figure 2, A and B; available at During therapy, however, declining serum osmolality (a consequence of urinary glucose excretion and insulin-mediated glucose uptake) results in movement of water out of the intravascular space, with a decline in intravascular volume (Figure 2, C).15 In addition, osmotic diuresis may persist for hours as markedly elevated glucose concentrations slowly decrease. Therefore ongoing urinary fluid losses early in treatment may be considerable. Because of the greater dehydration in HHS, the substantial ongoing urinary fluid losses, and the potential for rapid decline in intravascular volume during treatment (Figure 2, D), children with HHS require more aggressive replacement of intravascular volume during treatment than do children with DKA to avoid the vascular collapse that contributes to the high mortality rate.

9. Clinical Manifestations
Dehydration
Rapid, deep sighing (Kussmaul respirations)
Nausea, vomiting and abdominal pain
Progressive obtundation and loss of consciousness
Increased leukocyte count with Left shift
Non-specific elevation of serum amylase
Fever only when infection is present

10. Severity of DKA Mild: Venous pH <7.3 or bicarbonate <15mmol/L
Moderate: Venous pH <7.2, bicarbonate <10
Severe: Venous pH <7.1, bicarbonate <5mmol/L
Correlate severity with prognosis and ?disposition
Mild DKA,(with an established patient could be handled in the ER or even at home
Moderate in a monitored bed, stepdown unit
Severe in a ICU….
Ph<7.0 at presentation was an independent predictor of mortality
Stamatis P, Et al.

11. Frequency of DKA More common at diagnosis in younger children
Families who do not have access to medical care
Risk is increased in patients with:
Poor metabolic control, and previous DKA
Peripubertal and adolescent girls
Children with psychiatric disorders
Children with difficult family situations
Children who omit insulin
Insulin pump therapy

12. Clinical Assessment Assess the Fluid Status
Assess the degree of consciousness
Cap refill, Skin turgor, Hyperpnea(abnormally deep respirations),
Oliguria, hypotension, weak pulses, cool extremities

13. Challenges in the ER
Accurate fluid assessment of these children is difficult
Urine OP is obscured
Inevitably tachycardic
Kussmal respirations
History of the type of fluid to rehydrate is extremely important as well
Fagan 2008 article on assessment of fluid status in children.

14. Prospective consecutive case series Percentage loss of weight
Parents weight at presentation, inpatient discharge, and first follow-up clinic visit were used to calculate percent loss of body weight
33 episodes of DKA
Patients had moderate DKA 4-8%
67% of patients in their study were assessed to be severely dehydrated when only 12% , using percent loss of body weight
ECF—5-10% dehydrated
5-20 yr olds, three year time period
Speaks to clinical judgement and difficulty in assessing fluid status
Fluid and cerebral edema
Participants in the study were invited to use their harriet lane to assess the children to assess the dehydration
Used same scales, got weight same time in recovery when on feed again
Believe we still over hydrate due to the acidosis –kussmal respirations, vasoconstriction from the acidosis, poor
perfusion with the dehydration
Shock is rare in DKA
Reproducibilty of weights, small size

15. Biochemical Assessment
Obtain plasma glucose, electrolytes, osmolarity, venous pH, pCO2, calcium, phosphorus and Magnesium, HbA1C, CBC UA
B-hydroxybutyrate
Potassium
Cultures
CBc-elevated-as stress response
Bhydroxybutyrate to confirm diagnosis and then to see resolution
Potassium-concerned ekg, blood gas, serum

16. Goals of Therapy Correct Dehydration
Correct acidosis and reverse ketosis
Restore blood glucose to near normal
Avoid complications of therapy
Identify and treat precipitating event

17. Retrospective cohort study
Use of rehydration fluids with higher sodium content would positively influence natremia possibly reducing the incidence and severity of cerebral edema
Found that increases in sodium were an independent predicting factor against brain edema
Issues: Hypernatremia, change to hypotonic fluids hours after admission
2005, Spain, five year period, pH< 7.25 (p<0.01-na and brain edema)
Hypernatremia-push to go to isotonic fluids in the hospital-lower risk of inducing hyponatremia, ?ed whether it would be brain protective
change to hypotonic fluids after 12 hours-they think that this will have us using more fluids and will increase the likelihood of cerebral edema

18. After comprehensive review of the literature an expert panel including Lawson Wilkins Pediatric Endocrine society, European Society for Pediatric Endocrinology and the International Society for Pediatric and Adolescent Diabetes

19. Initial Fluid Management
Crystalloids not colloids
Replace fluid deficits
Decreased ECF-10ml/kg over 1-2 hours
Shock - 20ml/kg bolus
Wolfsdorf et al.

20. Fluids Replace deficit for next 4-6 hours with NS or LR
Can change fluids to ½ NS or a fluid of greater tonicity if the physician deems this necessary
The goal is then to rehydrate evenly over 48 hours
Depending on the degree of dehydration the fluid rate with be at an excess of 1.5 to 2 times maintenance therapy

21. Extremely common during treatment Two PICUs, Liverpool and London
Retrospective Chart review
Incidence of hyperchloremia increased from 6% to 94% over 20 hours of treatment
Base deficit decreased over treatment time however proportion due to hyperchloremia increased from 2-98%
2006
Increases to 50% by hour 4
Approximately 40% of the fluid was given in the first 4 hours –making that the greatest rise of the chloride
May be a cause for slow base deficit resolution—ketones over chloride

22. An Example Calculation..
Body weight in kilograms
Establish extent of dehydration
Infants Children
Mild: 5% = 50 ml/kg % = 30 ml/kg
Moderate:10% = 100 ml/kg 6% = 60 ml/kg
Severe: 15% = 150 ml/kg 9% = 90 ml/kg
This is your fluid deficit

23. An Example Calculation
Calculate maintenance fluid requirements for the next 48 hours:
200 ml/kg for the first 10 kg body weight
+ 100 ml/kg for the next 10 kg
+ 40 ml/kg for the remaining kg
Calculate the total amount of fluid to be given for our patient over the next 48 hours
If necessary bolus patient less than 30ml/kg, ideally slowly and this number should be subtracted from your fluid deficit

24. More Fluid Calculations…
Maintenance plus your deficit will equal what you need to give over 48 hours
Divide that number by 48 hours
Then you have your total fluid rate

25. Two Bag Method
We have a K phos and Kcl in our bags
Metzger DL.

26. Two Bag Method
Glucose > 350 mg/dl: Run NS + additives at 100% of calculated rate
Glucose 250 – 350 mg/dl: Run NS at 50% rate, run D10 NS at 50% rate
Glucose < 250 mg/dl: Run D10 NS + additives at 100% rate

27. Insulin therapy
To be started after our initial fluids after the first 1-2 hours in DKA
If given before this it has been shown in a case control study in the UK to have a 12 fold increased risk of cerebral edema
Dose: 0.1 unit/kg/hour
Rehydration will cause mild decreases in our blood glucose it doesn’t fix our problem
Woldfsdorf, J. Et Al.

28. 20 episodes of DKA in 19 children Bolus group and no bolus group
Significantly lowers glucose in first hour
“osmotic disequilibrium”
Precipitous drop in blood glucose
North shore, 1980
Bicarb given for pH less than 7.15, boluses of 20ml/kg, hypotonic fluids were used
Fort, P. Et al.

29. 38 children with 56 episodes of DKA
No statistically significant different change in serum glucose, osmolarity

30. Potassium Total body potassium deficits
Major losses from the Intracellular space
May be normal on presentation
Potassium
Hypokalemic
Normal potassium
Hyperkalemic
Solvent drag
Vomiting osmotic diuresis
But the insulin is going to drastically change all that
Hypokalemic-start on presentation with initial volume expansion
Normal potassium wait until after initial volume expansion
Hyperkalemic wait until after initial fluid resuscitation is given and insulin is started and patient and urinated
Woldfsdorf, J. Et Al.

31. Acidosis Severe acidosis reversible by fluid and insulin replacement
Stops further ketoacid production
Allows ketoacids to be metabolized
Bicarbonate administration may cause paradoxical CNS acidosis(Hale, Pj., Et Al.)
Metabolic acidosis is caused by the accumulation of ketone bodies acetone, acetoacetate, ane beta hydroxybutyrate
Ketoacid metabolism creates bicarb
Bicarb is rarely recommend except in patient who need rescucicitation and would likely need pressors

32. Retrospective consecutive case series
Initial pH < 7.15, Glucose >300
106 children in 16 yr time period, at tertiary university medical centers
57 treated with bicarb
No improved clinical outcome with adjunctive bicarbonate therapy
Possible longer hospitalization for the patients who received the bicarb
Loma linda, orlando fl, west virginia university
Of the 57( 9 had a pH less than 7 and 1 had a pH less than 6.73
Green, SM. Et al.

33. Mortality and Morbidity
Cerebral edema accounts for 75-87% of all DKA deaths(Nichols, D. Et Al.)
10-25% have significant residual morbidity
Other complications
Electrolyte abnormalities
DIC, Dural Sinus Thrombosis
Sepsis
Hypokalemia, hyerkalems, severhypophophotemia

34. Exact Pathophysiology unclear
Thought to be due to small organic compounds in the intracellular space
There as a defensive mechanism to the increasing osmolarity in the ECF compartment
With fluid resuscitation the ECF becomes hypotonic resulting in an influx a water into the neurons
The NA hydrogen exchanger pushes NA into the cells and thereby water too
Early risk factors for the development of cerebral oedema. The top portion depicts the BBB that may be less restrictive early in therapy for DKA. Hence a bolus of saline could expand the intracranial interstitial volume. A bolus of insulin could expand the intracerebral ICF volume by converting the inactive form of NHE to its active form (bottom portion)—this causes Na+ to enter and H+ to exit from cells. One ultimate source of H+ in the ICF is from macromolecules (proteins designated H•PTN+). The net result is the electroneutral and stoichiometric exchange of cations (a gain of monovalent Na+ and the change in protein charge form a cationic to a less cationic form, depicted in the ICF ovals).
Top:(Capillary hydrostatic pressure high-because on bolus of saline
Colloid osmotic pressure might fall by dilution
Bottom:When NHE is active, there should be a gain of Na+ and a loss of H+ in the ICF compartment; this will increase the number of solute molecules in the ICF16 because the bulk of the exported H+ were bound primarily to ICF proteins or entered cells along with β-hydroxybutyrate on the monocarboxylic acid transporter (fig 1).17–19 Since intracellular acidosis is usually present in patients with DKA and there is an insulin receptor in the brain,20 an intravenous bolus of insulin could have a more dramatic intracerebral effect if it were given early on, when the BBB might be less restrictive to the passage of insulin.8–1
Carlotti A P C P et al. Arch Dis Child 2003;88:

35. Late risk factors for the development of cerebral oedema.
Late risk factors for the development of cerebral oedema. The risk associated with an infusion of too large a volume of saline (left portion) is expansion of the interstitial volume of the brain. If this occurs, the patient may develop an increased ICP even if there is a less severe degree of brain cell swelling. As shown in the right portion, a rise in PNa is needed to prevent a fall in the effective Posm when there is a fall in PGlu. The PNa must be >140 mmol/l if the PNa on admission is close to 140 mmol/l.
Carlotti A P C P et al. Arch Dis Child 2003;88:

36. 181 randomly selected with DKA 174 match to the CE group
2001, multicenter study
Children <18 yr
61 children with CE
181 randomly selected with DKA
174 match to the CE group
Using logistic regression, they found that lower CO2 and higher BUN, and children treated with bicarbonate
10 centers-ca-australia,-RI-Boston _LA-ST louis
Match for age of presentation, onset of diabetes(est. vs newly diagnosed, initial serum glucose, initial serum venous pH
Dehydration and hyperventilation being more important for development for dka than osmolartiy or osmotic changes
Glaser, Nicole, Et al.

37. Cerebral Edema Diagnostic criteria
Abnormal motor or verbal response to pain
Decorticate or decerebrate posture
Cranial nerve palsy
Abnormal neurogenic respiratory pattern
Grunting, tachypnea, cheyne-stokes respirations

38. Cerebral edema Major Minor Vomiting Headache
Altered mentation/fluctuating level of consciousness
Sustained heart rate deceleration-not from improved volume or sleep
Age inappropriate incontinence
Vomiting
Headache
Lethargy or difficult to rouse
Diastolic blood pressure >90mmHg
Age <5yrs
One diagnostic, Two major, or one major and one minor have a sensitivity of 92%

39. Treatment of cerebral edema
Reduce fluid volume by 1/3
Mannitol 0.5-1gm/kg
Hypertonic saline 5-10ml/kg (alternative or second line therapy)
Intubation if impending respiratory failure, aggressive hyperventilation
Elevate the head of the bed
Then---CT to rule out thrombosis or other intracerebral causes
There have been studies that have shown that rapid falls in the osmolaritis have shown an increased incidence of DKA -CE

40. Were in two groups equally distributed
Retrospective Observational study, in Royal Children’s Hospital In Melbourne
67 children with DKA
Were in two groups equally distributed
Plasma osmolarity had a more gradual reduction in the 0.05u/kg/hr group
Younger children
Further research as whether this may reduce the risk of cerebral edema
Not randomized, these children tended to get more isotonic fluid in this study
Endocrinologist chose 0.1 and picu chose 0.05
2011
Hanshi, S, Et Al.l

41. Protocolized approach
Minimizes risks for young children with DKA especially for Cerebral Edema
ISPAD guidelines are currently the gold standards internationally
Woldfsdorf, J. Et Al.

42. Protocols, protocols, protocols….

43. Additional Protocols

44. Nursing Flowsheets

45. Consensus Statements

46. In Summary
Caution use of Hypotonic fluids in the first hours of DKA management
Assess the ECF contraction
Increased attention to serum sodium levels and Chloride levels
Delay in the introduction of insulin infusions
Protocols

47. Thank you! Any Questions?

48. References British Columbia DKA Toolkit. January 8, 2010.
Cefalu W. Diabetic Ketoacidosis. Critical Care Clinics 7(1): , 1991.
Carlotti A P C P et al. Arch Dis Child 2003;88:
Jeha, G, Et al. Treatment and Complication of Diabetic Ketoacidosis in children. Uptodate. September 2010.
Kawamata,,T, Et At. Tissue Hyperosmolality and Brain Edema in Cerebral Contusion. Neurosurg Focus. 2007;22(5):E5 © 2007 American Association of Neurological Surgeons.
Kitabchi, A. Et Al. Hyperglycemic Crices In Patients with diabetes: DIiabetic Ketoacidosis (DKA), and Hyperglycemic Hyperosmolar State
Fort, P., Et Al. Low Dose insulin infusion in the the treatment of diabetic ketoacidosis: bolus versus no bolus. The journal of Pediatrics. January 1980.
Glaser, Nicole, Et al. Risk Factors for Cerebral Edema in Children with Diabetic Ketoacidosis. NEJM. Volume 344, No. 4, Jan. 25, 2001.
Green SM., Et Al. Failure of Adjunctive Bicarbonate to improve outcome in severe Diabetic Ketoacidosis Ann Emerg Med Jan: 31(1):
Hale PJ, Crase J, Nattrass M. Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. Br Med J (Clin Res Ed) 1984 Oct 20: 289(6451): 1035 – 8.
Hanshi, S, Et Al. Insulin infusion at 0.05 versus 0.1 unit/kg/hr in children admitted to intensive care with diabetic ketoacidosis. Pediatric Critical Care Medicine 2011 Vol 12, no

49. References
Metzger, D. Diabetic Ketoacidosis in children and adolescents: an update and revised treatment protocol. BC Medical Journal. Vol. 52. no 1, Jan/Feb 2010.
Nicols, D. Disorders of glucose homeostasis. Rogers’ Textbook of Pediatric Intensive Care :
Orlowski, james., Et al. Diabetic Ketoacidosis in the Pediatric ICU. Pediatric Clin N Am 55 (2008)
Steel, S., Et al. Contin Educ Anaesth Crit Care Pain (2009) 9 (6): doi: /bjaceaccp/mkp034
Taylor, D., Et Al. The influence of hyperchloraemia on acid base interpretation in diabetic ketoacidosis. Intensive Care medicine. (2006) 32:
Toledo, J., Et al. Sodium Concentration in rehydration Fluids for children with ketoacidotic Diabetes: Effect on serum Sodium Concentration. J Pediatr 2009;154:
Woldfsdorf, J. Et Al. Diabetic Ketoacidosis in children and Adolescents with Diabetes. Pediatric Diabetes :10(suppl. 12):
Zeitler, P. Et al. Hyperglycemic Hyperosmolar Syndrome in Children: Pathophysiological Considerations and suggested guidelines for treatment. The Journal of Pediatrics. Vol 158, P January 2011.