DKA: Critical Care Lecture Series PICU Fellows Lecture

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

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

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.

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

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)

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.

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 www.jpeds.com). 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.

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

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.

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

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

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.

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

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

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

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

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

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

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

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

An Example Calculation.. Body weight in kilograms Establish extent of dehydration Infants Children Mild: 5% = 50 ml/kg 3% = 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

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

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

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

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

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.

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.

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

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.

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

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.

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

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;88:170-173

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;88:170-173

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.

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

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%

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

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

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.

Protocols, protocols, protocols….

Additional Protocols

Nursing Flowsheets

Consensus Statements

In Summary Caution use of Hypotonic fluids in the first 12-24 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

Thank you! Any Questions?

References British Columbia DKA Toolkit. January 8, 2010. Cefalu W. Diabetic Ketoacidosis. Critical Care Clinics 7(1): 89-108, 1991. Carlotti A P C P et al. Arch Dis Child 2003;88:170-173 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. 2007. 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. 1998 Jan: 31(1): 41-8. . 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 2. 137-140.

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. 2008 : 1599-1614. Orlowski, james., Et al. Diabetic Ketoacidosis in the Pediatric ICU. Pediatric Clin N Am 55 (2008) 577-587. Steel, S., Et al. Contin Educ Anaesth Crit Care Pain (2009) 9 (6): 194-199. doi: 10.1093/bjaceaccp/mkp034 Taylor, D., Et Al. The influence of hyperchloraemia on acid base interpretation in diabetic ketoacidosis. Intensive Care medicine. (2006) 32:295-301. Toledo, J., Et al. Sodium Concentration in rehydration Fluids for children with ketoacidotic Diabetes: Effect on serum Sodium Concentration. J Pediatr 2009;154:895-900. Woldfsdorf, J. Et Al. Diabetic Ketoacidosis in children and Adolescents with Diabetes. Pediatric Diabetes. 2009:10(suppl. 12): 118-113. Zeitler, P. Et al. Hyperglycemic Hyperosmolar Syndrome in Children: Pathophysiological Considerations and suggested guidelines for treatment. The Journal of Pediatrics. Vol 158, P9- 14. January 2011.