Presentation on theme: "DKA: Critical Care Lecture Series"— Presentation transcript:
1 DKA: Critical Care Lecture Series PICU Fellows Lecture
2 Objectives Review of the pathophysiology of DKA Review of Fluid ManagementCurrent DKA Management GuidelinesReview of Common complicationsCurrent Protocols
3 Biochemical criteria Hyperglycemia ~200mg/dL Venous pH<7.3 or bicarbonate <15Ketonemia and ketonuria
4 Pathophysiology Steel, S. Results from an absolute or relative deficiency of circulating insulinAbsolute deficiency occurs in previously undiagnosed type 1 or when patients on treatment do not take their insulin, purposefully or inadvertentlyRelative deficiency happens when counter-regulatory hormones increase due to stress:sepsis, trauma, GI illnessIncreases-- catecholamines, glucagon, cortisol and growth hormoneLow insulin with high counter-regulatory hormones causes an accelerated catabolic stateIncrease glucose production by the liver and the kidneyVia glycogenolysis and gluconeogenesisImpaired peripheral glucose utilization resulting in hyperosmolarity and hyperglycemiaIncreased lipolysis and ketogenesis resulting in metabolic acidosis and ketonemiaHyperglycemia exceeding the renal threshold and hyperketonemia cause the osmotic diuresis, dehydration and obligatory loss of electrolytesAggravated by vomitingThese mechanisms continues to increase the counter-regulatory hormones which worsen the processWithout intervention, life threatening metabolic acidosis and dehydration will occurSteel, S.
5 21Declining insulin prdn lowers the insulin:glucagon ratio-->leads to xs gluc prodn via glycogenolysisLow 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 formationModest 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 12Acidosis and dehydration eventually stimulates counter-regulatory hormone, cortisol, growth hormone, and catecholamine release.Cortisol-increase in FFA release from adipose tissue to fuel ketogenesisIncreased epi directly stimulates glycogenolysis and stim glucaneogenic precursosrs from muscle which allows gluconeogeniss to make a more substantial contribution to hyperglycemiaEpi and NE stimulate lypolysis and beta-oxidation of FFAs to form ketone bodiesCatecholamines 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 <15Ketonemia and ketonuriaGlucose >600pH>7.3Bicarbonate>15Small ketonuriaEffective serum osmolarity >330mOsomStupor or comaHyperglycemic hyperosmolar StateImportant to recognize the overlap of the twoEspecially when hhs has severe dehydration there will be a degree of acidosisAlso if a t1 dm is using high carb beverages to quench thirst their may be extreme hyperglycemiaCareful to take a good hand ppolyuria 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 patientsDespite 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 DehydrationRapid, deep sighing (Kussmaul respirations)Nausea, vomiting and abdominal painProgressive obtundation and loss of consciousnessIncreased leukocyte count with Left shiftNon-specific elevation of serum amylaseFever only when infection is present
10 Severity of DKA Mild: Venous pH <7.3 or bicarbonate <15mmol/L Moderate: Venous pH <7.2, bicarbonate <10Severe: Venous pH <7.1, bicarbonate <5mmol/LCorrelate severity with prognosis and ?dispositionMild DKA,(with an established patient could be handled in the ER or even at homeModerate in a monitored bed, stepdown unitSevere in a ICU….Ph<7.0 at presentation was an independent predictor of mortalityStamatis P, Et al.
11 Frequency of DKA More common at diagnosis in younger children Families who do not have access to medical careRisk is increased in patients with:Poor metabolic control, and previous DKAPeripubertal and adolescent girlsChildren with psychiatric disordersChildren with difficult family situationsChildren who omit insulinInsulin pump therapy
12 Clinical Assessment Assess the Fluid Status Assess the degree of consciousnessCap refill, Skin turgor, Hyperpnea(abnormally deep respirations),Oliguria, hypotension, weak pulses, cool extremities
13 Challenges in the ERAccurate fluid assessment of these children is difficultUrine OP is obscuredInevitably tachycardicKussmal respirationsHistory of the type of fluid to rehydrate is extremely important as wellFagan 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 weight33 episodes of DKAPatients 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 weightECF—5-10% dehydrated5-20 yr olds, three year time periodSpeaks to clinical judgement and difficulty in assessing fluid statusFluid and cerebral edemaParticipants in the study were invited to use their harriet lane to assess the children to assess the dehydrationUsed same scales, got weight same time in recovery when on feed againBelieve we still over hydrate due to the acidosis –kussmal respirations, vasoconstriction from the acidosis, poorperfusion with the dehydrationShock is rare in DKAReproducibilty of weights, small size
15 Biochemical Assessment Obtain plasma glucose, electrolytes, osmolarity, venous pH, pCO2, calcium, phosphorus and Magnesium, HbA1C, CBCUAB-hydroxybutyratePotassiumCulturesCBc-elevated-as stress responseBhydroxybutyrate to confirm diagnosis and then to see resolutionPotassium-concerned ekg, blood gas, serum
16 Goals of Therapy Correct Dehydration Correct acidosis and reverse ketosisRestore blood glucose to near normalAvoid complications of therapyIdentify 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 edemaFound that increases in sodium were an independent predicting factor against brain edemaIssues: Hypernatremia, change to hypotonic fluids hours after admission2005, 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 protectivechange 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 colloidsReplace fluid deficitsDecreased ECF-10ml/kg over 1-2 hoursShock - 20ml/kg bolusWolfsdorf 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 necessaryThe goal is then to rehydrate evenly over 48 hoursDepending 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 reviewIncidence of hyperchloremia increased from 6% to 94% over 20 hours of treatmentBase deficit decreased over treatment time however proportion due to hyperchloremia increased from 2-98%2006Increases to 50% by hour 4Approximately 40% of the fluid was given in the first 4 hours –making that the greatest rise of the chlorideMay be a cause for slow base deficit resolution—ketones over chloride
22 An Example Calculation.. Body weight in kilogramsEstablish extent of dehydrationInfants ChildrenMild: 5% = 50 ml/kg % = 30 ml/kgModerate:10% = 100 ml/kg 6% = 60 ml/kgSevere: 15% = 150 ml/kg 9% = 90 ml/kgThis 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 kgCalculate the total amount of fluid to be given for our patient over the next 48 hoursIf 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 hoursDivide that number by 48 hoursThen you have your total fluid rate
25 Two Bag MethodWe have a K phos and Kcl in our bagsMetzger DL.
26 Two Bag MethodGlucose > 350 mg/dl: Run NS + additives at 100% of calculated rateGlucose 250 – 350 mg/dl: Run NS at 50% rate, run D10 NS at 50% rateGlucose < 250 mg/dl: Run D10 NS + additives at 100% rate
27 Insulin therapyTo be started after our initial fluids after the first 1-2 hours in DKAIf given before this it has been shown in a case control study in the UK to have a 12 fold increased risk of cerebral edemaDose: 0.1 unit/kg/hourRehydration will cause mild decreases in our blood glucose it doesn’t fix our problemWoldfsdorf, 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 glucoseNorth shore, 1980Bicarb given for pH less than 7.15, boluses of 20ml/kg, hypotonic fluids were usedFort, 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 spaceMay be normal on presentationPotassiumHypokalemicNormal potassiumHyperkalemicSolvent dragVomiting osmotic diuresisBut the insulin is going to drastically change all thatHypokalemic-start on presentation with initial volume expansionNormal potassium wait until after initial volume expansionHyperkalemic wait until after initial fluid resuscitation is given and insulin is started and patient and urinatedWoldfsdorf, J. Et Al.
31 Acidosis Severe acidosis reversible by fluid and insulin replacement Stops further ketoacid productionAllows ketoacids to be metabolizedBicarbonate administration may cause paradoxical CNS acidosis(Hale, Pj., Et Al.)Metabolic acidosis is caused by the accumulation of ketone bodies acetone, acetoacetate, ane beta hydroxybutyrateKetoacid metabolism creates bicarbBicarb is rarely recommend except in patient who need rescucicitation and would likely need pressors
32 Retrospective consecutive case series Initial pH < 7.15, Glucose >300106 children in 16 yr time period, at tertiary university medical centers57 treated with bicarbNo improved clinical outcome with adjunctive bicarbonate therapyPossible longer hospitalization for the patients who received the bicarbLoma linda, orlando fl, west virginia universityOf the 57( 9 had a pH less than 7 and 1 had a pH less than 6.73Green, 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 morbidityOther complicationsElectrolyte abnormalitiesDIC, Dural Sinus ThrombosisSepsisHypokalemia, hyerkalems, severhypophophotemia
34 Exact Pathophysiology unclear Thought to be due to small organic compounds in the intracellular spaceThere as a defensive mechanism to the increasing osmolarity in the ECF compartmentWith fluid resuscitation the ECF becomes hypotonic resulting in an influx a water into the neuronsThe NA hydrogen exchanger pushes NA into the cells and thereby water tooEarly 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 salineColloid osmotic pressure might fall by dilutionBottom: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.8–1Carlotti 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 studyChildren <18 yr61 children with CE181 randomly selected with DKA174 match to the CE groupUsing logistic regression, they found that lower CO2 and higher BUN, and children treated with bicarbonate10 centers-ca-australia,-RI-Boston _LA-ST louisMatch for age of presentation, onset of diabetes(est. vs newly diagnosed, initial serum glucose, initial serum venous pHDehydration and hyperventilation being more important for development for dka than osmolartiy or osmotic changesGlaser, Nicole, Et al.
37 Cerebral Edema Diagnostic criteria Abnormal motor or verbal response to painDecorticate or decerebrate postureCranial nerve palsyAbnormal neurogenic respiratory patternGrunting, tachypnea, cheyne-stokes respirations
38 Cerebral edema Major Minor Vomiting Headache Altered mentation/fluctuating level of consciousnessSustained heart rate deceleration-not from improved volume or sleepAge inappropriate incontinenceVomitingHeadacheLethargy or difficult to rouseDiastolic blood pressure >90mmHgAge <5yrsOne diagnostic, Two major, or one major and one minor have a sensitivity of 92%
39 Treatment of cerebral edema Reduce fluid volume by 1/3Mannitol 0.5-1gm/kgHypertonic saline 5-10ml/kg (alternative or second line therapy)Intubation if impending respiratory failure, aggressive hyperventilationElevate the head of the bedThen---CT to rule out thrombosis or other intracerebral causesThere 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 Melbourne67 children with DKAWere in two groups equally distributedPlasma osmolarity had a more gradual reduction in the 0.05u/kg/hr groupYounger childrenFurther research as whether this may reduce the risk of cerebral edemaNot randomized, these children tended to get more isotonic fluid in this studyEndocrinologist chose 0.1 and picu chose 0.052011Hanshi, S, Et Al.l
41 Protocolized approach Minimizes risks for young children with DKA especially for Cerebral EdemaISPAD guidelines are currently the gold standards internationallyWoldfsdorf, J. Et Al.
46 In SummaryCaution use of Hypotonic fluids in the first hours of DKA managementAssess the ECF contractionIncreased attention to serum sodium levels and Chloride levelsDelay in the introduction of insulin infusionsProtocols
49 ReferencesMetzger, 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/mkp034Taylor, 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.