DKA & HYPERGLYCEMIC HYPEROSMOLAR STATE (HHS) D. Franzon, MD

Transcription

1 DKA & HYPERGLYCEMIC HYPEROSMOLAR STATE (HHS) D. Franzon, MD Pathogenesis: Physiology Diabetic ketoacidosis (DKA) is probably the most commonly encountered metabolic disorder in the PICU. The incidence of DKA is per 1000 person-years among patients with diabetes and it is a significant cause of morbidity and mortality with a mortality rate between 4 and 10% although in pediatrics, the mortality rate is 1-2%. Essential Pathophysiology of DKA: Absolute or relative deficiency of insulin Resultant excess of counter-regulatory hormones Increased hepatic glucose production and diminished glucose uptake by peripheral tissues cause the hyperglycemia in DKA leading to glycosuria, osmotic diuresis and dehydration Insulin Insulin has both stimulatory and inhibitory effects. o Stimulatory effects (+): anabolism glycogen storage; protein and fat storage in muscle, liver, and adipose tissue; enhances cellular uptake of ketone bodies. o Inhibitory effect (-): prevent catabolism glycogenolysis, gluconeogenesis, proteolysis, lipolysis, and ketogenesis. Insulin deficiency states, such as diabetes, effect end organ metabolic responses, which in turn increases serum glucose levels. o Liver: uninhibited hepatic ketogenesis and gluconeogenesis and glycogenolysis occur. o Muscle: anabolic functions are impaired and glucose fails to enter cells, glycogen is depleted, and catabolism takes place. o Fat tissue: lipolysis continues while fat absorption and triglyceride synthesis are blocked. Counter-Regulatory Hormones are elevated when insulin is deficient Glucagon stimulates beta-oxidation of fatty acids leading to the production of ketoacids: acetoacetate, and beta-hydroxybutyrate. This ketogenesis is a hallmark of DKA. Growth hormone, cortisol and catecholamines all enhance gluconeogenesis, block glucose uptake by muscle and promote lipolysis. Acidosis Overproduction of ketoacids, beta-hydroxybutyric acid, acetoacetic acid DKA & HHS 1

2 2 ketoacids dissociated at physiologic ph excess hydrogen ions bind bicarbonate decreased serum bicarbonate levels circulating ketone bodies in anion form lead to the anion gap acidosis of DKA Anion gap = [Na + (Cl - + HCO3 - ); normal anion gap = 12 Acetoacetate is converted to acetone by a spontaneous nonenzymatic process in direct proportion to its serum concentration; this is an important pathway by which excess acid is discarded by the body. The lungs or the kidneys in turn can excrete acetone. In normal circumstances, the ratio of B-hydroxybutyrate / acetoacetate is 2-3:1, but in DKA it may be as high as 15:1. Commonly used tests measure acetoacetate levels well but measure acetone poorly and don t measure beta-hydroxybutyrate at all, which may underestimate the degree of ketosis. Dehydration Hyperglycemia induces osmotic diuresis leading to total body water deficit often to 10-15% of body weight. The kidney can re-absorb glucose with serum levels up to 180mg/dL above which glucose is wasted and water follows. Electrolytes follow free water and are therefore also lost in the urine. Deficits of electrolytes, in general are as follows: o Na + : 5-13 mmol/kg o Cl - : 3-7 mmol/kg o K + : 3-15 mmol/kg o PO4/Mg/Ca ++ : 1-2mmol/kg of each NaCl With the osmotic diuresis, the water loss exceeds the NaCl loss. Because of the osmotic shift of water in both the extra- and intra-cellular space, plasma [Na + ] is usually low or normal in DKA i.e. intra-cellular water shifts to the extra-cellular matrix due to increased serum osmolality. In HHS however, the plasma [Na + ] can be increased. The measured [Na + ] can be corrected by adding 1.6 meq/l of [Na + ] for every 100mg/dL above 100mg/dL elevation in glucose. Keep in mind that the measured sodium level is the actual [Na] in the blood and that the corrected Na is a theoretical calculation that is a useful guideline for hydration. Extreme lipemia can also decrease the measured Na value and is an artifact. K+ There is profound total body [K + ] depletion in DKA and HHS. Urinary losses with osmotic diuresis, inadequate oral intake, and emesis, which are typical in DKA, lead to total body [K + ] depletion. DKA & HHS 2

3 At the time of presentation, however, plasma [K + ] is normal or elevated because of the shift that occurs from intracellular to extracellular space. Etiologies for this [K + ] shift include hyperglycemia / low insulin levels, acidosis, and proteolysis. (Recall that one of the treatments for hyperkalemia is glucose / insulin; the Na-K-ATPase pump is triggered by insulin driving [K + ] into the cells.) Once insulin therapy is initiated, hypokalemia is unmasked; therefore repletion should be initiated early in treatment. PO4/Mg/Ca ++ Profound hypophosphatemia often occurs in DKA resulting in depressed levels of erythrocyte 2,3-DPG which decreases the P50 of oxyhemoglobin (shifts the oxyhb curve leftward increasing O 2 affinity). Initially, acidosis counterbalances this by increasing the P50. Although replacement of PO4 is of theoretical benefit and it is standard of care in most institutions, studies have shown no clear benefit. PO4 ++ replacement can result in decreased levels of Mg/Ca ++ ; therefore these levels must also be closely monitored. In maintaince fluids, K + PO4 ++ rather than K + Cl - can be used to avoid the hyperchloremic acidosis sometimes seen during therapy. Diagnosis: Clinical Presentation History: polyuria, polydipsia, polyphagia, and weight loss over the preceding weeks Precipitating factor: often infections, but often unidentifiable Presenting signs: abdominal pain, vomiting and altered sensorium Physical exam: lethargy, dehydration, hyperpnea and acetone ( bitter almonds ) detected on their breath and often acutely ill PICU admission: patients with profound shock, altered level of consciousness, respiratory failure, arrhythmias, or severe acidosis Differentiating DKA and HHS DKA typically develops in younger, lean patients with type 1 diabetes. HHS is more likely in older, obese, type 2 diabetes patients and symptoms may develop more slowly. Physical exam clues that help differentiate DKA from HHS: o Acanthosis in axilla or neck area typical in Type 2 DM o Assess thyroid palpable thyroid maybe consistent with autoimmune mediated endocrinopathy type I DM o Kussmaul respirations deep respirations seen with type I DM o Acetone on breath c/w type I DM o Body habitus lean or large DKA & HHS 3

4 Laboratory Findings DKA: Serum glucose >300 mg/dl Blood ph < 7.3 Ketonuria, glucosuria [HCO3-] < 15 meq/l Elevated betahydroxybutyrate in blood. HHS: Hyperglycemia is more severe Blood ph may be > 7.30 Absent/trace ketones in urine [HCO3-] may not be low Serum osmolality >320 mmol/kg Osm = [glu/18] +[BUN/2.8] +[2(Na + K)] Other laboratory values that can be abnormal in DKA patients but may not represent significant comorbid disease are as follows: Elevated WBC: usually due to stress & dehydration Elevated amylase: usually nonpancreatic source, i.e. parotid, lipase must be checked since pancreatitis is associated with HHS Prolonged PT, PTT: etiology unclear Admission labs / studies for DKA patient: Comprehensive chemistry panel ABG / VBG CBC w/diff Serum osmoles Urine ketones Serum beta-hydroxybutyrate Serum lactate Insulin, C-peptide Hemoglobin A-1C T4, TSH Anti-Islet cell Ab, anti-insulin Ab (for new onset) U/A +/- Blood, urine culture +/- CXR and EKG Head CT if comatose Management of DKA in the PICU Fluids DKA patients usually present with severe dehydration of 10-15% deficit. Initial fluid therapy should be aimed at resuscitation and reversal of shock. Begin with 10-20ml/kg bolus of isotonic crystalloid (NS) and repeat if shock persists (i.e. tachycardia, poor perfusion, borderline or low BP). For patients in DKA, fluids must be administered to correct shock but over aggressive rapid hydration should be avoided. There is concern of rapid hydration inciting cerebral edema and no clear data exists to date supporting or refuting this theory. 3 components to fluid management in DKA: Deficit DKA & HHS 4

5 o The fluid deficit is typically replaced over the first 24 hours once the shock state is treated. Ongoing losses (urine, emesis) o Some patients will continue to have a significant ongoing osmotic diuresis throughout the early part of therapy. These losses should be accounted for and replaced to prevent persistent shock. Maintenance o Isotonic maintenance fluids are started as 0.9%NaCl (NS). Typically isotonic fluids (NS) are preferable in order to keep the serum Na+ from dropping during rehydration and to help prevent cerebral edema. However, if with therapy the corrected serum Na+ is becoming quite high (i.e. Na + > 155) the maintenance fluids can be changed to 1/2 or 3/4NS. o In the absence of hyperkalemia (K + <5.0 meq/l) and in the presence of adequate renal function, 40 meq/l of K + can be added to the fluids (generally half as K + Cl - and half as K + PO4 - as discussed previously). Example of a 20kg child: o Deficit: patient presents 15% dehydrated the calculated deficit is 3 Liters. She receives 30ml/kg of NS in the ED 600ml. The remainder of the fluid deficit should be replaced over 24 hrs: = 2400 or 100ml/hr of IVF. o On going losses: Suppose the same 20kg child is voiding 200 ml/hr, the losses can be replaced with either intermittent fluid blouses or with a urine output replacement cc per cc or ½cc per cc every 2-4hrs. Either NS or ½NS can be used for replacement depending on the corrected serum Na. Once the urine output has normalized, <5cc/kg/hr, the replacement can be stopped. o Maintaince: = 60 ml/hr (per the 4/2/1 rule) Total hourly fluid rate = deficit + maint + ongoing losses = 100ml/hr + 60ml/hr + urine replacement (i.e. 200 cc of NS x2hrs) Adding Dextrose Change IVF when o Blood sugar < 300mg/dL, D5 NS o Blood sugar < 200mg/dL, start D10 NS 2 bag system: one bag containing D5 fluids and a second bag with NS along with each bag having 20 meq K + Cl meq K + PO4 - are titrated to maintain a blood glucose of mg/dl. o For example: if the blood glucose is 230mg/dL with IVF at 160 ml/hr, start D5%NS bag at 80 ml/hr and decrease NS bag to 80 ml/hr = total fluids 160 ml/hr at D2.5%. DKA & HHS 5

6 o Suppose next glucose is 180mg/dL increase the D5% bag to 100 ml/hr and decrease the NS bag to 60 ml/hr. By appropriately titrating the glucose intake, rapid blood sugar decrease to hypoglycemic levels can be prevented. 2-4 grams of glucose per unit of insulin is required to maintain a stable blood glucose level. Insulin therapy A continuous infusion of regular insulin at 0.1 U/kg/hr. o If the blood glucose levels are decreasing too quickly, dextrose should be added to the IVF but the insulin infusion should continue at the same rate since it is the primary treatment to correct the acidosis. o It s easily adjustable and safe. o Hypoglycemia is generally avoided with a predictable, consistent drop in glucose o Potentially, less hypokalemia and more inhibition of lipolysis occurs with a consistent dose of insulin There is no established need for an initial IV bolus of 0.1 U/kg and no data to support subcutaneous insulin administration for DKA. This rate should produce a gradual decrease in glucose levels of about mg/dl per hour. In HHS patients, the insulin drip may require titration to achieve the desired rate of fall of glucose and to improve the hyperosmolar state. Patients with HHS are typically type-2 diabetics and are insulin resistant rather than deficient and therefore may require more insulin to correct the hyperosmolar state. *Note: Insulin attaches to IV tubing and glass. Therefore, the insulin infusion should be run through the tubing for 5-30 minutes prior to being attached to the patient to provide a consistent dose of drug delivery. Hyperglycemia corrects prior to the acidosis. The insulin infusion is continued until the following conditions are met: o HCO3 - > 18 o Blood ph > 7.3 o Anion gap < 12 o Improved level of consciousness (GCS 15) o Able to tolerate oral intake Transitioning from continuous infusion to SQ insulin: order of events o Check glucose, let the patient eat/drink, administer SQ dose per sliding scale, and then stop the insulin drip. Heplock the dextrose containing IVF only after confirming adequate oral intake without emesis in order to avoid hypoglycemia. o AT this point, the endocrinologist can initiate recommendations regarding a regular and long acting insulin regimen. DKA & HHS 6

7 10 key elements to managing DKA in the ICU: Attention to detail is important. (These are meant to be basic guidelines.) 1) Ensure 2 large bore IVs are present. A line for lab draws should be established: a large bore PIV or an arterial line. A central venous catheter would not be a first choice due to risk of thrombosis unless the patient presents in shock. 2) All patients should be placed on a cardiac monitor. Serum glucose should be monitored hourly and a chem.-10 with Na, K, Ca, Mg, PO 4 along with a blood gas should be done every 4 hours. 3) A Foley to monitor urine output is critical to assess ongoing losses and to direct fluid therapy. 4) Obtain hourly neuro assessments including a GCS. 5) With ongoing therapy and rehydration the serum sodium should rise. A decreasing sodium level can be a risk factor for cerebral edema. 6) A K+ level less than 3.0mEq/L should be corrected aggressively. Fatal arrhythmias can occur at values <2.0 7) NaHCO3 should not be administered to DKA patients despite the severity of acidosis. The risk of mortality and CNS complication are increased by bicarbonate administration. 8) The insulin drip should not be titrated; the acidosis will only correct with appropriate insulin administration. 9) Mannitol (0.25 gm/kg) should be at the bedside for acute cerebral edema (i.e. pupillary changes, acute change in LOC) 10) Order several bags of IV fluids with and without dextrose at the time of admission to seamlessly transition the patient to dextrose containing fluids as the blood sugars decrease to 300 mg/dl. The IV fluids can be Y together to achieve the desired dextrose concentration to maintain blood glucose levels between mg/dl. DKA & HHS 7

8 Complications Cerebral Edema: This is the most serious complication of DKA. The pathophysiology is unclear. The potential etiologies include: o Vasogenic edema: leaking of fluid across the blood-brain-barrier o Cytotoxic edema: neuronal swelling due to cellular injury or rapid extracellular osmolar changes Risk factors for cerebral edema include: o Children < 5 years of age o High BUN suggesting greater dehydration o Severity of acidosis o Bicarbonate administration o New diagnosis of diabetes o Sodium levels don t rise as expected with insulin treatment (i.e. fall in serum osmolality) Assure serum Na+ level is rising with rehydration Hourly neuro checks should be done for 12 hours after treatment initiation. Any changes in neurologic status necessitate a stat head CT. Patients with a GCS <8 necessitate intubation. o For intubation induction, use the appropriate medications to blunt a spike in the ICP. o Once intubated, assure the mechanical ventilation matches the patient s CO 2 level prior to intubation; i.e. if the patient is hyperventilating to a CO 2 level of 11, match it to prevent worsening ICP elevation. Mannitol should be administered, 0.5 gm/kg IV slow push, for acute mental status changes. Assure a foley is placed for the ensuing diuresis. If the serum Na + is dropping with therapy, consider hypertonic saline 3%NS in a small bolus of 3-5cc/kg. If head CT reveals cerebral edema or the patient has deteriorating neurologic status, consult neurosurgery for potential need of ICP monitoring. Persistent dehydration can also present with mental status changes. Therefore the patient s hydration status should be closely monitored and fluids aggressively replaced. Hypoglycemia can also present with mental status changes and must be ruled out while evaluating a patient with sudden drop in GCS. Hyperchloremic metabolic acidosis May occur as part of normal rehydration therapy and has no has no significant clinical consequences. However, if acidosis persists after the first 24 hours, urine ketones should be followed to assure the DKA is resolving. The length of insulin therapy is not prolonged due to hyperchloremic metabolic acidosis. DKA & HHS 8

9 ARDS Occasionally, DKA patients present in shock and may have low albumin at the time of presentation due to poor nutrition. Rapid fluid shifts during resuscitation and rehydration may lead to capillary leak and interstitial pulmonary edema and ARDS. It is a rare complication in the pediatric population. Thrombosis Because of severe dehydration and a general low flow state, a risk of thrombosis is present with central line placement. Thrombii have particularly been noted with femoral lines. Consider subclavian or IJ lines for patients in shock that require CVP monitoring or in whom access is difficult. Consider low dose heparin drip (10 U/kg/hr) to help prevent clot formation. Hypoglycemia Assure the IVF and insulin therapy is appropriately managed to prevent low blood sugar levels. Hypokalemia Can be avoided with frequent monitoring and meticulous attention to fluid management. Hypokalemia can cause fatal arrhythmias. Saline boluses, or calcium can amplify the decrease in potassium levels. Therefore, every effort should be made to maintain a level of 4.0 meq/l. DKA & HHS 9