DKA and Hypoglycemia

Diagnostic criteria
  1. Elevated sugars of >250
  2. Ketonemia or ketonuria (  In early DKA, acetoacetate concentration is low and could be falsely negative. Conversely, β-OHB is an early and abundant ketoacid, which may first signal the development of DKA ) 
  3. Acidosis​ with Ph<7.3 or Biacarb <18
  4. Elevated anion gap
There are two major hyperglycemic crises associated with diabetes: diabetic ketoacidosis and the hyperosmotic hyperglycemic state. Diabetic ketoacidosis primarily results from insulin deficiency and hyperglycemic hyperosmolar state (HHS) from severe insulin resistance. Both of the crises result in subsequent glucagon and counter-regulatory hormone excess from lack of suppression from insulin.
With the lack of insulin, there is decreased storage of glucose, increased breakdown of glycogen stores, and increased synthesis of glucose in both the liver and kidney. While elevated blood glucose from the increased glycogenolysis and gluconeogenesis is certainly a major problem, the cornerstone of DKA lies in ketogenesis. Insulin will inhibit lipolysis and oxidation of free fatty acids. Insulin also increases oxidation of ketones in the peripheral tissues. Thus there is both overproduction and underutilization of ketones in an insulin-deficient state. Also, glucagon itself will stimulate hormone-sensitive lipase, which in turn mobilizes adipose stores and converts triglycerides to free fatty acids. These free fatty acids are then transported across the mitochondrial membrane, and they are eventually used for synthesis of ketones, namely in the form of acetoacetic acid, which is oxidized to form betahydroxybutyrate or decarboxylated to form acetone. 
Conversely, in HHS there is usually enough insulin to suppress ketogenesis, but not control blood sugars. In HHNK, blood sugars are usually higher as ketoacidosis produces more severe symptoms and presentation is usually earlier. 
Symptoms of ketosis include nausea, vomiting, abdominal pain, and respiratory insufficiency. Increased ketone production results in the attempt for the body to buffer with bicarbonate. Because of this buffering, there is an increase in unmeasured anions that cause a gapped metabolic acidosis. 
LFTs, Amylase, lipase, WBC and CPK can all be elevated.
Venous PH is 0.03 less than arterial PH. 
Urine Ketones do not measure beta-hydroxybutyrate. Both serum and dipstick measurements are based on acetoacetate. 
Abdominal pain is very common as a result of the acidosis, but if it persists despite resolution of near normal pH, consider searching for an intra-abdominal cause of the initial decompensation into DKA.  
Blood glucose levels should be checked every hour until anion gap is closed. 
IV fluids: Elevated blood glucose shifts water into the extracellular compartment. However, the expansion of the extra-cellular compartment is short lived as the ability to reabsorb glucose at the level of the renal tubule is limited and osmotic diuresis occurs. Thus, glycosuria and polyuria occur with resultant hypovolemia. However, in patients who is not making any urine ( ESRD on IHD), the polyuria is non existent and they may not be volume depleted. Hence, determine volume status first and don't blindly give iv fluids for the sake of conforming to protocols or so called dilution of serum sugars.
Water losses are typically greater than electrolyte losses, and thus there is an increased serum osmolality and ocassionaly hypernatremia. When hypernatremia is present, changing fluids to 1/2NS is reasonable, once hypovolemia is corrected. 
Ultimately the total volume deficit should be replete within the first 24 h, with half of the estimated total body deficit given over the first 8–12 h. 
Choice of fluids: Most of the guidelines include normal saline as the intial fluid of choice. However, be aware that Ph of NS is 5.6 and to give such an acidic fluid to someone already in severe acidemia doesn't make much sense to me. Also, normal saline may increase the risk of hyperchloremic acidosis once DKA is resolved. My fluid of choice in DKA is balanced fluids with more neutral Ph like plasmalyte or ringer lactate. 
Insulin: The key element in the pathogenesis of DKA is insulin deficiency and hence, replacing insulin is the cornerstone of DKA therapy, with or without iv fluids. Insulin will quickly shift the potassium into the cells resulting in hypokalemia, sometime very severe to the point of rsking life. If DKA or HHS is suspected, never start any insulin without checking potassium levels. Sugars of even 1000 for another extra hour may not kill the patient but severe hypokalemia can. Initiate insulin only if the potassium is >3.5. 
Start with 0.1 u/kg/hr of regular insulin, with out any insulin bolus. When glucose is less than <200, add dextrose to fluids and decrease the rate to 0.05units/kg/hr. Keep serum glucose levels between 150-200 until DKAis resolved. 
Aim to correct sugar by 70-100 an hour to prevent rapid changes in osmolarity. If sugars are trending down nicely, continue the same insulin rate. If not, double the infusion rate every hour. Rapid lowering of glucose will result in rapid decrease in plasma osmolarity with a resultant cerebral edema. 
DKA is considered resolved when metabolic parameters are met: Sugars <200, absence of ketonemia, atleast two of the closure of anion gap or Bicarb>15 or PH>7.3, . However, don't get caught up strictly with the absolute numbers. Follow patient clinically. 
If long acting insulin is not started before starting insulin drip, overlap it with iv insulin for at least 2 hours. Intravenous insulin infusion should be continued for 2 hours after giving the subcutaneous insulin to maintain adequate plasma insulin levels. Immediate discontinuation of intravenous insulin may lead to hyperglycemia or recurrence of ketoacidosis. Patients with known diabetes may be given insulin at the dose they were receiving before the onset of hyperglycaemic crises. In patients with new onset diabetes, a multi-dose insulin regimen should be started at a dose of 0.5 U/kg per day, including regular or rapid-acting and basal insulin until an optimal dose is established. 
Myth 1: when starting insulin drip, should we always hold the basal long acting insulin ? 
That may not be the best management plan. For example, lets assume a patient who takes 96 units of lantus every day and he missed a dose and went into DKA. Technically, if we assume lantus acts over 24 hrs, 96 units per day is roughly 4 units per hour. If he is just placed on insulin drip without resuming his lantus, he should be needing an insulin drip of 4 units /hour forever, even if his anion gap is closed. By continuing the basal insulin, all we need to do is to replace the additonal insulin needs of the body with insulin drip. 
Patients in DKA not only needs the replacement of deficient doses of insulin but also ongoing needs. Also, if a person went into DKA due to an increased insulin requirements from infection, not only they need their basal insulin but also the excess requirements of their body. By continuing the basal insulin like lantus, they are on insulin drip much shorter and we also don't have to worry about bridging with long acting insulin after stopping the drip. Infact, as long as they are getting some form of insulin, they may not even need a drip. 
Myth 2: Should we always bolus insulin before staring the drip ? 
Bolus doses before starting drip is falling out of favour and studies didnot show any benefit. The benefit of a bolus dose is to achieve faster insulin levels than with a drip. However, it didn't reflect positively in the outcomes or the duration of DKA.  Diabetes Care. 2008;31(11):2081–5.  J Emerg Med. 2010 May; 38(4):422-7.​
Myth 3: Does insulin drip need to be continued until bicarb level returns to normal ?  
Insulin drip should be continued until the closure of anion gap or absence of serum ketones. ( In UK, they measure hourly bedside ketones instead of glucose). Some physicians mistakenly assume low bicarb as equivalent to persistent DKA and may continue insulin drip until bicarb is normalized.
Please remember that in DKA, almost all patients develop a non anion gap acidosis or hyperchloremic acidosis during the resolution phase of the ketoacidosis. This occurs because iv fluids reverses hypovolemia and improves renal function, which accelerates the loss of ketoacid anions with sodium and potassium in the urine. The loss of these ketoacid anion salts into the urine represent "potential" bicarbonate loss from the body. Insulin therapy will have no further effect on the acidosis when this stage evolves. This doesn't mean an ongoing DKA and hence, there is no need to continue insulin drip once the gap is closed. The hyperchloremic acidosis will slowly resolve as the kidneys excrete ammonium chloride (NH4Cl) and regenerate bicarbonate.
Also, intravenous administration of sodium and chloride-containing fluids leads to hyperchloremic metabolic acidosis and further HCO3 reduction. This is an important point as persistent decrease in plasma HCO3concentration should not be interpreted as a sign of persistent DKA, if ketosis and hyperglycemia resolved. 
Myth 4: Does DKA always need to be treated with insulin drip?
SQ Insulin vs. IV insulin: Patients were randomized to SQ lispro (0.3u/kg, followed by 0.1u/kg per hour until the blood sugar decreased to 250mg/dL, and then 0.05u/kg per hour until resolution of DKA) or IV infusion of regular insulin (a 0.1u/kg bolus followed by 0.1u/kg/hour until blood sugar decreased to 250mg/dl, and then 0.05u/kg/hour until resolution of DKA). There were no significant differences between the groups in the rate of decline of the plasma glucose level, correction of acid-base parameters, duration of insulin treatment or hospital stay, or amount of insulin given until DKA was resolved. Diabetes Care. 2004;27(8):1873–8.  Diabetes Care. 2009 Jul;32(7):1164-9.  Am J Med. 2004;117:291–6Int J Clin Pract. 2006 Apr; 60(4):429-33
Electrolyte therapy:
Most commonly,  physicians add 20meg kcl to the iv fluid bag and run it at 100cc/hr, to keep potassium above 4. please be aware that at 100cc/hr, it would take 10 hours for the patient to get 20meq of kcl. Some times, even with severe hypokalemia, we may fail to correct potassium soon enough thinking that they are already getting potassium as drip in the iv fluids. This may lead to adverse events. My personal preference is to correct potassium separately with extra doses of iv or oral Kcl. 
Sodium bicarbonate therapy: There is not much utility for bicarb drip in DKA unless Ph< 6.9. In a small randomized prospective study, the administration of bicarbonate in severe diabetic ketoacidosis (arterial pH 6.9–7.14) did not significantly affect the rate of glucose decline, ketone levels or correction of acidosis . Ann Intern Med. 1986;105:836–40 , Crit Care Med. 1999;27(12):2690–3Diabetes Care. 2002;25(11):2113–4. 
Most frequently, taking measures to stop ongoing ketosis will correct acidemia, as the production of new ketones is minimized and existing ketones will eventually get metabolized into bicarb. 
However, when patients go from anion gap acidosis to hyperchloremic acidosis, starting biacrb drip may correct acidemia faster than otherwise. Even with out bicarb drip, patients in hyperchloremic acidosis will slowly resolve their acidemia, if they are making enough urine and not getting anymore chloride rich fluids. 
C-Peptide is suppressed in exogenous insulin use 
Consider obtaining Cortisol level during hypoglycemia if adrenal suppression is suspected.   
Sulfonylurea overdose can last as long as 72 hours, even with shorter acting agents. 
Check for C-peptide levels, sulfonyl urea levels, insulin, cortisol 
Clinical features: 
Sulfonylurea agents have a time to peak effect of approximately 4-6 hours, patients who develop toxicity after exposure will invariably become hypoglycemic within eight hours.   
Hypoglycemia should initially be treated with intravenous dextrose boluses to restore normal blood glucose levels 
Octreotide (Somatostatin), a synthetically derived hormone that suppresses insulin release from beta islet cells, can act as a specific sulfonylurea antidote. It is given in a dose of 50 ug SC Q6.  
  • Hyperosmolarity is Osm >320
  • Pseuhyponatremia correction: add 1.6 to the sodium levels for every 100mg/dl of sugars above 200. 
  • DKA in dialysis patients : These patients have baseline anion gap acidosis with low bicarbonate. Without an elevated ketones, they are mistakenly labelled as DKA based on high glucose values. Also, even when they are hypervolemic, they are given lots of iv fluids by physicians trying to religiously follow the protocols and guidelines. 

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