DKA and HHS

Definition: DKA and Hyperglycemic hyperosmolar state are common potentially lethal complications of diabetes. Occurs in 5% of patients with T1DM annually; it is seen much less frequently in T2DM.

DKA is characterized by a plasma glucose level of >250 mg/dL in association with an arterial pH <7.30 or serum bicarbonate level of <15 mEq/L - 18 mEq/L and moderate ketonemia or ketonuria.

• It is a relative insulin deficiency with an excess of counterregulatory hormones (catecholamine, glucagon), leading to excess production and decreased utilization of glucose, osmotic diuresis, ketone production, and development of AG metabolic acidosis.

• Patients with type 2 diabetes also susceptible during acute illness (especially of African American or Hispanic descent) referred to as "ketosis-prone type 2 diabetes", likely due to greater relative insulinopenia

HHNS includes marked hyperglycemia (400 mg/dL or more) and elevated serum osmolality (>315 mOsm/kg), often accompanied by impaired mental status. It is a condition of severe hyperglycemia, increased serum osmolality, and profound dehydration. 30 - 40% of cases of T2DM. Less common than DKA. Ketoacidosis is absent.

Sx/Si:

• Malaise, generalized weakness, fatigue, PPP, N/V, fever, abd pain, tachycardia, deep, and labored breathing (Kussmaul), fruity odor, shock, and coma.

• Tachycardia, hypotension, orthostatic hypotension, tachypnea (Kussmaul respiration), respiratory distress, abdominal tenderness (may resemble acute pancreatitis or surgical abdomen), lethary/obtundation/cerebral edema/coma.

Precipitating causes:

• Non-compliant with medications, inadequate insulin administration, infections (pneumonia, UTI, gastroenteritis, sepsis), infarction (cardiac, cerebral, mesenteric, peripheral), trauma pregnancy, alcohol use, cocaine, recent dietary changes); mental status changes, comorbid states; medications (glucocorticoids, diuretics, lithium, phenytoin, beta-blockers, and CCB).

Labs:

• CBC with diff, electrolytes, ABG. AGMA and positive betahdroxybutyrate or ketones (semiquantitative measurement of acetone, acetoacetate, betahydroxybutyrate).

• Hyperglycemia

• Urine ketones

• Hyponatremia, hyperkalemia, azotemia, and hypersosmolality.

• Serum amylase, transaminase, and/or triglyceride levels may be elevated.

• ECG

• Cardiac enzymes, lactate, plasma osmolality, toxicology screen, urinalysis.

Dx:

• DKA:

  • Young, IDDM

  • Rapid onset

  • hyperglycemia (BG >250 mg/dL)

  • Acidosis pH <7.3 or HCO3 <15

  • Venous pH can be used after initial draw by adding 0.03 to venous pH value.

  • An increased AG

    • High anion gap reflects degree of acidosis and hydration, calculated as: Na⁺(Cl^- + HCO3^-) (meq/L). Use uncorrected Na⁺.

    • Normal anion gap (AG) = serum albumin x 3. High AG >10-12. mEq/L.

  • Ketosis (ketonemia or large ketonuria) - beta-hydroxybutyrate and acetoacetic acid.

  • Calculated osmolality should be compared with measured osmolality to exclude unmeasured osmoles (ethanol, methanol) if toxic ingestion is suspected

    • Serum osmolality (mOsm/L) = 2(Na⁺+K⁺ in mEq/L) + Glucose (mg/dL) /18 + BUN (mg/dL)/2.8

• HHNS:

  • Elderly

  • Gradual onset over days or weeks

  • Severe hyperglycemia, >600, no ketonemia

  • dehydration

  • absence of acidosis HCO > 15 - 20 mEq/L, pH >7.3

  • Sr osmolality >320 mOsm/kg

• Dilutional effect on sodium by hyperglycemic state, sodium appears falsely low;

  • Corrected by adding 1.6 mEq to the sodium value for every 100 mg/dL increase in glucose

  • Na + (Glu mg/dl - 100) x 1.6 divided by 100

• Metabolic acidosis > Sr. K+ elevation

• Depeltion of Mg > osmotic diuresis

• Phosphate initial elev, but after insulin adm, phos reenter cells > hypophosphatemia.

Clinical features:

• Altered mental status (usually when serum osmolality ≥360 mOsm/L), hypotension, and severe comorbidities identifies those at highest risk for a bad outcome

• Symptoms: polyuria, polydipsia, weight loss, dehydration, weakness, fatigue, nausea, vomiting, "air hunger", abdominal pain, fatigue, stupor, coma, seizures

• Signs: poor skin turgor, dry mucous membranes, absence of axillary sweat, tachycardia, orthostatic hypotension, Kussmaul respirations (rapid and deep breathing as respiratory compensation for metabolic acidosis), fruity breath odor from ketonemia, emesis and abdominal guarding, guaiac-positive stools resulting from hemorrhagic gastritis

Management of DKA:

• Confirm diagnosis (▲ plasma glucose, +ve serum ketones, metabolic acidosis)

• Assess what precipitated the episode (noncompliance, infection, trauma, infarction, cocaine)? Initiate appropriate w/up concurrently (cultures, ECG CXR)

• Admit to hospital; ICU for frequent monitoring or if pH <7 or unconscious.

• Assess:

  • Serum electrolytes (K+, Na+, Mg2+, Cl-, HCO3-, PO4.

  • Acid-base status: pH, HCO3-, PaCO2, beta-hydroxybutyrate

  • Renal function (creatinine, urine output)

  • NGT in patient who has altered mental status, vomiting to prevent aspiration of gastric contents.

• Fluid replacement: IV access. Typical fluid deficit DKA, 4 - 5 L, in HHNS, 6 - 10 L.

• Estimate by: Recent body wt of patient - current body wt of patient.

• Degree of dehydration is quantified as %: 7% - 9% of body weight. Hypotension indicates a loss of >10% of body fluids.

• In hours 1 & 2: Give 0.9NS initially, infuse rapidly 1-3 L or at 15 - 20ml/kg/h (1L/h), until vital signs have stabilized and UO is established. This can be done in the absence of cardiac compromise.

• If corrected Sr. Na+ >150 (severe hypernatremia) use 1/2 NS instead.

• Switch to 1/2 NS after 2 - 3 L of NS is given, contd. at 7.5 ml/kg/h, then as needed (150 - 300 ml/h). Do not exceed a change in osmolality >3 mOsm/kg/hr.

• Monitor UO. Foley if Pt. in coma. Also NG tube if in coma.

• I/O. Get patient into positive fluid balance.

• Short acting Insulin. 10 - 15 units (0.1 units/Kg ) IV bolus or 0.3 units/kg IM. Most centers do not give bolus doses.

• F/U 0.1 units/Kg/hr IV continuous infusion.

  • A sol of regular Insulin, 100 U in 500 ml of 0.9NS, infused at rate of 50 ml/hr gives 10 units/hr of insulin.

  • A solution of regular insulin, 100 U in 100 mL of 0.9NS, infused at a rate of 10 mL/hr gives 10 units/hr of insulin.

• Do capillary blood sugar check every hr, then q4h for the first 24 hr after DKA resolved. Check electrolytes q2hr and then q4 h for the first 24 hr after DKA resolved.

• Blood Glucose should fall at rate of 50 - 75 mg/dL/hr. If no response in 2-4 h, increase dose to 2-3 times.

• If initial serum potassium is <3.3 meq/L, do not give insulin until potassium is corrected to >3.3 meq/L.

• Excessively rapid correction of hyperglycemia at rates >100 mg/dL/hr should be avoided to reduce the risk of osmotic encephalopathy.

• When Sr. glu: 250 mg/dL, switch fluids to D5W in 0.45% saline at 125 - 250 mL/hr and insulin infusion decreased to 0.05 units/kg/hr.

• Maintenance insulin infusion rate 1 - 2 units/hr can be continued indefinitely, until the patient is clinically improved, the serum HCO3: >15 mEq/L, and the AG closed.

• Resolution of ketoacidosis includes blood glucose < 200 mg/dL, and two of the following: serum bicarbonate > 15 mEq/L, pH > 7.3, calculated anion gap < 12 mEq/L.

• Once the anion gap normalizes, and the patient is able to eat, switch the patient to long-acting Lantus insulin sc, considering a fixed rate. The insulin drip is to continue 1 - 2 hours after the patient has received subcutaneous insulin and has been fed. The insulin drip will be supplemented with dextrose infusion if Glucose levels also below 250.

• Keep an eye on the potassium. If the potassium falls below 4, start supplementing the IV drip with potassium.

  • Insulin infusion must continue for 2-3 hrs, after sc insulin has been given. Even relatively brief periods of inadequate insulin administration in this transition phase may result in DKA relapse.

  • Replace K+ if Pt. has UO (no renal failure) >50 ml/hr

    • If K⁺< 3.3 mEq/L, hold insulin and give 20 - 30 mEq/hr until K⁺ > 3.3 mEq/L.

    • If K⁺ between 3.3 - 5.2 mEq/lL, give 20-30 mEq Kphos in each liter of IV fluid to keep K⁺ between 4 - 5 mEq/lL.

    • If K⁺>5.2 mEq/L, do not give K⁺ but check serum K⁺ q2 hours.

  • Both basal and premeal doses of insulin will need to be restarted, so stopping at a logical time, for example, before breakfast or in the evening, is preferred.

  • TDD = 0.5 units/kg. Give 50% as Lantus (basal), and 50% as aspart (bolus) divided over 3 doses AC tid, given with the first bite of food. Adjust moderate to high correction dose.

• Check blood sugar q4hr and electrolytes q6hr.

• Bicarbonate is usually not required. Only when shock or coma, pH: <7.1, serum bicarbonate <5 mEq/L, cardiac and respiratory dysfunction, or severe hyperkalemia.

  • Sodium bicarbonate, 50 - 100 mEq in 500 mL of 0.45% saline + KCl (20 meq/L) infused over 30 - 60 minutes, repeat q2h till pH: >7.

  • 1 amp (44.6 mEq) Infuse till arterial pH: > 7. Watch out for hypokalemia

• Tx severe hypophosphatemia and hypomagnesemia: In patients with serum phosphate < 1.0 mg/dl, 20-30 mEq potassium phosphate in replacement fluids may be considered

  • Infuse at rate (3-4 mEq/hr).

  • Magnesium sulfate, 2 gm IVBP x 1 - 2 times PRN

• IV ABX

* Tx hypoglycemia with 50% dextrose IV where

ccD50 = (100 - BG mg/dl) x 0.4

Sr. Na tends to rise as hyperglycemia is corrected; failure to observe this trend or fall in serum sodium during initial therapy for DKA suggests that patient is being overhydrated with free water.

Closure of AG and normalization of serum bicarbonate are more reliable indices of metabolic recovery.

Serial serum ketones is not required, as ketonemia lags behind clinical recovery. Repeat beta-hdyroxybutyrate is more appropriate.

Common complications:

• Hypoglycemia, hypokalemia due to overtreatment with insulin and bicarbonate.

• Hypokalemia is the most frequent cause of death in treatment of DKA. Monitor Sr. K carefully.

• Hyperchloremic non-anion gap acidosis can be seen in recovery phase and is self-limited. The change to 0.45% saline will help minimize it. Or alternatively giving lactated Ringer's IV solution instead of NS.

• Fluid therapy can decrease glucose, but insulin is needed for resolution of ketonemia.

• Cerebral edema occurs in 0.3 - 1.0% of DKA episodes in children, rare in adults, and associated with high mortality rate. Symptoms include headache, seizures, sphincter incontinence, pupillary changes, high blood pressure, low heart rate, respiratory depression, and deterioration in consciousness. Preventive measures include gradual reduction of plasma osmolarity and glucose, and avoiding aggressive hydration. Treatment includes mannitol and mechanical ventilation.

Hyperglycemic Hyperosmolar State (HHS).

Typical Pt. is elderly with type 2 DM, with several weeks of polyuria, weight loss, and diminished oral intake, leading to altered mental status, lethargy, or coma.

• Profound dehydration, hyperosmolality, hypotension, tachycardia, and altered mental status.

• Nausea, vomiting, abdominal pain, and Kussmaul respirations typically seen in DKA is notably absent in HHS.

• Precipitated by MI, stroke, sepsis, pneumonia, and other serious infections

• Debilitating conditions (prior stroke or dementia) or social situation that compromises water intake usually contributes to the development of the disorder.

• Glucose >1000 mg/dL, Osm >350 mOsm/L, prerenal azotemia.

• Corrected Na is high

• No ketonemia or acidosis

• Small AG due to increased lactic acid

• Moderate ketonuria, if present, is secondary to starvation.

MANAGEMENT OF DKA

Disposition. Generally, patients with DKA will require admission to the hospital in an intensive-care setting. This allows access to cardiac monitoring and close observation while providing aggressive fluid resuscitation and electrolyte replacement. It also allows for the titration of insulin by infusion with frequent blood-glucose monitoring.

The patient's diet should be designated as nothing by mouth (NPO). Further carbohydrate and/or fat ingestion have the potential for undermining efforts to eliminate ketoacids and control blood glucose levels, and there is an increased risk of vomiting and aspiration in DKA.

Fluid management. Fluid resuscitation is the first step in DKA therapy.³ The total fluid deficit is estimated to be 3.0 to 6.0 L in DKA. Fluid is replaced as a crystalloid bolus to improve GFR followed by an infusion to maintain it.

As a rule, a bolus of 15-20 mL/kg (1.0-1.5 L) of normal saline³ is given in the first hour. This may prove overly aggressive for patients with cardiac compromise and should be adjusted accordingly.

The rate and fluid type of initial infusion following the bolus is based on the patient's hemodynamics, hydration, electrolyte levels, and urinary output. For hemodynamically stable patients with adequate urine output, start with 0.45% NaCl or 0.9% NaCl at 250-500 mL/hr. For patients with normal or high corrected serum sodium, use 0.45% NaCl. For patients with low corrected serum sodium, 0.9% NaCl is advised.³

Hemodynamically stable patients who require 40 mEq/L of potassium supplementation (see Potassium in the next column) should be given 0.45% NaCl, as the added potassium increases the osmolality of the solution.

Patients with cardiac compromise or poor urine output may become fluid-overloaded or could potentially experience too rapid a drop in serum osmolality and should have a slower infusion.

Regular insulin. Insulin may be given either in an IV bolus followed by infusion or by infusion alone. The ADA recommends a bolus of 0.1 units/kg followed by a continuous infusion of 0.1 units/kg/hr. If no bolus is given, the recommended initial IV infusion rate is 0.14 units/kg/hr.

Aim to decrease the serum glucose by at least 50-70 mg/dL in the first hour, followed by a steady decline until the level is ≤200 mg/dL. Once the glucose level has dropped below 200 mg, the goal is to maintain it between 150-200 mg/dL until the acidosis resolves.

Potassium. Potassium is the primary intracellular cation. About 98% of potassium is stored within the cells of the body. Only 2% is present in the extracellular fluid (ECF).

During the evolution of DKA, potassium is lost in a number of ways. Osmotic diuresis causes potassium loss through renal excretion. Both increased serum osmolality and the lack of circulating insulin cause potassium to move out of the cells and into the ECF, compounding this loss.

In addition, diuresis-induced hypovolemia increases aldosterone levels that promote sodium retention at the expense of potassium.⁵ Patients experiencing vomiting or diarrhea may also experience GI losses. In total, it is estimated that patients with DKA suffer a 3-5 mEq/kg potassium deficit.⁷

Despite these losses, the increased delivery of potassium to the ECF from the intracellular space usually causes the serum concentration of potassium to be normal and, in some cases, high. This regular concentration of the ECF potassium creates the illusion of normalcy, despite the fact that total body potassium stores are almost always low.

This concept becomes important in understanding the risk of potentially devastating hypokalemia in treating DKA. Insulin administration causes a rapid shift of potassium out of the ECF and into the cells. In addition, fluid resuscitation can be expected to cause a dilutional decrease in serum potassium concentration.

For this reason, the ADA recommendations encompass a three-tiered approach to potassium regulation during fluid and insulin therapy for DKA:

Patients with a serum potassium concentration >5.2 mEq/L should receive insulin and IV fluid without potassium, but the level should be checked every two hours.

Patients with a serum potassium concentration between 3.3 and 5.2 mEq/L should have 20-30 mEq of potassium added to each liter of IV fluid with a goal to maintain a level of 4.0-5.0 mEq/L. The addition of potassium to the infusion should be delayed until urine output has been established.

Patients with a serum potassium concentration <3.3 mEq/L should receive 20.0-30.0 mEq/hr of potassium until the concentration exceeds 3.3 mEq/L. These patients should not receive IV insulin until the serum potassium concentration is >3.3.

Other electrolytes. Sodium: Sodium concentration may vary. Both sodium and water are lost during osmotic diuresis; however, water tends to be lost in a proportionally greater amount. As the patient becomes dehydrated, this increases the serum sodium concentration.

On the other hand, increased serum osmolality draws water out of the cells, which dilutes the sodium and lowers the concentration.⁵ The sodium and water are replaced with fluid resuscitation.

Phosphate: Phosphate is the most abundant intracellular anion. Like potassium, it is present in small concentrations in the ECF, and its concentration decreases with insulin therapy. However, phosphate concentration is most important inside the cell, where it is involved in energy management and cell membrane maintenance. In DKA, phosphate replacement has not been shown to improve outcomes.³

Because IV phosphate replacement may induce hypocalcemia and hypomagnesemia,⁵ therapy should be limited to patients with serum concentrations <1.0 mg/dL or such complications associated with severe muscle weakness or cell membrane instability as cardiac compromise, respiratory depression and hemolytic anemia.

When given, 20.0-30.0 mEq/L is added to IV fluids, usually in the form of potassium phosphate, to replace some of the potassium chloride being administered.

Magnesium: Stored primarily in and on the bone and not hormonally regulated, magnesium may also be depleted due to renal excretion during osmotic diuresis. Levels should be checked and losses replaced.

Bicarbonate: It is tempting, in a case of metabolic acidosis with low bicarbonate, to try to increase both the pH and the bicarbonate level by administering sodium bicarbonate, but no evidence exists to suggest that this improves outcomes. Furthermore, sodium bicarbonate administration may cause physiologic deterioration,³ including hypokalemia attributable to intracellular potassium shift, worsened cerebral acidosis (theoretically caused by decreased respiratory compensation), decreased tissue oxygen uptake and cerebral edema.

The ADA does recommend bicarbonate replacement therapy for patients with a pH <6.9, as this level results in a multitude of deleterious vascular defects. Bicarbonate should be given as 100 mmol (2 amps) in 400 mL H₂O with 20.0 mEq potassium chloride over two hours. Repeat this therapy until the pH is >7.0.³

Osmolality. While it varies, osmolality in DKA may be high. Rapid correction of hyperosmolality risks cerebral edema, although in DKA this is primarily a complication seen in children and rarely in patients older than age 20 years.

Nevertheless, IV fluid and glucose correction goals are geared toward minimizing any risk to the patient. These goals include cautious fluid resuscitation, avoidance of over-correction of hyperglycemia, and the addition of dextrose to the IV fluid when serum glucose concentration decreases to <200 mg/dL. In any case, the osmolality should be corrected at a rate not to exceed 3 mOsm/kg/hr.

Monitoring. Appropriate therapy for DKA brings about remarkable results leading to resolution. But these interventions may cause a variety of dramatic and potentially harmful effects as well. It is important to monitor patients closely to assure steady progress and avoid adverse events:

• • To allow for precise titration of insulin therapy, perform glucose fingerstick checks every hour until stable³

  • To minimize the risk of excessive hemodilution, monitor and document urine output

  • Monitor electrolytes, BUN, and creatinine every two to four hours³

While pH is typically assessed on presentation as part of an arterial blood gas, subsequent checks may be performed every two to four hours³ on venous blood already drawn as part of electrolyte monitoring. The approximate value of the arterial pH can be obtained by adding 0.03 to the value of the venous pH.

If found to be high upon presentation, calculate serum osmolality every two to four hours.

Three types of ketones are produced in the liver in DKA. The first, acetoacetate, is later converted to acetone (which is acid/base neutral) and beta-hydroxybutyrate. The nitroprusside test is used to detect ketones in the serum or urine. However, this method detects only acetoacetate and acetone. It does not detect beta-hydroxybutyrate, the most abundant ketoacid produced.

This leads to two potential misinterpretations: (1) in the initial evaluation of DKA, low or moderate ketone levels do not rule out the possibility of significant ketoacidosis caused by undetected beta-hydroxybutyrate;¹ and (2) during insulin therapy, some beta-hydroxybutyrate is converted back to acetoacetate. This may cause the levels of acetoacetate to rise during appropriate therapy. If the nitroprusside test is used as a monitor, it may be misinterpreted as showing a worsening of ketosis.⁵

IN A PERFECT WORLD

In a patient with functioning kidneys, the administration of appropriate fluids stimulates osmotic diuresis and improvement in serum glucose levels, pH and ketoacid anion levels. In fact, the kidneys can excrete up to 30% of the ketoacid load.¹

The addition of insulin stops acid production by inhibiting fatty acid liberation from the adipose tissue and ketogenesis by the liver. It also induces glucose uptake, causing serum glucose concentration to fall.

Phosphate levels can be expected to fall to below normal values, but IV replacement is not usually indicated.

The expectation is that glucose levels will be controlled as a consequence of DKA therapy, but the primary goal is cessation of ketoacid overproduction and elimination of these acids from the blood. The insulin infusion should be continued until the ketoacidois is resolved. This can be expected to occur in 12 to 24 hours.

RESOLUTION

Resolution of DKA is determined by the ADA to include the following conditions:³

• • Blood glucose <200 mg/dL

  • Two of the following

  • HCO3- ≥15 mEq/L

  • Venous pH >7.3

  • Calculated anion gap ≤12 mEq/L

  • The decreased gap in combination with the normalization of the bicarbonate level indicates the clearing of the ketoacids

FEEDING/TRANSITION TO SUBCUTANEOUS INSULIN

The first mealtime after the acidosis has resolved and the patient feels that he or she can tolerate food is the time to begin feeding the patient. Subcutaneous insulin should be started simultaneously. Dosing of subcutaneous insulin is given in basal/bolus fashion calculated first as total daily dose (TDD), which is based on insulin therapy the patient received at home prior to losing control. Alternatively, TDD may be estimated at 0.5 to 0.8 units/kg/day in an individual who has not previously been treated with insulin.³ Total daily insulin requirements may be significantly elevated for a few days following the resolution of DKA due to persistently elevated counter-regulatory hormone concentrations. These elevations predispose the patient to going back into acidosis if insulin levels are inadequate or stress levels increase further.

Basal/bolus insulin therapy is generally broken down into long- and short-acting insulin as 50% basal and 50% bolus spread over three meals.

Half of the TDD is given once daily as long-acting basal insulin (usually glargine [Lantus] or detemir [Levemir]). The other half is given as such short-acting insulin analogues as aspart (NovoLog), divided into thirds given at mealtime.

For example, consider an individual weighing 90 kg with new onset type 1 diabetes who presents with DKA and is now controlled. Based on a TDD of 0.6 units/kg/day, a subcutaneous insulin strategy for this patient would include 54 units of insulin daily given as: 27 units basal (long-acting) insulin once daily; and 27 units short-acting insulin divided into thirds at mealtimes (nine units at each meal).

Not all patients tolerate their first meal. Some will vomit, and others may eat only a small portion. During the transitional period as DKA patients are started on PO nutrition, the subcutaneous insulin should be given immediately after the first meal. This prevents hypoglycemia from insulin overdose in the event the patient is unable to eat the full meal.

The insulin and the dextrose infusion should continue one to two hours after beginning subcutaneous insulin. This assures control in an uncertain phase and prevents ketoacid production prior to the basal insulin reaching steady state.³

POTENTIAL COMPLICATIONS

Hyper- or hypoglycemia may occur in patients presenting with severe metabolic derangement. Frequent glucose monitoring with careful titration of IV insulin dosing can help prevent this complication.

Hypokalemia can occur from intracellular shift of potassium with the administration of insulin. To minimize this risk, delay insulin administration when the serum potassium concentration is <3.3 mEq/L, and add potassium to the IV fluid when the concentration is <5.2 mEq/L.

Cerebral edema is a complication primarily seen in children and young adults with DKA. It is rarely seen in adults aged 20 years and older.⁵ While it has been speculated that cerebral edema results from too rapid correction of hyperosmolality, the literature has not supported this conjecture. Nevertheless, it is recommended that serum osmolality be corrected at a rate no greater than 3 mOsm/kg/hr in patients presenting in a hyperosmolar state.⁷

On the other hand, IV administration of sodium bicarbonate to correct the metabolic acidosis has been associated with development of cerebral edema.

Understanding that DKA occurs in the setting of relative insulin deficiency in concert with an inciting stressor should lead to the detection and treatment of the underlying stressor. This has become a major cause of mortality associated with DKA.³

DISCHARGE CONSIDERATIONS

Patient education is key. Noncompliance and/or inability to control diabetes dramatically increase the likelihood for recurrence. This doubles the cost of care for the patient³ and once again exposes him or her to the risks associated with DKA. The patient should have a follow-up appointment with the primary-care provider within seven to 10 days of discharge to assure adequate glucose control and to modify insulin dosing as needed.⁶

Diabetes education should be provided before leaving the hospital. Emphasize the significance of not omitting doses of insulin — especially the importance of continuing and appropriately adjusting basal insulin when patients get sick and may or may not be eating regular meals. Some patients will require referral to a specialized diabetes center for intensive education.

Risk stratification of DKA (glucose > 250 mg/dL)

*Adapted from Kitabchi et al (2007)

DDx:

Hypoglycemia, alcoholic ketoacidosis, lactic acidosis, sepsis, toxic ingestions, other conditions causing

AGMA (methanol, metformin, uremia, paraldehyde, INH, iron tablets, lactic acidosis, ethanol, ethylene glycol, salicylates).

Complications of DKA: Life-threatening

• Lactic acidosis

• Arterial thrombosis

• Cerebral edema

• ARDS

• Rebound ketoacidosis

NORMAL GLUCOSE MANAGEMENT

To fully understand the various facets of effective DKA treatment, it is necessary to be familiar with the roles of select hormones in managing glucose loads.

A nondiabetic adult holds only about 5 g of glucose in circulation at any given time. This is roughly the same amount of glucose contained in a bite-sized candy bar and about one-eighth of the amount found in a 12-oz can of cola. To prevent a doubling or tripling of the serum glucose concentration with the ingestion of common sugar loads, hormonal regulation of glucose concentration must be brisk and effective. On the other hand, to prevent hypoglycemia during periods of fasting, counter-regulation must be equally robust.

The liver is the primary glucose-regulating organ. It responds to insulin and glucagon, which are the main hormones responsible for glucose homeostasis. Both are produced and released by the pancreas. Their actions generally oppose each other in a regulatory/counter-regulatory balance.

Insulin. When the glucose load is absorbed into the blood, insulin is released from the beta cells of the pancreatic islets. The insulin serves a number of functions important to glucose regulation and utilization (Table 1). Overall, it stimulates glucose uptake and utilization as fuel. Insulin also allows for storage of excess glucose for later use. In this way, the presence of insulin provides a mechanism for removing excess glucose from circulation and preventing hyperglycemia, and is thus considered a regulatory hormone.

Glucagon. Glucagon is active primarily in the liver (Table 2), and its effect is essentially the opposite of that of insulin. Glucagon is released from the alpha cells of the pancreatic islets. Its release is inhibited by the presence of insulin and glucose and stimulated by the presence of catecholamines and glucocorticoids. For this reason, glucagon levels tend to increase during times of low blood-glucose concentrations and stress. It acts in a number of ways to increase serum glucose concentration and inhibit its storage. In this way, the presence of glucagon prevents hypoglycemia, and is thus considered a counter-regulatory hormone.

Table 3 lists the other major counter-regulatory hormones and their primary actions.

PREDISPOSING ABNORMALITIES

To develop DKA, the patient must experience a relative insulin deficiency⁴ (very little circulating insulin) in the setting of increased counter-regulatory hormone concentrations. This relative lack of insulin sets the stage for a series of events that result in elevation of blood glucose, breakdown of adipose tissue triglycerides, uncontrolled production of ketoacids and eventual overwhelming of the kidneys' capacity to compensate through increased excretion of glucose and ketoacids.

This cascading series of events may occur as a result of marked hypoinsulinemia, such as occurs in either new-onset type 1 diabetes or in a known type 1 diabetic patient who omits his or her insulin doses. Otherwise, DKA is typically set in motion by a stressor.

Inadequate insulin results in decreased glucose uptake in the liver, adipose tissue, and skeletal muscle, as well as increased glucose release from the liver. As a result, serum glucose levels rise while the tissues simultaneously are starved for fuel. Compounding this situation is a decrease in renal perfusion, which accompanies intravascular volume depletion, leading to decreased capacity for renal glucose clearance.

Stress increases the levels of counter-regulatory hormones, leading to decreased circulating insulin and increased insulin resistance.

HYPERGLYCEMIA TO DKA

The ability to exist in this state of "accelerated starvation" is determined by the individual's ability to self-hydrate and maintain adequate glomerular filtration rate (GFR) with renal clearance of glucose and ketoacids. This delicate balance is overwhelmed in the presence of significant stress.

The most frequent stressor is infection, which is found in 40% to 50% of patients with hyperglycemic crisis. Other possible precipitating stressors include MI, stroke, pancreatitis, trauma and alcohol or drug abuse.⁴ Stress increases the counter-regulatory hormone concentrations, compounding the dysregulation.

Breakdown of adipose tissue stores. Lack of insulin in the adipose tissue in the presence of catecholamines leads to enhanced lypolysis and free fatty acid delivery to the liver where, in the presence of glucagon, fatty acids are used in the production of ketoacids, an alternative fuel. With high glucagon levels and high fatty acid availability, ketoacids are rapidly produced. Gluconeogenesis and glycogenolysis are promoted while glucose uptake and utilization are further impaired. Serum glucose levels rise further. Lipolysis continues. Ketoacids are generated out of control. Alkaline buffers—primarily bicarbonate—are consumed. Ketoacid anion levels rise, and an anion gap metabolic acidosis results.

Renal compensation. The kidneys decrease glucose reabsorption, and excess glucose is released in the urine. Ketoacids and their associated anions are excreted in the urine as well. This leads to osmotic diuresis and the polydipsia/polyuria phenomenon. Through osmotic diuresis, the kidneys continue to excrete glucose, hydrogen ions and ketoacid anions. The fluid loss results in the depletion of various electrolytes, including potassium, sodium, phosphate and magnesium.

Dehydration is inevitable, and when it occurs to an extent great enough to decrease GFR, the kidneys' ability to compensate is lost. The acidosis worsens, as does the hyperglycemia. The patient is left with severe metabolic derangement, electrolyte abnormalities and in some cases acute renal failure.

Respiratory compensation. The presence of metabolic acidosis causes respiratory compensation in the form of increased minute ventilation to "blow off" CO₂and raise pH. In addition, acetone enters the alveoli and is exhaled, resulting in the characteristic "fruity breath."

PATIENT PRESENTATION

Signs and symptoms of DKA are dependent on the individual circumstances that drive the patient to seek care. The person may present with symptoms suggestive of infection, stroke, acute coronary syndrome, or other stressors. Such early symptoms of DKA as weight loss and polyuria with polydipsia may go unrecognized by the patient.¹

The various symptoms of electrolyte disturbance may precipitate a visit to the primary-care office or the emergency department (ED). As dehydration occurs, decreased skin turgor, tachycardia, hypotension and weakness develop.³

Eventually, the acidosis itself becomes symptomatic and may hide the symptoms of the stressor. Signs and symptoms include tachypnea (Kussmaul respirations), nausea and vomiting, abdominal pain and fruity breath. Late features include focal neurologic signs, lethargy and coma.¹

Late in its course, DKA can be readily detected using commonly obtained objective tools. However, it remains imperative that the provider caring for these patients recognize the following:

• • In patients presenting early, appropriate treatment of the presenting stressor and recognition of the risk of fulminant DKA can minimize the impact on the patient

  • In patients presenting later in the course when DKA is more apparent, it is essential to recognize that the patient suffers not only from DKA, but also from severe dehydration, marked electrolyte disturbances and the stressor, which, if undetected, could be devastating to the patient. In fact, in older patients with serious concomitant illness, the mortality associated with DKA is most frequently caused by the stressor.³

INITIAL EVALUATION

In consideration of the wide variety of potential stressors and the inability to predict where on the continuum of DKA a patient will present, the initial evaluation must begin with an assessment of mental status and airway, breathing, and circulation. Subsequent to this and the provision of emergent interventions as dictated by that assessment, address the patient's volume status. In addition, the search for the precipitating event should begin early in the process.⁵

Routine labs include a complete blood count, serum electrolytes, serum glucose level, blood urea nitrogen (BUN), creatinine, and anion gap. In an individual with DKA, these labs will reveal:

• • An elevated anion gap due to the presence of excess ketoacid anions

  • Low bicarbonate (HCO^3-) due to the decreased level of unbound alkaline buffer

  • Elevated serum glucose

If DKA was not previously suspected, these three findings provide a clue that it may be present. Additional testing targeted toward assessing for the presence and severity of DKA should include:¹

• • Urinalysis with glucose and ketones

  • Serum ketones

  • Arterial blood gases

  • Serum osmolality

  • ECG

TESTING RELATED TO THE STRESSOR

Additional testing aimed at identifying the stressor may be done in a situation-dependent fashion. Perform a chest x-ray to assess for pulmonary abnormalities. Draw urine, sputum, or blood cultures if infection is suspected. Other situational-dependent studies include imaging of the brain, abdomen, or other area as symptoms dictate.⁵ Finally, fluid or excretion testing should be performed as warranted (e.g., stool, emesis, effusions).

DIFFERENTIAL DIAGNOSIS

A myriad of conditions can cause metabolic acidosis. For diagnostic purposes, this broad diagnosis is divided into two types: anion gap and non-anion gap metabolic acidosis. The term gap simply refers to the difference between the number of positive ions (cations) and negative ions (anions). The total number of cations and anions in the serum are essentially equal. However, a typical basic metabolic panel does not measure all of the circulating ions (Table 4). The termgap refers to the difference between the primary cations and anions that are measured in a typical basic metabolic panel.

Sodium is the primary cation. Chloride and bicarbonate are the primary anions. The anion gap is the numeric result of subtracting the sums of the chloride and bicarbonate concentrations from that of the sodium: Na⁺ - (Cl^- + HCO^3-)

This gap becomes important in assessing etiology. In a case of metabolic acidosis attributable to ingestion or endogenous overproduction of an acid, the acid ionizes to form a hydrogen cation and an anion (depending on the type of acid). In a case of aspirin overdose, this could be salicylic acid anions; sepsis produces lactic acid anions; and in DKA, ketoacid anions are produced.

Multiple sources of measured and unmeasured anions may be present spontaneously. In the end, the total number of anions cannot significantly exceed the number of cations, so the more unmeasured anions that circulate, the less measured anions will be found. The anion gap essentially refers to an estimate of unmeasured anions in the serum.

In DKA, ketoacids are produced that ionize into hydrogen cations and ketoacid anions. These anions are not measured in a basic metabolic panel, so when their levels rise, so does the anion gap. DKA should be part of the differential diagnosis in any patient who presents with constitutional symptoms or positive ketones and a blood glucose concentration >250mg/dL. It should also be considered in any patient with diabetes who presents with any serious illness or stressor.⁶

The American Diabetes Association (ADA) defines DKA as a combination of hyperglycemia with a blood glucose ≥250 mg/dL, a metabolic acidosis with bicarbonate ≤18 mEq/L, an anion gap >10, and arterial pH ≤7.30 in the setting of moderate ketonemia or ketonuria.

Hyperosmolar hyperglycemic state (HHS) is another form of hyperglycemic crisis. This condition is more typically found in individuals with severely uncontrolled type 2 diabetes. These patients are insulin-resistant and possess enough circulating insulin to inhibit lipolysis and excess ketogenesis but not enough to stimulate glucose uptake and utilization. They tend to have a more severe degree of volume depletion and impaired renal function, which decreases the ability to excrete excess glucose.

Such individuals present with severe hyperglycemia and its associated hyperosmolality, but they do not have as large an elevation in anion gap or acidosis as seen in DKA.