Diabetic Ketoacidosis

Table 3. Recommendations

A.    Initial Assessment and Calculations

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

A1

A2

A3

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A5

What are the necessary initial steps to be done for a DKA patient before starting treatment?

How to assess the severity of dehydration in a DKA patient clinically?

How to calculate anion gap, corrected sodium and osmolarity?

When to suspect infection in a DKA patient?

When to consider admitting a DKA patient in the ICU?

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ISPAD 2022

We suggest in initial assessment of a patient with DKA to do the following:

· Obtain vital signs and weight of the patient. Measure height/ length to calculate surface area.

Note that despite severe dehydration, hypertension occurs in 12% of children with DKA. Such patients require volume replacement despite the hypertension and should be monitored particularly carefully for signs and symptoms of impending cerebral injury.

·  Insert two wide bore peripheral cannulas.

Do Immediate measurement of :

· blood glucose.

· blood or urine ketones.

· venous blood gases.

· serum electrolytes.

·  blood urea nitrogen and s-creatinine.

· complete blood count and C-reactive protein (CRP).

·  connect the patient to an ECG monitor and check T waves.

Assess consciouss level: Glasgow coma scale (GCS)

· assessment (table 4 ) Examine pupillary size and reflexes

Obtain appropriate specimens for cultures if there is evidence of infection e.g. fever.
Obtain history looking for the underlying cause of DKA: In newly diagnosed it is mainly delay in diagnosis. In known diabetics look for missed insulin dose (especially basal insulin) or infection or marked insulin deficiency in children who reached puberty but their basal insulin dose was not adjusted.

Assess the severity of dehydration (table 1) by:

·  Pulse rate and volume (weak rapid pulse in shock).

·  Capillary refill time (normal capillary refill is ≤1.5-2 seconds).

· Skin turgor ('tenting' or inelastic skin) or other signs of dehydration.

· Patient temperature and temperature of periphery (cold hands and feet indicate poor tissue perfusion and possible shock, hypothermia may also occur in shock).

· Urine output (ml/hour).

·  Blood pressure. Hypotension is a late sign in shock (blood pressure is maintained for a long time by sympathetic tone, stress hormones and increased osmotic pressure from marked hyperglycemia).

· conscious level (reduced in shock and is not alone indicative of brain edema).

Mild DKA assumes 5%, moderate DKA 7% and severe DKA 10% dehydration.

Calculate the following:

·  Anion gap = Na – (Cl + HCO3):

-  Normal is 12 ± 2 mmol/L

-  In DKA the anion gap is typically 20-30 mmol/L

- an anion gap >35 mmol/L suggests concomitant lactic acidosis (e.g. due to sepsis)

Corrected sodium = measured Na +  1.6 ([plasma glucose – 100]/100) mg/dL

Effective osmolality (mOsm/kg) = 2 (plasma Na) + (plasma glucose  mg/dl) / 18. Normal range is 275–295 mOsm/kg

·Suspect infection if the patient has fever, high CRP, or an anion gap more than 35 mmol/l and give antibiotics after  obtaining appropriate cultures. Leucocytosis with shift to the left may occur in DKA without presence of infection.

Consider Sepsis if acidosis is not improving (lactic acidosis) after   revising fluid and insulin infusions

We suggest ICU admission in the following conditions:

1. Children in severe DKA (pH< 7.1, HCO3^-< 5 mEq/L)

2. Children at increased risk of cerebral oedema

[e.g., <5 years of age, severe acidosis, low pCO2 (<21 mmHg), high blood urea nitrogen (> 20 mg/dl)].

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Table 4. Recommendations

A.     Fluid Therapy

Initial Resuscitation Fluid:

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

B1

In case of volume depleted patient starting fluid expansion before insulin therapy what is the best initial therapy?

ISPAD 2022

B1. We suggest the following treatment plan

B1. For children who are volume depleted but not in shock,

Volume expansion (resuscitation) should begin immediately with 0.9% saline, 10 to 20 ml/kg infused over 20–30 min to restore the peripheral circulation.

The initial fluid bolus SHOULD be subtracted from the calculated fluid deficit.

·  If tissue perfusion is poor the initial fluid bolus volume should be 20 ml/kg.

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In the child with DKA in shock, rapidly restore circulatory volume with 0.9% saline in 20 ml/kg boluses directly infused manually into a large bore cannula as quickly as possible with reassessment of circulatory status / tissue perfusion after each bolus.  If the child shock is fluid-responsive, give fluids as needed until circulation is restored guided by patient capillary refill time, pulse rate and volume, central venous pressure, urine output, peripheral temperature, and blood pressure. Rate of fluid infusion does NOT increase the risk of cerebral edema. If the child shock is nonfluid -responsive, consult the ICU to assess the need for vasoactive / inotropic drugs.

Boluses given to treat shock SHOULD NOT be subtracted from the calculated fluid deficit.

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B2

In a DKA patient what are the available resusciation therapy available and how to calculate the required amount according to each patient?

ISPAD 2022

Initial resuscitation should take 20-30 minutes,
Do not take longer as this may worsen the severity of DKA

Blood glucose may drop 75-100 mg/dl/hour in this initial  rehydration phase.

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Type of Resuscitation Fluid

  Use crystalloid, like normal saline, not colloid for initial volume expansion.

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B3

How to calculate the fluid deficit in a shocked patient?

ISPAD 2022

Subsequent Deficit and Maintenance Fluid:

· Calculate the total fluid requirement by adding the estimated fluid    deficit to the fluid maintenance requirements per 24 hours.

· Estimating Fluid Deficit: Assume 5% dehydration in mild DKA, 5-7% dehydration (6-10% in infants) in moderate DKA. Assume 7-10% dehydration in severe DKA (˃10-15% in infants).

In shocked patients, deficits may exceed 10% body weight

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ISPAD 2018

Use Table 1 for estimating severity of dehydration.

· Aim to replace the estimated fluid over 24 to 48 hours.

· ISPAD table (3) provides easy  precalculated volumes of replacement and maintenance fluids (provided in this document in implementation tools) can be used when 10% dehydration is assumed and the total fluid replacement will be given over 48 hours. The fluid volume in the table is   calculated per 24 hours and per hour based on body weight.

· For body weights >32 kg, the volumes have been adjusted so as not to   exceed twice the maintenance rate of fluid administration.

· Calculation of fluid infusion rates for obese children should be similar to those of other children. Using ideal body weight for fluid calculations for these children is not necessary. If fluid calculations for obese children exceed those typically used in adult protocols, then adult DKA fluid protocols can be used (e.g., 1 L maximum per bolus and 500 ml/h fluid infusion).

· I.V. fluids given in another hospital before assessment should be     subtracted from the calculations.

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ISPAD 2022

Replacement of urinary losses should not be routinely done but may only be necessary in some circumstances with severe diuresis, particularly in children with a mixed presentation of DKA and HHS. Careful monitoring of fluid intake and output is essential to ensure positive fluid balance to correct the underlying dehydration.

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B4

When to introduce glucose to the IV fluid to avoid hypoglycemia before DKA resolution?

ISPAD 2022

Type of subsequent fluid to use:

Use 0.9% saline to 0.45 saline or a balanced salt solution (Ringer’s lactate) with added potassium chloride for subsequent fluid replacement.

Introducing Glucose to IV Fluid to avoid hypoglycemia before resolution of DKA:

• Introduce glucose once blood glucose falls below 250-300 mg/dl or the rate of drop of BG exceeds 90mg/dl/hr and increase glucose concentration as needed to avoid hypoglycemia.

• Initially once BG falls below 250-300 mg/dl, or the rate of drop of BG exceeds 90mg/dl/hr, use 250 ml glucose 5% and 250 ml 0.9% saline (which gives 2.5% glucose in 0.45% saline)

If the rate of drop is still rapid or BG reaches 180 mg/dl.

• (usual renal threshold for glucose loss), increase glucose concentration in IV fluids by using 250 ml glucose 10% and 250 ml 0.9% saline (gives 5% glucose in 0.45% saline).

• Introduce 10% glucose if the rate of     hourly drop of BG exceeds 90 mg/dl/hr or BG reaches 90 mg/dl.

(e.g. use 200 ml of 25%  glucose and 300 ml of 0.9% saline which gives 10% glucose in 0.45% saline).

• Increase IV glucose concentration to 12.5% as needed according to drop of BG  (made by adding 250 ml glucose 25% and 250 ml of 0.9% saline to give 12.5% glucose in 0.45% saline).

NB. Glucose 10%= 10 gram glucose in 100 ml = 100 mg glucose in 1 ml

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Do NOT reduce the rate of insulin infusion to avoid hypoglycemia (as this will worsen the acidosis and metabolic derangements) but increase the concentration of glucose in IV fluids to avoid hypoglycemia

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B5

What is the sodium concentration needed in IV fluid to avoid complications?

ISPAD 2022

Sodium concentration in IV fluids:

Initial sodium is usually low (due to dilutional effect from osmotic movement of water to extracellular compartment and because of increased sodium free lipid fraction in the blood) and corrected sodium must be calculated.

· Serum sodium trends during DKA treatment largely reflect the balance of sodium and water losses at presentation and sodium concentration in IV fluids. Evidence showed that drop in corrected sodium concentration during treatment was not associated with cerebral injury.

· Sodium usually rises slowly (by 1.6 mmol/L for each 100 mg/dl decrease in  glucose concentration) or remains in normal range with drop in BG.

· If measured serum sodium concentration is low and does not rise appropriately with the fall in BG level, increase the sodium  content of the fluid (e.g. use 0.675% saline which is 3/4 normal saline, or higher sodium content fluid like 0.9% normal  saline).

· In the event that changes in serum sodium concentration are required, the sodium content of intravenous fluids should be adjusted, but not the rate of infusion.

· Hyperchloremia may occur with large volume fluid administration causing persistence of low serum bicarbonate. This usually resolves spontaneously. To make sure there is no deterioration of patient condition, evaluate other clinical and lab data, and calculate the anion gap or measure blood betahydroxybutyrate ketone level if available to ensure they are decreasing. The chloride load in IV fluid may be reduced by using Ringer’s lactate solution instead of saline.

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B6

When should we use bicarbonate therapy in case of acidosis?

ISPAD 2022

Acidosis and Bicarbonate therapy:

In general, DO NOT give bicarbonate as it may cause harm (increases risk  of hypokalemia, worsen tissue oxygenation, may cause paradoxical CNS acidosis and significantly increases the risk of development of cerebral edema later).

Bicarbonate may be indicated if:

1. in severe acidosis (pH< 6.9) with evidence of compromised  cardiac contractility. In ths case give bicarbonate after initial rapid boluses given rapidly within 30 minutes if the pH remains below 6.9.

2. for treatment of life-threatening hyperkalaemia

If bicarbonate is indicated, carefully give 1-2 mmol/kg over 60 minutes.

Major causes of persistent acidosis include insufficient fluid administration, incorrect preparation or administration of IV insulin or associated sepsis.

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B7

How to assess potassium deficit in a DKA patient and how to calculate?

ISPAD 2022

Potassium Therapy:

A-Assessment of serum potassium:

If immediate serum potassium measurements unavailable, an ECG is an alternative.

•  In ECG: T wave flattening and inversion, prominent U waves indicate hypokalemia while tall peaked T waves indicate hyperkalemia (figure 3).

•  Severe hypokalemia (< 2.5 mEq/l) is an ndependent marker of poor treatment outcome and mortality

Potassium Therapy:

A-Assessment of serum potassium:

If immediate serum potassium measurements unavailable, an ECG is an alternative.

•  In ECG: T wave flattening and inversion, prominent U waves indicate hypokalemia while tall peaked T waves indicate hyperkalemia (figure 3).

•   Severe hypokalemia (< 2.5 mEq/l) is an ndependent marker of poor treatment outcome and mortality.

B- Potassium Replacement:

• Usually there is an average of 5 mEq/ kg (range 3-6 mEq/kg) loss of potassium (lost in urine with polyuria).  Potassium shifts out of the cells in the presence of acidosis and with lack of insulin. Hypokalemia maybe more severe in malnourished children.

- Unless the patient is in renal failure with poor urine output, fluids should have added potassium.

- If initial s.K+ is below 3.5 mmol/L (hypokalemic child),

start potassium replacement at the time of initial fluid resuscitation.

•  If s.K+ is 2.5-3.5 mmol/L,start of insulin treatment may need to be delayed or reduced.

•  Do not start insulin therapy if the potassium level is at or below 3 mmol/L.

• When potassium is infused at the time of initial boluses, only 20 mmol/L potassium can be used if fluid is infused  at ≥ 10 ml/kg/hour (e.g. during initial resuscitation) because the maximum allowed rate of potassium infusion is 0.5 mmol/kg/hour.

• The maximum allowed concentration of potassium in a peripheral IV line is 60 mmol/L. Make sure there is no extravasation (potassium  is a caustic).

• Monitor s.K+ hourly in this case and do cardiac monitoring for any arrythmia.

• If hypokalemia persists despite a maximum rate of potassium     replacement, then the rate of insulin infusion can be reduced.

-  If s-K+ is 3.5-5 mEq/l (normal range),

•  start potassium chloride at a rate 40 mmol/L fluid at the time of starting insulin after the initial fluid resuscitation.

• Subsequent potassium replacement therapy should be based on serum K+ measurements (do s-K+ 2 hours after starting potassium then every 4 hours in this case).

- If initial s-K+ is above 5 mmol/L, wait until urine output is established  and s-K+ drops below 5 mmol/L to start potassium replacement. Measure potassium hourly to initiate potassium infusion once the serum level drops to normal range.

- Potassium replacement should continue throughout IV fluid therapy.

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B8

How to initiate and establish insulin therapy?

ISPAD 2022

Insulin Therapy:

A-Timing of starting insulin

· Start I.V. insulin infusion 1 hours AFTER starting fluid  replacement therapy; i.e., after the patient has received initial volume expansion. DO NOT take longer time in the initial bolus resuscitation to avoid further deterioration before starting insulin.

· Do not give an IV bolus of insulin at the start of therapy because:

--- It may precipitate shock by rapidly decreasing osmotic pressure.

--- It may exacerbate hypokalemia.

B-Insulin Route

·  Route of administration:  IV

·  If a child or young person with DKA is using insulin pump therapy,   start intravenous insulin therapy and disconnect the pump.

·  Infusion tubing should be flushed with the insulin solution before Administration

Central venous catheters should not be used for insulin administration because the large dead space may cause erratic insulin delivery

C- Insulin dose

•  Insulin therapy should begin  with 0.1 U/kg/h

(dilute 50 units regular (soluble) insulin in

50mL normal saline, 1 unit=1mL)

• Start at 0.05 unit /kg /hour if

The patient shows marked sensitivity to insulin as in:

---young children below age of 5 years,

---some known cases of diabetes who received a dose of insulin   prior to presentation in DKA

    ---less severe DKA (pH >7.15)

•   The insulin dose may be decreased further provided that metabolic  acidosis continues to resolve.

(For example, in a child below 5 years and mild DKA, insulin may  drop from 0.05 unit/kg/h, to 0.03 unit/kg/h).

•   Aim for a decrease in serum glucose of 35-90 mg/dl/hour after insulin is started.

•  Increase the rate of insulin infusion if the rate of drop of blood glucose is less than 35 mg/dl/hour.

• The dose of insulin should usually remain at 0.05–0.1 unit/kg/h and should NOT be reduced until resolution of DKA  (pH > 7.30, serum bicarbonate >18 mmol/L, closure of anion gap)

Resolution of DKA takes longer than normalization of blood sugar. So, increase glucose concentration in infused fluid (see fluid section) to be able to maintain insulin infusion without development of hypoglycemia until complete resolution of DKA.

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B9

What are the necessary investigation and clinical findings needed to be done in monitoring a DKA patient?

ISPAD 2022

· We suggest the following monitoring schedule:

· Hourly heart rate, respiratory rate, capillary refill time and blood pressure.

· Hourly fluid input and output with measurement of urine output (or more frequently, with the possibility of urinary catheterization when there is impaired   consciousness).

•  Hourly GCS assessment, neurologic assessment

Observe for warning signs of cerebral oedema, including headache, irritability, inappropriate slowing of heart rate and rise of blood pressure, repeated vomiting, increased drowsiness, incontinence, specific nerve palsies, change in pupillary size or reaction.

• Hourly capillary blood glucose monitoring

•  do the following laboratory measurements at 2 hours and every 2-4 hours (or hourly in severe cases until stabilization of the patient)

o venous blood gases

o s-sodium, s-potassium,

2o blood urea nitrogen, s-creatinine

o s-calcium, magnesium, phosphate. (should they be done every 4-6 hours according to need)

• Measure body weight each morning

. Serum may be lipemic, which in extreme cases can interfere with accuracy of electrolyte measurements in some laboratories (eg sodium).

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B10

Why does  phosphate depletion occur and how to manage?

ISPAD 2022

·       We suggest the following phosphate therapy in DKA

•  Phosphate depletion occurs in DKA due to osmotic losses in urine and shift of intracellular phosphate to extracellular compartment due to acidosis.

•  Phosphate level decreases further with treatment (fluid dilution and correction of acidosis causing intracellular movement of phosphate).

•      Hypophosphatemia occurs in 50-60% of children during treatment. continuation of intravenous therapy without food consumption beyond 24 hours is a risk factor for clinically significant hypophosphatemia.

•  Routine phosphate replacement is not routine unless treatment (e.g. with potassium phosphate) is available but Severe hypophosphatemia (< 1 mg/dl) with or without symptoms should be treated immediately.

• Careful monitoring of serum calcium and magnesium should be done during phosphate replacement to avoid hypocalcemia.

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B11

When to transition to SC Insulin?

ISPAD 2022

We suggest the following transition to subcutaneous Insulin plan:

·  Transition to subcutaneous therapy and stop intravenous   therapy at resolution of DKA which is WHEN ALL OF THE FOLLOWING occurs:

1.ketosis has resolved,

N.B. Absence of ketonuria (ketones in urine) should not be used as an endpoint for determining resolution of DKA. Ketonuria characteristically continues for several hours after serum β- hydroxybutyrate level returns to normal. Note that urine ketone strips measure acetoacetate and acetone while beta-hydroxybutyrate (BOHB) is the main ketone body in tissues. BOHB is eliminated by conversion to acetoacetate which is excreted in urine with DKA resolution.

2. pH>7.30, bicarbonate >18 mmol/L and closure of the anion gap.

3. Patient is fully conscious.

4. Patient can take oral fluids without nausea or vomiting.

·  Shift may be more convenient before a meal time.

·  Start subcutaneous insulin before stopping intravenous insulin:

---give short-acting regular insulin 30 min-1 hour before stopping IV insulin (rapid-acting analogues should be injected 15-30 minutes   before stopping IV insulin).

---timing of intermediate- or long-acting insulin should be determined by the individual patient’s SC insulin regimen. For example, for the patient on a basal-bolus insulin regimen, the first  dose of basal insulin may be started in the evening and IV insulin  stopped the next morning if DKA has resolved by the morning.

Do NOT use premixed insulin (to allow more flexibility of dosing insulin rather than a fixed basal to mealtime insulin ratio).

Five General Sick Day Diabetes Management Principles

1. More frequent BG and ketone (urine or blood) monitoring

2. DO NOT STOP INSULIN

3. Monitor and maintain hydration with adequate salt and water balance.

4. Treat the underlying precipitating illness

5. Sick day guidelines including insulin adjustment should be taught soon after diagnosis and reviewed at least annually with patients and family members with a goal of minimizing and/or avoiding DKA and similarly minimizing and/or avoiding illness associated hypoglycemia.

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Good Practice Statement

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B12

Cerebral eodema when does it occur , how to diagnose and how treat?

ISPAD 2022

We suggest the following management plan for cerebral oedema (CE):

A-Diagnosis:

The degree of cerebral edema that develops during DKA correlates with the degree of dehydration and hyperventilation at presentation, but not with initial osmolality or osmotic changes during treatment.

·   SUSPECT, who is at high risk?

-   younger age, especially below 5 years.

- new onset diabetes or long duration of symptoms.

-     severe acidosis.

-  high BUN at presentation (>20 mg/dl).

-   severe hypocapnia at presentation after adjusting for the degree of acidosis.

bicarbonate treatment for correction of acidosis.

In these cases, mannitol or hypertonic saline should be available at the bedside with dose calculated,

·  When does CE occur?

Usually within 12 hours after treatment is started but, uncommonly, may  occur before the start of treatment or rarely, it can occur within 24-48 hours after start of treatment

· Clinical Diagnosis:

Use criteria in table (4) : CE in DKA is a clinical diagnosis.

One diagnostic criterion, or two major criteria, or one major and two minor criteria have a sensitivity of 92%, a specificity of 96% and a false positive rate of only 4% for the early recognition of DKA-related cerebral oedema; early enough to allow for effective treatment.

· When to do cranial imaging?

Start treatment first as with any critically ill patient and do not delay until  imaging is done.

The primary indications for imaging are focal neurologic deficit (presence of signs of lateralization) for   suspicion of :

1.  intracranial hemorrhage which requires emergency neurosurgery

2.              cerebrovascular thrombosis which may require  anticoagulation

In both cases the patient will clinically present with focal or severe   progressive headache or focal neurologic deficit.

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ISPAD 2018

Treatment of CE:

A- If clinical diagnosis of CE is done, treat immediately. Transfer   patient to ICU.

B- Give the most readily available one of the following:

·  --mannitol 20%, give 0.5–1 g/kg over 10–15 minutes. Effect of mannitol is apparent after 15 minutes and lasts for 2 hours. It can be repeated after 30 minutes if necessary.

--hypertonic sodium chloride (3%), 2.5–5 ml/kg over 10–15 minutes. It can be used if mannitol is not available or in addition to mannitol if there is no response to mannitol after 30 minutes.

C-    Adjust rate of fluid infusion so as to avoid excessive fluids that might increase cerebral edema while also to maintain a normal blood pressure to avoid cerebral hypoperfusion.

Elevate the bed head to 30°.

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B13

How to manage a case of HHS?

ISPAD 2022

We suggest the following management of HHS:

Management of HHS:

1- The initial bolus
It should be ≥20 ml/kg of isotonic saline (0.9% NaCl) and additional boluses can be given rapidly if needed to restore peripheral perfusion.

2-  Subsequent Fluid replacement:
A fluid deficit of approximately 12% to 15% of body weight should be assumed and urinary losses should be added to the calculated fluids.
Use 0.45% to 0.75% NaCl replace the deficit over 24 to 48 h.
Isotonic (0.9%) saline should be restarted if perfusion and hemodynamic status appear inadequate as serum osmolality declines.
Adjust sodium concentration in fluids to promote a gradual decline in corrected serum sodium concentration and osmolality (A rate of 0.5 mmol/L per hour has been recommended for hypernatremic dehydration).
Mortality has been associated with failure of the corrected serum sodium concentration to decline with treatment.

3- During the initial few hours of rehydration, BG may decline more rapidly. After this phase, if there is a continued rapid fall in BG (>100 mg/dl per hour), add  2.5% or 5% glucose to the rehydration fluid.

4- Potassium should be added to IV fluids just as in the DKA protocol.

Bicarbonate is contraindicated

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6-  Start insulin once the drop of BG is less than 50 mg/dl/hour with fluids only. Give insulin at a dose of 0.025-0.05 U/Kg/hour. Adjust insulin to achieve a rate of drop of BG of 50-75 mg/dl/hour

7-  Treat hypophosphatemia as needed. Replace magnesium in the occasional patient who experiences severe hypomagnesemia and hypocalcemia during therapy. The recommended magnesium dose is 25 to 50 mg/kg per dose for 3 to 4 doses given every 4 to 6 h with a maximum infusion rate of 150 mg/min and 2 g/h.

8-  To prevent venous thrombosis, low molecular weight heparin should be considered, especially in children >12 years.

Cerebral edema is very rare in HHS and any change in mental status during therapy should be fully investigated

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