Diabetic Ketoacidosis

➡️Introduction

A practical guideline for the management of diabetic ketoacidosis in children and adolescents has been adapted to fit the Egyptian healthcare system. This process of customizing existing evidence-based clinical practice guidelines for local contexts offers a practical alternative to creating new ones from scratch, potentially enhancing their usefulness while conserving resources. This guideline aims to provide practical guidance for the diagnosis, treatment, and prevention of diabetic ketoacidosis in children and adolescents in Egypt, as well as the adaptation methods employed to create Egypt's first National Guideline for the management of diabetic ketoacidosis in children and adolescents using the Adapted ADAPTE method. The entire adaptation process, encompassing the setup, adaptation, and finalization phases, is thoroughly described. This involved a guideline adaptation group (GAG) and an external review group by experts in clinical content.

The finalized adapted CPG provides pediatricians and healthcare workers in the field of diabetes and endocrinology in Egypt with practical, evidence-based guidance for the management of diabetic ketoacidosis in children and adolescents. This initiative underscores the effectiveness of the Adapted ADAPTE method and emphasizes the significance of collaboration between clinical and methodological experts in adapting national guidelines.

➡️Scope

This guideline focuses on diagnosis and management of DKA in pediatric age group.

➡️Guidelines development and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

1- The International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines 2018 and 2022

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -   Adoption for most of the guideline recommendations.

         -   Adaptation for 2 recommendations according to GRADE criteria to be suitable to our Economic implications (Evidence-to-Decision (EtD) table was done)

         -   Development of Good Practice Statements

➡️Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

A. Diagnosis of DKA

The adapted CPG targets children aged 1 to 18 years presenting with diabetic ketoacidosis and is intended for use by various healthcare providers in the field namely paediatricians, diabetologists or endocrinologists, and intensivists.

B. Management of DKA

This section includes recommendations and good practice statements on management of DKA starting from initial resuscitation therapy, using IV insulin and when to wean off to SC insulin and when an ICU admission is indicated.

C. Prevention of DKA complications such as cerebral oedema and HHS

We can summarize the guidelines’ recommendations for DKA in the following:

We suggest in initial assessment of a patient with DKA to do the following (Very low, Conditional):

In Initial DKA Patient Assessment:

· Obtain vital signs and weight of the patient.

· 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 ketone, 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 conscious 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.

➡️Dehydration Severity Assessment in DKA Patient (Very low, Conditional):

· Assess the severity of dehydration (table 1) by:

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

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

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

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

E-     Urine output (ml/hour).

F-     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) (Low, Conditional).

G-    Conscious level (reduced in shock and is not alone indicative of brain edema) (Very low, Conditional).

➡️Calculating Anion Gap, Corrected Sodium and Osmolarity (Very low, Conditional):

·  Calculate the following in the DKA patient:

o   Anion gap = Na – (Cl + HCO3) (Normal = 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)

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

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

 

➡️Infection in DKA when to Suspect (High, Strong):

·  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. Leukocytosis 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:

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

o   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)].

➡️We suggest the following treatment plan (Very Low, Conditional):

·  Initial Resuscitation Fluid Therapy:

o   For children who are volume depleted but not in shock: Volume expansion (ressuscitation) 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.

o   For children with DKA in shock (High, Strong): 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 non fluid -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.

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

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

Type of ressuscitation fluids: Use crystalloid, like normal saline, not colloid or initial volume expansion.

·  Subsequent deficit and maintenance fluid (High, Strong):

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

B- 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).

C- In shocked patients, deficits may exceed 10% body weight.

Use Table (1) for estimating severity of dehydration.

D- Aim to replace the estimated fluid over 24 to 48 hours.

E- 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.

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

G-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).

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

I- 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 (Very Low, Conditional).

Type of subsequent fluid to use (High, Strong):

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

     - Introduce 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 90 mg/dl/hr and increase glucose concentration as needed to avoid hypoglycemia (Good Practice Statement).

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

-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.

 

Sodium concentration in IV fluids (High, Strong):

  -  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 the 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.

J-  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.

➡️Correction of acidosis and bicarbonate therapy (Low, Conditional):

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 in:

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

-  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.

o   Potassium therapy (Very low, Conditional)

A-    Assessment of serum potassium:

   -  If immediate serum potassium measurement is unavailable, an ECG is an alternative, 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 independent 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 may be more severe in malnourished children. Unless the patient is in renal failure with poor urine output, fluids should have added potassium.

  -   If the child is hypokalemic, start potassium replacement at the time of initial volume expansion and before starting insulin therapy. For children with initial potassium levels <3 mmol/L, defer insulin treatment and give a bolus of potassium (not to exceed 0.5 mmol/Kg/h), along with cardiac monitoring.

   -   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 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 5.5 mmol/L, wait until urine output is established and s-K+ drops below 5.5 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.

·       Insulin Therapy (Intermediate, Strong) :

A-    Timing of starting insulin

  -    Start I.V. insulin infusion 1 hour 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.

·   We suggest the following monitoring schedule (Very low, Conditional):

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

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

o   Hourly GCS assessment, neurologic assessment

o   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.

o   Hourly capillary blood glucose monitoring

o   Do the following laboratory measurements at 2 hours and every 2-4 hours (or hourly in severe cases until stabilization of the patient), venous blood gases, s-sodium, s-potassium, blood urea nitrogen, s-creatinine, s-calcium, magnesium, phosphate (should they be done every 4-6 hours according to need).

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

A-    Measure body weight each morning

o   We suggest the following phosphate therapy in DKA (Very low, Conditional)

o   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.

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

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

o    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.

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

We suggest the following transition to subcutaneous Insulin plan (Very low, Conditional):

B-     Transition to subcutaneous therapy and stop intravenous therapy at resolution of DKA WHEN ALL OF THE FOLLOWING occurs:

  -   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.

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

     - Patient is fully conscious.

   -    Patient can take oral fluids without nausea or vomiting.

o   Start subcutaneous insulin before stopping intravenous insulin:

-        Shift may be more convenient before a mealtime.

-        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

(ISPAD, 2018) (Good Practice Statement) :

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.

➡️We suggest the following management plan for cerebral oedema (CE) (Very low, Conditional):

A-    Diagnosis:

o   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.

o   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,

o   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

o   Clinical Diagnosis: CE in DKA is a clinical diagnosis.

One diagnostic criterion, or two major criteria, or one major and two minor criteria (table 5) 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.

o   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:

intracranial hemorrhage which requires emergency neurosurgery

cerebrovascular thrombosis which may require anticoagulation

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

C-     Treatment of CE:

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

  -   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°.

➡️We suggest the following management of HHS (Very low, Conditional):

A-    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.

B-     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.

C-     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.

D-    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.

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

F-     Bicarbonate is contraindicated.

G-    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

H-    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.

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

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

➡️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/