Symposium. Clinical Management of Diabetic Ketoacidosis

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1 Symposium Asrar Rashid *, Sanjay Perkar **, Praveen Khilnani ***, Sarah Ehtisham **** DOI / *Sr Consultant Pediatric intensive care unit, **PICU specialist, ****Senior consultant Pediatric endocrinologist, Mediclinic city hospital, Dubai, UAE. ***Senior Consultant Pediatric intensivist Mediclinic city hospital, Dubai, UAE and Rainbow Children s hospital, New Delhi, India Received:12-Oct-17/Accepted- 26-Oct-17, Published online:01-nov-17 ABSTRACT : Diabetic Ketoacidosis (DKA) is a commonly seen condition in Pediatric age group requiring admission to the PICU. The scope of this article is to discuss the management of children with moderate to severe DKA requiring hospitalization. Electrolyte disturbances such as hypoglycemia, hypokalemia, hypocalcemia, hypomagnesemia and severe hypophosphatemia can occur during the clinical course of DKA. Additionally, DKA can be associated with sepsis with serum C-reactive protein and interleukin-6 levels being useful in excluding an underlying infection, as well as confirming and monitoring sepsis. DKA can result in serious morbidity such as cerebral edema, cerebral infarction, venous and arterial stroke. Simultaneous pulmonary and cerebral edema with multiple CNS infarctions as a complication of DKA has also been described. Severe DKA can lead to cardiac failure, pulmonary edema and spinal cord edema resulting in tetraplegia. Current review emphasizes mainly regarding all the measures to reduce morbidity and potential mortality. To minimize morbidity, early recognition of diabetes is paramount especially when polyuria, polydipsia, lethargy and weight loss is described. The clinical suspicion of DKA should be confirmed quickly by biochemical evidence and appropriate treatment instituted. The International Society of Pediatric Diabetes introduced guidelines (ISPAD 2014) as well as British Society of Pediatric Endocrinology are also discussed to put it in clinical perspective. Key words: Insulin Dependent Diabetes Mellitus, Diabetic ketoacidosis, Cerebral Edema, DKA management, International DKA Guidelines, ISPAD 2014, British guidelines, BSPED Introduction The International Society of Pediatric Diabetes introduced guidelines (ISPAD 2014) to minimize complications from Diabetic Ketoacidosis (DKA) 1. The scope of this article is to discuss the management of children with moderate to severe DKA requiring hospitalization (Table 1). Aspects of the British Society of Pediatric Endocrinology are also included in the guidelines. 2 Electrolyte disturbances such as hypoglycemia, hypokalemia, hypocalcemia, hypomagnesemia and severe hypophosphatemia can occur during the clinical course of DKA. 3 Additionally, DKA can be associated with sepsis with serum C-reactive protein and interleukin-6 levels being useful in excluding an underlying infection, as well as confirming and monitoring sepsis. 4 Correspondence: Dr. Asrar Rashid MRCPCH (UK), Senior consultant Pediatrics and Pediatric intensive care, Mediclinic city hospital, Dubai health care city, Dubai, UAE. Phone: , asrar.rashid@mediclinic.ae DKA can result in serious morbidity such as cerebral edema, cerebral infarction 5, venous and arterial stroke 6 (due to hypercoagulability). 7 Lung pathology includes pulmonary edema 8, pulmonary embolism, subcutaneous emphysema, pneumothorax and respiratory distress syndrome and pulmonary mucormycosis 9, pneumomediastinum and aspiration pneumonia. Simultaneous pulmonary and cerebral edema with multiple CNS infarctions as a complication of DKA has also been described. 5 Any organ prone to hypoperfusion due to the extracellular fluid (ECF) contraction in DKA, is at risk e.g. bowel ischemia and acute renal failure. Acute pancreatitis may lead to DKA. 10 Also rhabdomyolysis has also been described in children. 11 Severe DKA can lead to cardiac failure, pulmonary edema and spinal cord edema resulting in tetraplegia. 12 To minimize morbidity, early recognition of diabetes is paramount especially when polyuria, polydipsia, lethargy and weight loss is described. Risk factors for DKA include younger age, a recent diagnosis of Insulin Dependent Diabetes, insulin omission and concomitant infection. The clinical suspicion of DKA 34

2 should be confirmed quickly by biochemical evidence (Table 2) with further investigations after resuscitation has occurred (Table 3). concentrations if there has been partial treatment or in the presence of pregnancy. The severity of DKA is determined by the degree of acidosis (Table 4). When ketosis is absent i.e. Beta-hydroxybutyrate Table 1: DKA Overall Management of DKA CLINICAL SIGNS Make diagnosis based on clinical history and examination PLAN OF CARE REFERRAL TO ABC LABORATORY TESTS RADIOLOGY TESTS POINT OF CARE TESTING CLINICAL IMPROVEMENT Definition Diabetic ketoacidosis (DKA) is defined by a serum glucose concentration of greater than 200 mg/dl with a venous ph less than 7.3 (or serum bicarbonate concentration less than 15 mmol/l) in association with ketonemia, glucosuria, and ketonuria. Rarely, DKA may occur with normal circulating glucose Resuscitate in the Emergency department from an A/B/C point of view and then admit to high dependency area for intensive monitoring. A patient with a high respiratory rate on presentation, suggests a more severe acidosis. Weight/Length of patient or estimate the weight according to age Do not start insulin before the fluid regimen (follow DKA Table 5 therapy guidelines) Pediatric Endocrinology & High dependency specialist/pediatric Intensivist Emergency assessment should follow the general guidelines for Pediatric Advanced Life Support (PALS) and includes: immediate measurement of BG blood or urine ketones serum electrolytes, blood gases and full blood count assessment of severity of dehydration and level of consciousness placement of two IV cannulae Nil by mouth whilst acidotic Insert a NG tube if obtunded Consider oral intake once ph normal with consultant permission Due to aspiration risk 2 cannulas for IV access CONFIRM diagnosis of DKA: Hyperglycemia [blood glucose (BG) >11 mmol/l ( 200 mg/dl)] Venous ph<7.3 or bicarbonate <15 mmol/l Ketonemia and ketonuria (check urine and blood for ketones) Consider Chest X-ray if febrile and respiratory symptoms Consider CT-scan of head if GCS reducing Measurement of ketonuria should not be used to judge the severity of acidosis or ketonemia as this only measures acetoactetate BOHB(beta hydroxyl butyric acid) serum levels can now be measured at the bedside As suggested clinically by a resolving respiratory rate, heart rate and acidosis normalisation of serum glucose, disappearance of ketones improving metabolic and physical status (BOHB) < 3 mmol/l, however there is hyperglycemia (>33 mmol/l), acidosis (large anion gap) and hyperosmolality (>320 mosm/l) the diagnosis of Hyperglycemic hyperosmolar state (HHS) should be considered. HHS is seen with increasing frequency as the presenting indication of type 2 DM. The overall mortality recorded among children and adults with 35

3 Table 2: DKA Work-up investigations LABORATORY TESTS: Full blood count Urea and Creatinine Hourly blood gases in the initial phase Hourly bedside glucose monitoring 4 hourly blood ketone monitoring 2-4 hourly (or more frequently, as clinically indicated in more severe cases) Serum Urea, Creatinine, Serum electrolytes, glucose, blood urea nitrogen, calcium magnesium, phosphorus, hematocrit, and blood gases Check bone profile 12 hourly Blood ketone concentrations, if available, should be monitored every 2 hours. Lipids and triglycerides can be grossly elevated causing the blood sample to show a visible rim of lipids. For newly diagnosed diabetes patients: HbA1c C peptide Anti GAD antibodies Anti islet cell antibodies Insulin autoantibodies Thyroid function test and thyroid antibodies Celiac screening anti IgA TTG/IgA anti Endomysial antibodies and Total serum IgA BEDSIDE: Capillary blood glucose concentration should be measured hourly (but must be cross-checked against 2-4 hourly laboratory venous glucose, as capillary methods may be inaccurate in the presence of poor peripheral circulation and acidosis). Blood glucose (BG) and blood or urine ketone concentrations can be measured in a bedside meter, while awaiting laboratory results. The anion gap is a better measure than the serum bicarbonate that treatment is progressing favourably As treatment progresses the anion gap starts to normalize before the resolution of the acidosis leading to a mild non-gap acidosis. High chloride content of fluids may be the cause of this gap resulting in hypercholremic metabolic acidosis Table 3: Useful Calcula ons Anion gap=na - (Cl+HCO3); Normal is 12 ± 2 mmol/l. In DKA, the anion gap is typically mmol/l An anion gap >35 mmol/l suggests concomitant lactic acidosis. Corrected sodium = measured Na+2 [(plasma glucose 5.6)/5.6] mmol/l OR measured Na+2 [(plasma glucose 100)/100] mg/dl Effective osmolality (mosm/kg)=2 (plasma Na)+plasma glucose mmol/l 36

4 DKA is <1% whereas the mortality among patients with HHS is ~10-fold higher than that associated with DKA alone. 13 Biochemical investigations The aim of biochemical investigations is three-fold. Firstly, to confirm hyperglycemia, secondly to assess the degree of metabolic acidosis (from blood gas and or serum bicarbonate levels) and then finally to confirm whether the acidosis is caused by elevated ketone levels. Elevated ketone levels were traditionally tested at the bedside by demonstrating elevated urinary ketone levels in the presence of hyperglycemia and acidosis. With advances in point-of-care device testing, ketosis can be measured at the bedside showing elevated serum beta-hydroxybutyrate (BOHB) levels or if unavailable then via the local laboratory. If BOHB testing is not available and one has excluded elevated serum lactate causing the acidosis, then it is possible to follow clinical progression by a sequential calculation of the anion gap. The relationship between the ph and the classification of the severity of acidosis has been described by the BSPED guidelines (table 4). Where should the child be admitted? Once stabilized the child can be moved from the acute area (emergency room). As most pediatric wards don t deal with insulin infusions the child in DKA should be discussed with the endocrinologist and Intensivist. Depending on local availability of resources, the child should be admitted to an area (PICU or High dependency unit) where vital signs, neurological status and laboratory results can be monitored frequently. Meticulous monitoring of the clinical and biochemical response to treatment is necessary so that timely adjustments in treatment can be made, when indicated by the patient s clinical or laboratory data. Given the regularity in which vital signs need to be recorded, medication changes need to be adjusted and fluid regimens modified, admission to the PICU/PHDU is ideal for the first 12 to 24 hours to undertake intensive investigations, to respond to critical situations and to prevent complications. If severe DKA or cerebral edema risk, then send to PICU 60 90% of all DKA deaths are due to Cerebral edema. 14,15 Children with severe DKA (long duration of symptoms, compromised circulation, or depressed level of consciousness) or those who are at increased risk of cerebral edema (i.e. <5 year of age, severe acidosis, low pco2, high blood urea nitrogen) should be considered for intensive care unit admission (pediatric preferred if available) or in a unit that has equivalent resources and supervision, such as a children s ward specializing in diabetes care. 16 If possible, intubation should be avoided as a sudden increase in pco2 during or following intubation. As may worsen cerebral edema by decreasing cerebrospinal fluid (CSF) ph. 17 What are the warning signs? Any symptom or sign suggesting neurological involvement such as headache, recurrence of vomiting, or a change in neurological status should alert the practitioner. Other signs include the inappropriate slowing of heart rate, rapidly increasing serum sodium concentration, rising BP and decreased oxygen saturation. What monitoring should be undertaken and when? Table 1 addresses the key points in clinical management and Table 2 details the laboratory and bedside testing. Therapeutic goals are to correct dehydration (Table 5) correct acidosis and reverse ketosis by replenishing insulin deficiency to move glucose intracellularly, slowly correct hyperosmolality and restoring BG to near normal. The objectives of fluid and electrolyte replacement therapy are to restore the circulating volume by restoring the intra and extracellular fluid deficit and in so doing restoring serum sodium. The resulting improvement in glomerular filtration enhances clearance of glucose and ketones from the blood. During treatment, one must monitor for complications (e.g. dyselectrolytemia and cerebral edema) whilst identifying and treating any precipitating events such as infection (e.g. pneumonia). Table 4 : Severity of Acidosis and DKA Classification (BSPED) Venous ph Bicarbonate Mild >7.2 and <7.3 <15 mmol/l Moderate >7.1 and <7.2 <10 mmol/l Severe <7.1 <5 mmol/l 37

5 Early Phase of Resuscitation Children with DKA will likely arrive to an acute admission area of a hospital facility such as an emergency room. Estimation of the level of dehydration has been shown in Table 5. Ideally fluid resuscitation would have occurred in the emergency department with a strategy for fluid maintenance therapy on the ward (see deficit fluid replacement). Table 5: Estimating the level of dehydration Consider giving antibiotics to febrile patients after obtaining appropriate cultures of body fluids. If blood glucose is very high in children, then one should pay attention to the child s neurological state. If the child is obtunded, then consider securing the airway and emptying the stomach by continuous nasogastric suction to prevent pulmonary aspiration Mild (infants 5%/ children 3 %) Moderate (infants 6%-10%/ children 4%-6%) Severe (infants >10%-15%/ children >6%-10%) Clinical state Alert Drowsy, irritable Lethargic/obtunded Blood pressure Normal Normal Low Heart rate Normal Increased/weak pulse Rapid/feeble pulse Capillary refill Normal =2 seconds >3 seconds Skin turgor Normal Tenting* Absent* Eyes Normal Slightly sunken/reduced eyeball turgor Sunken/soft eyeballs Oral mucosa / lips Moist Dry Very dry/parched Urine output Normal Reduced Anuric Dehydration category BSPED guidelines 5% 5% 5-10% *Note that with severe hyperosmolality, skin and subcutaneous tissue are doughy rather than hypoelastic At this stage Emergency assessment should follow the general guidelines for Pediatric Advanced Life Support (PALS). Give oxygen to patients with severe circulatory impairment or shock (discuss with PICU consultant). A cardiac monitor should be used for continuous electrocardiographic monitoring to assess T waves for evidence of hyper- or hypokalemia. A second peripheral intravenous (IV) catheter should be placed for convenient and painless repetitive blood sampling. An arterial catheter may, rarely, be necessary in some critically ill patients managed in an intensive care unit. In DKA there is a high risk of thrombosis so one should avoid placing a central venous catheter or especially in the very young; if a central catheter has been inserted, removal should be sought on clinical stability being reached. Avoid adding Insulin through a central line, unless it is the only available option, because its infusion may be interrupted when other fluids are given through the same line. Catheterization of the bladder usually is not necessary, but if the child is unconscious or unable to void on demand (e.g., infants and very ill young children) the bladder should be catheterized. in the unconscious or severely obtunded patient. Intubation should be avoided if possible as a sudden increase of pco2 during or following intubation may cause cerebrospinal fluid (CSF) ph to decrease and contribute to worsening of cerebral edema. As demonstrated by a prospective cohort of patients aged 5-20 years of age (included 33 episodes of DKA) correlation of clinical signs against 5-10% deficit in ECF volume was poor. 67% with DKA had been labeled with moderate dehydration (4% to 8%) dehydration. 17 Therefore the recommendation that initial fluid therapy for DKA should assume moderate dehydration with an adjustment made according to clinical response. In a randomized controlled trial, high-volume fluid infusion in the treatment of pediatric DKA patients significantly shortened metabolic normalization time without changing overall length of hospital stay. 18 Fluid replacement, as outlined, should commence prior to the initiation of insulin therapy (Table 6). As a fail-safe mechanism, junior doctors should inform senior colleagues of the assessment and subsequent 38

6 Table 6: IV Fluid Regimen for the Management of DKA INITIAL FLUIDS BOLUS RARELY & WITH CARE % saline 10 ml/kg for fluid resuscitation ONLY if the child has signs of compromised perfusion (diminished pulse volume and tachycardia). Use large bore cannula and REASSESS patient after each bolus. 2. Rarely Consider 2 nd Bolus after discussion with senior colleague: 0.9% saline 10 ml/kg for fluid resuscitation if the child has signs of compromised perfusion (diminished pulse volume and tachycardia). Use large bore cannula and reassess patient after each bolus. Patients with mild DKA usually do not have impaired peripheral circulation and therefore do not require fluid boluses. Rarely do children with DKA develop severe shock (tachycardia and poor perfusion) requiring the restoration of the circulatory volume with isotonic saline in 10 ml/kg boluses infused as quickly as possible through a large bore cannula with reassessment. after each bolus is required. INITIAL FLUID REPLACEMENT THERAPY INSULIN DOSE 3. Very Rarely Consider 3 rd Bolus after discussion with senior colleague: 0.9% saline 10 ml/kg for fluid resuscitation if the child has signs of compromised perfusion (diminished pulse volume and tachycardia). Use large bore cannula and reassess patient after each bolus. Calculate maintenance + deficit fluids as per infusion calculation on and give 0.9% Saline with no additives Record time of starting. Options instead of saline are Ringer s lactate or Plasmalyte (however since plasmalyte is buffered some institutions do not allow the addition of potassium which then hinders the amount of potassium that can be given) 1-2 hours after starting the maintenance fluids commence IV Insulin infusion at RANGE: units/kg/hr. One method of dilution is to take 50 units regular (soluble) insulin in 50mL normal saline, i.e. 1 unit=1ml. (Try to use a separate IV port) 0.05 units/kg/hour in under 5 years old units/kg/hour in 5-10 years old For patients who are severely volume depleted but not poorly perfused, fluid therapy should begin immediately with 0.9% saline infusion at the calculated maintenance rate. The dose of insulin should usually remain at unit/kg/h at least until resolution of DKA (ph>7.30, bicarbonate >15 mmol/l, BOHB <1 mmol/l, or closure of the anion gap). For some cases where the child is sensitive to the insulin rate the dose may need to reduced to 0.03 unit/kg/h to prevent hypoglycaemia. CHANGE OF MAINTAINANCE FLUIDS NEXT CHANGE OF MAINTAINANCE FLUIDS 0.1 units/kg/hour in over 10 years old 0.9% saline 500 ml with 20 mmol KCL added Once the child has passed urine and the serum potassium is falling and serum potassium is less than 5.5 mmol stop the maintenance fluid and start fluid with added potassium. Potassium addition to the fluid should only occur with respect to host institution guidelines to avoid the risk of drug errors. The serum sodium should rise with therapy. Ideally the sodium should rise by 0.5 mmol/l for every 1 mmol/l fall in BG. 0.45% saline + 5% dextrose with 20 mmol KCL added per 500 ml. Adjust sodium infusion to promote an increase in the measured serum sodium If serum sodium is falling it may indicate impending cerebral oedema. Once blood glucose 17 mmol/l or blood glucose falls greater than 5 mmol/l/hour then change the maintenance fluid [The sodium content of the fluid should be increased if the measured serum sodium concentration is low and does not increase as the plasma glucose concentration falls] * If the ketoacidosis does not improve in the first 2-4 hours consider insulin resistance due to dehydration, acidosis, infection. Also consider causes of decreased bio mechanism of insulin infusion including binding of insulin to the intravenous tubing. Also repeat the weight and fluid calculations to ensure the correct amount of fluid is being given treatment plan, when fluid boluses are being given and fluid given should be clearly documented to avoid errors. There are no data to support the use of colloid in preference to crystalloid in the treatment of DKA. In an adult study, patients with DKA resuscitated with plasmalyte instead of normal saline had a quicker initial resolution of the metabolic acidosis and less hyperchloremia, with a transiently improved urine output and blood pressure profile. 19 In calculating the rate of fluid administration, including the provision of maintenance fluid requirements, one should aim to replace the estimated fluid deficit over a period of 48 39

7 hours (subtract fluid boluses). Extracellular fluid (ECF) volume The effective osmolality in DKA is frequently in the range of mmol/kg. It is good practice to assess the degree of ECF contraction at the outset and then to follow changes in ECF volume from then on. An idea of the ECF compartment can be deducted from the increased serum urea nitrogen and hematocrit or hemoglobin concentration. Alternatively, plasma albumin or total protein concentration can be measured if anemia is suspected. Sodium Sodium as a measure of the degree of ECF contraction is prone to error for two reasons. Firstly, glucose is mainly restricted to the ECF, causing osmotic movement of water into the ECF leading to dilutional hyponatremia. A correction can be calculated (see Table 3). Secondly the low sodium content of the elevated lipid fraction of the serum in DKA. The latter is not a concern with most recent methods of sodium analysis. As a result, the serum sodium concentration is unreliable calculation of the corrected sodium, which represents the expected sodium should be undertaken. As the plasma glucose concentration decreases after administering fluid and insulin, the measured serum sodium concentration should increase and the glucose-corrected sodium concentration should slowly decrease. It is important to appreciate that the increase in measured serum sodium concentration does not indicate a worsening of the hypertonic state. A failure of measured serum sodium levels to rise or a further decline in serum sodium levels with therapy is thought to be a potentially ominous sign of impending cerebral edema. Too rapid and ongoing rise in serum sodium concentration may also indicate possible cerebral edema because of loss of free water in the urine from diabetes insipidus. Deficit replacement fluids Once the child has been resuscitated, calculate ongoing fluid therapy. Simply Fluid therapy = deficit replacement + maintenance fluid requirements. One should replace the estimated fluid deficit at an even rate over 48 h. Except for severely ill individuals; oral intake typically usually begins within 24 h. Urinary losses should not be added to the calculation of replacement fluid, except in occasional cases. Examples: A 20 kg, 6 year old boy who has a ph of 7.15, who did not have a sodium chloride bolus, will require To rehydrate :5% Deficit x 20 kg = 1000 ml Total Maintenance = 1500 ml Total Maintenance (over 48 hrs) = 3000 ml Rehydration = 1000 ml Total volume to be given over 48 hours = 4000 ml Hourly fluid rate = 84 ml/hour 5% deficit as suggested by the ph according to the guide- BSPED lines A 60 kg, 16 year old girl with a ph of 6.9, and who was given 1800 ml (30 ml/kg) 0.9% sodium chloride for circulatory collapse will require To rehydrate Deficit 10 % x 60 kg = 6000 ml 10ml/kg resuscitation Bolus fluid = 1800 ml Total Maintenance for 24 hours = 2300 ml Total Maintenance for 48 hours = 4600 ml Subtract bolus fluid given = 2800 ml Rehydration Deficit + (Maintenance-Bolus) = 8800ml Hourly fluid rate = 183 ml/hour 10% deficit as suggested by the ph according to the BSPED guidelines * For further Calculations please download App at Once the plasma glucose concentrations fall, there will be a decrease in vascular volume so one must ensure that enough fluid and salt has been administered to maintain adequate tissue perfusion. Therefore, subsequent fluid management (See Table 6) should be with an isotonic solution (0.9% saline, Ringer s lactate or Plasmalyte) for at least 4 6 h. Deficit replacement after 4 6 h should be with a (See Table 6) solution that has a tonicity 0.45% saline with added potassium chloride, potassium phosphate, or potassium acetate (see below under potassium replacement). The decision to change from an isotonic to a hypotonic solution will depend on the patient s hydration status, serum sodium concentration, and osmolality. As a failsafe mechanism, the calculated fluid regimen should NEVER exceed times the usual 40

8 daily maintenance requirement based on age, body surface area or weight. A gradual return to normal sodium and serum osmolality is desirable. The use of chloriderich intravenous fluids (added to the preferential renal excretion of ketones over chloride) can be associated with the development of hyperchloremia and hyperchloremic metabolic acidosis. 20 When the total base deficit is used to monitor biochemical improvement, the chloride acidifying effect may mask recognition of improvement in ketoacidosis. To prevent this misinterpretation, bedside BOHB level measurement will prevent confusion and can demonstrate that ketoacidosis has resolved. Researchers have developed a bedside calculation based on Stewart s physicochemical theory and regression analysis so now possible using a simple correction factor to quantify the confounding effect of hyperchloremia on both base deficit and bicarbonate in diabetic ketoacidosis. 21 The hyperchloremic acidosis does not require treatment per se but resolves spontaneously. The chloride load can be reduced by not giving potassium as potassium chloride and by using fluids such as Plasmalyte or Ringer s lactate in which a portion of the chloride is replaced by acetate or lactate, respectively. Insulin therapy Insulin is a cornerstone of DKA management as it is used to suppress ketogenesis. Accordingly, Insulin is never to be discontinued during treatment of DKA. Though Insulin therapy in DKA is essential to restore normal cellular metabolism and to normalize BG concentration and suppress lipolysis and ketogenesis, there is no role for an IV bolus of Insulin in DKA. It is now common practice to commence the insulin infusion 1 2 h after starting fluid replacement therapy; i.e., after the patient has received initial volume expansion. There is evidence that low dose IV insulin infusion is safe and effective, i.e. Dose: unit/kg/h. Insulin has an aldosterone-like effect leading to increased urinary potassium excretion, therefore potassium levels require monitoring (see below). To avoid severe hypokalemia dose of insulin infusion should be minimized. During initial volume expansion, the plasma glucose concentration falls steeply. Thereafter, and after commencing insulin therapy, the plasma glucose concentration typically decreases at a rate of 2 5 mmol/l/h, depending on the timing and amount of glucose administration. To prevent an unduly rapid decrease in plasma glucose concentration and hypoglycemia the next fluid contains 5% glucose when the plasma glucose falls to approximately mmol/l ( mg/ dl), or sooner if the rate of fall is precipitous. It may be necessary to use 10% or even 12.5% dextrose to prevent hypolgycemia while continuing to infuse insulin to correct the metabolic acidosis. If BG falls very rapidly (>5 mmol/l/h) after initial fluid expansion, consider using glucose even before plasma glucose has decreased to 17 mmol/l (300 mg/ dl). If biochemical parameters of DKA (ph, anion gap, BOHB concentration) do not improve, reassess the patient, review insulin therapy, and consider other possible causes of impaired response to insulin; e.g., errors in insulin preparation, infection. Potassium replacement Children with DKA can have significant total body potassium deficits in the order of 3 6 mmol/kg. Though total body potassium depletion is often present, but at presentation serum potassium levels can be normal, decreased or even increased. Renal dysfunction and insulin deficiency, due to hyperglycemia and reduction in potassium excretion, contributes to hyperkalemia. Administration of insulin and the correction of acidosis drive potassium back into the cells, decreasing serum potassium levels. The child can be at risk of cardiac arrhythmias due to any abrupt fall in serum potassium. Replacement therapy is required regardless of the serum potassium concentration, except if renal failure is present. If the child is hyperkalemic, one needs to delay potassium replacement therapy until urine output is confirmed. If the patient has hypokalemia, potassium replacement should be commenced at the time of initial volume expansion (Table 6). Otherwise, one needs to start replacing potassium after initial volume expansion (Table 6). If potassium is given with fluids a concentration of 40 mmol/l should be used. 41

9 Potassium replacement should continue throughout intravenous fluid treatment. Administration of potassium entirely as potassium phosphate can result in hypocalcemia whereas administration entirely as potassium chloride can worsen hyperchloremic metabolic acidosis. Thereby Potassium phosphate may be used together with potassium chloride or acetate; e.g., 20 mmol/l potassium chloride and 20 mmol/l potassium phosphate or 20 mmol/l potassium phosphate and 20 mmol/l potassium acetate. However, to avoid erroneous administration of potassium one should revert to local policies and procedures. The maximum IV potassium replacement rate recommended is usually 0.5 mmol/kg/h. If hypokalemia persists despite a maximal potassium replacement, then the insulin infusion rate may be reduced. Phosphate Phosphate is lost in DKA because of osmotic diuresis. Plasma phosphate levels fall after commencing treatment and this is worsened by insulin administration, which causes phosphate entry into cells. Clinically significant hypophosphatemia may happen if the child has IV Insulin therapy prolonged beyond 24 h without any oral food intake. Manifestations of severe hypophosphatemia depend on the chronicity and severity of phosphate depletion. Severe hypophosphatemia can occur during the treatment of DKA; however, symptoms are uncommon because the hypophosphatemia is usually acute and antecedent chronic phosphate deficiency does not usually exist. Severe hypophosphatemia can lead to muscle weakness, paralysis, rhabdomyolysis and hemolytic uremia. Although administration of phosphate is associated with a risk of hypocalcemia, phosphate replacement without significant hypocalcemia is possible using an IV solution containing a 50:50 mixture of potassium phosphate and potassium salt (potassium chloride or potassium acetate). Lacking the availability of energy rich phosphate compounds leads to decreased intracellular ATP levels impairing cellular functions. For example, a decrease in 2,3-diphosphoglycerate (DPG) levels increases the oxygen affinity of hemoglobin and reduces oxygen release to the tissues. Multiple organ systems could get affected. Manifestations of hypophosphatemia include: impaired respiratory muscle function and myocardial contractility, metabolic encephalopathy, muscle dysfunction with dysphagia, proximal myopathy and paralytic ileus. Rarely hematologic effects may occur and acute hypophosphatemia with pre-existing severe phosphate depletion can result in rhabdomyolysis. Severe hypophosphatemia associated with any of the above symptoms should be treated. However, the administration of phosphate has the risk of inducing hypocalcemia, which should be monitored. Resolution of Acidosis Severe acidosis is reversible by fluid and insulin replacement. Treatment of hypovolemia improves tissue perfusion and renal function, thereby increasing the excretion of organic acids. Insulin works to stop further ketoacids production, allowing ketoacids to be metabolized leading to the generation of bicarbonate. Trials have shown no clinical benefit from bicarbonate therapy and instead bicarbonate therapy may cause paradoxical CNS acidosis. In addition, rapid correction of acidosis with bicarbonate causes hypokalemia. However, bicarbonate administration may be rarely beneficial in patients with lifethreatening hyperkalemia. When oral fluid is tolerated, IV fluid should be reduced accordingly so that the sum of IV and oral fluids does not exceed the calculated IV rate (i.e., not more than times maintenance fluid rate). This fluid restriction should be applied for at least 48 hours from admission (72 hours if there is severe hyperosmolality at onset of treatment). When ketoacidosis has resolved, oral intake is tolerated, and the change to subcutaneous(sc) insulin is planned, the most convenient time to change to SC insulin is just before a mealtime. To prevent rebound hyperglycemia, the first SC injection should be given min (with rapid acting insulin) or 1 2 hours (with regular insulin) before stopping the insulin infusion to allow sufficient time for the insulin to be absorbed. With intermediate or long-acting insulin, the overlap should be longer, and the rate of IV insulin infusion gradually lowered. The dose and type of SC insulin should be according to local preferences and circumstances. After transitioning to SC insulin, frequent BG monitoring is required to avoid marked hyperglycemia or hypoglycemia. 42

10 Conflict of Interest: None Source of Funding: None References: 1. Wolfsdorf JI. ISPAD Clinical Practice Consensus Guidelines Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes 2014;15 Suppl 20: Diabetes (Type 1 and Type 2) in Children and Young People Diagnosis and Management.NICE Guideline, No. 18.National Collaborating Centre for Women s and Children s Health (UK). London: National Institute for Health and Care Excellence (UK); 2015 Aug. PMID: Whang R, Avasthi PS. Water and electrolyte disturbances associated with diabetic ketoacidosis. Rocky Mt Med J 1967;64(12): Gogos CA.Interleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis. Diabetologia 2001; 44(8): Dixon AN. Simultaneous pulmonary and cerebral oedema, and multiple CNS infarctions as complications of diabetic ketoacidosis: a case report. Diabet Med 2006;23(5): Siqueira LF.Cerebrovascular complications of diabetic ketoacidosis in children. Arq Bras Endocrinol Metabol 2011;55(4): Mozzillo E. Cerebral Accidents in Pediatric Diabetic Ketoacidosis: Different Complications and Different Evolutions. Horm Res Paediatr 2015;84(2): Brun-Buisson CJ. Recurrent high-permeability pulmonary edema associated with diabetic ketoacidosis. Crit Care Med 1985;13(1): Kebapci N. Pulmonary multinodular mucormycosis in type 1 diabetic patient with diabetic ketoacidosis. J Endocrinol Invest 2007;30(3): Pant N.Diabetic ketoacidosis presenting with acute pancreatitis and visceral vein thrombosis. Tenn Med 2011;104(5): Mercer S,Hanks L, Ashraf A. Rhabdomyolysis in Pediatric Patients With Diabetic Ketoacidosis or Hyperglycemic Hyperosmolar State: A Case Series. Glob Pediatr Health 2016;3: p X Christodoulidou M,Selmi F. Severe diabetic ketoacidosis leading to cardiac failure, pulmonary oedema and spinal cord oedema resulting in tetraplegia. BMJ Case Rep; Umpierrez G, Korytkowski M, Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol 2016; 12(4): Glaser N.Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med 2001; 344(4): Edge JA. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child 2001; 85(1): Tasker RC.Lutman D, Peters MJ. Hyperventilation in severe diabetic ketoacidosis. Pediatr Crit Care Med 2005; 6(4): Fagan MJ, Avner J,Khine H. Initial fluid resuscitation for patients with diabetic ketoacidosis: how dry are they? Clin Pediatr (Phila) 2008; 47(9): Bakes K.Effect of Volume of Fluid Resuscitation on Metabolic Normalization in Children Presenting in Diabetic Ketoacidosis: A Randomized Controlled Trial. J Emerg Med 2016; 50(4): Chua HR. Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care 2012;27(2): Mrozik LT,Yung M. Hyperchloraemic metabolic acidosis slows recovery in children with diabetic ketoacidosis: a retrospective audit. Aust Crit Care 2009; 22(4): Taylor D. The influence of hyperchloraemia on acid base interpretation in diabetic ketoacidosis. Intensive Care Med 2006;32(2): How to cite this article: Rashid A, Perkar S, Khilnani P, Ehtisham S. The. J Pediatr Crit Care 2017;4(4): How to cite this URL: Rashid A, Perkar S, Khilnani P, Ehtisham S. The. J Pediatr Crit Care 2017;4(4): Available from: 43