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National Collaborating Centre for Women's and Children's Health (UK). Diabetes (Type 1 and Type 2) in Children and Young People: Diagnosis and Management. London: National Institute for Health and Care Excellence (UK); 2015 Aug. (NICE Guideline, No. 18.)

  • Update information November 2016: Recommendations 123 and 180 have been amended to add information on when eye screening should begin. Please note the date label of [2015] is unchanged, as this is when the recommendation was written and the evidence last reviewed. The changes made in November 2016 are clarifications of the 2015 wording, not new advice written in 2016, so do not carry a [2016] date.

Update information November 2016: Recommendations 123 and 180 have been amended to add information on when eye screening should begin. Please note the date label of [2015] is unchanged, as this is when the recommendation was written and the evidence last reviewed. The changes made in November 2016 are clarifications of the 2015 wording, not new advice written in 2016, so do not carry a [2016] date.

Cover of Diabetes (Type 1 and Type 2) in Children and Young People

Diabetes (Type 1 and Type 2) in Children and Young People: Diagnosis and Management.

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18Diabetic ketoacidosis

18.1. Introduction

The 2004 guideline recommendations related to recognition and management of diabetic ketoacidosis (DKA) focused largely on British Society for Paediatric Endocrinology and Diabetes (BSPED) guidance. For the 2015 update the guideline development group developed specific review questions to allow detailed recommendations to be included in the guideline, rather than needing to refer to the external guidance in its entirety.

The group considered formally applying the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument to the BSPED guidance in accordance with the NICE guidelines manual. The AGREE II instrument is a guideline quality appraisal tool in which 23 items are grouped into 6 domains, each of which reflects a particular aspect of guideline quality: 2 further items provide an overall assessment of quality. However, the guideline development group concluded that the BSPED guideline would not fulfil the requirements of the AGREE criteria to the extent that it could be adopted. The group concluded, therefore, that it was necessary to follow the standard process of using systematic reviews of the evidence for the review questions related to recognition and management of diabetic ketoacidosis (DKA).

Section 18.2 to Section 18.6 address the specific review questions considered in the 2015 update and these update and replace the evidence reviews and discussion of the BSPED guidance presented in the 2004 guideline. Each of these reviews covered both type 1 and type 2 diabetes.

18.2. Recognition, referral and diagnosis

18.2.1. Symptoms, signs and biochemical indicators of diabetic ketoacidosis

18.2.1.1. Review question

What is the predictive value of symptoms, signs and biochemical abnormalities as indicators of diabetic ketoacidosis in children and young people?

18.2.1.2. Introduction

This question aimed to address the predictive value of particular symptoms, signs and biochemical abnormalities for the diagnosis of DKA in children and young people with either type 1 diabetes or type 2 diabetes. The symptoms identified by the guideline development group as being relevant to this question were polydipsia, polyuria (possibly manifesting as bedwetting), weight loss, dehydration, nausea or vomiting, abdominal pain, respiratory distress and an altered level of consciousness. Biochemical abnormalities to be included in this review were hyperglycaemia, ketosis and acidosis.

In this evidence review (including the associated evidence statements), diagnostic test accuracy measures were classified in accordance with the methods described in Section 3.2.

Sensitivity and specificity:

  • low – 74.9% or below
  • moderate – 75% to 89.9%
  • high – 90% or above.

Positive likelihood ratio:

  • not useful – less than 5
  • moderately useful – 5 to less than 10
  • very useful – 10 or more.

Negative likelihood ratio:

  • not useful – more than 0.5
  • moderately useful – more than 0.1 to 0.5
  • very useful – 0.1 or less.

18.2.1.3. Description of included studies

Four studies were identified as being relevant to this review question (Fearon 2002; Gilhotra 2007; Prisco 2006; Sheikh-Ali 2008). Two of the studies assessed the diagnostic test accuracy of serum beta-hydroxybutyrate levels in detecting DKA (Sheikh-Ali 2008; Prisco 2006) and the other 2 assessed the diagnostic test accuracy of end-tidal carbon dioxide measurements (Fearon 2002; Gilhotra 2007). No studies were identified which assessed the predictive accuracy of any symptoms or signs for detecting DKA.

The first study was a retrospective, non-consecutive case series conducted in the USA (Sheikh-Ali 2008). Relevant participants were identified using an electronic medical records coding system. Details were obtained for all children and young people hospitalised with uncontrolled diabetes. There were 129 participants, all of whom had type 1 diabetes. The mean age was 10.8±0.4 years (maximum 16 years). The aim of the study was to evaluate the utility of serum beta-hydroxybutyrate in detecting DKA as defined by a serum bicarbonate level of no more than 18 mEq/litre (milliequivalents of solute per litre). The study authors found that on average a serum beta-hydroxybutyrate level of at least 3 mmol/litre equated to a serum bicarbonate level of 18 mEq/litre. They reported data that could be used to calculate diagnostic test accuracy measurements for predicting serum bicarbonate of no more than 18 mEq/litre from measurements of serum beta-hydroxybutyrate of at least 3 mmol/litre.

A prospective case series conducted in Italy also assessed the diagnostic test accuracy of serum beta-hydroxybutyrate levels in detecting DKA (Prisco 2006). The study included 118 children and young people. The study authors assessed the diagnostic test accuracy of ketone levels when defining DKA in 2 different ways, either by a venous pH of less than 7.3 or by a blood glucose level of more than 250 mg/dl (13.9 mmol/litre).

Two prospective cohort studies assessed the use of end-tidal carbon dioxide measurements for the diagnosis of DKA. One study was conducted in the USA (Fearon 2002). Children and young people attending a paediatric emergency department who had known or suspected diabetes were recruited if they presented with hyperglycaemia. End-tidal carbon dioxide levels were measured to assess their predictive value for the diagnosis of DKA. Forty-four children and young people participated in the study, but 2 were excluded from analysis (1 did not give consent and the other was unable to tolerate the monitor without crying). The type of diabetes (type 1 or type 2) was not reported. Participants ranged in age from 2 to 18 years (the mean age was not reported). DKA was defined as a serum bicarbonate measurement of less than 15 mEq/litre with a serum glucose of more than 250 mg/dl and the presence of ketones on urine dipstick. These studies were not combined due to heterogeneity in design.

The final study was conducted in Australia (Gilhotra 2007). This study recruited children and young people with known or suspected type 1 diabetes presenting to a paediatric emergency department. Sixty-three children were enrolled but 5 were excluded (1 because the monitor was not tolerated and 4 because of missing data). The mean age was 10.7 years (range 1 to 18 years). DKA was defined as serum bicarbonate of less than 15 mEq/litre with ketonuria in children and young people with type 1 diabetes.

18.2.1.4. Evidence profile

The evidence profile for this review question (symptoms, signs and biochemical abnormalities as indicators of DKA) is presented in Table 65.

Table 65. Evidence profile for diagnostic test accuracy of serum beta-hydroxybutyrate and end-tidal carbon dioxide as indicators of diabetic ketoacidosis.

Table 65

Evidence profile for diagnostic test accuracy of serum beta-hydroxybutyrate and end-tidal carbon dioxide as indicators of diabetic ketoacidosis.

18.2.1.5. Evidence statements

Serum beta-hydroxybutyrate

One study (total 129 participants) showed that serum beta-hydroxybutyrate of 3 mmol/litre or more (defined by serum bicarbonate 18 mEq/litre or less) has a high sensitivity and moderate specificity for the diagnosis of DKA in children and young people. The positive likelihood ratio indicated that the test was moderately useful and the negative likelihood ratio indicated that it was very useful. The evidence for these findings was of very low quality.

One study (total 90 participants) showed that serum beta-hydroxybutyrate of 3 mmol/litre or more (defined by venous pH of less than 7.3) has a moderate sensitivity and low specificity for the diagnosis of DKA in children and young people. The positive and negative likelihood ratios indicated that the test was not useful. The evidence for these findings was of moderate quality.

One study (total 110 participants) showed that serum beta-hydroxybutyrate of 3 mmol/litre or more (defined by blood glucose more than 13.9 mmol/litre) has a low sensitivity and moderate specificity for the diagnosis of DKA in children and young people. The positive and negative likelihood ratios indicated that the test was not useful. The evidence for these findings was of moderate quality.

End-tidal carbon dioxide

Two studies (total 107 participants) showed that end-tidal carbon dioxide has a moderate sensitivity and high specificity for the diagnosis of DKA in children and young people (using a cut-point of 29 mmHg or less). The positive likelihood ratio indicated that this test was very useful. The negative likelihood ratio suggested that the test was moderately useful. The evidence for these findings was of low quality.

One study (total 58 participants) reported the diagnostic test accuracy of end-tidal carbon dioxide (using a cut-point of 30 mmHg or less) for the diagnosis of DKA in children and young people. The study reported a high sensitivity, moderate specificity, moderately useful positive likelihood ratio and very useful negative likelihood ratio. The evidence for these findings was of low quality.

One study (total 42 participants) reported the diagnostic test accuracy of end-tidal carbon dioxide (using a cut-point of less than 36 mmHg) for the diagnosis of DKA in children and young people. The study reported a high sensitivity, low specificity, not useful positive likelihood ratio and very useful negative likelihood ratio. The evidence for these findings was of high quality.

18.2.1.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence related to indicators of DKA in children and young people.

This question was not prioritised for health economic analysis as recognition in itself does not incur major opportunity costs and the guideline development group considered that best practice for management of this medical emergency is generally well established.

18.2.1.7. Evidence to recommendations

The guideline development group noted that there is no universally accepted definition of DKA and no compelling evidence for any definition. However, the group consensus was that the following would provide a reasonable definition:

  • blood glucose 11 mmol/litre or more, and
  • blood pH less than 7.3 or serum bicarbonate of less than 18 mmol/litre, and
  • confirmed ketosis (based on blood or urine testing).

Some previously published guidelines (BSPED 2013; Craig 2011; Walsdorf 2014) differ slightly from this approach, suggesting, for example, the use of less than 15 mmol/litre for serum bicarbonate. However, the group considered that the use of a higher serum bicarbonate threshold (less than 18 mmol/litre) would reduce the possibility of missing DKA. The group also noted that in children and young people who are receiving insulin treatment for diabetes and who present with DKA it is possible that the blood glucose may be in the normal range, and so in such individuals only the second and third bulleted criteria need to be fulfilled.

18.2.1.7.1. Relative value placed on the outcomes considered

Children and young people (with or without a prior diagnosis of diabetes) presenting with DKA may have symptoms consistent with diabetes (for example polyuria, polydipsia, weight loss and tiredness) and also symptoms which are recognised as occurring in ketoacidosis (for example nausea, vomiting, abdominal pain, respiratory distress, dehydration and reduced level of consciousness). Many of these clinical manifestations are non-specific and might be reported in other clinical contexts. The guideline development group considered that it was important to review available evidence on the predictive value of these various symptoms and signs. In addition, they wished to consider evidence on the predictive value of biochemical abnormalities associated with hyperglycaemia, acidosis and ketosis.

18.2.1.7.2. Consideration of clinical benefits and harms

DKA is a life-threatening complication of diabetes and so the harm associated with missing the diagnosis far outweighs the minimal harm from over-investigation. The tests to be undertaken to identify DKA or to rule it out consist of minimally invasive procedures such as blood testing for hyperglycaemia, pH and ketone levels. The guideline development group's view was that it was particularly important that the tests employed for the diagnosis of DKA should have a high sensitivity (90% or higher).

18.2.1.7.3. Consideration of health benefits and resource use

The cost of delayed or missed diagnosis of DKA is considerable and could result in death. The longer a diagnosis of ketosis is delayed, the sicker the child or young person becomes and the more intensive and protracted treatment is likely to be. For example, early ketosis causes nausea and vomiting and is easily mistaken for food poisoning or gastro-enteritis. This often leads to inadequate insulin being given for fear of causing hypoglycaemia. The individual then becomes much sicker. Near-patient beta-hydroxybutyrate, using ketone strips, is cheaper than a laboratory measurement and a more rapid diagnosis may bring important benefits for this life-threatening condition.

18.2.1.7.4. Quality of evidence

Although there was no available evidence on the predictive value of clinical symptoms or signs individually or in combination, the guideline development group made recommendations based on their clinical knowledge and experience regarding the clinical manifestations that should lead to investigation of DKA.

In the first instance they considered the clinical features that would raise the possibility of DKA in a child or young person not previously known to have diabetes. They agreed that if there was increased thirst, polyuria, recent unexplained weight loss or excessive tiredness (these are recognised clinical manifestations of diabetes mellitus) together with any of a number of other features (nausea or vomiting, abdominal pain, hyperventilation, dehydration or a reduced level of consciousness) then a capillary blood glucose measurement should be obtained. All of these other features are accepted in clinical practice as suggestive of DKA in a person in whom diabetes is suspected or confirmed. If the blood glucose was normal then DKA would be ruled out as an explanation for the symptoms. If the blood glucose was greater than 11 mmol/litre then DKA should be suspected as the likely explanation and the child or young person should immediately be sent to a hospital with acute paediatric facilities.

When children and young people with known diabetes develop DKA they would often have a raised blood glucose but this is not universal. The guideline development group noted that it was well recognised that it is possible for those with a prior diagnosis of diabetes who are receiving insulin therapy to have DKA with a normal glucose level. Some young children with type 1 diabetes and gastroenteritis can develop ketoacidosis with hypo- or normo-glycaemia because of relative insulin deficiency and starvation. This important point was therefore highlighted in a recommendation. The group recommended that DKA should be suspected in any child or young person with diabetes irrespective of the blood glucose level if they had any of the suggestive clinical features (nausea or vomiting, abdominal pain, hyperventilation, dehydration or a reduced level of consciousness). When DKA is suspected in a child or young person with known diabetes the blood ketones (beta-hydroxybutyrate) should be measured using a near-patient method if this is available. Those presenting to their GP, for example, might well have the testing equipment to hand. If the level of beta-hydroxybutyrate is elevated, then they should be sent immediately to a hospital with acute paediatric facilities because the diagnosis of DKA is likely. If it is not possible in this setting to measure the beta-hydroxybutyrate level then DKA should be suspected and they should be sent immediately to a hospital with acute paediatric facilities.

The guideline development group noted that 2 studies that evaluated diagnostic test accuracy of blood beta-hydroxybutyrate found evidence to support its use in diagnosis, but this was of very low to moderate quality. These studies investigated diagnostic test accuracy of beta-hydroxybutyrate only in terms of its ability to predict DKA based on a single parameter (blood glucose, blood pH or blood ketones), not the combination of these parameters (see below) required to definitively diagnose DKA. Thus the reference test in these studies was not a true ‘gold standard’ diagnosis of DKA. This limited the applicability of serum beta-hydroxybutyrate as a definitive test for diagnosing DKA. Nevertheless, if the level were elevated the guideline development group considered this made a diagnosis of DKA likely in this setting and if it were normal then DKA would be ruled out (ketosis being an essential component of DKA).

The guideline development group was concerned that whenever DKA was suspected or confirmed, the child or young person and their family members or carers should be fully aware of the serious nature of the concern and that urgent hospital assessment was mandatory – and they made a specific recommendation in this regard. Any delay in attending hospital carried a significant risk. The group recommended that when a child or young person did arrive at the hospital with suspected or confirmed DKA, investigations should be carried out to confirm the suspicion (or rule it out): these would include a capillary blood glucose, capillary blood ketones using a near-patient method (if near-patient testing for capillary blood ketones is not available, use a urine ketone test instead) and lastly a capillary or venous pH and bicarbonate test. These were essential to confirm the diagnosis. The group made a recommendation stating the diagnostic criteria for DKA based on the demonstration of acidosis and ketosis or ketonaemia. They made a recommendation that for the purposes of this guideline and its recommendations on management, DKA should be categorised as severe based on the finding of a blood pH below 7.1.

The group was aware that laboratory measurement of beta-hydroxybutyrate takes time and may delay the diagnosis of DKA. Rapid diagnosis is important in this setting as DKA is potentially life-threatening and the group agreed that near-patient testing on arrival at the hospital would facilitate rapid diagnosis and was advisable.

The only other included studies on diagnostic tests for DKA examined end-tidal nasal carbon dioxide measurement. Although 1 of these studies provided high-quality evidence suggesting that end-tidal nasal carbon dioxide had a high sensitivity and useful negative likelihood ratio, the group was not persuaded that it was of practical value. Moreover, this form of test was not in general use in this setting. There were concerns about the diagnostic test accuracy of measurements with this technique and, importantly, it was often poorly tolerated. The guideline development group did not recommend it.

18.2.1.7.5. Other considerations

The guideline development group was aware of evidence that there may be an increased risk of DKA in certain ethnic groups and children and young people living in deprived areas (Khare 2013). The group made recommendations about the importance of considering contributory factors in those who present with an episode of DKA with a view to reducing the risk of future episodes (see Section 18.7).

18.2.1.7.6. Key conclusions

The guideline development group recommended that the biochemical criteria required for the diagnosis of DKA should be as discussed above. The group specifically recommended that healthcare professionals should measure capillary blood glucose at presentation in children and young people without known diabetes who have increased thirst, polyuria, recent unexplained weight loss or excessive tiredness and any of the following:

  • nausea or vomiting
  • abdominal pain
  • hyperventilation
  • dehydration
  • reduced level of consciousness.

The group also recommended that if the blood glucose level is above 11 mmol/litre in a child or young person without known diabetes and they have symptoms that suggest DKA, then DKA should be suspected and the child or young person should be sent immediately to a hospital with acute paediatric facilities. A blood glucose of this level would be consistent with a diagnosis of diabetes, and when there are also symptoms suggestive of DKA immediate referral to hospital is essential because DKA is a life-threatening condition requiring urgent management.

The guideline development group emphasised that healthcare professionals should be aware that children and young people taking insulin for diabetes may develop DKA with normal blood glucose levels, and that they should suspect DKA (even if the blood glucose is normal) in children and young people with known diabetes and also in children and young people without known diabetes if any symptoms and signs are present that would trigger capillary blood glucose measurement.

The guideline development group further recommended that when DKA is suspected in a child or young person with known diabetes, blood ketones (beta-hydroxybutyrate) should be measured using a near-patient method if available, and if the level is elevated, the child or young person should be sent immediately to a hospital with acute paediatric facilities. This will identify those with DKA even if the blood glucose is in the normal range, as may happen in children and young people with type 1 diabetes who are using insulin therapy. The group considered whether a specific threshold for blood ketones should be stated in the recommendation about sending the child or young person to a hospital with acute paediatric facilities. The group concluded that a threshold should not be stated because the evidence reviewed for the guideline did not support ketone testing as being a specific test for DKA, and the recommendation should not risk preventing the child or young person being sent to hospital by including an arbitrary threshold that may not quite be met in individual circumstances. The recommendation is not about diagnosing DKA (this will be done in the hospital) and a child or young person with known type 1 diabetes should already have ketone testing equipment and advice about seeking help plus an individualised sick-day management plan so they will be able to detect elevated ketones. Children and young people with type 1 diabetes and their family members or carers (as appropriate) may have the necessary ketone testing strips with them when they present. When DKA is suspected in a child or young person with known diabetes and it is not possible to measure the blood ketones (beta-hydroxybutyrate) using a near-patient method, the child or young person should be sent immediately to a hospital with acute paediatric facilities for further investigation.

A further recommendation emphasised that if DKA is suspected or confirmed in a child or young person, health professionals should explain to them and to their family members or carers (as appropriate) that DKA is a serious matter that needs urgent hospital assessment.

18.2.2. Assessments and investigations at presentation and clinical monitoring and laboratory investigations during treatment

18.2.2.1. Review questions

What routine assessments and investigations should be used to guide management in children and young people who present with diabetic ketoacidosis (DKA)?

Which of the following should be performed as clinical monitoring during treatment of DKA in children and young people:

  • general observations (for example heart and respiratory rate and blood pressure)
  • body weight
  • hydration status
  • fluid balance
  • neurological observations
  • electrocardiographic (ECG) monitoring?

Which of the following laboratory investigations should be performed to monitor children and young people during treatment for DKA:

  • blood glucose
  • blood or urine ketones
  • serum urea or electrolytes
  • acid/base status?

18.2.2.2. Introduction

The review questions regarding routine assessments and investigations at presentation with DKA, and clinical monitoring and laboratory investigations during treatment of DKA, were considered together. The guideline development group prioritised the same outcomes for each of the questions as follows:

  • mortality
  • degree of dehydration confirmed by post-recovery weight
  • detection of hypovolaemia
  • detection of laboratory abnormalities (including hypoglycaemia, hypokalaemia, hyponatraemia, persistent acidosis and persistent ketosis)
  • detection of complications (including cerebral oedema, venous thrombosis and aspiration)
  • healthcare utilisation (for example duration of admission or requirement for ventilation as a proxy for severity of DKA or presence of cerebral oedema).

A combined literature search was conducted to cover all the questions and a single excluded studies list was generated.

The specific objective of the question regarding laboratory investigations to be performed during treatment of DKA was to assess the effectiveness and utility of various laboratory investigations used routinely in clinical practice to measure response to treatment and identify potential complications.

18.2.2.3. Description of included studies

No evidence was identified for inclusion for the question regarding routine assessments to be performed at presentation with DKA, nor for the question regarding clinical monitoring to be performed during treatment of DKA. However, 3 studies were identified which considered laboratory investigations to be performed during treatment of DKA (Noyes 2007; Prisco 2006; Vanelli 2003). One study was a randomised controlled trial (RCT) (Vanelli 2003) and the other 2 were case series (Noyes 2007; Prisco 2006). All 3 studies focused on blood ketone testing versus urine ketone testing rather than other laboratory investigations.

The RCT (Vanelli 2003) was conducted in Italy and included 33 children and young people (mean age 9.2±3.4 years) who had been admitted to hospital with severe DKA (pH 7.2 or less) or moderate DKA (pH 7.2 to 7.3). The participants were randomly allocated to urine ketone testing or capillary blood beta-hydroxybutyrate testing. The study reported mortality and duration of treatment, but none of the other outcomes prioritised by the guideline development group.

One case series (Prisco 2006) involved 118 consecutive children and young people with newly diagnosed type 1 diabetes of whom 38 (32%) had DKA. This study was also conducted in Italy. The mean age of the participants with DKA was 8.0±2.5 years and their mean venous pH level was 7.20±0.11. Hourly urine and capillary blood samples were used to monitor ketone bodies until metabolic control was achieved. Time to resolution of ketosis was compared for the 2 methods of assessment. The outcome was reported for the entire study group (including participants without DKA), rather than specifically participants with DKA.

The second case series (Noyes 2007) involved 25 children and young people (age range 1 to 14 years) who fulfilled the criteria for DKA. Over the study period the participants presented with a total of 40 episodes of DKA (that is, some participants had multiple episodes of DKA). The median pH at presentation was 7.18 (range 6.98 to 7.38). Blood ketones were checked every 4 hours and all urine passed was assessed by the dipstick method. Time to resolution of ketosis was compared for the 2 methods of measurement.

No evidence was identified with regard to the effectiveness of ketone testing in terms of the following outcomes:

  • degree of dehydration or detection of hypovolaemia
  • detection of complications (cerebral oedema, venous thrombosis or aspiration)
  • healthcare utilisation.

No evidence was identified for inclusion for the following laboratory investigations:

  • blood glucose
  • serum urea or electrolytes
  • acid/base status.

18.2.2.4. Evidence profile

The evidence profile for these review questions (specifically, the question related to laboratory investigations during treatment of DKA) is presented in Table 66.

Table 66. Evidence profile for comparison of blood ketone monitoring versus urine ketone monitoring during treatment of diabetic ketoacidosis.

Table 66

Evidence profile for comparison of blood ketone monitoring versus urine ketone monitoring during treatment of diabetic ketoacidosis.

18.2.2.5. Evidence statements

Mortality

One RCT (total 33 participants) reported no events in either group (blood ketone testing or urine ketone testing) during treatment of DKA. The evidence for this finding was of high quality.

Duration of treatment

One RCT (total 33 participants) reported that children and young people who received blood ketone monitoring during treatment of DKA had a quicker resolution of ketosis compared with those who underwent urine ketone monitoring. The evidence for this finding was of high quality.

One case series (total 28 participants) reported that the time to resolution of ketosis was quicker when blood ketones were monitored than when urine ketones were monitored. The evidence for this finding was of low quality.

One case series (total 99 participants) reported that the time to resolution of ketosis did not differ according to whether blood ketones or urine ketones were monitored. The evidence for this finding was of very low quality.

18.2.2.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence addressing assessments and investigations at presentation or clinical monitoring and laboratory investigations during treatment of DKA in children and young people.

This question was not prioritised for health economic analysis as the guideline development group considered there were other higher priorities within the guideline.

18.2.2.7. Evidence to recommendations

18.2.2.7.1. Relative value placed on the outcomes considered

The guideline development group considered which clinical factors should be recognised and which investigations should be recommended in children and young people with DKA at the time of presentation and subsequently during treatment. These would be important in determining treatment required at the outset and in guiding subsequent management. For these review questions the group set up the review protocols to focus predominantly on comparative studies as these would best inform clinical practice. Many different strategies for clinical assessment and monitoring could be considered and an appropriate strategy for laboratory and other investigations could both guide treatment and identify complications.

Particular concern related to the development of cerebral oedema and hypokalaemia, both of which are potentially life-threatening complications of DKA.

18.2.2.7.2. Consideration of clinical benefits and harms

The guideline development group agreed that close monitoring is essential for all children and young people presenting with DKA. They made recommendations regarding the observations and clinical assessment that should be performed both to determine the appropriate treatment strategy and subsequently during treatment. These were consistent with current practice and with existing guidance (for example guidance from the British Society for Paediatric Endocrinology and Diabetes [BSPED]). The group was especially concerned that signs of cerebral oedema should not be overlooked and they made a recommendation on the clinical findings that should be recognised as possible early signs of cerebral oedema, as well as signs that should be assumed to indicate cerebral oedema and require urgent specialist advice and treatment (see Section 18.6.1).

With regard to investigations, the guideline development group recommended that at presentation with suspected or known DKA, the following should be measured: capillary blood glucose, urea, electrolytes and levels of bicarbonate, blood gas and beta-hydroxybutyrate. The group noted that DKA should be diagnosed in children and young people with diabetes who have acidosis (indicated by blood pH below 7.3 or plasma bicarbonate below 18 mmol/litre) and either ketonaemia (indicated by blood beta-hydroxybutyrate above 3 mmol/litre) or ketonuria (++ and above on the standard strip marking scale). The group considered that it is not essential that the child or young person should also have hyperglycaemia because DKA can occur with normal blood glucose levels in those using insulin therapy. Moreover, a blood pH below 7.1 was considered indicative of severe DKA.

The group made recommendations regarding the frequency of repeat measurements following commencement of treatment and they recommended that there should be continuous ECG monitoring to provide evidence of developing hypokalaemia. Recognition of resolution of ketosis and acidosis was important. The evidence indicated that blood monitoring of beta-hydroxybutyric acid was preferable to urine monitoring because the latter persisted after resolution of blood ketosis. Monitoring of urea and electrolyte were essential to patient safety and were needed to guide the intravenous fluid regimen.

18.2.2.7.3. Consideration of health benefits and resource use

A single US study (Vanelli 2003) identified in the global search for economic evidence suggested that blood ketone testing reduced the time spent in intensive care by 6.5 hours compared with urine ketone testing, giving a total cost saving of €184 per patient. Another study demonstrated that blood ketone testing resulted in an earlier resolution of DKA (Noyes 2007). Therefore, the guideline development group considered that blood ketone testing was likely to be cost effective as the higher cost of blood ketone testing would be more than offset by a reduction in hospital costs associated with a quicker recovery time. This led the group to recommend that the use of a near-patient blood ketone (beta-hydroxybutyrate) testing method should be considered for rapid diagnosis and monitoring of DKA in children and young people in hospital. A strong recommendation for universal implementation of this method could not be justified on the basis of available evidence.

18.2.2.7.4. Quality of evidence

The studies identified for inclusion in the guideline review all focused on near-patient ketone monitoring. However, the guideline development group recognised that it was essential to make recommendations on the key aspects of clinical monitoring and investigation. These recommendations were therefore based on the group's clinical expertise and were consistent with current clinical practice and in keeping with existing guidelines.

18.2.2.7.5. Other considerations

There were no other considerations.

18.2.2.8. Key conclusions

The guideline development group recommended that when a child or young person with suspected or known DKA arrives at hospital, the following should be measured:

  • capillary blood glucose
  • capillary blood ketones (beta-hydroxybutyrate) if near-patient testing if available, or urine ketones if it is not
  • capillary or venous pH
  • bicarbonate.

The group further recommended that DKA should be diagnosed in children and young people with diabetes who have acidosis (indicated by blood pH below 7.3 or plasma bicarbonate below 18 mmol/litre) and either ketonaemia (indicated by blood beta-hydroxybutyrate above 3 mmol/litre) or ketonuria (++ and above on the standard strip marking scale). It is not essential that the child or young person should also have hyperglycaemia because DKA can occur with normal blood glucose levels in those using insulin therapy. The considered that a blood pH below 7.1 was indicative of severe DKA. This is an important indicator because clinical manifestations of severe DKA (such as severe dehydration) may not be recognised reliably against the background of other manifestations of DKA.

Specific recommendations related to clinical monitoring and laboratory investigations during treatment of DKA in children and young people are presented in Section 18.3 and Section 18.5. These cover:

  • informing the responsible senior clinician once a diagnosis of DKA in a child or young person is made
  • explaining to the child or young person with DKA and to their family members or carers (as appropriate) about their condition and the care that they may need
  • performing and recording clinical observations and laboratory investigations
  • providing an appropriate care setting
  • liaising with other healthcare professionals as needed (anaesthetists and/or paediatric critical care specialists)
  • when to suspect sepsis
  • ensuring that healthcare professionals performing monitoring know what to look for and when to seek advice
  • performing face-to-face reviews of the child or young person at diagnosis and then at least every 4 hours
  • updating the child or young person with DKA and their family members or carers (as appropriate) regularly about their progress.

The guideline development group recommended that children and young people with DKA should be cared for in a facility that can provide the level of care recommended in the guideline. All children and young people with DKA will require expert paediatric medical and nursing care, and most will require intravenous fluids and insulin. Some children and young people will require care in a high-dependency unit or a ward with one-to-one nursing care (those under 2 years who are at increased risk of developing cerebral oedema, and those with severe DKA [blood pH below 7.1] who are likely to be more severely dehydrated and are therefore at increased risk). Children and young people with DKA who are unconscious require urgent anaesthetic review and may need endotracheal intubation to protect their airway. Likewise, those with a reduced level of consciousness and vomiting may be at risk of aspiration and the group recommended that thought should be given to inserting a nasogastric tube to reduce this risk. In those with hypotensive shock, the guideline development group recommended discussion of inotropes with a paediatric critical care specialist. The group considered, therefore, that such facilities and expertise should be available in any hospital providing care for children and young people with DKA.

Although most children and young people with DKA do not have sepsis, the guideline development group recognised that DKA can be precipitated by sepsis and recommended that sepsis should be suspected if there is fever or hypothermia, hypotension, refractory acidosis or lactic acidosis.

18.2.3. Recommendations

186.

Measure capillary blood glucose at presentation in children and young people without known diabetes who have increased thirst, polyuria, recent unexplained weight loss or excessive tiredness and any of the following:

  • nausea or vomiting
  • abdominal pain
  • hyperventilation
  • dehydration
  • reduced level of consciousness. [new 2015]
187.

If the plasma glucose level is above 11 mmol/litre in a child or young person without known diabetes, and they have symptoms that suggest diabetic ketoacidosis (DKA) (see recommendation 186), suspect DKA and immediately send them to a hospital with acute paediatric facilities. [new 2015]

188.

Be aware that children and young people taking insulin for diabetes may develop DKA with normal blood glucose levels. [new 2015]

189.

Suspect DKA even if the blood glucose is normal in a child or young person with known diabetes and any of following:

  • nausea or vomiting
  • abdominal pain
  • hyperventilation
  • dehydration
  • reduced level of consciousness. [new 2015]
190.

When DKA is suspected in a child or young person with known diabetes (see recommendation 189) measure the blood ketones (beta-hydroxybutyrate), using a near-patient method if available. If the level is elevated, immediately send them to a hospital with acute paediatric facilities. [new 2015]

191.

When DKA is suspected in a child or young person with known diabetes (see recommendation 189) and it is not possible to measure the blood ketones (beta-hydroxybutyrate) using a near-patient method, immediately send them to a hospital with acute paediatric facilities. [new 2015]

192.

If DKA is suspected or confirmed in a child or young person, explain to them and to their family members or carers (as appropriate) that DKA is a serious matter that needs urgent hospital assessment. [new 2015]

193.

When a child or young person with suspected or known DKA arrives at hospital, measure their:

  • capillary blood glucose
  • capillary blood ketones (beta-hydroxybutyrate) if near-patient testing is available, or urine ketones if it is not
  • capillary or venous pH and bicarbonate. [new 2015]
194.

Diagnose DKA in children and young people with diabetes who have:

  • acidosis (indicated by blood pH below 7.3 or plasma bicarbonate below 18 mmol/litre) and
  • ketonaemia (indicated by blood beta-hydroxybutyrate above 3 mmol/litre) or ketonuria (++ and above on the standard strip marking scale). [new 2015]
195.

Diagnose severe DKA in children and young people with DKA who have a blood pH below 7.1. [new 2015]

18.3. Treatment of diabetic ketoacidosis – initial management

The recommendations related to initial management during DKA are based on evidence reviewed for the question about clinical monitoring and laboratory investigations during treatment for DKA (see Section 18.2.2).

18.3.1. Recommendations

196.

Inform the responsible senior clinician once a diagnosis of DKA in a child or young person is made. [new 2015]

197.

Explain to the child or young person with DKA and to their family members or carers (as appropriate) about their condition and the care that they may need. [new 2015]

198.

When DKA is diagnosed in a child or young person in hospital, record their:

  • level of consciousness
  • vital signs (heart rate, blood pressure, temperature, respiratory rate [look for Kussmaul breathing])
  • history of nausea or vomiting
  • clinical evidence of dehydration
  • body weight. [new 2015]
199.

When DKA is diagnosed in a child or young person in hospital, measure and record the capillary or venous:

  • pH and pCO2
  • plasma sodium, potassium, urea and creatinine
  • plasma bicarbonate [new 2015]
200.

Consider a near-patient blood ketone (beta-hydroxybutyrate) testing method for rapid diagnosis and monitoring of DKA in children and young people in hospital. [new 2015]

201.

Children and young people with DKA should be cared for in a facility that can provide the level of monitoring and care for DKA specified in Section 18 of this guideline. [new 2015]

202.

Children and young people with DKA should be cared for with one-to-one nursing either on a high-dependency unit (preferably a paediatric unit), or on a general paediatric ward, if:

  • they are younger than 2 years or
  • they have severe DKA (indicated by a blood pH below 7.1). [new 2015]
203.

Think about inserting a nasogastric tube if a child or young person with DKA has a reduced level of consciousness and is vomiting, to reduce the risk of aspiration. [new 2015]

204.

Seek urgent anaesthetic review and discuss with a paediatric critical care specialist if a child or young person with DKA cannot protect their airway because they have a reduced level of consciousness. [new 2015]

205.

Discuss the use of inotropes with a paediatric critical care specialist if a child or young person with DKA is in hypotensive shock. [new 2015]

206.

Think about sepsis in a child or young person with DKA who has any of the following:

  • fever or hypothermia
  • hypotension
  • refractory acidosis
  • lactic acidosis. [new 2015]

18.4. Fluid and insulin therapy

18.4.1. Route of administration for fluids

18.4.1.1. Review question

What is the appropriate route of administration for fluids in children and young people with diabetic ketoacidosis?

18.4.1.2. Introduction

The purpose of this review is to determine the most appropriate route of administration for fluids in children and young people with diabetic ketoacidosis (DKA). The search for this review included systematic reviews, RCTs and comparative observational studies including cohort studies and case-control studies. The same search criteria were used to identify evidence for this review question and the questions about rates of fluid administration and fluid composition in children and young people with DKA.

The guideline development group defined 7 priority outcomes:

  • mortality
  • time to resolution of dehydration
  • resolution of acidosis
  • resolution of blood ketosis
  • incidence of cerebral oedema
  • serum sodium concentration
  • healthcare utilisation as a proxy for severity of DKA or presence of cerebral oedema.

Subgroup analyses by type of diabetes and age group were to be undertaken where possible.

18.4.1.3. Description of included studies

No studies met the inclusion criteria for this review and no evidence table was generated. All studies were weeded out based on title and abstract and so there is no excluded studies list.

18.4.1.4. Evidence profile

No studies were identified for this review and so there is no evidence profile.

18.4.1.5. Evidence statements

No evidence was identified for inclusion in this review.

18.4.1.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence related to the appropriate route of administration for fluids in children and young people with DKA.

This review question was not prioritised for health economic analysis as the guideline development group considered that best practice for management of this medical emergency is generally well established.

18.4.1.7. Evidence to recommendations

18.4.1.7.1. Relative value placed on the outcomes considered

The outcomes prioritised by the guideline development group for this question reflected the serious nature of potential outcomes of DKA, including mortality and incidence of cerebral oedema.

18.4.1.7.2. Consideration of clinical benefits and harms

The guideline development group agreed that as a general principle oral fluid administration is preferable to intravenous fluids in children and young people if this is tolerated. The group recognised that some children and young people presenting with DKA would not yet have become seriously ill. In such cases the child or young person would appear alert and well. Provided children and young people appeared alert, did not have nausea or vomiting (which would impair their ability to tolerate oral fluids) and were no more than minimally dehydrated then intravenous fluid administration might not be required and insulin could be given subcutaneously rather than intravenously. This was in keeping with clinical practice and clinical experience showed this to be safe and effective. However, those who were seriously ill at presentation, with severe nausea, vomiting, hyperventilation or evidence of poor peripheral perfusion, would require intravenous fluids for rehydration.

18.4.1.7.3. Consideration of health benefits and resource use

The guideline development group accepted that for some children and young people with DKA, oral fluid administration – a cheaper method of fluid administration – would be appropriate and safe. However, seriously ill children and young people would require intravenous fluids, justifying the relatively small increased administration costs.

18.4.1.7.4. Quality of evidence

No evidence was identified for inclusion for this review question, but the guideline development group did not regard this topic as a priority for future research.

18.4.1.7.5. Other considerations

Although intra-osseous fluid administration was included in the protocol for this question, no relevant evidence was identified. The guideline development group recognised that this was an established technique in clinical practice in occasional cases where intravenous access proves impossible. They did not therefore make a specific recommendation about the use of intra-osseous fluids.

18.4.1.7.6. Key conclusions

Owing to the lack of evidence identified for inclusion the guideline development group's recommendations were based on their consensus view of good clinical practice.

18.4.2. Rate of rehydration

18.4.2.1. Review question

At what rate should children and young people with diabetic ketoacidosis be rehydrated?

18.4.2.2. Introduction

The purpose of this review question is to determine the optimal rate for rehydration with fluids in children and young people with DKA. The literature search for this review included RCTs and systematic reviews, and it allowed for the inclusion of comparative observational studies as the guideline development group felt it was unlikely that RCTs would exist that addressed this question. The same search criteria were used to identify evidence for this review question and those for appropriate routes of fluid administration and optimal fluid composition in children and young people with DKA.

The group initially identified the following 8 priority outcomes for this review question, as insufficient evidence was identified for inclusion in the guideline review to require the group to refine their selection of outcomes to the most important 7:

  • mortality
  • time to resolution of dehydration
  • rate of change in blood glucose concentration
  • resolution of acidosis
  • serum chloride concentration
  • incidence of cerebral oedema
  • serum sodium concentration
  • healthcare utilisation as a proxy for severity of illness.

Subgroup analyses were to be undertaken for type 1 and type 2 diabetes and/or by age group where possible.

18.4.2.3. Description of included studies

Six studies met the inclusion criteria for this review (Edge 2006; Felner 2001; Glaser 2001; Glaser 2013; Lawrence 2005; Mahoney 1999). One was a pilot study for an RCT (Glaser 2013), 1 was a matched case-control study (Edge 2006), 1 was a retrospective case-control study (Glaser 2001) and 1 was a retrospective chart review with data presented in a case-control format (Mahoney 1999). One study was a prospective case-control study which also used retrospective data from medical records (Lawrence 2005). The sixth study was a partially randomised retrospective chart review (Felner 2001).

Study locations included the UK (Edge 2006), the USA (Felner 2001; Glaser 2001; Glaser 2013; Mahoney 1999) and Canada (Lawrence 2005). The number of participants ranged from 9 to 61 for cases and 42 to 186 for controls. The RCT had a total sample size of 18 children and young people (Glaser 2013). The partially randomised study included 60 and 30 individuals in the intervention and control groups, respectively (Felner 2001). Mean ages ranged from 8.5 to 11.4 years. One study presented baseline characteristics as medians (Glaser 2013); median ages were 11.5 and 15 years in the intervention and control groups, respectively. Participants in 4 studies had type 1 diabetes (Edge 2006; Felner 2001; Glaser 2001; Glaser 2013). Two studies did not report the type of diabetes (Lawrence 2005; Mahoney 1999).

In 1 study the percentage of white participants ranged from 53% to 73% (Glaser 2001). In a second study the percentage of white participants ranged from 47% to 70% across treatment groups, while black participants accounted for 17% to 37% and Hispanics 13% to 17% (Felner 2001). The remaining 4 studies did not report ethnicity (Edge 2006; Glaser 2013; Lawrence 2005; Mahoney 1999).

Of the guideline development group's priority outcomes evidence was identified for: cerebral oedema; time to resolution of acidosis; healthcare utilisation (indicated by admission to the intensive care unit (ICU); and changes in serum sodium and chloride as proxies for serum sodium and chloride levels. No evidence was identified for mortality, time to resolution of dehydration or rate of change in blood glucose concentration.

Two studies compared specific rates of rehydration (Felner 2001; Glaser 2013). Since data from all the other included studies were presented in a case-control format, risks for cerebral oedema are presented as the risk in cases relative to controls. One study investigated the risk of brain swelling as a proxy for mild cerebral oedema (Glaser 2013).

No subgroup analyses by diabetes type or age were possible.

18.4.2.4. Evidence profile

The evidence profiles for this review question (rate of rehydration during treatment for DKA) are presented in Table 67 to Table 69.

Table 67. Evidence profile for an increased rate of fluid administration in children and young people with diabetic ketoacidosis – case-control studies.

Table 67

Evidence profile for an increased rate of fluid administration in children and young people with diabetic ketoacidosis – case-control studies.

Table 68. Evidence profile for a slower rate of fluid administration compared with a faster rate of fluid administration in children and young people with diabetic ketoacidosis – randomised study.

Table 68

Evidence profile for a slower rate of fluid administration compared with a faster rate of fluid administration in children and young people with diabetic ketoacidosis – randomised study.

Table 69. Evidence profile for a slower rate of fluid administration compared with a faster rate of fluid administration in children and young people with diabetic ketoacidosis – partially randomised study.

Table 69

Evidence profile for a slower rate of fluid administration compared with a faster rate of fluid administration in children and young people with diabetic ketoacidosis – partially randomised study.

18.4.2.5. Evidence statements

Cerebral oedema

One study (total 212 participants) found evidence of an increased risk of cerebral oedema for the second tertile of total fluids administered in the first 4 hours of treatment versus the referent tertile. The quality of evidence for this outcome was moderate. The same study found no evidence for an increased risk of cerebral oedema for volume of fluids of between the third tertile of total fluids administered in the first 4 hours of treatment versus the referent tertile. The quality of evidence for this outcome was low. This study identified an overall trend of increasing risk of cerebral oedema with increasing tertile of fluid administration.

One study (total 63 participants) found evidence of an increased risk of cerebral oedema per 1 ml/kg/hour increase in fluids. The quality of the evidence for this outcome was low. Another study (total 244 participants) found no evidence for an increased risk of cerebral oedema with a 5 ml/kg/hour increase in rate of fluid rehydration. The quality of the evidence for this outcome was low.

One study (total 195 participants) found a difference in fluid administration rates within the first 4 hours of treatment in children and young people with brain herniation compared with those without brain herniation. The quality of the evidence for this outcome was very low.

One study (total 36 participants) found no difference in the risk of brain swelling on MRI scan in children and young people who received a slower rate of fluid therapy compared with those who received a faster rate of fluid therapy. The quality of the evidence for this outcome was very low.

Time to resolution of acidosis

One study (total 90 participants) found a reduction in the time to resolution of acidosis in children and young people who received a slower rate of fluid therapy compared with those who received a faster rate of fluid therapy. The quality of the evidence for this outcome was very low.

Change in serum sodium

One study (total 90 participants) found no difference in the change in serum sodium concentration in children and young people who received a slower rate of fluid therapy compared with those who received a faster rate of fluid therapy. The quality of the evidence for this outcome was very low.

Change in serum chloride

One study (total 90 participants) found no difference in the change in serum chloride concentration in children and young people who received a slower rate of fluid therapy compared with those who received a faster rate of fluid therapy. The quality of the evidence for this outcome was very low.

Admission to ICU

One study (total 90 participants) found no difference in the change in rates of admission to ICU in children and young people who received a slower rate of fluid therapy compared with those who received a faster rate of fluid therapy. The quality of the evidence for this outcome was very low.

18.4.2.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence related to the rate at which children and young people with DKA should be rehydrated.

This question was not prioritised for health economic analysis as the guideline development group considered that best practice for management of this medical emergency is generally well established.

18.4.2.7. Evidence to recommendations

18.4.2.7.1. Relative value placed on the outcomes considered

The guideline development group identified mortality and incidence of cerebral oedema as the most important outcomes for this question (because the serious nature of DKA carries a risk of severe adverse consequences). The group also regarded the following as important outcomes (because quicker recovery or return to normal biochemical values would be beneficial): time to resolution of dehydration; rate of change in blood glucose concentration; resolution of acidosis; serum chloride concentration; and serum sodium concentration. Healthcare utilisation was also considered as a proxy for severity of illness.

18.4.2.7.2. Consideration of clinical benefits and harms

The guideline development group was cognisant of the fact that in children and young people the severity of fluid deficit is difficult to determine accurately. Studies have shown that agreement between clinical symptoms and signs and actual percentage dehydration is poor. The NICE clinical guideline on diarrhoea and vomiting in children under 5 looked at this in some detail and concluded that it was possible only to distinguish between those with no clinical evidence of dehydration, those with some evidence and those with very pronounced findings suggesting imminent or actual hypovolaemic shock. The clinical manifestations of dehydration may be even more difficult to interpret in DKA. For example, urine output is maintained even in severe dehydration because of osmotic diuresis, the oral mucous membranes may tend to be dry due to hyperventilation associated with acidosis rather than as a result of dehydration, and acidosis leads to peripheral vasoconstriction resulting in prolonged capillary refill time which is normally considered to indicate the presence of severe dehydration. In principle, if a recent weight record is available for comparison then a child or young person's weight on presentation can be used to estimate the degree of dehydration (based on percentage weight loss). This is much less reliable, however, in children and young people presenting with DKA, because in that setting tissue-wasting as a consequence of poorly controlled diabetes may have contributed to any observed weight loss. Insulin deficiency has a direct tissue catabolic effect. This factor may be more significant in those who are not known to have diabetes prior to developing DKA because they may have experienced insulin deficiency for a longer period of time prior to presentation. In this context the guideline development group noted that a study considered in the evidence reviews for assessment, monitoring and investigation at presentation with DKA and during management of DKA (Koves 2004) relied on weight to determine the severity of dehydration and may therefore have overestimated dehydration. Reliance on weight loss to calculate the percentage of dehydration will always overestimate fluid loss in children and young people with DKA because these children and young people will have lost body weight associated with catabolism due to insulin deficiency.

The guideline on diarrhoea and vomiting in children under 5 recommended that in children with possible or suspected dehydration due to diarrhoea and vomiting the degree of dehydration should, therefore, be assessed as being 0%, 5% or 10% dehydrated as a pragmatic approach to fluid management. Using these estimates as a starting point rehydration would be given and the response to the fluid replacement given would be kept under clinical review. This was considered a safe approach in that even if this sometimes overestimated the required fluid volume, giving more fluid than is essential was not associated with significant risks and reduced the risk of under-hydration and delayed recovery. The volume of fluid replacement would be increased only if subsequent clinical assessment showed persistent symptoms or signs of dehydration. The guideline development group for this guideline considered this, but concluded that a somewhat different approach was required in those presenting with dehydration due to DKA. Existing guidelines in the UK (BSPED) at the time this guideline was being developed advised that based on the clinical assessment, children and young people should be categorised as having mild (equivalent to 3%) dehydration, moderate (5%) dehydration or severe (8%) dehydration. The group favoured coming into line with other guidance, recognising that clinical assessment of dehydration is not possible. Although there were concerns associated with rapid or excessive administration of fluid during DKA, the increase in replacement fluid is likely to be offset by the recommended reduction in maintenance fluid.

In simple dehydration (for example that associated with gastroenteritis), the principle is to attempt quite rapid rehydration to expedite recovery. The guideline development group concluded that the evidence suggests that when this approach is taken in children and young people with DKA, there is an increased risk of cerebral oedema. Moreover, these children and young people will usually require intravenous therapy for a significant period of time because the acidosis resolves gradually with insulin therapy. The group also recommended avoidance of fluid bolus administration unless there are signs of shock associated with poor urine output or hypotension. If a bolus is to be given, the group recommended 10 ml/kg rather than 20 ml/kg for the same reason. In keeping with current international practice, the group believes that aiming to give intravenous fluid replacement of the deficit evenly over 48 hours is an appropriate approach.

The guideline development group recommended using a pH of less than 7.1 as a threshold for treating the child or young person as if there is 10% dehydration because this is a marker for severe DKA. Severity of DKA is predominantly defined by the level of acidosis. A pH of less than 7.1 is generally recognised as a threshold for severe DKA and is likely to be associated with more severe dehydration.

18.4.2.7.3. Consideration of health benefits and resource use

The recommendations made by the guideline development group are largely in line with current practice and will have minimal cost impact in the context of the overall management of the condition. This practice has evolved over time and clinical experience indicates that it is safe and effective.

18.4.2.7.4. Quality of evidence

The guideline development group noted a lack of evidence related to several of their prioritised outcomes, namely mortality, time to resolution of dehydration and rate of change in blood glucose concentration. Also, the evidence that was identified for inclusion in the guideline review was of very low or low quality.

18.4.2.7.5. Other considerations

The guideline development group was aware that a clinical guideline on intravenous fluids therapy in children was being developed for NICE contemporaneously with the development of this guideline. The group acknowledged that recommendations in this guideline related to the rate of fluid administration for rehydration in children and young people with DKA should be distinguished from recommendations related to other indications for fluid therapy. For this reason, and noting that incorrect rates of rehydration in children and young people with DKA could have serious adverse consequences, the guideline development group was careful to specify in the guideline recommendations the population of children and young people to which they referred.

18.4.2.7.6. Key conclusions

The guideline development group's recommendations took account of the evidence and their clinical expertise and experience. The group recommended the following assumptions related to the fluid deficit (degree of dehydration) in children and young people with DKA:

  • assume a 5% fluid deficit in mild to moderate DKA (indicated by a blood pH of 7.1 or above)
  • assume a 10% fluid deficit in severe DKA (indicated by a blood pH below 7.1).

18.4.3. Fluid composition

18.4.3.1. Review question

What is the optimal fluid composition (including glucose, potassium and bicarbonate additives) for rehydrating children and young people with diabetic ketoacidosis?

18.4.3.2. Introduction

The purpose of this review question is to determine the optimal composition of fluids used for rehydration in children and young people with DKA. The additives considered included glucose, potassium and bicarbonate. The search protocol for this review included RCTs and systematic reviews, and allowed for the inclusion of comparative observational studies as the guideline development group felt that it was unlikely that RCTs would exist that addressed this question. The same search criteria were used to identify results for this review and the reviews for appropriate rates of fluid administration and fluid composition in children and young people with DKA.

The guideline development group initially identified up to 8 priority outcomes for each fluid or additive addressed by the review question (but as there was insufficient evidence subsequently identified for inclusion in the review, the group was not required to narrow their selection to 7 outcomes for each component). These are summarised in Table 70.

Table 70. Outcomes prioritised by the guideline development group for each fluid or additive covered by the review.

Table 70

Outcomes prioritised by the guideline development group for each fluid or additive covered by the review.

Subgroup analyses were to be undertaken for type 1 and type 2 diabetes and/or by age group where possible.

18.4.3.3. Description of included studies

Seven observational studies met the inclusion criteria for this review (Becker 1983; Edge 2006; Glaser 2001; Green 1998; Lawrence 2005; Mar 1981; Savas-Erdeve 2011). One study was a partially randomised prospective cohort study (Becker 1983), 1 was a retrospective case-control study (Glaser 2001), 1 was a matched case-control study (Edge 2006) and 3 were retrospective chart reviews (Green 1998; Marr 1981; Savas-Erdeve 2011). One study was a case-control study that combined prospective surveillance with a retrospective chart review (Lawrence 2005).

Four studies were conducted in the USA (Becker 1983; Glaser 2001; Green 1998; Marr 1981), 1 in the UK (Edge 2006), 1 in Canada (Lawrence 2005) and 1 in Turkey (Savas-Erdeve 2011). The number of participants ranged from 32 to 427. Three studies involved children and young people with type 1 diabetes (Edge 2006; Glaser 2001; Savas-Erdeve 2011). The type of diabetes type was unclear for the other 4 studies (Becker 1983; Green 1998; Lawrence 2005; Marr 1981).

Six of the studies compared ‘additive versus no additive’ (Becker 1983; Edge 2006; Glaser 2001; Green 1998; Lawrence 2005; Savas-Erdeve 2011). The remaining study (Marr 1981) grouped additives together. This study addressed the effect of bicarbonate, and participants who received bicarbonate were grouped as follows:

  • sodium bicarbonate, or sodium bicarbonate and saline
  • sodium bicarbonate and saline and lactate Ringers, or sodium bicarbonate and lactate Ringers.

Evidence was identified for 3 of the interventions specified by the guideline development group. One study compared the effect of different concentrations of sodium within fluids (Savas-Erdeve 2011), 1 compared the effect of phosphate with no phosphate (Becker 1983) and the remaining 5 studies compared the effect of bicarbonate with no bicarbonate (Edge 2006; Glaser 2001; Green 1998; Lawrence 2005; Marr 1981). Outcomes reported in the studies were:

  • plasma sodium and plasma carbon dioxide for the addition of sodium
  • serum calcium for the addition of phosphate
  • duration of hospitalisation, duration of acidosis and risk of cerebral oedema for the addition of bicarbonate.

No evidence was identified for the addition of glucose or potassium to rehydration fluids.

No evidence was identified for the following outcomes: mortality; time to resolution of dehydration; rate of change of blood glucose concentration; resolution of blood ketosis; serum chloride concentration; incidence of hypoglycaemia; or incidence of hypokalaemia. No studies were identified which assessed the optimal composition of rehydration fluids in children and young people with type 2 diabetes. No subgroup analyses by age group and/or diabetes type were possible.

18.4.3.4. Evidence profile

The evidence profiles for this review question (optimal fluid composition for rehydration during DKA) are presented in Table 71 to Table 74.

Table 71. Evidence profile for comparison of 75 mEq/l concentration of sodium with 100 mEq/l concentration of sodium for the treatment of diabetic ketoacidosis in children and young people with type 1 diabetes.

Table 71

Evidence profile for comparison of 75 mEq/l concentration of sodium with 100 mEq/l concentration of sodium for the treatment of diabetic ketoacidosis in children and young people with type 1 diabetes.

Table 72. Evidence profile for comparison of bicarbonate with no bicarbonate for the treatment of diabetic ketoacidosis in children and young people.

Table 72

Evidence profile for comparison of bicarbonate with no bicarbonate for the treatment of diabetic ketoacidosis in children and young people.

Table 73. Evidence profile for the use of bicarbonate in treating diabetic ketoacidosis in children and young people with type 1 diabetes.

Table 73

Evidence profile for the use of bicarbonate in treating diabetic ketoacidosis in children and young people with type 1 diabetes.

Table 74. Evidence profile for comparison of phosphate with no phosphate for the treatment of diabetic ketoacidosis in children and young people.

Table 74

Evidence profile for comparison of phosphate with no phosphate for the treatment of diabetic ketoacidosis in children and young people.

18.4.3.5. Evidence statements

Sodium
Plasma sodium

One study (total 64 participants) found no statistically significant difference in plasma sodium at any time point from baseline through to 24 hours' follow-up in children and young people with DKA who received 75 mEq/l of sodium compared with those who received 100 mEq/l of sodium. The quality of the evidence for this outcome was very low.

Plasma carbon dioxide

One study (total 64 participants) found no statistically significant difference in plasma carbon dioxide at any time point from baseline through to 24 hours' follow-up in children and young people with DKA who received 75 mEq/l of sodium compared with those who received 100 mEq/l of sodium. The quality of the evidence for this outcome was very low.

pH

One study (total 64 participants) found no statistically significant difference in plasma pH at any time point from baseline through to 24 hours' follow-up in children and young people with DKA who received 75 mEq/l of sodium compared with those who received 100 mEq/l of sodium. The quality of the evidence for this outcome was very low.

Bicarbonate
Duration of hospitalisation

One study (total 78 participants) found a statistically significant increase in duration of hospitalisation in children and young people with DKA who received bicarbonate compared with those who did not receive bicarbonate. The quality of the evidence for this outcome was very low.

One study (total 212 participants) found no statistically significant difference in duration of hospitalisation in children and young people with DKA who received bicarbonate compared with those who did not receive bicarbonate. The quality of the evidence for this outcome was very low.

Risk of cerebral oedema

Three studies (total 950 participants) found a statistically significant increased risk of cerebral oedema in children and young people with DKA who received bicarbonate compared with those who did not receive bicarbonate. One of these studies found no statistically significant difference after adjustment for confounding variables. The quality of the evidence for this outcome was very low to moderate.

Duration of acidosis

One study (total 78 participants) found a statistically significant reduction in the duration of acidosis in children and young people with DKA who received bicarbonate compared with those who did not receive bicarbonate. The quality of the evidence for this outcome was very low.

Bicarbonate

One study (total 244 participants) found a statistically significant increase in the risk of cerebral oedema in children and young people with DKA who received treatment with bicarbonate compared with those who did not receive bicarbonate. The quality for the evidence was moderate.

Phosphate
Serum calcium

One study (total 22 participants) found no statistically significant difference in serum calcium levels in children and young people with DKA who received phosphate therapy compared with those who did not receive phosphate therapy. The quality of the evidence for this outcome was very low.

18.4.3.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence related to the optimal fluid composition (including glucose, potassium and bicarbonate additives) for rehydrating children and young people with DKA.

This question was not prioritised for health economic analysis as the guideline development group considered that the costs were small relative to the potential benefits and that clinical effectiveness would drive cost effectiveness.

18.4.3.7. Evidence to recommendations

18.4.3.7.1. Relative value placed on the outcomes considered

The most important outcomes prioritised for this review question were mortality and incidence of cerebral oedema (because DKA and associated conditions such as cerebral oedema can be life-threatening). Time to resolution of dehydration, rate of change of blood glucose concentration, incidence of hypoglycaemia, resolution of acidosis and resolution of blood ketosis, serum chloride concentration, hypokalaemia, serum sodium concentration, serum calcium concentration and carbon dioxide concentration were also considered important (because a faster recovery and normalisation of biochemical parameters is beneficial). Healthcare utilisation was also selected as an outcome for consideration (as a proxy for severity of DKA or presence of cerebral oedema).

18.4.3.7.2. Consideration of clinical benefits and harms

The guideline development group considered that there is little published evidence regarding the use of 0.9% saline (sodium chloride) or other intravenous solutions in DKA. The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidance recommends giving 0.9% saline for the first 4 to 6 hours of treatment. The British Society for Paediatric Endocrinology and Diabetes (BSPED) guidance recommends giving 0.9% saline for the first 12 hours of treatment. The guideline development group believed that risk of cerebral oedema was greatest during the first 12 hours of treatment which is why this timeframe had been chosen. The group was aware, however, of published studies showing an association between falling sodium concentrations (corrected for glucose) and the risk of cerebral oedema (Durward 2011; Fiordalisi 2007). The recommendation to use 0.9% saline for both rehydration and maintenance fluid in children and young people with DKA is consistent with guidance issued by the National Patient Safety Agency (NPSA).

Children and young people may present with normal or even elevated plasma potassium concentrations but in DKA there is always a significant total body potassium deficit. Furthermore, once insulin is administered potassium concentrations in the blood fall precipitously. The guideline development group therefore recommended that potassium should be added to intravenous fluid infusion at the start of treatment. Hypokalaemia is an important cause of death in children and young people with DKA.

It is known that hypophosphataemia occurs in children and young people presenting with DKA. However, clinical experience and current practice indicate that intravenous phosphate administration is not necessary. The guideline development group was aware of the possibility that phosphate administration could induce hypocalcaemia. For these reasons the group did not make a recommendation to add phosphate to the intravenous fluid regimen. This was in keeping with existing guidelines such as those from the BSPED.

The guideline development group recommended that bicarbonate should not normally be given as part of the treatment for DKA. There was evidence that bicarbonate administration is associated with an increased risk of cerebral oedema. Moreover, in DKA the acidosis is primarily due to ketoacidosis and it responds to treatment with insulin.

The guideline development group recommended adding 5% glucose to the intravenous fluid infusion once blood glucose falls below 14 mmol/litre. This level was chosen based on established international practice. In the event that blood glucose falls below 6 mmol/litre the group recommended increasing the glucose concentration of intravenous fluid infusions above 5% to prevent hypoglycaemia.

18.4.3.7.3. Consideration of health benefits and resource use

DKA and its consequences, including the possibility of death, provides an overriding rationale for optimising fluid management, and thus resource use is considered to be appropriate if such serious adverse outcomes can be prevented.

18.4.3.7.4. Quality of evidence

Evidence was lacking for most outcomes except bicarbonate and the evidence that was identified for inclusion was graded mainly as very low quality. This did not, however, prevent the guideline development group from formulating recommendations based on the available evidence for bicarbonate along with their clinical experience and practice relevant to the other fluids and additives considered in the review protocol (sodium, glucose, potassium and phosphate).

18.4.3.7.5. Other considerations

There were no other considerations.

18.4.3.7.6. Key conclusions

The guideline development group's recommendations took account of the evidence and their clinical expertise and experience. The group recommended the use of 0.9% sodium chloride without added glucose for both rehydration and maintenance fluid in children and young people with DKA until the blood glucose concentration is below 14 mmol/litre.

The group recommended that healthcare professionals ensure that all fluids (except any initial bolus) administered to children and young people with DKA contain 40 mmol/litre potassium chloride, unless they have renal failure The group further recommended changing fluids to 0.9% sodium chloride with 5% glucose and 40 mmol/litre potassium chloride once the blood glucose concentration falls below 14 mmol/litre.

The group recommended that if, during treatment for DKA, a child or young person's blood glucose falls below 6 mmol/litre the glucose concentration of the intravenous fluid infusion should be increased.

The group recommended that intravenous sodium bicarbonate should not be given to children and young people with DKA.

18.4.4. Intravenous insulin therapy

18.4.4.1. Starting and stopping intravenous insulin therapy

18.4.4.1.1. Review question

When should intravenous insulin therapy be started and stopped in children and young people with diabetic ketoacidosis?

18.4.4.1.2. Introduction

The purpose of this review question is to establish when intravenous insulin therapy should be started and stopped in children and young people with DKA. The review allowed the inclusion of observational studies in addition to RCTs and systematic reviews.

The guideline development group identified several key outcomes for this review:

  • mortality
  • rate of change of blood glucose
  • incidence of hypoglycaemia
  • incidence of cerebral oedema
  • resolution of acidosis
  • hypokalaemia
  • resolution of blood ketosis
  • healthcare utilisation.

For the part of the question regarding when to start intravenous insulin therapy the intervention was delayed insulin and the comparator immediate insulin. For the part of the question about stopping intravenous insulin outcomes were to be compared according to the blood ketone concentration at which insulin was stopped. Subgroup analyses by type of diabetes and age group were to be undertaken where possible.

The only study identified for inclusion for this review question (Edge 2006) included the Chair of the DKA subgroup as the primary author. To avoid any conflict of interest in the recommendations arising from the review question the NCC-WCH Clinical Director for Children's Health chaired the discussions. Although the Chair of the DKA subgroup participated in discussion of the evidence and formulation of the recommendations, she did not have a casting vote on the agreement of recommendations.

18.4.4.1.3. Description of included studies

A single study was identified for inclusion in this review (Edge 2006). This was a case-control study which addressed the timing at which to start insulin therapy in children and young people with type 1 diabetes and DKA. The study included 43 cases and 169 controls from England, Scotland and Wales. The mean ages of the participants were 8.5 years and 8.9 years for cases and controls, respectively.

Of the guideline development group priority outcomes, only risk of cerebral oedema was reported. Cases were defined as having a diagnosis of DKA-related cerebral oedema. Controls were defined as having a diagnosis of DKA without cerebral oedema. Controls were matched to cases based on age, sex, whether or not diabetes was newly diagnosed and the month of admission. Adjustments were also made for baseline biochemical measures to take account of the severity of acidosis. No subgroup analyses were possible.

No evidence was identified for: mortality, rate of change of blood glucose, hypoglycaemia incidence, resolution of acidosis, hypokalaemia or healthcare utilisation. No evidence was identified which addressed the time at which insulin therapy should be discontinued in children and young people with DKA.

18.4.4.1.4. Evidence profile

The evidence profile for this review question (timing of insulin therapy in children and young people with DKA) is presented in Table 75.

Table 75. Evidence profile for the effect of insulin administered within 1 hour of fluid replacement compared with insulin administered at least 1 hour after fluid administration on the risk of cerebral oedema.

Table 75

Evidence profile for the effect of insulin administered within 1 hour of fluid replacement compared with insulin administered at least 1 hour after fluid administration on the risk of cerebral oedema.

18.4.4.1.5. Evidence statements
Risk of cerebral oedema

One study (total 212 participants) found an increased risk of cerebral oedema in participants who received insulin therapy within 1 hour of starting rehydration. The same study found an increased risk of cerebral oedema when adjustment was made for baseline biochemical measures of acidosis. The quality of the evidence for both outcomes was moderate.

18.4.4.1.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence relating to starting and stopping intravenous insulin therapy.

This question was not prioritised for health economic analysis as the timing of starting or stopping intravenous insulin therapy does not have resource implications.

18.4.4.1.7. Evidence to recommendations
Relative value placed on the outcomes considered

The guideline development group was concerned to determine whether early or late commencement of intravenous insulin therapy in DKA might have associated risks or benefits. The group prioritised 7 outcomes as being of potential clinical importance: mortality, rate of change of blood glucose, incidence of hypoglycaemia, resolution of acidosis, incidence of cerebral oedema, incidence of hypokalaemia and healthcare utilisation.

Mortality was important because DKA is an important cause of mortality in people with diabetes. The rate of change of blood glucose concentration was not considered to be a primary objective. Nevertheless, the guideline development group considered it likely that studies would be likely to report this outcome. Hypoglycaemia was an important adverse outcome to be avoided. Resolution of acidosis was also likely to be reported in research studies, although again the group did not consider that this was likely to be a decisive clinical consideration when making recommendations. Cerebral oedema was an important outcome because it was a potential cause of both morbidity and mortality in DKA. It is the cause of death in 80% of children under 12 years who die from diabetes and it is a major cause of permanent disability (Edge 1999). Children and young people are more vulnerable than adults to the development of cerebral oedema. Hypokalaemia was considered an important outcome because it is a cause of mortality in DKA. Finally, healthcare utilisation (for example duration of admission or need for mechanical ventilation) was important. The need for mechanical ventilation was seen as a proxy for incidence of cerebral oedema.

Consideration of clinical benefits and harms

The guideline development group considered that since the included study found an increased risk of cerebral oedema in participants who received intravenous insulin within 1 hour of fluid therapy it is possible that there are physiological reasons why this might occur. For example, it might be that insulin affects some of the membrane transport systems (especially the Na/H transporter) and at the time of rapid changes in osmolality that might be deleterious.

The primary aim of starting insulin therapy in this setting is to resolve ketosis rather than to reduce the blood glucose level. Commencing intravenous fluid therapy prior to insulin is known to be effective in in lowering blood glucose as well as treating dehydration. The guideline development group recognised that there was a lack of published clinical studies regarding the relative risks and benefits associated with early versus deferred insulin administration, but deferring it for at least 1 hour after starting intravenous fluid replacement was in keeping with current practice and clinical experience suggested that this was a safe strategy.

Consideration of health benefits and resource use

The timing of when to start intravenous insulin administration is not associated with any difference in resource use and so the health benefits and harms are the only relevant considerations in this review question. For example, it is thought that there may be an increased risk of cerebral oedema if intravenous insulin therapy is started too soon after fluid therapy which has to be set against a delay in the resolution of ketosis.

Quality of evidence

The evidence from the only study included in the review regarding the risk of cerebral oedema with early versus deferred commencement of insulin therapy was of moderate quality. The finding that deferring insulin until at least 1 hour after starting rehydration was associated with a reduced risk of cerebral oedema was still significant when adjustment was made for the severity of acidosis in the patient groups.

Other considerations

There were no other considerations.

Key conclusions

Based on their considerations, the guideline development group recommended that in children and young people with DKA intravenous insulin therapy should be withheld for at least 1 hour after beginning intravenous fluid therapy. Specifically, the group recommended starting an intravenous insulin infusion 1 to 2 hours after beginning intravenous fluid therapy in children and young people with DKA.

There was no available evidence regarding the timing of conversion from intravenous insulin to subcutaneous insulin therapy, but based on physiological principles and the importance of insulin therapy to treat ketosis, the guideline development group concluded that this should happen after resolution of ketosis and made a recommendation accordingly. Specifically, the group suggested considering stopping intravenous fluid therapy for DKA in a child or young person if ketosis is resolving provided the child or young person is alert and they can take oral fluids without nausea or vomiting. The group recommended not changing from intravenous insulin to subcutaneous insulin until ketosis is resolving and the child or young person with DKA is alert and they can take oral fluids without nausea or vomiting.

The guideline development group was aware that children and young people with known diabetes might be using insulin therapy before presentation with DKA and the group's recommendations made provision for this in terms of insulin delivery systems that might be in place. Specifically, the group recommended that if a child or young person with DKA is using insulin pump therapy, the pump should be disconnected when starting intravenous insulin therapy and the pump should be restarted at least 60 minutes before stopping intravenous insulin. Similarly, the group recommended that healthcare professionals, in discussion with a diabetes specialist, should think about continuing subcutaneous basal insulin during treatment for DKA in a child or young person who was already using a basal insulin before the onset of DKA. The group recommended starting subcutaneous insulin in a child or young person with DKA at least 30 minutes before stopping intravenous insulin.

18.4.4.2. Dosage of intravenous insulin

18.4.4.2.1. Review question

How should the dosage of insulin be calculated for children and young people with diabetic ketoacidosis (DKA)?

18.4.4.2.2. Introduction

The objective of this review question is to determine the most appropriate dose of insulin to treat DKA in children and young people with either type 1 diabetes or type 2 diabetes. Specifically, the question addresses whether a low dosage of insulin (0.025 U/kg/hour or 0.05 U/kg/hour) may result in fewer adverse outcomes compared with the current ‘standard’ dosage of 0.1 U/kg/hour.

The guideline development group identified priority outcomes as being:

  • mortality
  • rate of change of blood glucose
  • incidence of hypoglycaemia
  • resolution of acidosis
  • resolution of blood ketosis
  • incidence of cerebral oedema
  • hypokalaemia
  • healthcare utilisation.

Subgroup analyses were to be undertaken for type 1 and type 2 diabetes and by age group where possible. The review includes observational studies because no RCTs met the inclusion criteria.

18.4.4.2.3. Description of included studies

Three retrospective cohort studies were identified for inclusion in this review (Al Hanshi 2011; Kapellen 2012; Puttha 2010). The studies were carried out in Australia, Germany and the UK, respectively. All 3 studies assessed DKA in children and young people with type 1 diabetes. As no studies addressing DKA associated with type 2 diabetes were identified for inclusion in the review no subgroup analyses by diabetes type were possible.

The number of participants ranged from 64 to 93. The age range of participants was 1.25 to 17.7 years across the 3 studies as a whole. Two of the studies included participants with narrower age ranges of approximately 6 years (Kapellen 2012; Puttha 2010). One study compared the standard dosage of insulin with a lower dose of 0.025 U/kg/hour (Kapellen 2012). The other studies compared the standard dosage of insulin with a lower dose of 0.05 U/kg/hour (Al Hanshi 2011; Puttha 2010).

Data were reported for 4 of the guideline development group's priority outcomes: change in blood glucose from admission, change in blood pH from admission, incidence of hypoglycaemia and incidence of hypokalaemia. One study reported results for children under the age of 5 years in a subgroup analysis (Puttha 2010). Four further outcomes were not reported in sufficient detail to be included in GRADE profiles:

  • 1 study reported a case of cerebral oedema using a case-report approach (Kapellen 2012)
  • 1 study reported time to normalise acidosis, but no confidence intervals or p-values for between-group differences were reported (Kapellen 2012)
  • 1 study reported duration of hospital stay, but it was not clear whether the reported values were means or medians and confidence intervals were not reported (Puttha 2010)
  • 1 study reported the time to normalise blood glucose, but no confidence intervals were provided and it was not clear whether the values were means or medians (Kapellen 2012).

No studies reported results for mortality or resolution of ketosis.

18.4.4.2.4. Evidence profile

The evidence profile for this review question (dosage of intravenous insulin) is presented in Table 76.

Table 76. Comparison of insulin dosage of 0.025 U/kg/hour or 0.05 U/kg/hour with a dosage of 0.1 U/kg/hour in children and young people with type 1 diabetes and DKA.

Table 76

Comparison of insulin dosage of 0.025 U/kg/hour or 0.05 U/kg/hour with a dosage of 0.1 U/kg/hour in children and young people with type 1 diabetes and DKA.

18.4.4.2.5. Evidence statements
Change in blood glucose from admission

One study (total 67 participants) found a smaller reduction in plasma glucose from admission in a low-dosage insulin group (0.05 U/kg/hour) compared with the standard dosage group (0.1 U/kg/hour). This study also found that insulin dosage was correlated with plasma glucose at 12 hours' follow-up, adjusted for the baseline value and age. Another study (total 93 participants) did not find a difference in change in blood glucose between the low and standard dosage groups (with low dosage of 0.05 U/kg/hour). The quality of the evidence for these outcomes was very low.

Subgroup analysis: children aged less than 5 years

One study (total 11 participants) found no difference in the change in blood glucose between groups (low dosage of 0.05 U/kg/hour). The quality of the evidence for this outcome was very low.

Incidence of hypoglycaemia

One study (total 64 participants) found that the incidence of hypoglycaemia was higher in participants who received a low dosage of insulin (0.025 U/kg/hour) compared with the standard dosage. The quality of the evidence for this outcome was very low.

One study (total 121 participants) found that the incidence of hypoglycaemia was lower in the low insulin group (0.05 U/kg/hour) compared with the standard dosage. The quality of the evidence was very low.

Incidence of hypokalaemia

One study (total 121 participants) found that the incidence of hypokalaemia was lower in participants who received a low dosage of insulin (0.025 U/kg/hour) compared with the standard dosage. The quality of the evidence for this outcome was very low.

Change in blood pH from admission

One study (total 93 participants) found no difference in the change in blood pH from admission between groups (low dosage of 0.05 U/kg/hour). The quality of the evidence for this outcome was very low.

Subgroup analysis: children aged less than 5 years

One study (total 11 participants) found no difference in the change in blood pH between groups (low dosage of 0.05U/kg/hour). The quality of the evidence for this outcome was very low.

Time to resolution of acidosis (pH more than 7.3)

One study (total 93 participants) found no difference in the time to resolution of acidosis (blood pH more than 7.3) between participants who received a low dosage of insulin (0.05 U/kg/hour) compared with those who received the standard dosage. The quality of the evidence for this outcome was very low.

18.4.4.2.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence related to the dosage of insulin for children and young people with DKA.

This question was not prioritised for health economic analysis as the guideline development group considered there were more important priorities for health economic analysis.

18.4.4.2.7. Evidence to recommendations
Relative value placed on the outcomes considered

The guideline development group wanted to determine whether low-dosage intravenous insulin (for example 0.05 U/kg/hour or 0.25 U/kg/hour) or standard-dosage insulin (0.1 U/kg/hour) during DKA might have associated risks or benefits. They prioritised the following outcomes as being of potential clinical importance: mortality, rate of change of blood glucose, incidence of hypoglycaemia, resolution of acidosis, resolution of ketosis, incidence of cerebral oedema, incidence of hypokalaemia and healthcare utilisation.

Mortality was important because DKA is an important cause of mortality in people with diabetes. The rate of change of blood glucose concentration was not considered to be a primary objective. Nevertheless, the guideline development group considered it likely that studies would report this outcome. Hypoglycaemia is an important adverse outcome, but it should be avoided if adequate intravenous glucose is administered. Resolution of acidosis and ketosis was an important outcome because this is a key objective with insulin therapy during DKA. The primary purpose of insulin in the management of DKA is to switch off ketone production. Cerebral oedema is an important outcome, because it is a potential cause of both morbidity and mortality in DKA. It is the cause of death in 80% of children under 12 years who die from diabetes and it is also a major cause of permanent disability (Edge 1999). Children and young people are more vulnerable than adults to the development of cerebral oedema. Hypokalaemia is an important outcome because it is a cause of mortality in DKA. Finally, healthcare utilisation (for example duration of admission or need for mechanical ventilation) is important. The need for mechanical ventilation is seen as a proxy for incidence of cerebral oedema.

Consideration of clinical benefits and harms

The guideline development group recognised that using a standard insulin dosage of 0.1 units/kg/hour was widespread and appears to be safe and effective. However, some centres do routinely use a lower dose of 0.05 U/kg/hour and again experience was that this was safe and effective. There was limited evidence from comparative studies to determine the optimal insulin dosage and the available evidence could not address the important outcome of mortality. The resolution of acidosis appeared to be equivalent when dosages of 0.05 U/kg/hour and 0.1 U/kg/hour were compared (this outcome was not reported for a dosage of 0.025 units/kg/hour). There was a lack of evidence regarding the relative risks of adverse events such as the incidence of cerebral oedema, hypoglycaemia and hypokalaemia.

Consideration of health benefits and resource use

There was no evidence for any difference between the insulin dosages evaluated. The guideline development group's recommendations allow for the standard insulin dosage of 0.1 units/kg/hour but also permit a lower dose of 0.05 units/kg/hour and will therefore have minimal cost impact, especially in the context of the overall management of the condition. Thus the guideline development group's recommendations will not affect resource use.

Quality of evidence

In all of the included studies the available evidence was of very low quality. The finding in 1 study that hypoglycaemia was more common in participants treated with 0.025 units/kg/hour compared with 0.1 units/kg/hour was contrary to what would be expected. The study authors noted that there was no difference in the incidence of hypoglycaemia during the first 12 hours of treatment and that the difference between the treatment groups was found only later in the course of treatment (when participants were making the transition from intravenous to subcutaneous insulin). Importantly, the children and young people in the 2 treatment groups in this study were being managed in different centres. This raises the possibility that factors other than the dosage of intravenous insulin were responsible for the observed difference in outcomes in this study. It was noteworthy that the children and young people in the centre using the low-dosage insulin regimen received about twice as much intravenous fluid as those in the standard-dosage centre, presumably reflecting differences in either fluid management policy or severity of dehydration in the participants. Those studies that compared 0.05 units/kg/hour with 0.1 units/kg/hour found no difference in the incidence of hypoglycaemia.

There was no evidence for mortality or incidence of cerebral oedema.

Other considerations

There were no other considerations.

Key conclusions

In accordance with current practice in the UK, and taking account of the lack of good quality comparative studies, the guideline development group recommended that in children and young people requiring intravenous insulin for DKA a dosage of between 0.0 5 U/kg/hour and 0.1 U/kg/hour be used. The group also recommended, given the critical role of insulin in resolving ketosis, that if the blood glucose level was to fall excessively during intravenous insulin therapy while ketosis persisted, insulin treatment should be maintained in a dosage of at least 0.05 U/kg/hour while the glucose level should be managed by increasing the rate of intravenous glucose administration (see Section 18.4.3). The guideline development group, taking account of the lack of quality evidence on this topic, made a research recommendation on the need to conduct an RCT to determine the optimal dosage of intravenous insulin in children and young people with DKA.

18.4.5. Recommendations

207.

Treat DKA with oral fluids and subcutaneous insulin only if the child or young person is alert, not nauseated or vomiting, and not clinically dehydrated. [new 2015]

208.

If DKA is treated with oral fluids and subcutaneous insulin, ensure that the child or young person is recovering by monitoring for resolution of ketonaemia and acidosis. [new 2015]

209.

Treat DKA with intravenous fluids and intravenous insulin if the child or young person is not alert, is nauseated or vomiting or is clinically dehydrated. [new 2015]

210.

Do not give oral fluids to a child or young person who is receiving intravenous fluids for DKA unless ketosis is resolving, they are alert, and they are not nauseated or vomiting. [new 2015]

211.

Do not give an intravenous fluid bolus to children and young people with mild or moderate DKA (indicated by a blood pH of 7.1 or above). [new 2015]

212.

Do not routinely give an intravenous fluid bolus to a child or young person with severe DKA (indicated by a blood pH below 7.1). [new 2015]

213.

Do not give more than one intravenous fluid bolus of 10 ml/kg 0.9% sodium chloride to a child or young person with severe DKA (indicated by a blood pH below 7.1) without discussion with the responsible senior paediatrician. [new 2015]

214.

In children and young people with DKA, calculate their total fluid requirement for the first 48 hours by adding the estimated fluid deficit (see recommendation 215) to the fluid maintenance requirement (see recommendation 216). [new 2015]

215.

When calculating the fluid requirement for children and young people with DKA, assume:

  • a 5% fluid deficit in mild to moderate DKA (indicated by a blood pH of 7.1 or above)
  • a 10% fluid deficit in severe DKA (indicated by a blood pH below 7.1). [new 2015]
216.

Calculate the maintenance fluid requirement for children and young people with DKA using the following ‘reduced volume’ rules:

  • if they weigh less than 10 kg, give 2 ml/kg/hour
  • if they weigh between 10 and 40 kg, give 1 ml/kg/hour
  • if they weigh more than 40 kg, give a fixed volume of 40 ml/hour.

These are lower than standard fluid maintenance volumes because large fluid volumes are associated with an increased risk of cerebral oedema. [new 2015]

217.

Aim to replace the fluid deficit evenly over the first 48 hours in children and young people with DKA, because faster rehydration is associated with an increased risk of cerebral oedema. [new 2015]

218.

Use 0.9% sodium chloride without added glucose for both rehydration and maintenance fluid in children and young people with DKA until the plasma glucose concentration is below 14 mmol/litre. [new 2015]

219.

Ensure that all fluids (except any initial bolus) administered to children and young people with DKA contain 40 mmol/litre potassium chloride, unless they have renal failure. [new 2015]

220.

If more than 20 ml/kg of fluid has been given by intravenous bolus to a child or young person with DKA, subtract any additional bolus volumes from the total fluid calculation for the 48-hour period. [new 2015]

221.

Do not give intravenous sodium bicarbonate to children and young people with DKA. [new 2015]

222.

Think about inserting a urinary catheter if it is not possible to accurately measure urine output for a child or young person with DKA. [new 2015]

223.

Do not give children and young people with DKA additional intravenous fluid to replace urinary losses. [new 2015]

224.

Start an intravenous insulin infusion 1-2 hours after beginning intravenous fluid therapy in children and young people with DKA. [new 2015]

225.

When treating DKA with intravenous insulin in children and young people, use a soluble insulin infusion at a dosage between 0.05 and 0.1 units/kg/hour. Do not give bolus doses of intravenous insulin. [new 2015]

226.

If a child or young person with DKA is using insulin pump therapy, disconnect the pump when starting intravenous insulin therapy. [new 2015]

227.

In discussion with a diabetes specialist, think about continuing subcutaneous basal insulin in a child or young person who was using a basal insulin before the onset of DKA. [new 2015]

228.

Change fluids to 0.9% sodium chloride with 5% glucose and 40 mmol/litre potassium chloride once the plasma glucose concentration falls below 14 mmol/litre in children and young people with DKA. [new 2015]

229.

If during treatment for DKA a child or young person's plasma glucose falls below 6 mmol/litre:

  • increase the glucose concentration of the intravenous fluid infusion, and
  • if there is persisting ketosis, continue to give insulin at a dosage of least 0.05 units/kg/hour. [new 2015]
230.

If the blood beta-hydroxybutyrate level is not falling within 6-8 hours in a child or young person with DKA, think about increasing the insulin dosage to 0.1 units/kg/hour or greater. [new 2015]

231.

Think about stopping intravenous fluid therapy for DKA in a child or young person if ketosis is resolving, they are alert, and they can take oral fluids without nausea or vomiting. [new 2015]

232.

Do not change from intravenous insulin to subcutaneous insulin in a child or young person with DKA until ketosis is resolving, they are alert, and they can take oral fluids without nausea or vomiting. [new 2015]

233.

Start subcutaneous insulin in a child or young person with DKA at least 30 minutes before stopping intravenous insulin. [new 2015]

234.

For a child or young person with DKA who is using insulin pump therapy, restart the pump at least 60 minutes before stopping intravenous insulin. Change the insulin cartridge and infusion set, and insert the cannula into a new subcutaneous site. [new 2015]

18.4.6. Research recommendations

19.

What is the optimal dosage of intravenous insulin for managing diabetic ketoacidosis (DKA) in children and young people?

18.5. Monitoring during therapy

The evidence and recommendations related to monitoring during therapy are considered alongside those for assessments and investigations at presentation (see Section 18.2.2).

18.5.1. Recommendations

235.

Monitor and record the following at least hourly in children and young people with DKA:

  • capillary blood glucose
  • vital signs (heart rate, blood pressure, temperature, respiratory rate [look for Kussmaul breathing])
  • fluid balance, with fluid input and output charts
  • level of consciousness (using the modified Glasgow coma scale). [new 2015]
236.

Monitor and record the level of consciousness (using the modified Glasgow coma scale) and the heart rate (to detect bradycardia) every 30 minutes in:

  • children under 2 years with DKA
  • children and young people with severe DKA (indicated by a blood pH below 7.1).

This is because these children and young people are at increased risk of cerebral oedema. [new 2015]

237.

Monitor children and young people receiving intravenous therapy for DKA using continuous electrocardiogram (ECG) to detect signs of hypokalaemia, including ST-segment depression and prominent U-waves. [new 2015]

238.

Ensure that healthcare professionals performing the monitoring described in recommendations 235, 236 and 237 know what to look for and when to seek advice. [new 2015]

239.

At 2 hours after starting treatment, and then at least every 4 hours, carry out and record the results of the following blood tests in children and young people with DKA:

  • glucose (laboratory measurement)
  • blood pH and pCO2
  • plasma sodium, potassium and urea
  • beta-hydroxybutyrate. [new 2015]
240.

A doctor involved in the care of the child or young person with DKA should review them face-to-face at diagnosis and then at least every 4 hours, and more frequently if:

  • they are aged under 2 years
  • they have severe DKA (indicated by a blood pH below 7.1)
  • there are any other reasons for special concern. [new 2015]
241.

At each face-to-face review of children and young people with DKA, assess the following:

  • clinical status, including vital signs and neurological status
  • results of blood investigations
  • ECG trace
  • cumulative fluid balance record. [new 2015]
242.

Update the child and young person with DKA and their family members or carers (as appropriate) regularly about their progress. [new 2015]

18.6. Complications of diabetic ketoacidosis

18.6.1. Intravenous osmotic agents

18.6.1.1. Review question

What is the effectiveness of intravenous osmotic agents in the management of cerebral oedema associated with diabetic ketoacidosis?

18.6.1.2. Introduction

The objective of this review question is to assess the effectiveness of intravenous osmotic agents in the treatment of cerebral oedema associated with DKA in children and young people with type 1 or type 2 diabetes.

The main intervention of interest to the guideline development group was the urgent administration of mannitol or hypertonic saline while the child or young person is still on a general paediatric ward. The setting in which intravenous osmotic agents are administered and the duration of treatment were also of interest. The main outcomes of interest were mortality, persistent neurological deficit and healthcare utilisation.

Subgroup analyses were to be undertaken for type 1 and type 2 diabetes, previously recognised diabetes or first presentation and/or by age group where possible. The search strategy covered observational studies as well as RCTs, although no RCTs met the inclusion criteria.

18.6.1.3. Description of included studies

One retrospective cohort study (DeCourcey 2013) was identified for inclusion in this review. The study was carried out in the USA. The study assessed DKA and cerebral oedema in children and young people aged less than 19 years who were treated in tertiary care hospitals. The study was assumed to be related specifically to type 1 diabetes and therefore there are assumed to be no studies relevant to DKA in children and young people with type 2 diabetes. Therefore no subgroup analyses by diabetes type were possible.

The study included 1632 participants with cerebral oedema associated with DKA. The age range of participants was 8.7 to 15.2 years. The study compared outcomes in participants who received mannitol alone, those who received 3% hypertonic saline alone and those who received both mannitol and hypertonic saline as a combined treatment. The study reported the proportion of participants whose treatment involved admission to an intensive care unit (ICU).

Sufficient data were available on 2 of the guideline development group's priority outcomes: mortality and healthcare utilisation (which the study authors expressed as severity of illness). The group's other priority outcome (persistent neurological deficit) was not reported. The study did not report duration of treatment. Mortality subgroup analyses by previously recognised diabetes or first presentation and by age group were not reported separately for any of the treatment groups, although overall mortality by ICD-9 diagnosis codes for diabetes with hyperosmolar state and diabetes with coma, and for different age groups, were reported.

18.6.1.4. Evidence profile

The evidence profile for this review question (intravenous osmotic agents for the management of cerebral oedema) is presented in Table 77.

Table 77. Effectiveness of intravenous osmotic agents in the treatment of cerebral oedema associated with diabetic ketoacidosis in children and young people with type 1 diabetes.

Table 77

Effectiveness of intravenous osmotic agents in the treatment of cerebral oedema associated with diabetic ketoacidosis in children and young people with type 1 diabetes.

18.6.1.5. Evidence statements

Mortality

One study (total number of participants is not calculable) found that use of hypertonic saline alone was associated with higher mortality than use of mannitol alone, adjusted for discharge year, hospital clustering, gender, predictors of severity (mechanical ventilation, brain imaging with CT scan and ICD-9 code [250.2 and 250.3]) after non-significant predictors of mortality (age, race and ICU admission) were sequentially removed. Participants treated with both agents were excluded from odds ratio (OR) analysis in the study. The quality of the evidence for this outcome was very low.

Healthcare utilisation

The study (total 1501 participants) was not able to determine whether healthcare utilisation (which the study authors expressed as severity of illness) was a consequence of the treatment as it could not ascertain what clinical criteria were used to warrant treatment. The study found more children and young people treated with hypertonic saline alone were admitted to ICU than those treated with mannitol alone. The same study found a few more children and young people treated with mannitol alone had mechanical ventilation and brain imaging with CT scan than hypertonic saline alone. The quality of the evidence for these outcomes was very low.

18.6.1.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence relating to the effectiveness of intravenous osmotic agents in the management of cerebral oedema associated with DKA.

This question was not prioritised for health economic analysis as the guideline development group considered that the costs were small relative to the potential benefits and that clinical effectiveness would drive cost effectiveness.

18.6.1.7. Evidence to recommendations

18.6.1.7.1. Relative value placed on the outcomes considered

The guideline development group specified mortality as the highest-priority outcome and this was reported in the included study. Long-term neurological problems were also selected as a priority outcome but these were not reported in the included study. However, the absence of evidence for this outcome did not prevent the group making recommendations.

18.6.1.7.2. Consideration of clinical benefits and harms

The guideline development group noted that cerebral oedema is potentially life threatening and that prompt action to treat cerebral oedema is essential once the condition is detected. The guideline development group was aware that mannitol has been the standard treatment for cerebral oedema but that increasingly hypertonic saline (sodium chloride) is being used in intensive care units (ICUs) for treatment of non-DKA related cerebral oedema and in some settings hypertonic saline is now recommended as first-line treatment.

A possible benefit of hypertonic saline over mannitol is that it can be given repeatedly with persisting benefit whereas mannitol becomes less effective with repeated administration.

The group also noted that mannitol is more readily available on paediatric wards (although this does not hold true for ICUs).

18.6.1.7.3. Consideration of health benefits and resource use

The guideline development group emphasised that effective treatment of cerebral oedema will save lives and noted that it may improve neurological outcomes. The treatment options considered by the group – mannitol and hypertonic saline – were both noted to be low cost, and the group noted that the intention was not to recommend either mannitol or hypertonic saline in preference to the other, but to recommend the use of whichever of the 2 treatments would be readily already available, and therefore it was expected that there would be no uplift in cost associated with the recommendation.

Illustrative costs for mannitol and hypertonic saline are illustrated below, based on the unit costs reported in Table 78. They suggest that for the pack sizes listed the costs would be similar.

Table 78. Unit costs of osmotic agents.

Table 78

Unit costs of osmotic agents.

Following the upper limit of the guideline recommendations a girl aged 12 years weighing 40 kg would require:

  • Mannitol 20% – 40 g or 200 ml which could be supplied from 1 bag of 250 ml solution
  • Hypertonic saline 2.7% – 200 ml which could be supplied from 1 bag of solution.
18.6.1.7.4. Quality of evidence

The guideline development group noted that the evidence for their priority outcome of healthcare utilisation was slightly indirect in that the study authors reported severity of illness rather than a direct measure of healthcare resource use. The group also noted that a record of administering mannitol or hypertonic saline would provide a reasonable marker for presence of cerebral oedema, although this could not be ascertained with certainty.

The group noted that the evidence was seriously indirect due to the methods used in the study. In particular, the group felt that there was strong risk of bias because hypertonic saline was reported to be used more frequently in ICU settings and it was plausible that the relevant participants would have been more unwell than the other participants. This meant that no conclusions could be drawn in terms of comparing the effectiveness of mannitol and hypertonic saline.

Where both treatments (mannitol and hypertonic saline) were used it was impossible to tell which was used first and again the guideline development group thought it was likely that participants who received both treatments would have been more unwell than the other participants. Therefore nothing could be concluded about the potential benefit of using both treatments sequentially, nor the order in which the treatments were used.

18.6.1.7.5. Other considerations

The dosages for mannitol and hypertonic saline recommended by the guideline development group are broadly in keeping with general statements in the summaries of product characteristics (SPCs) for these products and with ISPAD guidance which reflects current practice in the UK. The guideline development group wished to include the dosages in the recommendations so that the information would be to hand when management of cerebral oedema was necessary, rather than healthcare professionals having to check the dosages separately and thus delay potentially life-saving treatment.

18.6.1.7.6. Key conclusions

The guideline development group concluded that cerebral oedema in children and young people with DKA should be treated promptly using mannitol or hypertonic saline (sodium chloride), whichever is most readily available in the non-ICU setting. Specifically, the group recommended that if cerebral oedema is suspected in a child or young person with DKA, they should be treated immediately with the most readily available of mannitol (20%; 0.5 to 1 g/kg over 10 to 15 minutes) or hypertonic sodium cholride (2.7% or 3%; 2.5 to 5 ml/kg over 10 to 15 minutes). The same treatment should be given to any child or young person with DKA who develops any of the following signs: deterioration in level of consciousness; abnormalities of breathing pattern, for example respiratory pauses; oculomotor palsies; pupillary inequality or dilatation.

The group further recommended that after starting treatment for cerebral oedema with mannitol or hypertonic sodium chloride in a child or young person with DKA, specialist advice on further management, including which care setting would be best, should be sought immediately.

18.6.2. Anticoagulant prophylaxis

18.6.2.1. Review question

What is the effectiveness of routine anticoagulant prophylaxis to prevent venous thrombosis in children and young people with DKA?

18.6.2.2. Introduction

The objective of this review question is to determine whether anticoagulant prophylaxis is effective in preventing venous thrombosis in children and young people with DKA. The guideline development group noted that deep vein thrombosis, visceral thrombosis and cerebral thrombosis would all be relevant in this review question.

18.6.2.3. Description of included studies

For this question the search included both RCTs and comparative observational studies. However, no studies were identified that met the inclusion criteria.

18.6.2.4. Evidence profile

There is no evidence profile for this review question because no studies were identified for inclusion.

18.6.2.5. Evidence statements

No evidence was identified for inclusion for this review question.

18.6.2.6. Health economics profile

A systematic literature search did not identify any relevant published economic evidence relating to routine anticoagulant prophylaxis to prevent venous thrombosis in children and young people with DKA.

This question was not prioritised for health economic analysis as the guideline development group considered there were more important priorities for health economic analysis.

18.6.2.7. Evidence to recommendations

18.6.2.7.1. Relative value placed on the outcomes considered

The guideline development group prioritised the following physical outcomes for consideration in this review question:

  • mortality
  • incidence of venous thrombosis (of any type, including deep vein thrombosis, visceral thrombosis and cerebral thrombosis)
  • incidence of pulmonary embolism
  • healthcare utilisation (for example duration of admission, admission to intensive care)
  • adverse events, including bleeding and thrombocytopaenia.

The group also prioritised the satisfaction of children, young people and families with the intervention as an outcome for consideration.

The group's priorities reflected the serious nature of potential outcomes associated with venous thrombosis and pulmonary embolism, including the possibility of death, and their selection of priority outcomes reflects this alongside the importance of offering treatments that are acceptable to children and young people with DKA and their families.

18.6.2.7.2. Consideration of clinical benefits and harms

The guideline development group recognised that there is a risk of venous thrombosis in children and young people with DKA (this was based on the group's knowledge of relevant case reports). The extent of this risk has, however, not been accurately quantified.

The group's view was that the use of central venous catheters increases the risk of thrombosis (again this is based on the group's knowledge of case reports).

The group noted that the risk of venous thromboembolism (VTE) in children and young people with DKA compared with other children in an intensive therapy unit (ITU) environment is unknown, and there are potential harms associated with anticoagulant prophylaxis and treatment (the main harm being bleeding).

Overall, the guideline development group noted the lack of evidence for this review question and concluded that there was no general consensus regarding the role of anticoagulant prophylaxis for children and young people with DKA, either in terms of benefits or harms.

18.6.2.7.3. Consideration of health benefits and resource use

The guideline development group did not enter into detailed consideration of the cost effectiveness of alternative management strategies based on anticoagulant prophylaxis because they did not wish to recommend this form of treatment due to a lack of evidence related to its clinical effectiveness.

18.6.2.7.4. Quality of evidence

No evidence was identified for inclusion for this review question, but the guideline development group did not view this area as a priority for future research.

18.6.2.7.5. Other considerations

There were no other considerations.

18.6.2.7.6. Key conclusions

The guideline development group concluded that anticoagulant prophylaxis was not to be recommended for children and young people with DKA and they agreed not to make any recommendations on this topic. The group did, however, recommend that healthcare professionals should be aware of the increased risk of venous thromboembolism in children and young people with DKA, especially those with central venous catheters.

18.6.3. Recommendations

243.

Immediately assess children and young people with DKA for suspected cerebral oedema if they have any of these early manifestations:

  • headache
  • agitation or irritability
  • unexpected fall in heart rate
  • increased blood pressure. [new 2015]
244.

If cerebral oedema is suspected in a child or young person with DKA, treat immediately with the most readily available of mannitol (20%, 0.5-1 g/kg over 10-15 minutes) or hypertonic sodium chloride (2.7% or 3%, 2.5-5 ml/kg over 10-15 minutes). [new 2015]

245.

Immediately treat for cerebral oedema using the most readily available of mannitol (20%, 0.5-1 g/kg over 10-15 minutes) or hypertonic sodium chloride (2.7% or 3%, 2.5-5 ml/kg over 10-15 minutes) if a child or young person with DKA develops any of these signs:

  • deterioration in level of consciousness
  • abnormalities of breathing pattern, for example respiratory pauses
  • oculomotor palsies
  • pupillary inequality or dilatation. [new 2015]
246.

After starting treatment for cerebral oedema with mannitol or hypertonic sodium chloride in a child or young person with DKA, immediately seek specialist advice on further management, including which care setting would be best. [new 2015]

247.

If a child or young person with DKA develops hypokalaemia (potassium below 3 mmol/litre):

  • think about temporarily suspending the insulin infusion
  • discuss hypokalaemia management urgently with a paediatric critical care specialist, because a central venous catheter is needed for intravenous administration of potassium solutions above 40 mmol/litre. [new 2015]
248.

Be aware of the increased risk of venous thromboembolism in children and young people with DKA, especially those with central venous catheters. [new 2015]

18.7. Avoiding future episodes of diabetic ketoacidosis

The recommendations related to avoiding future episodes of diabetic ketoacidosis are based on the 2004 guideline recommendations and general recommendations arising from the evidence reviews for the 2015 update. There is, therefore, no specific evidence to recommendations section for this topic.

18.7.1. Recommendations

249.

After a child or young person with known diabetes has recovered from an episode of DKA, discuss with them and their family members or carers (if appropriate) the factors that may have led to the episode. [new 2015]

250.

Think about the possibility of non-adherence to therapy in children and young people with established type 1 diabetes who present with DKA, especially if the DKA is recurrent. [2004, amended 2015]

251.

Advise children and young people who have had an episode of DKA and their family members or carers (if appropriate) how to reduce the risk of future episodes. In particular, advise them of the importance of managing intercurrent illnesses. [new 2015]

Copyright © 2015 National Collaborating Centre for Women's and Children's Health.
Bookshelf ID: NBK343412

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