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Acute Metabolic Emergencies in Diabetes: DKA, HHS and EDKA

Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1307)

Abstract

Emergency admissions due to acute metabolic crisis in patients with diabetes remain some of the most common and challenging conditions. DKA (Diabetic Ketoacidosis), HHS (Hyperglycaemic Hyperosmolar State) and recently focused EDKA (Euglycaemic Diabetic Ketoacidosis) are life-threatening different entities. DKA and HHS have distinctly different pathophysiology but basic management protocols are the same. EDKA is just like DKA but without hyperglycaemia. T1D, particularly children are vulnerable to DKA and T2D, particularly elderly with comorbidities are vulnerable to HHS. But these are not always the rule, these acute conditions are often occur in different age groups with diabetes. It is essential to have a coordinated care from the multidisciplinary team to ensure the timely delivery of right treatment. DKA and HHS, in many instances can present as a mixed entity as well. Mortality rate is higher for HHS than DKA but incidences of DKA are much higher than HHS. The prevalence of HHS in children and young adults are increasing due to exponential growth of obesity and increasing T2D cases in this age group. Following introduction of SGLT2i (Sodium-GLucose co-Transporter-2 inhibitor) for T2D and off-label use in T1D, some incidences of EDKA has been reported. Healthcare professionals should be more vigilant during acute illness in diabetes patients on SGLT2i without hyperglycaemia to rule out EDKA. Middle aged, mildly obese and antibody negative patients who apparently resemble as T2D without any precipitating causes sometime end up with DKA which is classified as KPD (Ketosis-prone diabetes). Many cases can be prevented by following ‘Sick day rules’. Better access to medical care, structured diabetes education to patients and caregivers are key measures to prevent acute metabolic crisis.

Keywords

Anion gap ARDS (Acute Respiratory Distress Syndrome) Cerebral Oedema CSII (Continuous Subcutaneous Insulin Infusion) Fixed Rate Intravenous Insulin Infusion (FRIII) Hypokalaemia Osmolality Variable Rate Intravenous Insulin Infusion (VRIII) 
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1 Introduction

DKA and HHS are two similar yet in many ways different metabolic emergencies of diabetes are encountered in emergency departments. Hyperglycemia, despite being the common ground for both conditions, is different in magnitude for each emergency, being more severe in HHS. Ketoacidosis is the hallmark of DKA found mostly in T1D due to absolute insulin deficiency. In HHS, ketoacidosis is nominal unless a mixed variety, which is due to residual insulin sufficient to prevent ketosis. It was thought that DKA is specific condition for T1D and HHS for T2D but this does not hold anymore. More and more cases of DKA are being reported in T2D and HHS in T1D. Similarly, the characteristic age distribution of acute hyperglycemic emergencies is not valid anymore. It is also not uncommon to find out mixture of two entities presenting in same patient.

Both of these conditions require immediate hospitalization and therefore have negative impact on the economy of a country. DKA primarily affects T1D and may be the first manifestation in up to 25% of cases (Dabelea et al. 2014; Jefferies et al. 2015; Rewers et al. 2008). More recently, EDKA is being found in T1D and T2D patient on SGLT2i (Peters et al. 2015). So there should be high index of suspicion in an unwell person with diabetes without hyperglycaemia on SGLT2i and EDKA should be ruled out. Up to 42% of DKA hospitalisations are due to readmissions for DKA within 1 year (Edge et al. 2016). It is a matter of solace that DKA mortality rates have fallen significantly in last 20 years from 7.96% to less than 1% (Umpierrez and Korytkowski 2016) Unfortunately, the mortality rates are still higher in patients over 60 years old with comorbidities, in low-income countries and in non-hospitalised patients (Otieno et al. 2006). The recent updated mortality in HHS is around 5–16% globally (Umpierrez and Korytkowski 2016). This high mortality rates necessitates early diagnosis and effective prevention programmes. Cheaper insulin should be readily available globally (Greene and Riggs 2015). The most common cause of mortality is cerebral oedema in children and young adults. On the other hand, the main causes of mortality in adults and elderly with HHS are diverse and many. The major causes are severe hypokalaemia, cardiac dysrhythmia, severe hypoglycaemia, ARDS, pneumonia, ACS (Acute Coronary Syndrome) and sepsis (Wolfsdorf et al. 2018).

Efforts should be directed to decrease hospitalization rate and acute metabolic crisis of diabetes by introducing structured diabetes education and provision of better healthcare to less developed areas. There exist some subtle differences in management protocols of DKA, EDKA and HHS patients. The purpose of this review is to provide the latest insights of epidemiology, pathophysiology, management and prevention of acute metabolic emergencies of diabetes.

2 Classification and Diagnostic Criteria

History, clinical examination, signs & symptoms and biochemical tests are required to aid diagnosis of condition. The classical triad of DKA includes hyperglycemia, ketonaemia and high anoin gap metabolic acidosis. The biochemical criterion set by JBDS, BSPED and ISPAD for diagnosis of DKA (Dhatariya 2014; Wolfsdorf et al. 2018; BSPED 2020) are as follows:

  • Ketonaemia (blood level > 3 mmol/l) or ketonuria (2+ on dipstick)

  • Hyperglycemia (>11 mmol/l) or known diabetic patient)

  • Acidosis (HCO3− < 15 mmol/l and/or venous pH <7.3)

Classification of DKA is generally based upon anion gap, HCO3, pH and cognitive status of patient.

Table 1 Classification of DKA in adults and children (BSPED 2020; Kitabchi et al. 2009; Sheikh-Ali et al. 2008; Kelly 2006).
Table 1

Classification of DKA in adults and children

Variables

Mild

Moderate

Severe

Blood glucose

Adult: >13.9 mmol/L (> 250 mg/dL)

Children: >11 mmol/L (> 200 mg/dL)

Vitals (Pulse, SBP, SpO2)

P < 100 or > 60 bpm, SBP >100; SpO2 > 95%

P < 100 or > 60 bpm, BP >100; SpO2 > 95%

P > 100 or < 60; BP <90; SpO2 < 92%

Anion gap (mEq/L; mmol/L)

>10

>12

>16

Dehydration

5%

> 5 to 7%

>7 to ≥10%

Venous pHa

Adult: 7.24 to 7.3

Adult: 7.00 to <7.24

Adult: <7.00

Children: 7.2 to 7.29

Children: 7.1 to 7.19

Children: <7.1

Serum osmolality mOsm/kg

Variable

Variable

Variable

Mental status

Alert

Alert/ drowsy

Stupor/ coma

Venous HCO3b

Adult: 15 to 18

Adult: 10 to <15

Adult: < 10

(mEq/L, mmol/L)

Children: < 15

Children: < 10

Children: < 5

Serum/capillary BOHBc (mmol/L)

≥ 3.8 to <6 in adults; ≥ 3 to <6 in children

≥ 3.8 to <6 in adults; ≥ 3 to <6 in children

≥ 6 both adult and children

Urine STICKS-AcAcd

> 2+ in urine sticks

> 2+ in urine sticks

> 2+ in urine sticks

GCS

14–15

14–15

< 12

aVenous pH: just 0.02–0.15 units higher than arterial; bvenous HCO3: just 1.88 mmol/L lower than arterial; cBOHB: 3 β-hydroxybutyrate found in blood mainly; dAcAc acetoacetate found in urine mainly

Table 2 ADA, JBDS and AACE/ACE diagnostic criteria of DKA (Karslioglu French et al. 2019). The table is reproduced with permission.
Table 2

Diagnostic criteria of DKA in adults

Criteria

ADA

JBDS

AACE/ACE

Publication year

2009

2013

2016

Plasma glucose

>13.9 mmol/L

>11 mmol/L

NA

(250 mg/dL)

(>200 mg/dL) or known diabetes

pH

Mild: 7.25–7.30; moderate: 7.00–7.24; severe: <7.00

Mil & moderate <7.3

Severe: <7.0

<7.3

Bicarbonate, mmol/L or mEq/L

Mild: 15–18; moderate: 10–14.9; severe: <10

<15 but >5

Severe: <5

NA

Anion gap: Na+–(Cl− + HCO3−)

Mild: >10; moderate: >12; severe: >12

Mild & moderate

>10 but <16

Severe: >16)

>10

Urine acetoacetate (nitroprusside reaction)

Positive

Positive

Positive

Blood BOHB, mmol/L

NA

Mild & moderate ≥3

Severe: >6

≥3.8

Mental status

Mild: alert; moderate: alert or drowsy; severe: stupor or coma

NA

Drowsy, stupor, or coma

The diagnostic criteria of DKA differs in many ways between societies. There is no consensus on all four key parameters such as ketonaemia/ketonuria, HCO3, pH and glucose values. Table 2 shows the diagnostic criteria formulated by key societies of diabetes.

JBDS criterion to classify severe DKA is slightly different and includes both physical and biochemical parameters.

Table 3 Diagnostic criteria of HHS by ADA and JBDS (Karslioglu French et al. 2019), reproduced with permission.
Table 3

Diagnostic criteria of HHS in adults

Criteria

ADA

UK

Publication year

2009

2015

Plasma glucose

> 33.3 mmol/L (600 mg/dL)

≥30 mmol/L (540 mg/dL)

pH

>7.30

>7.30

Bicarbonate

>18 mmol/L

>15 mmol/L

Anion gap: Na+–(Cl− + HCO3−)

NA

NA

Urine acetoacetate (nitroprusside reaction)

Negative or low positive

NA

Blood BOHB

NA

<3

Osmolality, mmol/kg

>320

≥320

Presentation

Stupor or coma

Severe dehydration and feeling unwell

For DKA the prominent biochemical features are ketonemia and high anion gap acidosis. In HHS the circumstances are different as this condition is characterized by high osmolality and severe dehydration secondary to severe hyperglycemia. However in clinical practice, a mixed picture of DKA and HHS can also be encountered. It is also important to remember that some degree of acidosis in HHS can also be found due to nominal ketogenesis in some cases.

Table 4 Differences between DKA, HHS and EDKA (Rosenstock et al. 2018; Dandona et al. 2018; Mathieu et al. 2018; Blau et al. 2017; Rosenstock and Ferrannini 2015).
Table 4

Key differences between DKA, HHS AND EDKA

Variables

DKA

HHS

EDKA

Predominant feature

Ketonemia and high anion gap metabolic acidosis

Very high glucose and serum osmolality

Ketonemia and high anion gap metabolic acidosis

Glucose level

mmol/L (mg/dL)

High: >13.9 (> 250)

Very high: ≥ 33.3 (≥600)

Normal: <11 (<200)

Ketones

mmol/L

High (>3 mmol/L in blood or 2+ in urine)

Normal

High (>3 mmol/L in blood or 2+ in urine)

Serum osmolality mOsm/kg

Raised

> 320

Raised

Predominant diabetes type and comorbidities

T1D, less frequently in T2D and GDM

T2D, less frequently in T1D, T2D in children and in 6q24 genotype TNDa

T1D, LADA, T2D on SGLT-2i, with pregnancy, glycogen storage disease, alcoholism, very low calorie diet, severe liver diseases etc.

Age

Young patient

Older patient

Mostly young patients but adults might also have

Predominant phenotype

Lean

Obese

Lean to obese

Complications

.7–10% risk of cerebral oedema, iatrogenic hypoglycaemia, hypokalaemia, ARDS and a small risk of arterial or venous thromboembolism

Iatrogenic hypoglycaemia, hypokalaemia, MI, DIC, higher risk of pulmonary, arterial or venous thromboembolism

Same like DKA

aTND transient neonatal diabetes

Euglycaemic DKA (EDKA/euDKA)

was first reported in 1973 (Munro et al. 1973). It should be suspected in any diabetes patients who is on SGLT2i with classic symptoms. Diagnosis can be made with the classical cutoff level of pH, HCO3 and ketone with normoglycaemia (Dhatariya 2016). Many studies have shown evidence that use of SGLT2i in T1D and in LADA cases have higher incidence of EDKA. In advanced T2D there are few case reports published recently (Rosenstock and Ferrannini 2015). Reduced carbohydrate intake, depleted glycogen reserve due to alcoholism, SGLT2i in T1D, reduction of insulin might precipitate EDKA.

Ketosis-Prone Diabetes (KPD)

KPD also called ‘Flatbush diabetes’ is found in certain ethnic minorities like African-Americans, Asians, sub-Saharan Africans and African-Caribbean. The genotype looks like idiopathic T1D but phenotype looks like T2D. Usually a middle aged obese man presents with DKA at diagnosis of new onset diabetes. Initial aggressive insulin therapy settles the acute stage. Subsequently, diet alone or a combination with oral hypoglycaemics can achieve glycaemic without need of insulin (Lebovitz and Banerji 2018). There are four types of classification of KPD such as ‘ADA’, ‘modified ADA’, ‘BMI based’ and ‘Aβ’ exist.

KPD classification ‘Aβ’ is based on the presence/ absence of autoantibodies and the presence/ absence of β-cell functional reserve. This is the most used and the most acceptable classification. The four subgroups are:
  1. 1.

    A + β − (present autoantibodies but absent β-cell function)

     
  2. 2.

    A + β + (present autoantibodies but present β-cell functional reserve)

     
  3. 3.

    A − β − (absent autoantibodies and absent β-cell function) and

     
  4. 4.

    A − β + (absent autoantibodies but present β-cell functional reserve).

     

A + β − and A − β − patients are immunologically and genetically distinct from each other but they share clinical characteristics of T1D with very low β-cell function. Whereas, A + β + and A − β + patients are immunologically and genetically distinct from each other but they share clinical characteristics of T2D with preserved β-cell functional reserve. Group 4 has the largest share of KPD with 76% (Balasubramanyam et al. 2006).

3 Epidemiology

DKA is no more considered as a metabolic emergency of only T1D (Bedaso et al. 2019; Jabbar et al. 2004; Takeuchi et al. 2017; Mudly et al. 2007). It is estimated that out of all DKA cases, around 34% occur in T2D (Kitabchi et al. 2009). Up to 25–40% cases of T1D present as DKA at first diagnosis (Duca et al. 2017). Apart from key precipitating factors, socio-economic factors also act as a causative factor of DKA. These are low income, limited access to health care facilities and illiteracy (Dabelea et al. 2014).

Desai et al. made a very large retrospective observational study that included 56.7 million hospitalisations during 2007–2014 with diabetes out of which 0.9% had DKA and HHS. Younger patients show (Fig. 1) highest rate of admissions with lowest mortality and the trend is reverse for older patients (Desai et al. 2019). According to a survey in USA, more than two-thirds of children presenting with HHS have T1D (Ng et al. 2020). These are mostly obese T1D and adolescent T2D. From Prospective Diabetes registry in Germany comprising 31,330 patients, DKA admission rate was 4.81/100 patient-years (Karges et al. 2015). A multinational data from 49,859 children with T1D across three registries and five nations found higher odds of DKA in females (OR 1.23), in ethnic minorities (OR 1.27) and in those with HbA1c ≥ 7.5% (OR 2.54) (Maahs et al. 2015).
Fig. 1

Age-specific prevalence and morality of DKA and HHS (Desai et al. 2019). The figure is reproduced with permission

Table 5 Studies on SGLT2i in T1D with EDKA incidences (Rosenstock et al. 2018; Mathieu et al. 2018; Blau et al. 2017).
Table 5

SGLT2i use and EDKA rates in T1D

Studies

SGLT2i Molecule

Drug ARM

Placebo ARM

Event Rate/1000 PT YR

‘EASE’ Trial

Empagliflozin

0.8%, 4.3% and 3.3%

1.2%

59.4, 50.5 and 17.7 events respectively

2.5 mg, 10 mg and 25 mg

DEPICT-1 & 2

Dapagliflozin

2.6% and 4% for 5 mg; 2.2% and 3.4% for 10 mg

1.9% (21.5 events/1 K patient yr)

58.3 and 47.6 events respectively

5 mg and 10 mg

52-wk & 24-wk study

TANDEM-1 & 2 study

Sotagliflozin 200 mg and 400 mg

2.3%–3.4% for 200 mg and 3%-3.4%

0–0.6% (0–3.8 events/1 K patient year)

30–34 events

‘FEARS’ DATA

SGLT2i: Canagliflozin, Empagliflozin, Dapagliflozin

CANA-48 cases,

N/A

Overall: 14-fold increase of DKA out of which 71% EDKA

DAPA-21 cases,

EMPA-4 cases

The hospitalization rate of HHS is less compared to DKA. According to an estimate it accounts for only 1% of diabetes related hospitalizations. In contrast to DKA, the mortality rate in HHS is considerably higher. It is 15% for HHS compared to 2–5% for DKA (Umpierrez et al. 2002). The possible explanations for this higher mortality rate for HHS are older age and presence of co-morbid conditions (Kitabchi et al. 2009).

4 Pathophysiology

4.1 DKA

Glucose homeostasis is maintained by the intricate balance of two hormones, insulin and glucagon. There are four axes (Fig. 2) which control glucose homeostasis. These are ‘Brain-islet axis’, ‘Liver-islet axis’, ‘Gut-islet axis’ and ‘Adipocytes/ myocytes-islet axis’. These axes interplay with positive and negative feedback to maintain glucose homeostasis (Röder et al. 2016).
Fig. 2

Interplay of pancreas with brain, liver, gut, adipose and muscle tissue to maintain glucose homeostasis (Röder et al. 2016). The figure is reproduced with permission

In DKA this hormonal balance of body is tilted towards counter-regulatory hormones due to absolute insulin deficiency. Due to this shift in balance, while liver uninhibitedly keeps on producing more glucose, peripheral tissues are not able to utilize glucose from blood in the absence of insulin (Gosmanov and Kitabchi 2000). The liver is able to secrete high amounts of glucose due to presence of two metabolic pathways namely gluconeogenesis and glycogenolysis. The gluconeogenic enzymes fructose 1, 6 bisphosphatase, phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, and pyruvate carboxylase are mainly involved. These are stimulated by an increase in the glucagon to insulin ratio and by an increase in circulating cortisol concentrations (DeFronzo and Ferrannini 1987; Stark et al. 2014). This insulin counterregulatory hormone mismatch activates hormone sensitive lipase activity which leads to increase formation of FFAs from the triglycerides (Fig. 3). This FFAs are then beta oxidised to form acetylcoenzyme A into AcAc (Acetoacetic acid) and BOHB (Beta hydroxybutyrate) in hepatic mitochondria. These are major ketone bodies, resulting ketonemia and acidosis (Dhatariya 2016; Barnett and Barnett 2003).
Fig. 3

Pathogenesis of DKA and HHS. Reproduced with permission (Karslioglu French et al. 2019)

Ketogenesis

Conversion of FFAs into ketones in the hepatic mitochondria needs certain conditions. These are lower insulin to glucagon ratio, reduction in activity of acetyl CoA carboxylase and low levels of malonyl CoA. These eventually trigger transportation of FFAs inside mitochondria by CPT-1(Carnitine Palmitoyltransferase-1) for conversion to ketones. FFAs in hepatic mitochondria are then broken down into acetyl CoA by beta-oxidation. Two acetyl-CoA molecules are converted into acetoacetyl-CoA by enzyme thiolase. Then this acetoacetyl-CoA is converted into HMG-CoA by HMG-CoA synthase. Then HMG-CoA is converted into acetoacetate by HMG-CoA lyase. Acetoacetate then converted into either acetone through nonenzymatic decarboxylation or into BOHB by beta-hydroxybutyrate dehydrogenase. In extra-hepatic tissues acetone is either excreted via urine or exhaled and BOHB is converted into acetoacetate by beta-hydroxybutyrate dehydrogenase. This end product acetoacetate is converted back to Acetyl CoA by beta-ketoacyl-CoA transferase (Fig. 4). This way ketogenesis continues till intervention is done (Dhillon and Gupta 2019). They are preferred over glucose in absence of insulin by many peripheral tissues like brain, and skeletal muscles (Barnett and Barnett 2003; Dhillon and Gupta 2019).
Fig. 4

Metabolic pathways of ketogenesis

Acidosis

As the concentration of Acetoacetic acid and β-hydroxybutyric acid increases in blood, they dissociates completely at physiological pH converting into acetoacetate and β-hydroxybytyrate respectively. This conversion yields hydrogen ion with each molecule which is at normal physiological state buffered by bicarbonate. In DKA the enormous amount of hydrogen ion forms due to ketogenesis. At one point bicarbonate buffering system fails and hydrogen ion concentration shoots up leading to falling blood pH and low bicarbonate (Dhatariya 2016; Barnett and Barnett 2003). The increased serum levels of glucose and ketones contributes towards osmotic diuresis and hence electrolytes disturbances and dehydration (Karslioglu French et al. 2019).

4.2 HHS

The pathogenesis of HHS differs from DKA significantly. Measurable insulin in T2D is higher than in DKA patients, which is sufficient to suppress lipolysis and ketogenesis but inadequate to regulate hepatic glucose production and promote peripheral glucose utilization. Studies have shown the half-maximal concentration of insulin for anti-lipolysis is lower than for glucose utilization by peripheral tissues (Pasquel and Umpierrez 2014; Miles et al. 1983; Umpierrez et al. 1996). The counter-regulatory hormones are high in HHS due to presence of stresses like infection, and myocardial infarction. The reason behind more severe dehydration and hyperglycemia in HHS is that it develops over several days of continued osmotic diuresis. This leads to hypernatremia, especially in older patients with renal impairment. This is worsened by inability to drink adequate water to keep up urinary losses resulting in profound dehydration. Furthermore, this hypovolemia deteriorates glomerular filtration rate as clinically shown by higher creatinine values in HHS and it eventually leads to severe hyperglycaemic state (Umpierrez et al. 2002; Kitabchi et al. 2006).

4.3 EDKA

In T2D on SGLT2i, the lower insulin to glucagon ratio stimulates lipolysis which makes around 20% enhanced lipid oxidation. This happens at the expense of markedly reduced carbohydrate oxidation, which falls by 60%. In the face of lower glucose concentrations, nonoxidative glucose disposal by glycogen synthesis and lactate release also fall by 15% (Rosenstock and Ferrannini 2015). Reduced insulin level causes reduced formation of acetyl-CoA, so inhibition of CPT-I is less. This promotes transport of FFAs into mitochondria and hence ketogenesis (Diaz-Ramos et al. 2019). BOHB levels rises by two folds in fasting and fed state. Plasma lactate level decreases to 20% which reflects reduced carbohydrate utilization. In T1D where absolute insulin deficiency prevails and if carbohydrate availability is drastically reduced then the mild ketosis would lead to ketoacidosis (Rosenstock and Ferrannini 2015) (Fig. 5).
Fig. 5

Mechanism of development of EDKA with SGLT2i (Diaz-Ramos et al. 2019). The slide is reproduced with permission

5 Precipitating Factors

The predominant trigger for an acute DKA episode is insulin omission or non-adherence, whereas in HHS infections are most common precipitating factors. In EDKA, there is common association with the use of SGLT2i which ensures good glycaemic control that might lead to reduction in insulin dosage. These triggers higher secretion of counter-regulatory hormones in DKA, HHS and EDKA. Table 6: Precipitating factors in DKA, HHS and EDKA (Pasquel and Umpierrez 2014; Laine 2010; Adeyinka and Kondamudi 2020).
Table 6

Precipitating factors of DKA, HHS AND EDKA

DKA

HHS

EDKA

Strong factors

Reduction or repeated omission of insulin dose. Infection: most common are respiratory and UTI

Infections especially UTI and pneumonia in 30–60% cases

Reduction in insulin dose at the context of good glycaemic control in patients on SGLT2i

Non-compliance with insulin, poor control, h/o previous episode

Non adherence to insulin or oral antidiabetic medications

Reduction in carbohydrate intake

Gastroenteritis with persistent vomiting, dehydration. Binge alcohol intake, cocaine or substance abuse

Alcohol abuse, restricted water intake in nursing home residents with diabetes

Alcohol, cocaine or substance abuse

Failure to stop SGLT2i prior surgery

Acute MI in middle aged T1D or T2D

Acute MI, CVA

Acute MI in middle aged T1D or T2D

Eating disorders, psychiatric disorders, parental abuse, peripubertal and adolescent girls

Depression

Eating disorders, psychiatric disorders

Weak factors

Pancreatitis, CVA in elderly T1D or T2D, pregnancy

Post cardiac or orthopedic procedure where osmotic load is increased, pregnancy

Chronic alcoholism, pregnancy

Endocrine diseases: Acromegaly, hyperthyroidism, Cushing syndrome

Delay in insulin initiation postoperatively, TPN

Glycogen storage disease

Drugs: corticosteroids, thiazides, Pentamidine, sympathomimetics, second-generation antipsychotics, cocaine, immune checkpoint inhibitors

Drugs: corticosteroids, thiazides, beta-blockers, didanosine, phenytoin, Gatifloxacin, cimetidine, atypical antipsychotics-clozapine, olanzapine

 

Remembering 7 ‘I’ can be easy to remember the causes

1. Insulin: Deficiency/insufficiency

5. Infarction: ACS, stroke

2. Iatrogenic: Steroids, thiazides, atypical antipsychotic drugs

6. Inflammation: Acute pancreatitis, cholecystitis

3. Infection: Commonest cause

1.7. Intoxication: Alcohol, cocaine

4. Ischaemia: Gut, foot

6 Clinical Presentation

DKA and EDKA evolve in hours to days but HHS develops gradually over several days to weeks. Results of a systematic review which included 24,000 children from 31 countries suggested that those who are very young and belong to ethnic minorities are more to present acutely in such manner. Other major risk factors include lean built of body, errors in diagnosis of T1D, treatment delays, infection as presenting complaint etc. Presence of T1D in family history, on the other hand, makes it unlikely that DKA would be the first presentation (Usher-Smith et al. 2011). Up to 25% patients with new-onset T1D present with DKA (Choleau et al. 2014; Jefferies et al. 2015; Usher-Smith et al. 2011).

Table 7 Features of clinical presentations of DKA, HHS and EDKA (BSPED 2020; Hardern 2003; Trence and Hirsch 2001; Hamdy 2019; Nyenwe et al. 2010; Usher-Smith et al. 2011).
Table 7

Clinical presentations of DKA, HHS AND EDKA

Parameter

DKA

HHS

EDKA

History

Short h/o unwellness, hours to days

Unwellness for days to weeks

Moderate length

h/o failure to comply with insulin therapy

Often a preceding illness like dementia, immobility predisposes

h/o SGLT2i intake and not stopped prior surgery

h/o mechanical failure of CSII

h/o alcoholism, poor carb intake

Most common early features

Polyuria, polydipsia and polyphagia

Polyuria, polydipsia

Lesser osmotic symptoms but other DKA features are present

Nausea, vomiting and anorexia

weight loss, weakness, lethargy

loss of appetite, diffuse abdominal pain

Seizures which may be resistant to anticonvulsive and phenytoin may worsen HHS, muscle cramps

Malaise, generalized weakness, fatigue

Rapid weight loss in new-onset T1D

Uncommon: Abdominal pain

Late features

Dry mucous membrane, poor skin turgor

Same as DKA but dehydration is profound

Same as DKA but dehydration is moderate

Sunken eyes, hypothermia

Acute focal or global neurologic changes: drowsiness, delirium, focal or generalized seizures, coma, visual changes, hemiparesis, sensory deficits

Tachycardia, hypotension,

Kussmaul breathing, acetone breath, laboured breath, tachypnea

Altered mental status, reduced reflexes

Features of possible intercurrent infection

Constitutional symptoms: fever, cough, chills, chest pain, dyspnea, arthralgia

Same as DKA and infectious components are most common precipitants in HHS

Same as DKA but very less frequently any infectious components are seen

In an otherwise healthy child without any family history of diabetes who presents as with urinary symptoms, it is challenging to diagnose T1D (Rafey et al. 2019). Up to 20% people present with HHS as first presentation of new-onset T2D (Pasquel and Umpierrez 2014). EDKA is difficult to diagnose without detail history and work-up as there is usually very low index of suspicion with normoglycaemia.

7 Laboratory Investigations

The laboratory investigations in DKA, HHS and EDKA are aimed primarily for diagnosis and to determine its severity. Then the next step is to identify the underlying causes, early identification of complication and monitoring of response to therapy. As acute metabolic decompensation is an emergency so just after history, clinical examination and provisional diagnosis management starts. Blood and urine samples are taken to do initial investigations without delay. Work-up for DKA and EDKA are same. Table 8 Initial and subsequent work-ups in the management of DKA and HHS (Wolfsdorf et al. 2018; Savage et al. 2011; Scott et al. 2015; Khazai and Umpierrez 2020; Gosmanov and Nimatollahi 2020; Rawla et al. 2017).
Table 8

Work-up for DKA, HHS and EDKA

Initial tests to order

Tests

DKA results

HHS results

Comments

Plasma glucose

> 13.9 mmol/L (>250 mg/dL)

>33.3 mmol/L (>600 mg/dL)

Elevated except in EDKA it is <11 mmol/L (<200 mg/dL)

Venous blood gas

pH varies from 7.00 to 7.30

Usually >7.30

Venous pH is just 0.03 lower than arterial pH. As arterial sampling is painful and risky so venous sample is now commonly taken

Capillary or serum ketones

BOHB ≥3.8 mmol/L in adults and ≥ 3.0 mmol/L in children

BOHB is negative or low

Out of three ketones, BOHB (beta hydroxybutyrate) is early and abundant ketone that is checked first from serum or point-of-care device. In early DKA, acetoacetate (AcAc) can be measured, its result has a high specificity but low sensitivity. Acetone not done as it is volatile

HbA1c level

Usually high

Usually high

To evaluate the glycaemic control it is done but in good glycaemic control acute hyperglycaemic crisis may precipitate

Urinalysis

Positive for glucose and ketones. Positive for leukocytes and nitrites if there is an infection

Positive for glucose and but usually not ketones. Positive for leukocytes and nitrites if there is an infection

In mixed presentation of DKA and HHS urine ketone also found in HHS

Serum bicarbonate

From 18 mEq/L or mmol/L to <10 depending the grade

> 15 mEq/L

Bicarbonate is an important test to diagnose and grade

Serum bun

Increased due to dehydration

Markedly increased due to severe dehydration

Pre-renal azotaemia

Serum creatinine

Increased due to dehydration

Markedly increased due to severe dehydration

Once dehydration is corrected the creatinine level returns to normal

Serum sodium

Usually low

Variable, usually low but can be high

Total Na deficit in DKA is 7–10 mEq/kg and in HHS is 5–13 mEq/kg. Hypernatraemia with hyperglycaemia indicates profound dehydration

Serum potassium

Usually elevated

Usually elevated but decreased in severe cases

Total deficit of K in DKA is 3–5 mEq/kg and in HHS 4–6 mEq/kg. K is elevated initially due to extracellular shift caused by insulin deficiency or insufficiency, hypertonicity and acidaemia. Low K on admission is a sign of severe case

Serum chloride

Usually low

Usually low

Cl loss is 3–5 mEq/kg in DKA and 5–15 mEq/kg in HHS

Serum magnesium

Usually low

Usually low

Mg deficit is 1–2 mEq/kg in DKA and 0.5 to 1 mEq/kg in HHS

Serum calcium

Usually low

Usually low

Ca deficit is 1–2 mEq/kg in DKA and 0.5–1 mEq/kg in HHS

Serum phosphate

Normal or elevated

Usually low

1 mmol/L deficit in DKA but initially shows normal or elevated. After insulin therapy it decreases. In HHS 3–7 mmol/kg is lost due to diuresis

CBC

Usually elevated

Usually elevated

Leukocytosis correlates with ketones but >25,000/ microliter indicates infection and indicates further evaluations

LFT

Usually normal

Usually normal

Abnormal results due to fatty liver or congestive heart failure may be found

Serum amylase

Usually elevated

Usually elevated

In majority of DKA cases amylase is elevated but mostly due to nonpancreatic causes. In HHS if elevated then pancreatitis should be ruled out

Serum lipase

Usually normal

Usually normal

In elevated amylase level measuring lipase level is useful to differentiate pancreatitis

Serum osmolality

Variable

High, usually ≥320 mOsm/L

Twice measured Na and K plus Glucose makes the osmolality. Urea usually not counted as it is freely permeable. A linear relationship is there between effective osmolality and mental state in HHS. Neurological deficits begin above 320 and stupor or coma come above 340 mOsm/L

Additional tests to consider

Chest X-RAY

May have findings of pneumonia

Variable, may be compatible with pneumonia

The commonest infections are pneumonia and UTI

ECG

May show findings of MI or hyperkalaemia or hypokalaemia

May show findings of MI or hyperkalaemia or hypokalaemia

Precipitating CAD and severe electrolyte abnormalities are common in both DKA and HHS

Cardiac biomarkers

In suspected MI should be done

In suspected MI should be done

Cardiac troponins are elevated in suspected MI

Body fluid culture

To rule out sepsis blood, urine or sputum culture are needed

To rule out sepsis blood, urine or sputum culture are needed

Fever, leukocyte count >25,000/microliter should raise the question of infective focus

Creatinine phosphokinase

In cocaine abuse rhabdomyolysis is common

Less common

↑ In rhabdomyolysis. pH and serum osmolality mildly elevated. Blood glucose and ketone are normal. Myoglobinuria/hemoglobinuria + in urine

Serum lactate

Normal if concomitant lactic acidosis absent

Normal if concomitant lactic acidosis absent

Elevated in lactic acidosis

8 Differential Diagnosis

The acute hyperglycemic emergencies DKA and HHS are at the top of differential list for each other. The only biochemical feature that differentiates DKA from EDKA is serum glucose level: normal in EDKA and raised in DKA. The distinguishing feature of HHS is presence of high serum osmolality due to extremely high serum glucose levels. The hyperglycemia in HHS is generally greater than 30 mmol/l (Scott et al. 2015; Westerberg 2013).

Ketoacidosis besides being present in diabetes can also occur during starvation and alcoholism. It is important to rule out other causes of high anion gap acidosis like salicylate poisoning, methanol intoxication and lactic acidosis (Keenan et al. 2007). Since abdominal pain and vomiting episodes are often present in such patients, other etiological causes of acute abdomen like pancreatitis and gastroenteritis should also be considered in differential diagnosis (Keenan et al. 2007).

Due to presence of focal neurological deficit, HHS is very commonly confused with stroke (Umpierrez et al. 2002).

Table 9 Differential diagnosis of acute hyperglycaemic crisis (Westerberg 2013; Rawla et al. 2017; Keenan et al. 2007).
Table 9

Differential diagnosis of DKA, HHS and EDKA

Condition

Differentiating features

Tests to rule out

HHS

HHS patients are usually older and commonly with T2D. Symptoms evolve insidiously, more frequently mental obtundation and shows focal neurological signs. Blood glucose is very high in HHS whereas in EDKA it is normal, other distinguishing features are similar to DKA

Blood glucose >33.3 mmol/L, serum osmolality is >320 mOsm/kg and ketones are normal or mildly elevated. Anion gap is variable but usually <12 mEq/L, pH is >7.30 and bicarbonate is >15 mEq/L

DKA

DKA patients are younger and leaner T1D, usually present with abdominal pain and vomiting

pH < 7.30, HCO3 < 15 mmol/L, anion gap >12 mEq/L and ketones are strongly positive

Lactic acidosis

DKA and HHS like presentation but in pure form of lactic acidosis blood glucose and ketone are normal but lactate is raised. History of diabetes may not be there

In T1D with sepsis, lactic acidosis sometime precipitate. Bicarbonate, pH and anion gap are similar to DKA but lactic acid >5 mmol/L. Blood glucose and ketones are normal

Starvation ketosis

Starvation ketosis mimics partly with DKA. It is the consequence of prolonged inadequate availability of carbohydrate. Which results compensatory lipolysis and ketogenesis to provide fuel substrate for muscle

Blood glucose is normal or low, blood ketone is normal but urine contains huge amount of ketones. Blood pH is normal and anion gap is just mildly elevated

Alcoholic ketoacidosis

It results in chronic alcoholics who skips meals and depends on ethanol as main source of calorie for days to weeks. Ketoacidosis is triggered when alcohol and calorie intake abruptly decreases. Signs of chronic liver disease such as spider naevi, palmer erythema, leukonychia, easy bruising, jaundice and hepatomegaly might be present

There is mild to moderate metabolic acidosis with elevated anion gap. Serum and urine ketones are positive. There might be hypoglycaemia

Salicylate poisoning

History is crucial to differentiate. Salicylate poisoning results an anion gap metabolic acidosis with respiratory alkalosis

Salicylate is positive in blood and urine, blood glucose is normal or low, ketones are negative, osmolality is normal. Interestingly, salicylate makes false-positive and false-negative urinary glucose presence

Paracetamol overdose

History is very crucial to differentiate. Confusion, hyperventilation, tinnitus and signs of pulmonary oedema might be found

A positive result for serum and urine paracetamol could be found but might not be in toxic range. Blood sugar may be normal or low

Toxic substance ingestion

History is crucial to differentiate. Common toxic substances are methanol, ethanol, ethylene glycol and propylene glycol. Paraldehyde ingestion makes strong odour in breath

Serum screening for toxic substances might yield the clue. Calcium oxalate and hippurate crystals in urine indicate ethylene glycol ingestion. These organic toxins can produce anion gap and osmolar gap due to low molecular weight

Stroke

Symptoms develop rapidly, in seconds to minutes. There might be limb and facial weakness

Cranial CT or MRI is diagnostic

Uremic acidosis

High BUN and creatinine but normal glucose. A history also important

Very high serum creatinine and BUN are found

9 Management: General

Successful management of DKA, HHS and EDKA needs 5 major components to rectify as follows (Hamdy 2019):
  1. 1.

    Correction of dehydration

     
  2. 2.

    Correction of hyperglycaemia and ketoacidosis

     
  3. 3.

    Correction of electrolyte abnormalities

     
  4. 4.

    Identification of comorbid and precipitating factors and

     
  5. 5.

    Frequent monitoring and prevention of complications

     

Once acute metabolic crisis of diabetes is recognized the patient needs to be hospitalized in emergency or acute medical unit or in HDU (High Dependency Unit) or in ICU depending on grading.

Table 10 The markers of severity in DKA, HHS and EDKA for HDU/ICU admission (Savage et al. 2011; Scott et al. 2015).
Table 10

Markers of severity that requires HDU/ICU admission

Markers of severity

DKA/EDKA

HHS

Venous pH

pH < 7.1

< 7.1

Blood ketones

> 6 mmol/L

> 1 mmol/L

Serum bicarbonate, anion gap

< 5 mmol/L, > 16 mmol/L

 

Potassium

< 3.5 mmol/L or > 6 mmol/L

< 3.5 mmol/L or > 6 mmol/L

Systolic BP, pulse

< 90 mmHg, >100 or < 60 bpm

< 90 mmHg, >100 or < 60 bpm

Urine output

< 0.5 mL/kg/h or evidence of AKI

< 0.5 mL/kg/h or evidence of AKI

Mental status, SpO2

GCS <12 or abnormal AVPU, <92%

GCS <12 or abnormal AVPU, <92%

Sodium, osmolality

 

>160 mmol/L, >350 mOsm/kg

Comorbidities

Hypothermia, ACS, CHF or stroke

Hypothermia, ACS, CHF or stroke

The markers of severity should be assessed and recorded (Table 11).
Table 11

Typical water and electrolyte deficits in DKA, EDKA and HHS (Umpierrez et al. 2002; Savage et al. 2011; Scott et al. 2015)

Variables

DKA/EDKA (deficit/kg body wt)

HHS (deficit/kg body wt)

Water

100 ml

100–200 ml

Na+

7–10 mEq

5–13 mEq

K+

3–5 mEq

5–15 mEq

Cl−

3–5 mEq

4–6 mEq

PO4−

5–7 mEq

3–7 mEq

Mg2+

1–2 mEq

1–2 mEq

Ca2+

1–2 mEq

1–2 mEq

Management should start with prompt assessment of ABCDE (Airway, Breathing, Circulation, Disability-conscious level and Exposure-clinical examination) at emergency department. Acute metabolic crisis in diabetes leads to profound water and electrolyte loss due to osmotic diuresis by hyperglycaemia. In EDKA due to very nominal rise of glucose, water deficit is not profound like DKA but is significant due to ketoacidosis. Without finding the cause of acute metabolic crisis, the management is not complete. Without preceding a febrile illness or gastroenteritis, DKA in a known diabetes patient is usually due to psychiatric disorders such as eating disorders and failure of appropriately administering insulin (Wolfsdorf et al. 2018). Comparatively more aggressive fluid replacement in HHS is needed than DKA to expand intra and extra vascular volume. The purpose is to restore normal kidney perfusion, to normalize sodium concentration and osmolality. DKA usually resolves in 24 h but in HHS correction of electrolytes and osmolality takes 2–3 days. Usually HHS occurs in elderly with multiple co-morbidities, so recovery largely depends on previous functional level and precipitating factors. In EDKA if SGLT2i is suspected, it should be stopped immediately and should not restart unless another cause for DKA is found and resolved (Evans 2019).

9.1 Management: From Admission to 24–48 Hours

Table 12 Shows the details of management from admission onwards (Wolfsdorf et al. 2018; BSPED 2020; Savage et al. 2011; Scott et al. 2015; Evans 2019) (Fig. 6).
Table 12

Management of DKA, EDKA and HHS IN adults and children

Intervention

DKA, EDKA and HHS

Monitoring, ongoing lab work-up

0–60 min: Resuscitate, diagnose and treatment

ABCDE

Fast assessment to grade patient: Shocked, comatose, moderate or mild cases

First tests: CBC, U & E, and venous blood gas: pH, HCO3, CRP, glucose, ECG, CXR, infection screen if indicated by blood and urine culture

In shocked and comatose patients with vomiting an airway, N/G tube have to insert

HOURLY: Capillary blood glucose, ketones, cardiac monitoring, BP, pulse, respirations, pulse oximetry, fluid input/ output chart, neurological observations

100% oxygen by face mask

IV cannula have to put and blood and urine sample have to take. Cardiac monitor with pulse oximetry have to attach to assess pulse, BP, T wave etc.

TARGET: Reduction of glucose by 3 mmol/L/h, ketones by 0.5 mmol/L/h and increasing HCO3 by 3 mmol/L/h

Blood and urine sample to send for culture for infection screening

Elderly HHS patients are at high risk of pressure sore. Foot assessment should be done and should apply heel protectors in those with neuropathy, PVD or lower limb deformity

Bedside diagnosis

Capillary blood test, point of care blood ketone test and if not available urine dipsticks for 15 s where a > ++ indicates positive

Comatose and shocked patients should move to HDU/ICU immediately after starting IV fluid

Use of blood gas machine at bedside can promptly test pH, urea, electrolytes, glucose etc. while first blood sample is sent to laboratory

Initial fluid replacement

Crystalloid fluid such as normal saline is best for volume expansion rather than colloid fluid. Typical fluid deficit is 100 mL/kg and should be corrected within 24–48 h

All children with mild, moderate or severe DKA who are not shocked should receive an initial bolus of 10 mL/kg 0.9% NaCl IV over 60 min stat

Shocked children should get bolus of 20 mL/kg 0.9% NaCl IV over 15 min stat

The maintenance fluid in children should be calculated from Holliday-Segar formula. It is: 100 mL/kg/day for first 10 kg body weight, then 50 mL/kg/day for next 10 kg and 20 mL/kg/day for each kg above 20 kg. This amount should be divided by 24 to get hourly maintenance amount

A 5%, 7% and 10% fluid deficit is assumed for mild, moderate and severe DKA respectively. Initial bolus should be subtracted from deficit and then divided by 48 h and adding this to hourly maintenance fluid volume

HOURLY RATE = [DEFICIT- INITIAL BOLUS] /48 + MAINTANANCE PER HOUR

Alert, not clinically dehydrated, no nausea or vomiting children do not always need IV fluids even their ketone is high. They might tolerate oral rehydration and s.c insulin but they do require continuous monitoring to ensure improvement and ketone is falling

Adult DKA, EDKA patients should get 1–1.5 L 0.9% NaCl saline in first hour. In DKA average 6 L fluid loss occurs. Slower administration in young, elderly, pregnant, heart and renal failure cases

Adult HHS patients should get 1–1.5 L 0.9% NaCl in first hour provided cardio-renal status allows. In HHS average 7–9 L fluid loss occurs

Insulin therapy

Insulin should start immediately in DKA and HHS if potassium level is >3.3 mEq/L. A 50 units of soluble insulin (e.g. Actrapid) in 49.5 mL of 0.9% NaCl saline to be mixed to make 1 unit/mL to administer through infusion pump

 

Two types of insulin regimens are used in DKA and HHS. First one is fixed rate IV regular insulin infusion as known as FRIII (fixed rate intravenous insulin infusion) at 0.14 units/ kg/ h with no initial bolus. Second one is 0.1 units/kg/h IV bolus followed by FRIII at a rate of 0.1 units/kg/h continuous IV infusion

In EDKA insulin infusion with 5–10% dextrose in saline helps to settle ketoacidosis

In young children with mild to moderate DKA 0.05 units/ kg/h is sufficient to control and in severe DKA and in adolescent patients 0.1 units/kg/h should start after 1 h of fluid replacement therapy

In children with HHS insulin need is less. So a dose of 0.025 to 0.05 units/kg/h should start after 1 h of fluid replacement

Insulin pump should stop when FRIII is started. Long acting basal insulin should continue at the usual dose throughout the treatment, it helps to shorten the length of stay after recovery

If blood glucose does not fall by 10% or 3 mmol/L in first hour then a dose of 0.14 units/kg of regular insulin should be given IV bolus and then to continue FRIII at running dose

Once blood glucose falls near 13.9 mmol/L (250 mg/dL), then insulin infusion should be reduced to 0.02–0.05 units/kg/h and a 5% dextrose in saline have to add while maintaining blood glucose 11–17 mmol/L (200–300 mg/dL)

Rapid reduction of blood glucose should be avoided to prevent sudden osmolar changes and cerebral oedema

Insulin injection by a sliding scale is no longer recommended

Potassium replacement

In acute metabolic crisis in diabetes potassium loss is around 3–15 mEq/kg. Insulin therapy, correction of acidosis and hyperosmolality drive potassium into cells causing serious hypokalemia. So to prevent complications of hypokalemia like respiratory paralysis and cardiac dysrhythmia insulin therapy should be withheld if K level is <3.3 mEq/L at baseline while fluid therapy is going on

 

If K is >5.5 mmol/L = NO potassium

If K is 3.5–5.5 mmol/L = 20–40 mmol/L mixed with 0.9% NaCl saline

If K is <3.5 mmol/L = 40 mmol/L over 1–2 h with cardiac monitoring

Urine output of >50 mL/h should be there while patient on K therapy. The hydration status should be evaluated clinically regularly. If eGFR is <15 mL/min then consultation with renal team is needed before adding K

If K level falls <3.3 mEq/L in any time during therapy, insulin should be withheld and K 40 mmol/L should be added in each liter of infusion fluid

Vesopressor and anticoagulant therapy

If hypotension persists after initial forced hydration, then a vasopressor agent should be administered. Dopamine or Noradrenaline can be used. Dopamine increases stroke volume and heart rate whereas Noradrenaline increases mean arterial pressure

 

Dopamine 5–20 micrograms /kg/min IV infusion, subject to adjustment as per response

Noradrenaline 0.5–3 micrograms/min IV infusion and titration as per response. Can be used maximum 30 micrograms/min

Diabetes and hyperosmolality make increased risk of venous thromboembolism (VTE). It is similar to patients with acute renal failure, acute sepsis or acute connective tissue disease

The risk of VTE is greater in HHS than DKA. Hypernatraemia and increased antidiuretic hormone promote thrombogenesis

Patients with HHS who are at risk or suspected with thrombosis or ACS should receive prophylactic low molecular weight heparin (LMWH) during admission. There are increased risk of VTE beyond the discharge, so LMWH should continue for 3 months after discharge (Keenan et al. 2007)

 

1–6  Hour: Assessment and monitoring therapy

Fluid Replacement Continues, FRIII Continues, K replacement if needed

0.9% NaCl 1 l over 2 h, then

WORK-UP:

2 HOURLY serum K, HCO3, venous blood gas for pH

HOURLY: Capillary blood glucose, ketones, cardiac monitoring, BP, pulse, respirations, pulse oximetry, fluid input/ output chart, neurological observations

0.9% NaCl 1 l over 2 h, then

0.9% NaCl 1 l over 4 h

After first hour therapy of 1–1.5 L if signs of severe dehydration such as orthostatic hypotension or supine hypotension, poor skin turgor etc. persists then 1 l per hour have to continue till signs resolved

These patients’ when symptoms are resolved then continue to receive infusion fluid on the basis of corrected sodium

CORRECTED Na+ = MEASURED Na+ + (GLUCOSE in mmol/L- 5.6)/3.5

In hyponatraemic patients: 0.9% NaCl at 250–500 mL/h and when blood glucose reaches 11 mmol/L (200 mg/dL), fluid should be changed to 5% dextrose with 0.45% NaCl at 150–250 mL/h

In hypernatraemic or eunatraemic patients: 0.45% NaCl at 250–500 mL/h and when blood glucose reaches 11 mmol/L (200 mg/dL), it should be changed to 5% dextrose with 0.45% NaCl at 150–250 mL/h

Continue FRIII

In young children with mild to moderate DKA 0.05 units/ kg/h is sufficient to control and in severe DKA and in adolescent patients 0.1 units/kg/h should start after 1 h of fluid replacement therapy

In children with HHS insulin need is less. So a dose of 0.025 to 0.05 units/kg/h should start after 1 h of fluid replacement

Continue basal insulin if taking before K replacement if needed

If infection is suspected by and evidenced by CXR, DC >25,000, neutrophil >80% then a broad spectrum injectable antibiotic have to start. Culture report takes time so need not wait for that

Bicarbonate therapy

At pH >7.0 insulin therapy blocks lipolysis and resolves ketoacidosis without use of HCO3. Use of HCO3 in these cases may cause hypokalemia, decreased tissue oxygen uptake and risk of cerebral oedema

Arterial pH 6.9–7.0 = 50 mmol NaHCO3 in 200 mL sterile water with 10 mEq KCl may be administered over an hour till pH >7.0

Arterial pH < 6.9 = 100 mL of NaHCO3 in 400 mL sterile water with 20 mEq KCL at the rate of 200 mL/h for 2 h until pH >7.0

Phosphate, magnesium and calcium therapy

Very rarely used though there are some nominal deficits. But in symptomatic cases these are supplemented

 

Significant malnutrition is associated with such deficits

 

6–24 HR: Improvement & resolution monitoring

Fluid Replacement Continues, FRIII Continues, K replacement if needed

0.9% NaCl 1 l over 4 h, then

WORK-UP:

6 HOURLY and then 12 HOURLY serum K, HCO3, venous blood gas for pH

HOURLY: Capillary blood glucose, ketones, cardiac monitoring, BP, pulse, respirations, pulse oximetry, fluid input/ output chart, neurological observations

0.9% NaCl 1 l over 6 h, then

0.9% NaCl 1 l over 6 h.

Continue FRIII

K replacement if needed

Once blood glucose falls near 13.9 mmol/L (250 mg/dL), then insulin infusion should be reduced to 0.02–0.05 units/kg/h and a 5% dextrose in saline have to add while maintaining blood glucose 11–17 mmol/L (200–300 mg/dL)

Resolution criteria FOR DKA, EDKA and HHS

Criteria for resolution in DKA, EDKA (except glucose)

 1. Plasma glucose <11 mmol/L (< 200 mg/dL)

 2. Serum HCO3 is >18 mEq/ L

 3. Blood ketones <0.6 mmol/L

 4. Venous pH is >7.3, and

 5. Anion gap is <10

Criteria for resolution of HHS:

 1. Plasma glucose <14–16.7 mmol/L (250–300 mg/dL)

 2. Plasma osmolality <315 mOsm/kg

 3. Improvement in haemodynamic and mental status

Resolution pitfalls: Urinary ketone clearance takes time even after resolution. As BOHB from blood converts to form AcAc after resolution which is abundant in urine

HCO3 alone cannot be relied as resolution of DKA. It is due to high amount of 0.9% NaCl saline infusion causes hypercholeraemic acidosis which lowers HCO3

 

24–48 Hours: resolution & discontinuation of FRIII

FRIII to VRIII

If DKA/ HHS is resolved: Ketones <0.6 mmol/L but NOT eating & drinking then switch from FRIII to VRIII (Variable Rate Intravenous Insulin Infusion)

 

VRIII is based on standard rate such as glucose <4 mmol/L = 0 units/kg/h, 4.1–8 mmol/L = 1 units/kg/h, 8.1–12 mmol/L = 2 units/kg/h and so on

VRIII to S.C. Insulin

VRIII can be discontinued at mealtime. If earlier taking subcutaneous insulin the same insulin can restart with the diabetes team advice of titration

 

VRIII have to continue 30–60 min after first subcutaneous insulin injection

For newly diagnosed T1D and T2D: Insulin therapy

Total last 24 h insulin should be added and 30% reduction is done. This value have to divide by 5 and 1/5th is given with each meal as rapid acting insulin and 2/5th can be given as basal analogue insulin which is called BASAL BOLUS REGIMEN

 

The 30% reduced amount from last 24 h total insulin use can be used as TWICE DAILY REGIMEN. The amount have to divide by 3 and 2/3 have to take with breakfast and 1/3 with evening meal within the interval of 12 h

VRIII TO CSII

To reconnect the insulin pump, normal basal rate have to start and a mealtime bolus have to be given. VRII then have to stop 1 h later

 
Fig. 6

DKA and HHA management algorithm reproduced with permission (Cardoso et al. 2017)

9.2 Management: Acute Hyperglycaemic Crisis Due to COVID-19

The pandemic COVID-19 infection increases the risk of precipitating atypical DKA, HHS or mixed crisis and stress hyperglycaemia with ketones. The recent guideline from ABCD (Association of British Clinical Diabetologists) named ‘COVID: Diabetes’ (COncise adVice on Inpatient Diabetes) has outlined to manage COVID-19 in hyperglycaemic crisis in diabetes (ABCD 2020). This guideline is based on UK experience of COVID-19 management and will be updated further when more evidences will be available. COVID-19 infection in known or unknown people with diabetes increases the risk of acute hyperglycaemia with ketones, DKA and HHS. Poorly controlled elderly diabetes patients are more susceptible to COVID-19 and its complications. Because hyperglycaemia can subdue immunity by disrupting the normal function of WBC and other immune cells. Good glycaemic control and following sick day rules are key to reduce risk apart from taking personal protection and social distancing.

Table 13 shows COVID-19 specific management of acute hyperglycaemic crisis paraphrased from the ‘COVID: Diabetes’ guideline (ABCD 2020).
Table 13

COVID-19 and acute hyperglycaemic crisis in diabetes (ABCD 2020)

Changes seen

Key difference with COVID-19

Action suggested

Risk of early admission

T2D and those on SGLT2i are greater risk

On admission blood glucose checking for everyone

COVID-19 precipitates DKA or HHS or atypical mixed type

Ketones for all diabetes admission

Ketones for everybody with admission glucose >12 mmol/L

Risk of hyperglycaemia with moderate ketones due to stress hyperglycaemia

SGLT2i and Metformin tablets should be immediately stopped on admission

Safety of ACEi, ARB and NSAID should be reviewed

10–20% glucose should be used where ketosis persists even usual protocol of DKA is used

Severely sick on admission

Fluid infusion rate may differ in DKA/ HHS and there is evidence of ‘lung leak’ or myocarditis

After correcting dehydration, rate of fluid infusion should be adjusted in lung leak or myocarditis cases

Early diabetes specialist team and critical care team involvement needed

Inpatient area

Due to huge demand infusion pumps may not be enough as huge need in ICU

Subcutaneous insulin have to start with basal insulin support to manage hyperglycaemia, DKA or HHS or mixed cases

ICU

Insulin resistance is significantly increased in T2D admitted in ICU

Insulin infusion protocols need amendment. It is seen patients need 20 units/h even

Higher doses of insulin is required

Patients sometime nursed prone so feeding may be interrupted accidentally with risk of hypoglycaemia

9.3 Management: Some Controversial Issues

  • 0.9% NaCl vs Hartmann’s solution: In a recent RCT (Yung et al. 2017), comparing Hartmann’s solution with 0.9% NaCl in 77 children with DKA, it was observed that slightly quicker resolution of acidosis can be achieved with Hartmann’s solution in severe DKA. There was however, no difference regarding time required to shift from intravenous to subcutaneous insulin.

  • 0.9%NaCl vs Ringer Lactate solution: A RCT showed no benefit from using Ringer Lactate solution compared with 0.9% NaCl in terms of pH normalization. But Ringer Lactate solution made longer time to reach blood glucose level of 14 mmol/L because lactate converts into glucose (Van Zyl et al. 2011).

  • 0.9%NaCl vs Plsma-Lyte 148: The concern regarding excessive administration of normal saline in DKA is hyperchloremia which can lead to non-anion gap metabolic acidosis. Although self-limiting in nature, this hyperchloremic metabolic acidosis is now believed to have a harmful impact on multiple organs of body like kidneys, myocardium etc. (Eisenhut 2006; Kraut and Kurtz 2014). Plasma-Lyte 148 when compared to normal saline has shown to decrease occurrence of hyperchloremia (Andrew and Patrick 2018; Chua et al. 2012). A systematic review by Gershkovich et al. (Gershkovich et al. 2019) might help aid the decision regarding fluid choice in future.

  • 0.9% NaCl vs Ringer Acetate solution: Though Ringer Acetate is not a popular choice but it has almost similar composition like Ringer Lactate. But its use in hepato-renal emergencies are established (Ergin et al. 2016). Figure 7 shows water shift in hyperglycaemic emergencies with different infusion fluids. The figure is reproduced with permission (Cardoso et al. 2017).

  • Infusion rate: Regarding infusion rate, rapid administration is feared to increase likelihood of cerebral edema especially in children and young adults. The JBDS guidelines therefore recommend gradual correction of fluid deficit over 48 h unless clear signs of hypovolemic shock are present (Dhatariya 2014).

  • Arterial or venous sample: the difference between venous and arterial pH is 0.02–0.15 and the difference between arterial and venous HCO3 is 1.88 mmol/L. These neither affect the diagnosis nor the treatment. But getting arterial sample is risky and painful. So venous sample is widely accepted.

  • The target with fluid administration in HHS is to achieve an hourly drop of 3–8 mOsm/kg in osmolality and 5 mmol/L in glucose. Some adjustments in fluid administration rate and solution type are required if these targets are not being met (Scott et al. 2015). These scenarios are mentioned in Table 14 (Scott et al. 2015).

Fig. 7

ICC Intracellular compartment, ISC Interstitial compartment, IVC Intravascular compartment. Panel A: Total body water distribution in normal state; Panel B: After correction of water deficit with 5% Dextrose water shows suboptimal replenishment of IVC, ISC and excessive rehydration of ICC; Panel C: Correction with 0.9% NaCl made exclusive distribution in extracellular compartment resulting excessive hydration of IVC and ISC; Panel D: Correction with 0.45% NaCl shows replenishment similar to fluid lost from IVC, ISC and ICC. It is probably the best option; Panel E: Correction with 0.225% resulted in suboptimal replenishment of IVC, ISC but excessive hydration of ICC

Table 14

Scenarios with serum osmolality and fluid infusion

Scenario

Solution

Plasma osmolality declining at appropriate rate but plasma sodium increasinga

Continue 0.9% normal saline

Plasma osmolality declining inappropriately (<3 mOsm/kg/h) or increasing with inadequate fluid balance

Increase rate of 0.9% normal saline

Plasma osmolality increasing with adequate fluid balance

Switch to 0.45% normal saline

Osmolality falling at rate > 8 mOSm/kg/h

Decrease rate of 0.9% normal saline

aWith fall in serum glucose level, rise in serum sodium level is expected due to shift of water in intracellular space. Drop of blood glucose by 5.5 mmol/L = rise of Na by 2.4 mmol/L (Scott et al. 2015)

9.4 Management: DKA and EDKA IN Pregnancy

DKA is an emergency during pregnancy and may cause fetal loss which is around 10–25%. The incidence rate is 1–3%. The main causes and precipitating factors are (Savage et al. 2011):

  • Starvation: accelerated maternal response ends up in DKA in women with diabetes

  • Increased flux of glucose from mother to fetus and placenta: due to increased transporter GLUT-1.

  • Higher progesterone level: induces respiratory alkalosis which results in metabolic acidosis that reduces buffering capacity.

  • Precipitating factors: UTI, hyperemesis gravidarum, new onset T1D, KPD, insulin omission, insulin pump malfunction, glucocorticoid use for inducing fetal lung maturity, use of terbutaline to prevent premature labour.

  • DKA and EDKA management is same like non-pregnant cases.

9.5 Management: Key Calculations

Table 15 shows the key calculations needed during management of acute hyperglycaemic crisis (Wolfsdorf et al. 2018).
Table 15

Key calculations

Anion gap

Anion gap = Na – (Cl + HCO3); normal is12 ± 2 mmol/L

In DKA anion gap is 20–30 mmol/ L.

An anion gap >35 mmol/L suggests concomitant lactic acidosis

Corrected sodium

Corrected Na = measured Na +2 (Glucose-5.6)/5.6

Corrected Na is needed to estimate fluid replacement in DKA/HHS when dehydration is mild to moderate

Web based calculation: https://www.mdcalc.com/sodium-correction-hyperglycemia

Effective osmolality

Serum osmolality = 2Na + glucose + urea

Fluid calculation in children

REQUIREMENT = DEFICIT + MAINTENANCE

Holliday – Segar formula:

100 mL/kg/day for first 10 kg

50 mL/ kg/day for next 10 to 20 kg

20 mL /kg/day for each kg above 20 kg

Hourly rate = ({deficit – Initial bolus} /48 h) + maintenance/h

10 Complications

The probable complications of DKA and HHS are tabulated in Table 16 (Savage et al. 2011; Scott et al. 2015; Khazai and Umpierrez 2020).
Table 16

Complications of DKA, EDKA AND HHS

Complications

Cause and remedy

Risk probability

Hypoglycaemia

High dose insulin can cause

In HHS risk probability is more than DKA as insulin sensitivity is more in HHS

Management protocol should follow throughout and frequent monitoring is needed. 5–10% dextrose saline is needed with FRIII when sugar came down

The episode happens for short duration only

Hypokalemia

Use of excessive high dose of insulin and use of HCO3 can cause it

Risk is high in both DKA and HHS

Potassium level should be monitored frequently and replacement should be done if inadequate

Pulmonary or arterial or venous thromboembolism

DKA and HHS patients are at risk of thromboembolism especially in case of central venous catheter use in shock patients

Risk is medium to low. Messenteric vessel thrombosis in extreme rare cases may be found

Prophylactic LMWH should be given in high risk patients based on clinical evaluation

Nonanion gap hyperchloremic acidosis

It occurs due to loss of ketoanions through urine which are needed for HCO3 formation

The risk is low

Moreover, due to high amount of 0.9% NaCl saline infusion, increased amount of chloride reabsorption occurs. Hyperchloremic acidosis resolves during management

In DKA in pregnancy this is seen sometime

Cerebral edema, central pontine myelinolysis

Cerebral edema (CE) incidence is 0.7–10% of children under 5 years of age. It is rare in adults with DKA and in HHS

Avoidance of aggressive hydration and maintaining blood glucose <11 mmol/L can prevent

Headache, lethargy, papillary changes and seizure are key manifestation

Risk of CE is low if following guidelines properly

Mortality rate of CE is high and it is around 57–87% of all deaths of DKA (Kitabchi et al. 2009)

ARDS, DIC

Iatrogenic reduction in colloid osmotic pressure may lead to accumulation of water in lungs, decrease lung compliance and hypoxemia

Risks are very low

Monitoring blood oxygen saturation, lowering fluid intake and adding colloid fluid can correct ARDS

DIC is a rare complication of HHS

Stroke, AMI

Stroke and MI are rare complication in HHS. Predisposing factors are volume depletion with increased viscosity, increased levels of PAI-1, hyperfibrinogenaemia etc.

Risk is low in cases where the guideline for fluid repletion is followed properly

Early adequate hydration is helpful

Coma

Rarely associated in HHS with serum osmolality <330–340 mOsm/kg and in hypernatraemic than hyperglycaemic

Risk is very low

ICU management is needed

Foot ulceration

Rarely occurs in DKA in children and young adults buy in elderly could happen in obtunded or uncooperative cases. The heels should be protected and daily foot checks should be done

High risk in elderly cases of HHS

In HHS patients who are usually elderly with comorbidities it is a high risk especially in those who are obtunded or need to long stay to recover. The heels should be protected and daily foot checks should be done

Cerebral Edema

Cerebral edema (CE)’ is rare and most feared iatrogenic complication of DKA in younger children and in newly diagnosed T1D. It is associated with high mortality and neurodisability & neurocognitive difficulties in survived cohorts. Headache, lethargy, papillary changes and seizure are key manifestation.

Risk of CE found in a study with higher plasma urea, lower arterial pCO2 and NaHCO3 therapy in DKA (Glaser et al. 2001). Interleukin-1 and 6 (IL-1 and IL-6) are the cytokines that initiate the inflammatory response accompanied by DKA. It is postulated that this IL-1 is linked with the pathogenesis of CE. NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin 3 domain) is an inflammasome which generates active form of IL-1 in response to hyperglycaemia acts as osmosensors to cause CE in DKA. It contributes to CE and infarction by making tight junctions leaky (Eisenhut 2018). Some studies have found that initial bolus of rehydration fluid and bolus insulin might have a role (Carlotti 2003).

Table 17 shows the diagnosis of cerebral edema in DKA (Wolfsdorf et al. 2018).
Table 17

Diagnosis of cerebral EDEMA

A. Diagnostic criteria

 Abnormal verbal or motor response to pain

 Decorticate or decerebrate posture

 Cranial nerve palsy

 Abnormal neurogenic breathing pattern (like grunting, tachypnea, Cheyne-Stoke respiration, apneusis)

B. Major criteria

 Altered/fluctuating state of consciousness

 Sustained decreasing heart rate (>20 beats per minute) not attributable to any other reason

 Age-inappropriate incontinence

C. Minor criteria

 Vomiting

 Headache

 Lethargy

 DBP >90 mmHg

 Age < 5 years

If one diagnostic criterion or 2 major criteria or 1 major and 2 minor criteria are present, then diagnostic sensitivity for cerebral edema is 92% with false positive rate of only 4%. However signs that occur before start of treatment should not be included

The management of cerebral edema is difficult and involves careful administration of fluids with strict blood pressure control and infusion of mannitol or hypertonic saline. Mannitol is administered at dose of 0.5–1 g/kg body weight. The calculated dose is administered over a period of 10–15 min and if necessary repeated after 30 min (Wolfsdorf et al. 2018). If mannitol is not available or if there is no response to mannitol, 3% hypertonic saline can be given at calculated dose of 2.5–5 ml/kg. The time for administration is again 10–15 min (Wolfsdorf et al. 2018).

Regarding mannitol versus hypertonic saline selection, controversies exist but recent data suggests lower mortality rate with mannitol (Wolfsdorf et al. 2018).

Figure 8 Pathogenesis of cerebral edema in DKA. The figure is reproduced with permission (Carlotti 2003)
Fig. 8

A bolus of saline could expand the intracranial interstitial volume. A bolus of insulin could expand the intracerebral ICF volume (Scott et al. 2015)

.

11 Prevention

Management of acute hyperglycemic emergencies is not complete until steps are taken to prevent recurrence of future episodes. Diabetes education is an important component of prevention strategy. The education should be tailored to the individual’s requirement. This is only possible after trigger has been identified. Ideally this should be delivered by a specialized diabetes educator (Karslioglu French et al. 2019).

Proper education regarding sick day rules is essential to prevent recurrence. The important components of sick day management include education regarding hydration, glucose and ketones monitoring, continuation of basal insulin and timely contact with health care provider (Karslioglu French et al. 2019). Since the process of ketogenesis occurs in the absence or deficiency of insulin, its recurrence can be avoided. One of the major reasons for recurrence of DKA is non-compliance with insulin in teenagers of less privileged areas who are being most commonly affected. These patients can benefit from targeted community support programs (Dabelea et al. 2014).

Patient on insulin pump is at high risk of DKA in case of pump failure. Therefore one should be educated regarding its care. One should also have an emergency contact number for technical support. In case of pump failure, one might require multiple daily injections to prevent DKA as insulin reserve in body is very limited for a patient on insulin pump. Therefore one must be educated in this regard and advised to carry a reserve of long-acting insulin (Jesudoss and Murray 2016; Rodgers 2008).

12 Conclusion

DKA, EDKA and HHS are avoidable metabolic emergencies both of which can be decreased in incidences with education regarding diabetes management in sick days. The management principles are different for each condition but generally require hospitalization and intravenous fluids with electrolytes. While close monitoring during episode has decreased mortality rate, there are still some controversial areas like fluid choice for rehydration. Due to availability of updated guidelines management is much better now. The structured diabetes education and abiding by sick day rules made significant improvement in reducing the recurrences of acute metabolic crisis of diabetes.

References

  1. ABCD (2020) COncise AdVice on Inpatient Diabetes (COVID: Diabetes): Front Door Guidance National Inpatient Diabetes COVID-19 Response Team COVID-19 Infection in People with or without Previously Recognised Diabetes Increases the Risk of the EMERGENCY States of Hyperglycaemia with Ketones, Diabetic Keto Acidosis (DKA) and Hyperosmolar Hyperglycaemic State (HHS), 9 April 2020Google Scholar
  2. Adeyinka A, Kondamudi NP (2020) Hyperosmolar Hyperglycemic Nonketotic Coma (HHNC), Hyperosmolar hyperglycemic nonketotic syndrome. PubMed, Stat Pearls Publishing. www.ncbi.nlm.nih.gov/books/NBK482142/#
  3. Andrew W, Patrick D (2018) P18 plasma-Lyte 148 vs 0.9% saline for fluid resuscition in children: electrolytic and clinical outcomes. Arch Dis Child 103(2):e1.22–e1.e1Google Scholar
  4. Balasubramanyam A et al (2006) Accuracy and predictive value of classification schemes for ketosis-prone diabetes. Diabetes Care 29(12):2575–2579PubMedGoogle Scholar
  5. Barnett C, Barnett Y (2003) Ketone bodies. In: Encyclopedia of food sciences and nutrition. Academic, Amsterdam, pp 3421–3425Google Scholar
  6. Bedaso A, Oltaye Z, Geja E, Ayalew M (2019) Diabetic ketoacidosis among adult patients with diabetes mellitus admitted to emergency unit of Hawassa university comprehensive specialized hospital. BMC Res Notes 12(1):137PubMedPubMedCentralGoogle Scholar
  7. Blau JE et al (2017) Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data. Diabetes Metab Res Rev 33(8):e2924Google Scholar
  8. BSPED (2020) BSPED interim guideline for the management of children and young people under the age of 18 years with diabetic ketoacidosis, 1 January 2020Google Scholar
  9. Cardoso L et al (2017) Controversies in the management of hyperglycaemic emergencies in adults with diabetes. Metabolism 68(68):43–54PubMedGoogle Scholar
  10. Carlotti APCP (2003) Importance of timing of risk factors for cerebral oedema during therapy for diabetic ketoacidosis. Arch Dis Child 88(2):170–173PubMedPubMedCentralGoogle Scholar
  11. Choleau C, Maitre J, Filipovic Pierucci A, Elie C, Barat P et al (2014) Ketoacidosis at diagnosis of type 1 diabetes in French children and adolescents. Diabetes Metab 40(2):137–142. Elsevier MassonPubMedGoogle Scholar
  12. Chua H-R et al (2012) Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care 27(2):138–145PubMedGoogle Scholar
  13. Dabelea D, Rewers A, Stafford J, Standiford D, Lawrence J, Saydah S et al (2014) Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study. Pediatrics 133(4):e938–e945PubMedPubMedCentralGoogle Scholar
  14. Dandona P et al (2018) Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabetes Care 41(12):2552–2559PubMedGoogle Scholar
  15. DeFronzo RA, Ferrannini E (1987) Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev 3(2):415–459PubMedGoogle Scholar
  16. Desai R et al (2019) Temporal trends in the prevalence of diabetes decompensation (diabetic ketoacidosis and hyperosmolar hyperglycemic state) among adult patients hospitalized with diabetes mellitus: a Nationwide analysis stratified by age, gender, and race. Cureus 11(4).  https://doi.org/10.7759/cureus.4353
  17. Dhatariya K (2014) Diabetic ketoacidosis and hyperosmolar crisis in adults. Medicine 42(12):723–726Google Scholar
  18. Dhatariya K (2016) Blood ketones: measurement, interpretation, limitations, and utility in the management of diabetic ketoacidosis. Rev Diabet Stud 13(4):217–225PubMedGoogle Scholar
  19. Dhillon KK, Gupta S (2019) Biochemistry, Ketogenesis. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK493179/. Accessed 15 May 2020
  20. Diaz-Ramos A et al (2019) Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: a case report and review of the literature. Int J Emerg Med 12(1):27PubMedPubMedCentralGoogle Scholar
  21. Duca LM et al (2017) Diabetic ketoacidosis at diagnosis of type 1 diabetes predicts poor long-term glycemic control. Diabetes Care 40(9):1249–1255PubMedGoogle Scholar
  22. Edge JA et al (2016) Diabetic ketoacidosis in an adolescent and young adult population in the UK in 2014: a national survey comparison of management in paediatric and adult settings. Diabet Med 33(10):1352–1359PubMedGoogle Scholar
  23. Eisenhut M (2006) Causes and effects of hyperchloremic acidosis. Crit Care 10(3):413PubMedPubMedCentralGoogle Scholar
  24. Eisenhut M (2018) In diabetic ketoacidosis brain injury including cerebral oedema and infarction is caused by interleukin-1. Med Hypotheses 121:44–46PubMedGoogle Scholar
  25. Ergin B et al (2016) The role of bicarbonate precursors in balanced fluids during haemorrhagic shock with and without compromised liver function. Br J Anaesth 117(4):521–528PubMedGoogle Scholar
  26. Evans K (2019) Diabetic ketoacidosis: update on management. Clin Med 19(5):396–398Google Scholar
  27. Gershkovich B et al (2019) Choice of crystalloid fluid in the treatment of hyperglycemic emergencies: a systematic review protocol. Syst Rev 8(1):228PubMedPubMedCentralGoogle Scholar
  28. Glaser N, Barnett P, McCaslin I et al (2001) Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med 344:264–269PubMedGoogle Scholar
  29. Gosmanov AR, Kitabchi AE (2000) Diabetic ketoacidosis [Updated 2018 April 28]. In: Feingold KR, Anawalt B, Boyce A et al (eds) Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279146/
  30. Gosmanov AR, Nimatollahi LR (2020) Diabetic ketoacidosis – symptoms, diagnosis and treatment | BMJ Best Practice. Bestpractice.Bmj.Com. February. https://bestpractice.bmj.com/topics/en-us/162. Accessed 15 Apr 2020
  31. Greene JA, Riggs KR (2015) Why is there no generic insulin? Historical origins of a modern problem. N Engl J Med 372(12):1171–1175PubMedGoogle Scholar
  32. Hamdy O (2019) Diabetic Ketoacidosis (DKA): practice essentials, background, pathophysiology. Medscape.Com. 31 May. https://emedicine.medscape.com/article/118361-overview
  33. Handelsman Y et al (2016) American association of clinical endocrinologists and American college of endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract 22(6):753–762PubMedGoogle Scholar
  34. Hardern RD (2003) Emergency management of diabetic ketoacidosis in adults. Emerg Med J 20(3):210–213PubMedPubMedCentralGoogle Scholar
  35. Jabbar A, Farooqui K, Habib A, Islam N, Haque N, Akhter J (2004) Clinical characteristics and outcomes of diabetic ketoacidosis in Pakistani adults with type 2 diabetes mellitus. Diabet Med 21(8):920–923PubMedGoogle Scholar
  36. Jefferies C et al (2015) 15-year incidence of diabetic ketoacidosis at onset of type 1 diabetes in children from a regional setting (Auckland, New Zealand). Sci Rep 5(1):P3Google Scholar
  37. Jesudoss M, Murray R (2016) A practical guide to diabetes mellitus, 7th edn. Jaypee Brothers, New DelhiGoogle Scholar
  38. Karges B, Rosenbauer J, Holterhus PM et al (2015) Hospital admission for diabetic ketoacidosis or severe hypoglycemia in 31,330 young patients with type 1 diabetes. Eur J Endocrinol 173(3):341–350Google Scholar
  39. Karslioglu French E et al (2019) Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ 365(1114):l1114PubMedGoogle Scholar
  40. Keenan CR et al (2007) High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses. J Thromb Haemost 5(6):1185–1190PubMedGoogle Scholar
  41. Kelly A-M (2006) The case for venous rather than arterial blood gases in diabetic ketoacidosis. Emerg Med Australas 18(1):64–67PubMedGoogle Scholar
  42. Khazai N, Umpierrez G (2020) Hyperosmolar hyperglycaemic state – symptoms, diagnosis and treatment | BMJ best practice. Beta-Bestpractice.Bmj.Com. March. https://beta-bestpractice.bmj.com/topics/en-gb/1011. Accessed 15 Apr 2020
  43. Kitabchi AE et al (2006) Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 29(12):2739–2748PubMedGoogle Scholar
  44. Kitabchi A, Umpierrez G, Miles J, Fisher J (2009) Hyperglycemic crises in adult patients with diabetes. Diabetes Care 32(7):1335–1343PubMedPubMedCentralGoogle Scholar
  45. Kraut JA, Kurtz I (2014) Treatment of acute non-anion gap metabolic acidosis. Clin Kidney J 8(1):93–99PubMedPubMedCentralGoogle Scholar
  46. Laine C (2010) Diabetic Ketoacidosis. Ann Intern Med 152(1):ITC1Google Scholar
  47. Lebovitz HE, Banerji MA (2018) Ketosis-prone diabetes (Flatbush diabetes): an emerging worldwide clinically important entity. Curr Diab Rep 18(11):120PubMedPubMedCentralGoogle Scholar
  48. Maahs DM, Hermann JM, Holman N et al (2015) Rates of diabetic ketoacidosis: international comparison with 49,859 pediatric patients with type 1 diabetes from England, Wales, the U.S., Austria, and Germany. Diabetes Care 38(10):1876–1882PubMedGoogle Scholar
  49. Mathieu C et al (2018) Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 24-week results from a randomized controlled trial. Diabetes Care 41(9):1938–1946PubMedGoogle Scholar
  50. Miles JM et al (1983) Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin Investig 71(6):1554–1561PubMedGoogle Scholar
  51. Mudly S, Rambiritch V, Mayet L (2007) An identification of the risk factors implicated in diabetic ketoacidosis (DKA) in type 1 and type 2 diabetes mellitus. S Afr Fam Pract 49(10):15-15bGoogle Scholar
  52. Munro JF et al (1973) Euglycaemic diabetic ketoacidosis. BMJ 2(5866):578–580PubMedGoogle Scholar
  53. Ng S, Edge J, Timmis A (2020) Practical management of hyperglycemic hyperosmolar state (HHS) in children [Internet] [cited 6 April 2020]. Available from: http://www.a-c-d-c.org/wp-content/uploads/2012/08/Practical-Management-of-Hyperglycaemic-Hyperosmolar-State-HHS-in-children-2.pdf
  54. Nyenwe EA et al (2010) Acidosis: the prime determinant of depressed sensorium in diabetic ketoacidosis. Diabetes Care 33(8):1837–1183PubMedPubMedCentralGoogle Scholar
  55. Otieno CF et al (2006) Diabetic ketoacidosis: risk factors, mechanisms and management strategies in Sub-Saharan Africa: a review. East Afr Med J 82(12).  https://doi.org/10.4314/eamj.v82i12.9382
  56. Pasquel FJ, Umpierrez GE (2014) Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care 37(11):3124–3131PubMedPubMedCentralGoogle Scholar
  57. Peters AL et al (2015) Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium–glucose cotransporter 2 inhibition. Diabetes Care 38(9):1687–1693PubMedPubMedCentralGoogle Scholar
  58. Rafey MF et al (2019) Prolonged acidosis is a feature of SGLT2i-induced euglycaemic diabetic ketoacidosis. Endocrinol Diabetes Metab Case Rep 1:1–5Google Scholar
  59. Rawla P et al (2017) Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep 2017(1):1–4. www.ncbi.nlm.nih.gov/pmc/articles/PMC5592704/Google Scholar
  60. Rewers A et al (2008) Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the search for diabetes in youth study. Pediatrics 121(5):e1258–e1266PubMedGoogle Scholar
  61. Röder PV et al (2016) Pancreatic regulation of glucose homeostasis. Exp Mol Med 48(3):e219–e219PubMedPubMedCentralGoogle Scholar
  62. Rodgers J (2008) Using insulin pumps in diabetes: a guide for nurses and other health care professionals. Wiley, ChichesterGoogle Scholar
  63. Rosenstock J, Ferrannini E (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38(9):1638–1642PubMedGoogle Scholar
  64. Rosenstock J et al (2018) Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care 41(12):2560–2569PubMedGoogle Scholar
  65. Savage M et al (2011) Joint British diabetes societies guideline for the management of diabetic ketoacidosis. Diabet Med 28(5):508–515PubMedGoogle Scholar
  66. Scott AR et al (2015) Management of hyperosmolar hyperglycaemic state in adults with diabetes. Diabet Med J Br Diabet Assoc 32(6):714–724Google Scholar
  67. Sheikh-Ali M et al (2008) Can serum –hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 31(4):643–647PubMedGoogle Scholar
  68. Stark R, Guebre-Egziabher F, Zhao X, Feriod C, Dong J, Alves T et al (2014) A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis. J Biol Chem 289(11):7257–7263PubMedPubMedCentralGoogle Scholar
  69. Takeuchi M, Kawamura T, Sato I, Kawakami K (2017) Population-based incidence of diabetic ketoacidosis in type 2 diabetes: medical claims data analysis in Japan. Pharmacoepidemiol Drug Saf 27(1):123–126PubMedGoogle Scholar
  70. Trence DL, Hirsch IB (2001) Hyperglycemic crises in diabetes mellitus type 2. Endocrinol Metab Clin N Am 30(4):817–831Google Scholar
  71. Umpierrez G, Korytkowski M (2016) Diabetic emergencies – ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol 12(4):222–232PubMedGoogle Scholar
  72. Umpierrez GE et al (1996) Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Am J Med Sci 311(5):225–233PubMedGoogle Scholar
  73. Umpierrez GE et al (2002) Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Diabetes Spectr 15(1):28–36Google Scholar
  74. Usher-Smith JA et al (2011) Factors associated with the presence of diabetic ketoacidosis at diagnosis of diabetes in children and young adults: a systematic review. BMJ 343(1):d4092–d4092PubMedPubMedCentralGoogle Scholar
  75. Van Zyl DG et al (2011) Fluid management in diabetic-acidosis – Ringer’s lactate versus normal saline: a randomized controlled trial. QJM 105(4):337–343PubMedGoogle Scholar
  76. Westerberg DP (2013) Diabetic ketoacidosis: evaluation and treatment. Am Fam Physician 87(5):337–346PubMedGoogle Scholar
  77. Wolfsdorf JI et al (2018) ISPAD clinical practice consensus guidelines 2018: diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatr Diabetes 19:155–177PubMedGoogle Scholar
  78. Yung M et al (2017) Controlled trial of Hartmann’s solution versus 0.9% saline for diabetic ketoacidosis. J Paediatr Child Health 53(1):12–17PubMedGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Cardiff University, Cardiff, Heath ParkCardiffUK
  2. 2.Shukat Khanam Cancer Hospital and Research CentreLahorePakistan

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