Diabetic ketoacidosis

Diabetic ketoacidosis is a state of insulin deficiency, characterised by rapid onset, extreme metabolic acidosis, a generally intact sensorium, and only mild hyperglycaemia. DKA comes up frequently in the CICM SAQs, but usually as an ABG interpretation exercise. This chapter focuses on the medical side of DKA, including its causes, manifestations, complications, and management strategies. Questions which have required such thinking have included the following:

  • Question 2 from the first paper of 2017 (a HONKish DKA)
  • Question 1 from the second paper of 2016 (differences between HONK and DKA)
  • Question 17 from the first paper of 2014 (differences between HONK and DKA)
  • Question 2  from the second paper of 2009 (general approach to management)
  • Question 15  from the second paper of 2000 (whether or not saline is appropriate)

Definition of diabetic ketoacidosis

How does one discriminate between DKA and HONK even when in about 30% of instances the two disorders coexist? Arbitrary definitions exist, proposed by the American Diabetes Association.

In summary:

  • DKA presents with acidosis as the major feature
  • HONK presents with hyperglycaemia as the major feature
Discriminating Between HONK and DKA
Domain

Features suggestive of DKA

Features suggestive of HONK

Demographic
  • Young
  • Known Type 1 diabetic
  • Elderly
  • Known Type 2 diabetic
History
  • Rapid clinical course
  • History of noncompliance with insulin
  • Abdominal pain
  • Shortness of breath
  • Prolonged course
  • History of noncompliance with oral antihyperglycaemic agents and insulin
  • Polydipsia, polyuria, weight loss
  • Neurological symptoms
Examination
  • Tachypnoea
  • Normal level of consciousness, or only slightly decreased
  • Coma
  • Seizures
Biochemistry
  • Severe acidosis
  • Severe ketosis
  • Mild hyperglycaemia
  • Renal function normalises rapidly
  • Mild acidosis
  • Little ketosis; mainly lactate is raised
  • Severe hyperglycaemia
  • Established renal failure

Precipitating factors for DKA

DKA requires a trigger. This takes the shape of a fairly binary distinction. Either there has been an absolute lack of insulin, or the tissue response to insulin has been decreased.

Precipitating Factors for Diabetic Ketoacidosis

Lack of Insulin

  • New diagnosis of diabetes
  • Poor treatment compliance
  • Dietary mismanagement

Drugs which trigger DKA

  • Corticosteroids
  • Phenytoin
  • Diuretics
  • Catecholamine inotropes
  • TPN

Physiological stress

  • Infection
  • Systemic inflammatory response
  • Myocardial infarction
  • Surgery
  • Substance abuse

Physiological stress tends to provoke a stress response - I suppose that is why they call it "the stress response". As a part of this response, neurohormonal influences on fuel metabolism promote the mobilisation of metabolic substrates, with some associated insulin resistance and with a decrease in endogenous insulin secretion (driven by the sympathetic nervous system as well as by circulating adrenaline). One of the consequences of this is "stress-induced hyperglycaemia" which can turn a non-diabetic person hyperglycaemic. One can imagine what this sort of response would do to a person with a preexsiting insulin intolerance, or pancreatic endocrine defect.

Mechanisms of ketosis

The basis of ketosis is the reduction in the effect of insulin, coupled with the increase in the action of anti-insulin hormones such as glucagon, cortisol, catecholamines and human growth hormone. Much of the physiology which underlies this is covered in the chapter on the physiological response to starvation.

mechanism of ketosis in DKA

In essence, there are three components, which can contribute unequally:

  • Stress, which produces changes in the use of metabolic substrates:
    • Increased glycogenolysis
    • Increased gluconeogenesis
    • Increased lipolysis (and thus ketogenesis)
  • Lack of insulin
  • Resistance to insulin

Mechanism of ketone acidosis

Ketones are acidic. The acidosis which develops due to an excess of ketones is discussed in the section on metabolic acidosis. Additionally, a lactic acidosis can develop in association with ketoacidosis. And on top of that, there are now an excess of free fatty acids in the bloodstream, which are also acidic (but which do not contribute extesnively to the acidosis per se.)

The ketone bodies - with the exception of acetone - are well dissociated at physiological pH, and produce a nice excess of hydrogen ions. The result is a depletion of the buffering systems, and a drop in pH.

The physiological distinction between DKA and HONK

One can view HONK as a "pre-ketotic hyperglycaemia". The key pivot point where HONK can progress to ketosis seems to be the glucagon-driven initiation of lipolysis, which leads to the synthesis of all the offensive ketones. The difference in HONK is that there is still enough insulin around to prevent this from happening, whereas in DKA the insulin-glucagon balance is shifted in favour of glucagon.

mechanisms of metabolic differences between DKA and HONK

As a result, the Type-1 diabetic DKA patient with zero insulin on board reacts to hyperglycaemia not by quietly dehydrating osmotically over the period of a week, but rather by becoming severely acidotic, and developing unpleasant symptoms which lead them to present early.

Diagnostic features of ketoacidosis

In order to qualify as a DKA you must strive towards the following diagnostic criteria:

  • pH <7.25
  • HCO3- < 18
  • urine/serum ketones positive
  • Anion gap >10

The clinical features of DKA can be presented in a nice table. And of course, the presence of ketones is the most specific findings. Dont use those nitroprusside sticks, they tend to ignore the presence of β-hydroxybutyrate which is the most prevalent etone in DKA. Rather, go with the finger prick ketones.

Clinical Manifestations of Ketoacidosis

Respiratory

Tachypnoea

Deep Kussmaul breathing

Low PCO2

Cardiovascular

Tachycardia

Hypotension due to hypovolemia

Reduced skin turgor and dry mucosa

Biochemical

Pseudohyponatremia

High anion gap metabolic acidosis

Hyperkalemia (due to acidosis) - but in fact the total body K+ stores are depleted

Hypophosphatemia

Hypomagnesemia

Hyperlipidemia

Neurological

Anxiety and agitation

Obtundation and coma (if hyperosmolar)

Gastrointestinal

Vomiting and diarrhoea

Abdominal cramps

Ileus

Exhaled "fruity" odour of ketones

Renal

Acute renal failure

Polyuria

Hematological

Leucocytosis

These are all features of hyperosmolarity, hypovolemia and metabolic acidosis; both direct effects and compensatory mechanisms.

Complications of Diabetic Ketoacidosis

Having your pH drop to 6.9 is not a consequence-free experience.

Several unpleasant complications may result:

Renal failure as a complication of DKA is generally viewed as a relatively short and uneventful affair. These people come with a history of osmotic diuresis and decreased oral intake, which usually points to hypovolemia as the cause of their kidney injury. Beyond that, there may also be a factor which has contributed to both the DKA and the renal damage - for instance, septic shock or heart failure due to myocardial infarction. However, in spite of this, most of the patients tend to recover their renal function without resorting to dialysis.  Orban et al (2014) performed a retrospective review of 94 patients admitted with DKA, and found that though exactly 50% of them had some degree of renal failure (at minimum in the R class of the RIFLE definition) only 3% required CRRT, and in the rest the AKI resolved with only fluid administration (4L  on average). 

Management of DKA

Fluid resuscitation

These patients will be between 5 and 10 litres behind in their fluid balance. Generally speaking, about 100ml/kg of water is missing. Oh's Manual suggests that there is no specific difference between the fluid management in DKA and in HONK. They recommend the following fluid resuscitation schedule for both:

  • 15-20ml/kg in the first hour (and use colloid if they are shocked)
  • 4-14ml/kg in the second hour (of 0.45% NaCl)
  • 4-14ml/kg again in the third hour (use 0.9% NaCl if the sodium is low)
  • When glucose is under 15mmol/L, Oh's Manual recommends to start 5% dextrose 100-250ml/hr, as well as some other sort of sodium-containing fluid to prevent hyponatremia.

With this regimen, for a 70kg DKA/HONK patient, one ends up giving about 1.5-3L in the first 3 hours. There is no reference in The Manual, but closer inspection has revealed that they derive this fluid ressucitation regimen from the Consensus Statement of the American Diabetes Association.

Choice of fluids in resuscitation of DKA

Rationale for fluid resuscitation

  • DKA patients have a significant fluid deficit due to glucose and ketone diuresis
  • Rehydration is a major part of therapy for DKA

Physiological basis for fluid resuscitation with balanced crystalloid

  • Isotonic saline is a standard rehydration fluid
  • However, the large volumes which will be required may have undesirable consequences
  • Isotonic saline contains 150mmol/L of chloride
  • The excess of chloride may contribute to the metabolic acidosis
  • This contribution may delay recovery from ketoacidosis

Advantages of saline

  • Isotonic saline is a cheap widely available fluid
  • Its high sodium content can promote the retention of fluid in the intravascular space
  • It is safe to use in most settings
  • Volume replacement will result in a more rapid resolution of ketoacidosis and lactic acidosis in DKA
  • Normal anion gap acidosis due to the extra chloride may be mild and transient

Disadvantages of saline

  • Normal anion gap metabolic acidosis may develop
  • Work of breathing may increase due to acidosis
  • Existing (already near-depleted) buffer systems may be further depleted by this NAGMA.

Evidence and opinion in the literature

Several studies are available to guide decision-making, which I will summarise:

Insulin therapy

If you can do little about the insulin resistance of the stress-response state, at least you can supplement the missing insulin.

How much? Well; it has been demonstrated that a normal low-dose "physiological replacement" infusion works just as well if not better than high dose insulin. That study used a dose rate of 1u/hr, unadjusted to weight. Oh's Manual recommends 0.1u/kg/hr, which would work out to be 7u/hr for a normal sized person. Local policies differ.

The target of therapy is to achieve the following metabolic goals:

  • Increase the HCO3- by 3mmol/L every hour
  • Decrease the BSL by 3mmol/L every hour
  • Decrease the blood ketone concentration by 0.5mmol/L every hour
  • Maintain normal electrolyte balance while doing so.

Once the BSL is reduced to below 15-12mmol/L, the infusion of insulin can be decreased to more accurately match the patient's requirements - around 0.02-0.05u/Kg/hr, or 1.4-3.5 units per hour.

Electrolyte replacement

Table 58.1 on page 631 of the new Ohs Manual presents a list of electrolyte deficits which develop in DKA. There is no reference for this table, but if one digs deep enough one is able to unearth a 2003 article which contains this table within it. I will summarise the relevant features:

  • Water deficit: 100ml/kg
  • Sodium deficit: 7-10mmol/kg
  • Potassium deficit: 3-5mmol/kg
  • Chloride deficit: 3-5mmol/kg
  • Phosphate deficit: 1-1.5mmol/kg
  • Magneisum deficit: 1-1.5mmol/Kg
  • Calcium deficit: 1-2mmol/Kg

Thus, the 70kg DKA patient stands to be infused with up to 7 litres of water, 700mmol of sodium, 350mmol of potassium, 350mmol of chloride, and about 140mmol each of phosphate, magnesium and calcium. In reality, the total infusion requirement may be greater due to diuresis.

References

UpToDate has a nice summary of this topic for the paying customer.

Oh's Intensive Care manual: Chapter 58  (pp. 629) Diabetic  emergencies  by Richard  Keays

Umpierrez, Guillermo E., Mary Beth Murphy, and Abbas E. Kitabchi. "Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome." Diabetes Spectrum15.1 (2002): 28-36.

ARIEFF, ALLEN I., and HUGH J. CARROLL. "Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of theraphy in 37 cases." Medicine 51.2 (1972): 73-94.

Alberti, K. G. M. M., et al. "Role of glucagon and other hormones in development of diabetic ketoacidosis." The Lancet 305.7920 (1975): 1307-1311.

Kitabchi, Abbas E., et al. "Management of hyperglycemic crises in patients with diabetes." Diabetes care 24.1 (2001): 131-153.

Foster, Jennifer Ruth, Gavin Morrison, and Douglas D. Fraser. "Diabetic ketoacidosis-associated stroke in children and youth." Stroke research and treatment 2011 (2011).

Edge, J. A., et al. "The risk and outcome of cerebral oedema developing during diabetic ketoacidosis." Archives of disease in childhood 85.1 (2001): 16-22.

Woodrow, G., A. M. Brownjohn, and J. H. Turney. "Acute renal failure in patients with type 1 diabetes mellitus." Postgraduate medical journal 70.821 (1994): 192-194.

Bonfanti, R., et al. "Disseminated intravascular coagulation and severe peripheral neuropathy complicating ketoacidosis in a newly diagnosed diabetic child." Acta diabetologica 31.3 (1994): 173-174.

Chua, Horng-Ruey, et al. "Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis." Journal of critical care 27.2 (2012): 138-145.

Stowe, Michele L. "Plasma-Lyte vs. Normal Saline: Preventing Hyperchloremic Acidosis in Fluid Resuscitation for Diabetic Ketoacidosis." (2012).

Jivan, Daksha. "A comparison of the use of normal saline versus Ringers lactate in the fluid resuscitation of diabetic ketoacidosis." (2013).

Basnet, Sangita, et al. "Effect of Normal Saline and Half Normal Saline on Serum Electrolytes During Recovery Phase of Diabetic Ketoacidosis." Journal of intensive care medicine 29.1 (2014): 38-42.

Hillman, K. "Fluid resuscitation in diabetic emergencies—a reappraisal."Intensive care medicine 13.1 (1987): 4-8.

Wagner, Arnd, et al. "Therapy of severe diabetic ketoacidosis. Zero-mortality under very-low-dose insulin application." Diabetes care 22.5 (1999): 674-677.

Chiasson, Jean-Louis, et al. "Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state." Canadian Medical Association Journal 168.7 (2003): 859-866.

Kitabchi, Abbas E., et al. "Hyperglycemic crises in adult patients with diabetes a consensus statement from the American Diabetes Association." Diabetes care 29.12 (2006): 2739-2748.

Orban, Jean-Christophe, et al. "Incidence and characteristics of acute kidney injury in severe diabetic ketoacidosis." PLoS One 9.10 (2014): e110925.