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 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.
- DKA presents with acidosis as the major feature
- HONK presents with hyperglycaemia as the major feature
Features suggestive of DKA
Features suggestive of HONK
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.
Lack of Insulin
Drugs which trigger DKA
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.
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.
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.
Deep Kussmaul breathing
Hypotension due to hypovolemia
Reduced skin turgor and dry mucosa
High anion gap metabolic acidosis
Hyperkalemia (due to acidosis) - but in fact the total body K+ stores are depleted
Anxiety and agitation
Obtundation and coma (if hyperosmolar)
Vomiting and diarrhoea
Exhaled "fruity" odour of ketones
Acute renal failure
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:
- Cardiac arrest due to bizarre electrolytes
- Brain injury or stroke (due to hypocapneic vasoconstriction)
- Cerebral oedema
- Renal failure due to hypotension and possibly other reasons (eg. whatever the precipitant for the DKA was, be it sepsis or acute MI)
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
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
- Most guidelines for DKA resuscitation were written by endocrinologists rather than critical care specialists.
- Most of these guidelines still promote the use of normal saline, even though the acidosis-promoting effects of saline are well recognised.
- Normal saline has been treated as the default fluid of choice because the evidence for other fluids had been lacking.
- Most recent evidence comparing a "balanced" resuscitation crystalloid solution (Plasmalyte 148) with saline has suggested that though the metabolic acidosis resolves faster with Plasmalyte, the duration of ICU stay is not affected.
- Furthermore, there is some evidence that lactate-containing solutions (eg. Harmanns) may delay the resolution of ketoacidosis and achievement of normoglycaemia by contributing substrate (lactate) for hepatic gluconeogenesis, and thus by contributing additional glucose to the already hyperglycaemic patient.
Several studies are available to guide decision-making, which I will summarise:
- Plasmalyte is better than saline: more rapid correction of acidosis (multiple authors agree on this)
- Ringers lactate and normal saline are equivalent (unpublished data)
- Half-saline may be better than normal saline (at least among children) - Oh's Manual also recommends it for adults, on the basis of an 1987 opinion; the rationale is that the urine of a DKA patient has about 60-70mmol of Na+ in it, and so does 0.45% saline.
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.
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.