RISK FACTORS FOR CEREBRAL OEDEMA PRIOR TO THERAPY OF DKA

The fact that cerebral oedema is present in close to 5% of patients prior to therapy for DKA^1,2 strongly suggests that there are risk factors which might be present before therapy begins. We speculate that one of these factors is that the blood-brain barrier (BBB) might be less restrictive on admission in patients with DKA, because CT scans in several studies have shown a diminished diameter of the ventricular system prior to therapy for DKA.^8–10 If this represents brain swelling, it was evident despite a contracted ECF volume (should shrink the brain ECF volume) and a higher effective P_osm (should diminish the ICF volume unless there was a large increase in ICF solutes in brain cells).

A fortuitous recent observation could provide insights into why cerebral oedema might develop in a specific patient prior to therapy for DKA.¹¹ We reported data from a 17 year old female who had multiple admissions for DKA because she was not compliant with recommended therapy. On the last admission, she presented with an extremely high P_Glu (70 mmol/l (1260 mg/dl)), but she did not have obvious ketoacidosis. She excreted 1 litre of urine in the first 100 minutes in the emergency department. The major basis for her extremely large polyuria was a glucose induced osmotic diuresis that was likely caused by the intake of sweetened fruit juice. Her P_Glu at the start and end of this first 100 minute interval remained at 70 mmol/l and her P_Na did not change appreciably—hence her effective P_osm was virtually constant. When she no longer had access to sweetened fruit juice in the emergency department, she drank tap water. In the next 100 minute period, there was a sudden fall in her effective P_osm because her P_Glu fell by 30 mmol/l while there was only a minor change in her P_Na. This fall in effective P_osm could represent a clinically occult basis for the development of cerebral oedema.¹¹ To suspect its presence, a more detailed history of the type of fluid intake is needed in a patient with an extremely large urine output. By finding a change in the ingested fluid from sugar containing fruit juice to tap water, one might be alerted to the possibility that there was an occult fall in the effective P_osm (equation 1). Without this detailed history or without having the first two sets of blood values, the physician in the emergency department would not be aware of this potential risk factor for the development of cerebral oedema.

RISK FACTORS FOR CEREBRAL OEDEMA EARLY IN THE THERAPY OF DKA

Infusion of saline

With the background of a less restrictive BBB discussed above, dangers associated with a large intravenous bolus of saline can be anticipated by analysing Starling forces across capillary membranes (fig 1, top portion). An intravenous bolus of saline distributes initially in the plasma volume and reaches the brain; there is little mixing with the large ECF compartment. There are two major reasons for this saline bolus to cause the exit of fluid across the BBB into the interstitial fluid compartment of the brain. First, capillary hydrostatic pressure might be higher because of an expanded plasma volume. Second, the colloid osmotic pressure might fall because of lowering of the plasma albumin concentration by dilution. The colloid osmotic pressure is also influenced directly by the net valence on plasma proteins (the Donnan effect). Kamel and colleagues¹² showed that a rapid infusion of saline caused a significant decline in the net anionic charge on plasma proteins. Based on this reasoning, it should be potentially dangerous to give a bolus of saline to children with DKA unless there was a definite haemodynamic indication to do so (for example, low blood pressure). In our experience, haemodynamic collapse is not common in children with DKA. If there is a haemodynamic indication, up to 3 mmol NaCl per kg isotonic saline should be infused over 90 minutes. Once the blood pressure stabilises, the rate of infusion of NaCl should be much slower, with an upper limit reaching a positive balance of 6 mmol NaCl per kg over 24 hours to replace the likely deficit of Na⁺.¹³

Bolus of insulin

The Na⁺/H⁺ exchanger (NHE) in cell membranes is normally inactive because it catalyses an electroneutral exchange and its substrates have a much higher concentration (ECF Na⁺ and ICF H⁺) than its products (ICF Na⁺ and ECF H⁺) in steady state (fig 1, bottom portion). Following a large intravenous bolus of insulin, this NHE could become active.^14,15 The other activator of NHE is a higher H⁺ concentration in the ICF compartment.^14,15 When NHE is active, there should be a gain of Na⁺ and a loss of H⁺ in the ICF compartment; this will increase the number of solute molecules in the ICF¹⁶ because the bulk of the exported H⁺ were bound primarily to ICF proteins or entered cells along with β-hydroxybutyrate on the monocarboxylic acid transporter (fig 1).^17–19 Since intracellular acidosis is usually present in patients with DKA and there is an insulin receptor in the brain,²⁰ an intravenous bolus of insulin could have a more dramatic intracerebral effect if it were given early on, when the BBB might be less restrictive to the passage of insulin.^8–10 Although large doses of insulin were given in the past to patients with a serious degree of DKA, the incidence of cerebral oedema was quite low. This might reflect a less aggressive infusion of saline and/or the administration of insulin by the subcutaneous route.

While NaHCO₃ would lower the ECF H⁺ concentration, this should only become important for Na⁺ entry into brain cells when their NHE is activated. If true, a combination of a bolus of insulin together with NaHCO₃ and administration of both early in time could make this “trio” become important risk factors. In contrast, if insulin and NaHCO₃ were administered later when the BBB is more intact, they might be less likely to cause cerebral oedema.

RISK FACTORS FOR CEREBRAL OEDEMA LATER IN THERAPY FOR DKA

Rapid fall in P_glu

A rapid decline in P_Glu would be a risk factor if there were a slower decline in the concentration of glucose and related metabolites in the brain.^3,4,8,9,21 The actual importance of this risk factor is not clear because the major fall in P_Glu occurs much earlier than the clinical onset of cerebral oedema.

Fall in effective P_osm

A fall in P_Glu would lead to a decline in the effective P_osm if P_Na did not rise by an appropriate amount (fig 2, right portion). The P_Glu usually falls by 5 mmol/l/h over the initial six hours of therapy. If the P_Glu on admission were close to 50 mmol/l, the decline in P_Glu would be close to 30 mmol/l. To avoid a fall in the “effective” P_osm, the P_Na must rise by 15 mmol/l or half the fall in P_Glu (30 mmol/l). This is not a problem when the P_Na is close to 125 mmol/l with a blood sugar of 50 mmol/l, which is common in adults with DKA.²² Therefore the target for the P_Na would be 140 mmol/l in an adult population. In contrast, because the initial P_Na is often close to 140 mmol/l on admission in a paediatric patient with a P_Glu close to 50 mmol/l,^23–25 there is a therapeutic dilemma. If the goal of therapy were to maintain a constant effective P_osm over the initial 12–24 hours, P_Na should rise to close to 155 mmol/l in these patients. This value itself tends to make clinicians uncomfortable with the need to defend the effective P_osm vigorously. Although limited data were available in our preliminary study,²³ it seemed advisable to maintain a constant effective P_osm, because the eight patients who did not develop cerebral oedema had an effective P_osm of 341 ± 7 mOsm/kg H₂O from the 7 to the 24 hour time (P_Na rose to 156 ± 1 mmol/l). In contrast, the six patients who developed cerebral oedema during therapy had a fall in their effective P_osm to 307 ± 7 mOsm/kg H₂O over this period (P_Na remained at 140 ± 1 mmol/l).

CONCLUDING REMARKS

Clinical management of DKA should change. Each mode of therapy should be administered aggressively only if it deals with a threat to life. The cautions listed below are most important in a paediatric population because they are at greater risk of developing cerebral oedema. A constant infusion rather than a bolus of insulin should be given as the only seconds to minutes emergency that is reversed by insulin is life threatening hyperkalaemia (see Halperin and colleagues²⁶). Isotonic saline should be infused rapidly only if there is a significant degree of hypotension. An upper target for a positive Na⁺ balance is 6 mmol/kg in the first 24 hours. Isotonic saline is the preferred intravenous solution during the first day because the aim is to prevent a fall in the effective P_osm. In our opinion, it is advisable to select an appropriate target for the rise in P_Na to decrease the degree of fall in the effective P_osm. One must be vigilant concerning both the infusions given and the clinical picture, because if the CNS status does not continue to improve, cerebral oedema should be suspected. In this setting, we would give a rapid infusion of hypertonic saline or mannitol before there is irreversible brain damage. One should not limit the impression of the danger of cerebral oedema to mortality or gross cerebral function loss because cerebral oedema could lead to a loss of subtle cerebral functions that might not be easily recognised. Finally, this discussion points out a potential difficulty in interpreting data from large multicentre studies unless timing of therapy, prior deficits of Na⁺ for instance (haemodynamic signs), and combinations of risk factors are included in the analysis.