Diabetic Keto-acidosis with cerebral oedema in search of an optimal strategy for mechanical ventilation Case : A 16 yr old girl with

h IDDM for 8 yrs duration presented to A/E with a GCS of 3. She was known to be poorly compliant with treatment and was living in Foster care. She had had an Hypo earlier that day and had been advised to omit here Novorapid and re-check her blood glucose on the glucometer later on. But she was found unresponsive at 1900 hrs that day. On arrival to A/E, she had a partially obstructed airway, HR = 140 /min, RR = 45/min and a mean BP = 45 mmHg. Initial gas showed a pH = 6.84, PaCO2 =1.4, PaO2=47.3, BE=-31, Lactate =7.2. Lab results showed Na 143, Na[Corrected] 171, K 8.1, Glucose 76, Osmolality 445, Creatinine 278,Urea 11.3, Hb 127, WCC 41.8. She had an urgent RSI with ketamine and suxamethonium and after resuscitation including cardiac massage and adrenaline boluses, was transferred to PICU for ongoing care. Questions : 1.What pCO2 should be targeted in managing patients with DKA who have been intubated and ventilated ? 2. Should there be different targets dependant on the absence/presence of documented cerebral oedema ? 3. What is the role of corrected Na in the monitoring and Mx of cerebral oedema in these patients ? Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Edge et al conducted a national case control study of 43 cases of cerebral oedema documented in the UK over a 1 year period. In this study, baseline acidosis and abnormalities of sodium, potassium and urea concentrations were important predictors of risk of cerebral oedema. Additional risk factors identified were early administration of insulin and high volumes of fluid. The pathophysiology of cerebral oedema in DKA is a complex phenomenon and proposed mechanisms are mainly derived from nonrandomised, retrospective reports of case series or experimental animal studies. Dillon et al proposed a mechanism of cerebral ischaemia, hypoxia and increased capillary permeability secondary to vasoconstriction due to hypovolemia and hypocapnoea associated with DKA. Another proposed mechanism is the prolonged hypo-osmolar state leading to the development of cerebral intra-cellular osmoles (taurine and myo-inositol) and during the treatment phase of DKA, they may attract intracellular fluid leading to the development of cerebral oedema. Recent MRI studies, however, point to causation by vasogenic cerebral oedema, rather than cytotoxic cerebral oedema. Ketones in addition to causing osmotic diuresis are though to be pro-inflammatory agents affecting the endothelial cells of the blood brain barrier. In severe metabolic acidosis, mechanical ventilation aimed at nearnormal PaCO2 will result in worsening acidosis .If for different [HCO3] values (i.e., A, 4 mmol/L and B, 8 mmol/L) were present simultaneously in blood and CSF, respectively, what would be the effect of exposure to similar levels of, and changes in, PCO2, assuming that pKa values for these fluids were similar? In humans, pH of CSF (pHCSF, 7.32) is normally 0.08 units lower than pHART. CSF PCO2 (48 mm Hg) is

about 8 mm Hg higher than arterial, and [HCO3]CSF (23 mmol/L) is about the same as that in blood . There are homeostatic mechanisms that keep CSF and brain interstitial pH relatively constant, despite changes in pHART . The changes in pHCSF, in response to changes in pHART, depend on the blood-brain barrier: It is relatively impermeable to hydrogen (H) and HCO3 ions but freely permeable to CO2. Hence, change in PaCO2 is followed rapidly by a change in pHCSF that parallels pHART. The effect of CO2 on CBF is mediated, solely, by CSF and extracellular fluid [H]; that is, when PaCO2 increases, molecular CO2 diffuses across the bloodbrain barrier to increase local PCO2 of vascular smooth muscle, reduce extracellular fluid pH, and produce vasodilation. The reverse occurs when PaCO2 is decreased. However, when there are significant changes and differences between [HCO3]ART and [HCO3]CSF, the relationship with PaCO2 is complex and results in different responses in pHART and pHCSF. Considering that metabolic acidosis in DKA occurs over a few days CSF bicarbonate reduces gradually along with CSF pCO2, which more readily equates with blood pCo2.In a mechanically ventilated child, if PCO2 is allowed to rise rapidly, it will quickly equilibrate with CSF pCO2 allowing it to rise, while CSF bicarbonate remains low causing worsening of CSF pH acutely. Reduction in CSF pH will worsen cerebral hyperaemia predisposing to cerebral oedema. If this hypothesis is correct, normocapnia should be avoided in ventilated children with cerebral oedema in DKA. Contrary to this hypothesis, Marcin et al identified intubation with associated hyperventilation wih poorer neurologic outcome in a retrospective review of 61 children with cerebral oedema with DKA.11/17 DKA patients with cerebral oedema who were intubated and hyperventilated in the fires few hours of life had a poorer neurologic outcome compared to 3/28 in the non-intubated group. Durward and colleagues have applied Stewarts strong ion theory in preference to Handerson Hasselbach equation for CSF pH homeostasis. They propose that CSF pH is largely determined by two independent variables pCO2 and CSF strong ion difference, as it is almost albumin free. Hence weak acids only play a minor role. With acute change in CSF acid- base disturbances, there would be compensatory fall in CSF Chloride (trying to keep the CSF chloride to Na ratio constant). This would result in a relatively small change in cerebral pH relative to plasma. But animal and clinical data do not suggest any acute changes in CSF electrolytes in response to rising CSF pCO2. Any prospective studies exploring the plasma and CSF electrolyte and acid base alteration in thses grouo of patients is ethically challenging. Based on current evidence, it is best, if possible, to avoid mechanical ventilation in cerebral oedema with DKA. If a child does require intubation and ventilation, his/her pre-clinical state should be taken into appoint and considered analytically to manage his/her mechanical ventilation. A low normal pCo2 should be aimed for to avoid the iatrogenic aggravation of cerebral oedema in these children. In a retrospective cohort study of 53 children, Durward et al studied the primary hypothesis that The trajectory of glucose-corrected sodium would provide an early marker for development of cerebral oedema.

The role of glucose-corrected serum sodium as a potential early marker of cerebral oedema development has been suggested by this study. This is because the directional change (rather than the rate of change) can be utilised: in that, the typical trajectory for a patient developing late cerebral oedema was a fall in glucose-corrected sodium, compared to the slow rise seen among those who did not (see above). This is in contrast to the directional changes for effective osmolality and glucose, where both variables changed in the same direction for the control and late onset oedema groups, albeit at different rates. The authors caution that data were included within the trajectory estimates that were collected after the development of cerebral oedema, meaning that aspects of treatment (e.g., administration of hypertonic saline) may have altered the trajectories. Hence, this study must be viewed as predominantly hypothesis generating in terms of the potential utility of glucose-corrected sodium as a marker of cerebral oedema development. This requires prospective evaluation in a multicentre study. References: 1. Edge et al. The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children. Diabetologia. 2006 Sep;49(9):2002-9. Epub 2006 Jul 18. 2. Levin D L. Cerebral edema in diabetic ketoacidosis. Pediatr Crit Care Med2008 ; 9 : 320 9. 3. Edge JA, Roy Y, Bergomi A, et al. Conscious level in children with diabetic ketoacidosis is related to severity of acidosis and not to blood glucose concentration.Pediatr Diabetes 2006 ; 7 : 11 15 4. Durward A et al The temporal relationship between glucose-corrected serum sodium and neurological status in severe diabetic ketoacidosis. Arch Dis Child 2011;96:5057.