Is Bicarbonate Treatment indicated in severe DKA?

1. Is Bicarbonate Treatment indicated in severe DKA? Paul Ko April 22, 2003

2. The Evidence • Adults: -Viallon A, Zeni F et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999; 27:2690-2693. • Pediatrics: -Glaser N, Barnett P, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med, 2001, 344: 264-269.

3. Viallon A, Zeni F et al. Does Bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999; 27:2690-2693. • Retrospective Study of DKA admitted to the ED of a university hospital in France over 5 yr period (1991-96). • 39 consecutively admitted patients in DKA (pH 6.83-7.08) divided into 2 groups: Group 1 patients with bicarbonate treatment (n=24), Group 2 those without treatment (n=15) • Both groups received similar standard therapeutic protocol treatment for DKA.

4. Viallon A, Zeni F et al. Does Bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999; 27:2690-2693. • 2 groups similar in clinical characteristics of the patients in terms of severity, clinical (RR, HR, GCS, BP, etc) and biochemical characteristics. • Plotted over 24 hrs after admission, variations in arterial mean pH, bicarbonate concentration, PaCO2, venous blood glucose, kalemia, anion gap not significantly different. • Time to normalization of pH (>7.30) not different in 2 groups (8 +/- 1 vs. 8 +/- 1.2 hrs)

5. Viallon A, Zeni F et al. Does Bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999; 27:2690-2693. • No difference noted in the two groups in clearance of urine ketones (16.3 +/- 12.2 hrs vs. 19.6 +/- 13.5) • Treatment comparison in 2 groups in quantity of IV NS solution, glucose solution, insulin and sodium infused did not differ. • No significant difference in decrease of blood K+ but there was greater supplementation of K+ in pt who received bicarbonate therapy (366 +/- 74 mmol vs 188 +/-109 mmol; p<.001)

6. Viallon A, Zeni F et al. Does Bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999; 27:2690-2693. • Conclusion: No demonstrated difference in use of bicarbonate in recovery (based on biochemical or clinical parameters) of severe DKA w/ pH 6.9-7.1 • Limitation: Limited size of study, retrospective in nature, also unclear how/why patients were selected to receive bicarbonate or not. Decision may have been subjective in nature.

7. Glaser N, Barnett P, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med 2001, 344: 264-269. • Retrospective multi-center study from 1982-1997 in 10 pediatric centers of children <= 18 yrs old admitted with DKA (n=6977) with evidence of cerebral edema or infarct (n=61). • 2 control groups (3 children in each of two control for each child with cerebral edema): a) random control- any children with admission for DKA b) matched control-DKA admission matched to study group in age, onset of diabetes, venous pH at presentation and serum glucose concentration) • Each group compared to the study group using multiple logistic regression analysis.

8. Glaser N, Barnett P, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med, 2001, 344: 264-269. • Comparing the study group to the random group showed cerebral edema significantly associated with higher serum urea nitrogen (*RR 1.7 for each 9mg/dl rise) and lower initial partial pressure of arterial CO2 (RR 3.4 for each decrease of 7.8mm Hg) • Comparing study group to matched control group also showed association with same 2 variables. Bicarbonate therapy was only therapeutic variable of significant association with increase risk of cerebral edema (RR 4.2).

9. Relative Risk vs. Odds ratio: • Relative risk= in a cohort studies, it is the ratio of disease incidence in people who are exposed divided by disease incidence in people who are free of exposure. If >1, it is a risk factor for disease, <1 means exposure was protective. • Odds ratio= in a case control study, it compares odds of exposure in individuals with disease with odds of exposure in individuals who are free of disease • The computed numbers in this study are actually odds ratio, but because of the low incidence of disease, the odds ratio approximates the relative risk and are used interchangeably.

10. Glaser N, Barnett P, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med, 2001, 344: 264-269. Multivariate Analysis of Risk Factors for Cerebral Edema comparing Study group vs. Matched Control Group: Variables Relative Risk P Values Initial BUN (per incr 9mg/dl) 1.8 (1.2-2.7) 0.008 Initial serum bicarbonate (per incr 3.6 mmol/l) 1.2 (0.5-2.6) 0.73 Initial partial press art CO2 (per decr 7.8mmHg) 2.7 (1.4-5.1) 0.002 Rate incr serum Na conc (per incr 5.8mmol/l/hr) 0.6 (0.4-0.9) 0.01 Rate decrease serum glucose (per decr 190mg/dl/hr) 0.8 (0.5-1.4) 0.41 Rate incr serum bicarb (per incr 3mmol/l/hr) 0.8 (0.5-1.1) 0.15 Administration of insulin bolus 0.8 (0.3-2.2) 0.62 Treatment with bicarbonate 4.2 (1.5-12.1) 0.008 Rate infusion IVF (per incr 5ml/kg/hr) 1.1 (0.4-3.0) 0.91 Rate infusion of Na (per incr 0.6 mmol/kg/hr) 1.2 (0.6-2.7) 0.59 Rate infusion insulin (per incr 0.04U/kg/hr) 1.2 (0.8-1.8) 0.30

11. Glaser N, Barnett P, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med, 2001, 344: 264-269. • Overall: Systematic and comprehensive retrospective analysis of cerebral edema in children. • Shows increased risk (RR 4.2) of edema associated with bicarbonate treatment. • Flaws: Unclear indications for use of bicarbonate in this study, whether patients received treatment or not was at discretion of physician.

12. HUPism • There is no evidence for the use of bicarbonate treatment in DKA even when there is severe acidosis (pH 6.9-7.1). • In pediatrics, there is also no indication for use of bicarbonate and is actually associated with increase risk of cerebral edema.