sodium bicarbonate therapy for patients with severe metabolic acedemia in icu

sodium bicarbonate therapy for patients with severe metabolic acedemia in icu , soda bicarb in icu - journal club
bicar trial

1. JOURNAL CLUB BICAR-ICU TRIAL Sodium bicarbonate therapy for patients with severe metabolic acidemia in the intensive care unit (BICAR-ICU) Dr Swapnil ApolloHospitals

2. Background Acute acidaemia is frequently observed during critical illness, reported incidence varying from14% to 42%. Persistent acidaemia carries with poor prognosis, with a mortality rate as high as 57% when the pH stays below 7⋅20. Sodium bicarbonate infusion for treatment of severe metabolic acidaemia is a possible treatment option but remains controversial. Surveys and observational studies have, however , reported that more than half of critical care physicians or nephrologists would consider sodium bicarbonate infusion for a patient with severe metabolic acidaemia whatever its cause.

3. 2017 Surviving Sepsis Campaign stated that “the effect of sodium bicarbonate administration on hemodynamics and vasopressor requirements at lower pH(than 7.15) as well as the effect on clinical outcomes at any pH level, is unknown” and that “no studies have examined the effect of bicarbonate administration on outcomes”. A bsence of high-level evidence leaves ICU clinicians uncertain whether sodium bicarbonate infusion is beneficial, ineffective, or indeed harmful to patients with severe acidemia. So this study was carried out to evaluate whether sodium bicarbonate infusion would improve these outcomes in critically ill patients.

4. Clinical Question needed to be answered: In critically ill patients with severe metabolic acidaemia (pH ≤7⋅20), does the infusion of sodium bicarbonate , compared with no infusion, to reach and maintain a targeted pH of 7⋅30 decrease primary composite outcome of mortality by day 28 or presence of at least one organ failure at day 7?

5. Study Design Multicenter , open-label, randomized, controlled, phase 3 trial N=389 ICU patients with severe acidemia – Bicarbonate (n=195) – Control (n=194) Setting : 26 ICUs in France Enrolment: May 2015- May 2017 Analysis : 1.Planned interim and 2.Intention-to-treat Primary outcome: All-cause mortality at day 28 and the presence of ≥ 1 organ failure at day 7

6. Elaboration about design: Stratified randomisation according to study site and three pre-specified factors: age with a cutoff of 65 years, presence or absence of suspected sepsis and presence or absence of Acute Kidney Injury Network (AKIN ) score of 2 or 3. Computer generated allocation sequence. No physician or nurse blinding. Rationale was sodium bicarbonate infusion influences arterial pH levels and because routine arterial blood gases must be done in critically ill patients. Deferred consent process for emergency situations

7. On the basis of a previous study, a total of 376 patients were needed for an 80% statistical power to show an absolute difference of 15% between groups in the primary outcome at a two -sided α level of 0⋅ 03 (0 ⋅02 for the interim analysis and 0⋅03 for the analysis ), assuming that the administration of sodium bicarbonate would be associated with a decrease from 45% to 30% in the primary endpoint.

8. Study Population Inclusion Criteria Adult patients age ≥18 years Admission to ICU with severe acidemia, defined as pH ≤7.20, PaCO2 ≤ 45 mm Hg, and sodium bicarbonate concentration ≤ 20 mmol/L Sequential Organ Failure Assessment (SOFA) score of 4 or more, or arterial lactate concentration of 2 mmol/L or more

9. Exclusion Criteria Respiratory acidosis Proven digestive or urinary tract loss of sodium bicarbonate (volume loss ≥ 1500 mL /day) Stage IV chronic kidney disease Ketoacidosis Sodium bicarbonate infusion within 24 hours before screening

10. Interventions Randomized to a group in an open label fashion: – Control - No bicarbonate – Bicarbonate 4.2% sodium bicarbonate intravenously with aim of goal arterial pH of ≥7.30 during 28-day ICU admission or ICU discharge; – recommended infusion at 125-250 mL in 30 min, with max 1L in 24 hours after inclusion

11. Management common to both groups Indications for renal-replacement therapy (RRT) were standardised RRT was strongly recommended in the event of hyperkalemia (>6⋅ 5mmol/L ) with electrocardiogram signs or cardiogenic pulmonary oedema with no urine output, or both At 24 h after inclusion, RRT was recommended when two of three criteria were present: – urine output less than 0⋅3 mL /kg per h for at least 24 h – arterial pH less than 7⋅20 despite resuscitation – hyperkalemia (>6⋅5 mmol/L) Each study site chose the method of RRT according to the local guidelines

12. Outcomes Comparisons are control vs. bicarbonate . Primary Outcomes Composite all-cause mortality at day 28 and the presence of ≥1 organ failure at day 7. Note that the following outcomes were not defined as primary outcomes All-cause mortality at day 28 ≥ 1 organ failing at day 7 Pre-specified subgroup analysis patients with AKIN scores of 2-3 (n=182) composite of death from any cause by day 28 and the presence of at least one organ failure at day 7 All-cause mortality at day 28 ≥ 1 organ failing at day 7

13. Secondary Outcomes Renal replacement during ICU stay Time from enrolment to initiation of renal replacement therapy (hours) Renal replacement therapy-free days during ICU stay in survivors Renal replacement therapy-free days during ICU stay

14. Primary outcome table

15. Secondary outcome table:

16. Other secondary outcome table:

17. Other secondary outcome table 2:

18. Mortality outcome:

19. Adverse Events ≥ 1 lab with serum Na >145 mmol/L 29% vs. 49% (absolute difference 19.9, 95 % CI 10.4 to 29.4; P<0.001) ≥ 1 lab with serum Ca <0.9 mmol/L 15% vs. 24% (absolute difference 9.7, 95 % CI 1.8 to 17.5; P=0.017) ≥ 1 lab with blood pH >7.45 9% vs. 16% (absolute difference 7.1, 95% CI 0.6 to 13.6; P=0.032)

20. Strengths An important clinical question is evaluated with patient focussed outcome measures Multicentre Baseline characteristics were well balanced Data for the primary outcome were available for all patients

21. Weaknesses Composite primary outcome. 24 % of the control group received bicarbonate Physicians were not blinded. The protocol suggested a range of 4⋅2% sodium bicarbonate volume (125–250 mL per infusion) in bicarbonate group rather than using a formula to calculate the base deficit and provide a tailored sodium bicarbonate infusion; therefore, we cannot extrapolate whether different ways of administration would have resulted indifferent outcomes No data was collected for mechanical ventilation settings which may have influenced the patients acid-base status

22. Conclusion In this trial, reported that in the overall population sodium bicarbonate infusion was not associated with an improvement in the primary outcome ( ie , composite criteria of organ failure at day 7 and any cause of death at day 28). In patients with acute kidney injury (with Acute Kidney Injury Network scores of 2 or 3 at enrolment), the primary outcome occurred less frequently in the bicarbonate group than in the control group. Additionally , the number of days alive and free from renal-replacement therapy was higher in the bicarbonate group than in the control group both in the overall study population and in pre defined stratum of patients with acute kidney injury.

23. Practice recommendations Anion Gap Metabolic Acidosis: The human body maintains an essentially neutral net electrical charge through the retention and excretion of ions (notably H+) and anions (notably Cl- and HCO3-). Addition or retention of other anions will increase the anion gap and cause a net negative charge, causing retention of H+ ions and leading to a metabolic acidosis. In general, administration of bicarbonate to this scenario will balance the pH but will not remove the additional anions that are the root cause of the pathologic acidosis and would presumably provide little benefit to patient outcomes. Lactic Acidosis: Previous to the BICAR-ICU trial, most available data suggests no benefit of bicarbonate. Notably two small prospective physiological studies of 14 and 10 patients, respectively, demonstrated no hemodynamic response or difference in response to catecholamines. Additional retrospective and observational studies did not result in clear conclusions. The BICAR-ICU trial did not specifically evaluate this population and thus current guidelines recommend against bicarbonate administration unless pH falls below 7.15 or bicarbonate falls below 5 mEq/L (at which point small changes in bicarbonate concentration can lead to potentially fatal changes in pH). In general, DON’T GIVE IT

24. Diabetic and Alcoholic Ketoacidosis: A prospective RCT of 21 patients in severe DKA showed no benefit of bicarbonate therapy . Limited data in pediatric DKA and adult AKA populations show similar findings . There is evidence that bicarb administration is associated with worse outcome in pediatric patients. It is feasible to give bicarbonate to patients in extremis (pH<6.9) in the adult population to theoretically prevent cardiovascular collapse. In general , DON’T GIVE IT except when pH<6.9 and with extreme caution in the pediatric patient

25. Toxic Ingestions (methanol, ethylene glycol, toluene, salicylates , etc.): In general, along with specific therapies, bicarbonate infusion is a mainstay of therapy as systemic and urinary alkalinization removes these anions through ion trapping of metabolites . GIVE IT , along with specific antidotes and possible dialysis

26. Uremic Acidosis: Uremic acidosis results from the inability of the injured kidney to excrete anions such as phosphates, sulfates , and nitrates and so removal of these substances is the mainstay of therapy. Administration of bicarbonate does not directly impact this end, and data supporting its use is limited. However, it is the current practice of many nephrologists to treat uremic acidosis with bicarbonate infusion to prevent the need for RRT. It is intuitive that bicarbonate can prevent RRT as bicarbonate therapy both corrects pH and also temporarily improves hyperkalemia (depending on the concentration of the solution). This was again demonstrated in the BICAR-ICU trial with a reduced need for RRT in the treatment group, as well as a mortality benefit in a subgroup with AKI. Though further investigation is needed, it is reasonable to give bicarbonate in this population in consultation with nephrology. GIVE IT , judiciously in severe acidemia and in consultation with a nephrologist

27. Non-Anion Gap Metabolic Acidosis: In general, this results from loss of total body bicarbonate or retention of additional chloride. It is thus, theoretically reasonable to treat this population with bicarbonate because you are directly addressing the underlying pathophysiology . Renal Losses, including Renal Tubular Acidosis (RTA): Several types exist, but the pathophysiology lies in the inability of the kidneys to re-absorb bicarbonate resulting in increased urinary losses. The mainstay of therapy is bicarbonate, both oral and IV if severe . GIVE IT

28. Gastrointestinal Losses (pancreatic fistula, diarrhea , uretal diversion, etc.): Excessive loss of bicarbonate through the GI tract causes a systemic acidosis. Removing the offending pathology (repairing the fistula) is the mainstay of therapy with bicarbonate replacement as a temporizing measure . GIVE IT, in severe cases

29. Hyperchloremic Metabolic Acidosis: Usually, as the result of iatrogenic over-administration of chloride rich fluids (normal saline). Therapy involves stopping administration of high chloride content fluids and/or switching to a more pH neutral solution such as Lactated Ringer’s or sodium bicarbonate in dextrose . GIVE IT, in severe cases

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