Jaber S; Paugam C, Futier E et al.
Aim of Study
To evaluate whether sodium bicarbonate infusion would improve clinical outcome in critically ill patients with severe metabolic acidosis
Design and Location
Multicentre, open label randomised controlled phase 3 trial.
26 ICUs in France. Inclusion criteria
- Adult patients (18 or over)
- Admitted within 48 hours to ICU with severe acidaemia
- pH 7.20, pCO2<4.5mmHg, bicarbonate <20mmol/L
- SOFA score 4 or more
- Arterial lactate 2 mmol/L or more
Written informed consent from patient/relative; if patients are unable to consent and proxies are not contactable at time of inclusion, deferred consent process was used. Written permission to pursue the research was obtained soon as possible; if consent was not obtained, data not used. Independent safety committee.
One to one randomisation to hypertonic 4.2% sodium bicarbonate, infused with the aim of achieving arterial pH of 7.3 or more.
All cause mortality by 28 days after randomisation and presence of at least one organ failure at 7 days after randomisation.
Use, duration and number of days alive free of live support interventions (renal replacement therapy, mechanical ventilation, vasopressors); SOFA score; total fluid intake between enrolment and day 2 after randomisation, adverse events of electrolytes, ICU acquired infections, length of stay in ICU.
Power calculation made; assuming sodium bicarbonate would be associated with decrease from 45% to 30% in primary endpoint, and less than 8% would withdraw from the study, total of 400 patients would need to be randomised. Intention to treat analysis. No imputation for missing values.
Baseline characteristics compared; unadjusted chi-squared test.
Multiple logistic regression for primary outcome
Survival: Kaplan-Meier and Cox proportional hazards
Covariates in the models used dichotomised according to the median; included in the multivariable analysis if p<0.15 in univariate analysis.
Characteristics of patients were well balanced between the two groups.
- Sepsis present in 61%
- Acute kidney injury in 47%
- Invasive mechanical ventilation in 83%
- Vasopressors in 80%.
88% of patients adhered to the planned treatment in their randomisation group.
Sodium bicarbonate infused in 24% of control patients after randomisation.
50% of controls and 60% of bicarbonate group patients achieved a targeted pH of 7.30 was reached and maintained for at least 36 hours from enrolment.
The primary outcome occurred in 71% in the control group and 66% in the intervention group.
Probability of survival at day 28 between both groups was not significant
- 46% in control group (40-54)
- 55% in bicarbonate group (49-63)
- P= 0.09
In multivariable (around 30 variables) analysis, sodium bicarbonate treatment was significantly associated with fewer deaths
In those with AKIN score 2-3 acute kidney injury, the primary outcome occurred in 82% of patients in control group and 70% of patients in bicarbonate group.
Univariate and multivariable analysis showed that bicarbonate treatment was significantly associated with better outcome;
- Crude hazard ratio 0.65 (0.44-0.97)
- Adjusted hazard ratio 0.59 (0.39-0.90)
Renal replacement therapy was started earlier in the control group
Number of days alive free from renal-replacement therapy was also lower in the control group.
Hyperkalaemia and acidaemia were main reasons for initiation in control group; serum creatinine and urea were the main reasons in the bicarbonate group.
Number of days free from mechanical ventilation not different between two groups.
Number of days free from vasopressor was not different between two groups.
Length of ICU stay did not differ significantly between treatment groups for the overall population.
Metabolic alkalosis, hypernatraemia and hypocalcaemia were observed more frequently in the bicarbonate group but with no life-threatening complications reported.
In critically ill patients with severe metabolic acidaemia, the infusion of sodium bicarbonate, compared with no infusion to reach and maintain a targeted pH of 7.30 did not result in reduced mortality by day 28 or presence of at least one organ failure at day 7.
However, sodium bicarbonate infusions seemed to decrease the need for renal replacement therapy during ICU stay, and resulted in fewer deaths by day 28 in those with acute kidney injury at trial enrolment.
Stated Limitations from the Study
- No specific control solution was recommended in the control group; there is no fluid without an effect on acid-base balance
- Physicians caring for the patients in ICU could not be blinded due to regular monitoring of ABGs in routine care
- 2% sodium bicarbonate given to the bicarbonate group rather using a formula to calculate the base deficit and provide a tailored sodium bicarbonate
- Mechanical ventilation settings not collected
- Heterogenous causes of acidaemia, even if sepsis/haemorrhage were more common.
Discussion from Journal Club Meeting (?Change of Practice)
- A thoughtfully designed, pragmatic trial
- Large cohort of patients that were well balanced
- Intention to treat analysis
- Outcomes of patients with advanced AKI were analysed seperately
- Fast recruitment of patients with a robust consent system.
- The first large randomised controlled trial in humans on this treatment
- 24% of the patients in the control group received sodium bicarbonate infusion after randomisation
- 52% of patients in the control group were dialysed and therefore may have received sodium bicarbonate treatment.
- Is the target blood pH too high? 16% of patients in the bicarbonate group had at least one blood pH>7.45 after enrolment
- Is the study adequately powered?
- The absolute risk reduction of the primary outcome was 5.5%, but possibly up to 15.2% (the lower limit of the confidence interval)
- The absolute risk reduction in mortality was 9% (number needed to treat 12), possibly up to 19.4% (number needed to treat 5)
- Why is it that after multivariable analysis the effect of sodium bicarbonate on mortality at 28 days becomes statistically significant when it was not on univariable analysis?
- Was dialysis really necessary in some of these patients?
- The difference in sodium and chlorine concentrations is important in determining pH and bicarbonate concentration (Peter Stewart, 1978).
- When sodium bicarbonate is given, the strong sodium ion remains free, and carbon dioxide and bicarbonate are controlled by ventilation.
- Use of sodium bicarbonate would have spared usual saline use and reduced chlorine intake
- The above would widen the difference in sodium and chlorine concentrations, thus worsening pH à indications for dialysis!
Things that perhaps could have been done differently
- Composite primary outcome has important limitations; ie organ dysfunction, the mechanism of which could have been completely unrelated to the death.
- May have been better to choose death/new receipt of renal replacement therapy or persistent renal dysfunction (KDIGO guidelines) as a composite primary outcome.
- pH dependent decrease in the concentration of ionised calcium
- Intracellular acidification due to tissue accumulation of carbon dioxide.
- Therefore, central venous blood gases to assess tissue acid-base status may have been useful to look for intracellular acidification.
This study may perhaps persuade those who give sodium bicarbonate for metabolic acidosis to reconsider. However, it is usually given as a ‘Hail Mary’ for patients with grave prognosis. This is the first trial – further trials in different populations followed by meta-analysis will help identify whether sodium bicarbonate is truly helpful.
Summary by Dr D Pan. Journal Club Meeting 02 May 2019.