Sodium Bicarbonate for the Treatment of Severe Metabolic Acidosis With Moderate or Severe Acute Kidney Injury in the Critically Ill: a Randomized Clinical Trial
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 640
- 试验地点
- 1
- 主要终点
- Day 90 all-cause mortality
研究概览
简要总结
Severe metabolic acidemia in the critically ill (pH equal or less than 7.20; PaCO2 equal or less than 45mmHg and bicarbonate concentration equal or less than of 20 mmol/l) is associated with a 50% rate of day 28 mortality. Moderate to severe acute kidney injury is a frequent cause of metabolic acidemia in the critically ill. When both severe metabolic acidemia and moderate to severe acute kidney injury are observed, day 28 mortality is approximatively 55-60%. Severe acidemia has been shown to be a biomarker of severity but may also contribute by itself to outcome. Investigators recently performed a multiple center randomised clinical trial (BICARICU-1) that suggests that sodium bicarbonate infusion titrated to maintain the pH equal or more than 7.30 is associated with a higher survival rate (secondary endpoint) in patients presenting both severe metabolic acidemia and moderate to severe acute kidney injury patients. Whether sodium bicarbonate infusion may improve long term survival (Day 90, primary outcome) in these severe acute kidney injury patients is currently unknown.
详细描述
Acute acidemia is frequently observed during critical illness, its reported incidence varying from 14%to 42%. Persistent acidemia has been associated with poor prognosis, with a mortality rate as high as 57% when the pH stays below 7⋅20 more than 24h. Along with case-specific treatment, improvement of tissue perfusion and supportive measures such as mechanical ventilation and renal-replacement therapy are the cornerstones of severe metabolic acidemia management in critically ill patients. Given that an acidotic cellular environment can cause cellular dysfunction, intravenous bicarbonate administration to increase the pH may also be beneficial. In a survey performed in North America, more than two thirds of the program directors in nephrology or intensive care units (ICU) declared that they used bicarbonate for the treatment of acidemia with hyperlactatemia.Despite the frequency of its use in ICUs across the world, the effect of bicarbonate infusion for the treatment of metabolic acidemia remains controversial. Small physiological studies,along with retrospective and/or observational studies, have failed to draw clear conclusions. Reluctance to use bicarbonate may be related to the absence of cardiovascular effects in two physiological studies and to the potential side effects, principally intracellular acidification due to the accumulation of carbon dioxide and the risk of hypocalcemia. However, bicarbonate could compensate the deleterious effects of acidotic cells on cardiovascular and oxygen delivery and might delay or avoid unnecessary early renal-replacement therapy. Among the organ failure that are associated with acidemia, acute kidney injury (AKI) is often observed. Moderate to severe AKI (KDIGO 2-3) occurs in 35-40% of the critically ill patients . The mainstay of AKI management is to identify and correct causative factors while providing supportive care and treating acute complications. Clinical manifestations include encephalopathy and pericardial effusion. Other potentially dangerous complications include metabolic abnormalities of hyperkalaemia and acidosis, and fluid overload. Despite correcting causative and providing supportive care AKI-associated mortality remains high. In intensive care settings, in-hospital mortality rates of moderate to severe AKI with severe acidemia has been reported to be over 50% . Medical treatment of acidemia with AKI may involve administration of intravenous sodium bicarbonate. Interestingly, a recent literature review performed by the Cochrane group showed that no prospective randomized study has ever evaluated the impact intravenous sodium bicarbonate as a medical treatment to correct severe acidemia during AKI .
Investigators conducted a prospective multicenter, randomized controlled trial to evaluate whether bicarbonate infusion would improve outcome in critically ill patients with severe metabolic acidemia (defined as an arterial pH equal or less than 7.20; PaCO2 equal or less than 45mmHg and bicarbonate concentration equal or less than of 20 mmol/l). Specifically, investigators hypothesized that, compared with no bicarbonate, early bicarbonate infusion would result in an improvement in the primary outcome (ie, composite criteria of organ failure at day 7 and any cause of death at day 28).
The findings of the BICARICU-1 trial suggest that in the overall non-selected patients, sodium bicarbonate infusion is not associated with clinical outcome (no difference in the primary outcome and the Kaplan-Meier method estimate of the probability of survival at day 28 between the control group and bicarbonate group: (46% [95% CI 40-54] vs 55% [49-63]; p=0⋅09)). In the overall non-selected patients, the absolute risk reduction of the composite outcome was 5.5%, with the possibility of being as large as 19.4% (the lower limit of the confidence interval), and concerning the hard endpoint mortality at 28 days, the absolute risk reduction was 9% (NNT=12), with the possibility of being as large as 19.4% (NNT=5) (p=0.07). Moreover, in multivariate analysis, after adjusting for important clinical covariates, the effect of sodium bicarbonate on mortality at 28 days became statistically significant (HR=0.727, 95% CI 0.54-0.98, p=0.035).
In the a-priori defined clinical stratum of patients with moderate to severe acute kidney injury (Acute Kidney Injury Network scores of 2 or 3 at enrolment), sodium bicarbonate infusion was 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) and a reduced rate of mortality from enrolment to day 28 between the control group and bicarbonate group : 63% [95% CI 52-72] vs 46% [35-55]; p=0⋅0283. 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 the a-priori defined stratum of patients with moderate to severe acute kidney injury.
Knowledge gap and research hypothesis
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged from 18 years old
- •Admitted in the ICU where the BICARICU-2 trial takes place
- •Within 6h before enrolment, the patient MUST present on the same arterial blood gas (the last available before enrollment) the 3 following criteria:
- •pH ≤ 7.20 ; Bicarbonatemia ≤ 20 mmol/l ; AND PaCO2 ≤ 45mmHg ;
- •Moderate to severe acute kidney injury ("Kidney Disease Improving Global Outcome", KDIGO group of 2 or 3)
- •Within 48h of ICU admission, a total SOFA ≥ 4 OR an arterial lactate concentration ≥ 2 mmol/l
- •Signed informed consent form. According to the French law, considering the severity of the illness, the fact that most of these patients would be unable to consent (sedation or potential delirium) and that their proxies might not be contactable at the time of inclusion, a deferred consent process for emergency situations will be enabled. When deferred consent will be used, written permission to pursue the research will be obtained from the patient or proxy as soon as possible. If this consent is not obtained, the patient's data will not be used and they will be withdrawn from the trial.
- •Subjects must be covered by public health insurance
排除标准
- •Pure respiratory acidosis (defined by pH 7.20, PaCO2 >50 mmHg, bicarbonatemia equal or greater than (PaCO2-40)/10 + 24), digestive or urinary tract proven loss of fluid (equal or greater than 1500ml/24h) with concomitant loss of sodium bicarbonate, chronic kidney insufficiency (creatinine clearance ≤ 10ml/min), proven tubular acidosis, ketoacidosis, exogenous acids poisoning (aspirin, methanol, ), PaCO2 > 45 mmHg and spontaneous breathing, sodium bicarbonate infusion or renal replacement therapy within 24h prior to screening prior to screening or imminent in the next 6h.
- •Pregnant or breast feeding patient
- •Patient who is in a dependency or employment with the sponsor or the investigator
- •Patient who was enrolled in another study and who is in the exclusion period for any enrolment in the present study
- •Life expectancy less than 48h
- •Consent refusal from the patient or his/her next of kin and the impossibility to enrol using the emergency procedure
- •Patients protected by law (Art.L 1121-5, 1121-6, 1121-8 du Code de la santé publique)
- •Absence of a French Health Care Insurance coverage
研究组 & 干预措施
Sodium bicarbonate group
Patients randomly assigned to bicarbonate group will receive intravenous 4.2% sodium bicarbonate titrated from 125ml to 250ml in 30min at physician's discretion to target a pH equal or above 7.30. Bicarbonate infusion will be repeated up to 1000ml per 24h. Arterial blood gases will be repeated from 3 to 6 times during the first 24h at physician's discretion
干预措施: Sodium bicarbonate infusion (Drug)
结局指标
主要结局
Day 90 all-cause mortality
时间窗: Day 90
Day 90 all cause mortality
次要结局
- Day 180 all-cause mortality(Day 180)
- Quality of Life of participant(up to Day 180)
- Functional autonomy of patient(up to Day 180)
- Organ Failure(up to 7 days after enrolment)
- Overall fluid balance and solutions intake(Day 2)
- Hospital acquired infections(ICU discharge or Day 28)
- Electrolytes adverse events during the ICU stay(ICU discharge or Day 28)
- Organ Support Day 90 alive free days(Day 90)
- ICU length of stay(up to Day 90)
- Day 28 all-cause mortality(Day 28)
- Hospital length of stay(up to day 180)