Intensive Care Med DOI 10.1007/s00134-015-3649-9
Alexandre Braga Libo´rio Danilo Teixeira Noritomi Tacyano Tavares Leite Candice Torres de Melo Bezerra Evandro Rodrigues de Faria John A. Kellum
Received: 28 October 2014 Accepted: 8 January 2015
ORIGINAL
Increased serum bicarbonate in critically ill patients: a retrospective analysis
E. R. de Faria Pronefron Section, Fresenius Medical Group, Fortaleza, CE, Brazil
Ó Springer-Verlag Berlin Heidelberg and ESICM 2015
J. A. Kellum Department of Critical Care Medicine, The Center for Critical Care Nephology, Take-home message: In critically ill patients, a high serum bicarbonate level and University of Pittsburgh School its duration are associated with a longer of Medicine, Pittsburgh, PA, USA duration of mechanical ventilation, longer ICU length of stay and higher hospital mortality. Abstract Purpose: Although Electronic supplementary material The online version of this article (doi:10.1007/s00134-015-3649-9) contains supplementary material, which is available to authorized users.
A. B. Libo´rio ()) T. T. Leite C. T. de Melo Bezerra Department of Clinical Medicine, Universidade Federal do Ceara´, Av. Abolic¸a˜o, 4043 Ap 1203, Ed. Jangada, Fortaleza, CE CEP 60165-082, Brazil e-mail: [email protected] Tel.: 55 8599987995 D. T. Noritomi Unidade de Terapia Intensiva, Hospital Paulistano, Sa˜o Paulo, SP, Brazil
metabolic alkalosis is a common occurrence, no study has evaluated its prevalence, associated factors or outcomes in critically ill patients. Methods: This is a retrospective study from the Multiparameter Intelligent Monitoring in Intensive Care II database. From 23,529 adult patient records, 18,982 patients met the inclusion criteria. Results: Serum bicarbonate levels demonstrated a U-shaped association with mortality with knots at 25 and 30 mEq/l. Of the total included patients, 5,565 (29.3 %) had at least one serum bicarbonate level measurement [30 mEq/l. The majority were exposed to multiple factors that are classically associated with metabolic
Introduction Metabolic alkalosis can be accompanied by several physiological effects, including hemodynamic consequences as a result of direct effects or by means of ionized calcium concentration reduction, which causes potential
alkalosis (mainly diuretic use, hypernatremia, hypokalemia and high gastric output). Patients with increased serum bicarbonate exhibited increased ICU LOS, more days on mechanical ventilation and higher hospital mortality. After multivariate adjustment, each 5-mEq/l increment in the serum bicarbonate level above 30 mEq/l was associated with an odds ratio of 1.21 for hospital mortality. The association between increased serum bicarbonate levels and mortality occurs independently of its possible etiologies. Conclusion: An increased serum bicarbonate level is common in critically ill patients; this can be attributed to multiple factors in the majority of cases, and its presence and duration negatively influence patient outcomes. Keywords Metabolic alkalosis Mortality Critically ill care Acid-base disorders Electronic database Epidemiology
cardiac arrhythmias and respiratory suppression [1]; hypokalemia, which causes muscle weakness [2]; and difficult mechanical ventilation weaning [3, 4]. Considering the main etiologies [dehydration, diuretic use, renal replacement therapy (RRT), hypokalemia and gastric suctioning], critically ill patients are especially prone to
developing metabolic alkalosis. While metabolic acidosis has long been associated with adverse outcomes and has been a matter of several laboratory and clinical studies [5, 6], relatively little attention has been devoted to metabolic alkalosis. The impact of alkalosis on mortality in general patients has only been evaluated in one unadjusted study of critically and non-critically ill patients, in which the majority of patients had respiratory alkalosis [7]. Given that metabolic alkalosis represents up to half of all acidbase disturbances in hospitalized patients [8] and is often caused by medical interventions, it is concerning that no large studies have been performed in critically ill patients evaluating the prevalence, etiology and clinical consequences of increased serum bicarbonate levels. In the present report, we reported the prevalence rate of increased serum bicarbonate levels and the associated factors during ICU stays. Moreover, we hypothesized that increased serum bicarbonate is associated with the main outcomes of critically ill patients.
Definitions and outcomes Acute kidney injury (AKI) was defined according to the creatinine-based Kidney Disease Improving Global Outcome (KDIGO) criteria [10]. Briefly, only serum creatinine levels were used to classify AKI stage. Given that the MIMIC-II database does not contain previous serum creatinine measurements, the lowest value during the hospital stay was used to determine baseline renal function. We calculated the strong ion difference (SID = Na? ? K? ? Ca2? ? Mg2? - Cl-; all in mEq/l) with electrolytes measured on the same day maximum serum bicarbonate levels were achieved. Recorded outcomes included the number of days on mechanical ventilation per 1,000 patient days of ICU stay, hospital LOS, hospital mortality and post-discharge mortality. Post-discharge mortality was assessed through data from the Social Security Death Index (SSDI) during a 9-month period after hospital discharge. The SSDI is not perfect and may contain incorrect and/or missing data. Only the first ICU admission was considered from each patient.
Methods Study design and setting
Blood gas measurement
The multiparameter intelligent monitoring in intensive care II (MIMIC-II) project is maintained by the Laboratory for Computational Physiology at the Massachusetts Institute of Technology (MIT) and contains de-identified data on patients hospitalized at an ICU at Beth Israel Deaconess Medical Center from 2001 to 2008 [9]. The database is freely available, so any researcher who accepts the data-use agreement and has attended ‘‘protecting human subjects training’’ can apply for permission to access the data. The Institutional Review Boards of the Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center approved the use of the database and granted a waiver of informed consent. A description of MIMIC-II database is detailed in the Supplemental Appendix.
Venous and arterial blood samples were considered, and in patients with abnormal CO2 partial pressure values, the standard serum bicarbonate level was calculated. Each patient had serum bicarbonate levels measured at admission (within 36 h of admission to the ICU). Additionally, patients were classified according to the maximum serum bicarbonate level measured during their ICU stay. Because our objective was to evaluate only the metabolic component of alkalosis, we preferred using the standard bicarbonate level when the pCO2 level was out of the normal range. By using this approach, we could guarantee that variations in pH were due to pCO2 variations only in the normal range. To verify the association between the duration of increased serum bicarbonate levels with the outcome in each subject, we calculated the proportion of days with a high serum bicarbonate level as the number of days with serum bicarbonate \30 mEq/l.
Participants We included all adult patients with an ICU length of stay (LOS) [24 h who had at least one serum bicarbonate measurement within the first 36 h after ICU admission. Patients with serum bicarbonate [28 mEq/l associated with acidemia (serum pH\7.35) and CO2 partial pressure [45 mmHg were considered to have pure respiratory acidosis and were excluded from the study. Additionally, patients with extremely high serum bicarbonate levels ([70 mEq/l) were excluded because a measurement/ archival error was likely.
Statistical analysis First, we used descriptive statistics, including the mean with standard deviation, median and interquartile range or frequencies, to describe the population as appropriate. Next, we investigated the association between the maximum serum bicarbonate level as a continuous variable and in-hospital mortality. All tests were two sided, and p \ 0.05 was considered significant.
Based on the initial exploration of maximum serum bicarbonate levels for hospital mortality, which revealed a U-shaped association, we assessed a cubic spline regression model with serum bicarbonate as a continuous variable and identified two knots at 24 and 31 mEq/l. The values were then categorized as \25 or [30 versus 25–30 mEq/l. This same approach was made using SBE with one knot at -1 and 5 mEq/l. After testing for collinearity, multiple covariate analyses were applied. We adjusted for age, gender, simplified acute physiology score (SAPS-I), sequential organ failure assessment (SOFA), main comorbidities, type of admission (clinical or surgical), diuretic use, either previous to or during the ICU stay, alkali administration, hypo-/hyperkalemia, hypo-/hypernatremia, RRT and gastric output, minimum serum bicarbonate level, partial CO2 pressure [45 mmHg, AKI severity, and mechanical ventilation during ICU stay. For interpretation, we provided odds ratio (OR) values for each 5-mEq/l increase or decrease. Because ICU discharge and mortality represent competing risks, we used the cumulative incidence function to analyze time to hospital discharge and mortality over 28 days. Statistical analyses were performed using SPSS 19.0 for Windows and R-project. A complete statistical analysis description is shown in the supplementary material.
Results Population The MIMIC-II database contains the records of 32,425 patients, of which 24,581 were adults aged C15 years at the time of admission. In total, 5,403 patients were excluded because their ICU LOS was less than 24 h, and another 68 patients were excluded because of insufficient data on the serum bicarbonate levels. In addition, 124 patients with serum bicarbonate levels greater than 28 mEq/l were considered to have pure respiratory acidosis, and 4 other patients were excluded because they had serum bicarbonate levels [70 mEq/l (Fig. 1). The main data regarding demographics, illness severity, acid-base status, and main outcomes of the excluded patients are displayed in the supplementary Table 1. Therefore, the final analytic cohort contained 18,982 patients (80 % of all adult patients admitted to the ICU during the period). The mean age upon admission was 63.8 ± 17.5 years, and 8,159 were females (43.0 %). The mean SOFA and SAPS-I scores on admission were 5.9 ± 4.0 and 13.5 ± 5.9, respectively. The overall ICU and in-hospital mortality were 7.7 and 11.5 %, respectively (Table 1).
Admission age
Alexandre Braga Libo´rio Danilo Teixeira Noritomi Tacyano Tavares Leite Candice Torres de Melo Bezerra Evandro Rodrigues de Faria John A. Kellum
Received: 28 October 2014 Accepted: 8 January 2015
ORIGINAL
Increased serum bicarbonate in critically ill patients: a retrospective analysis
E. R. de Faria Pronefron Section, Fresenius Medical Group, Fortaleza, CE, Brazil
Ó Springer-Verlag Berlin Heidelberg and ESICM 2015
J. A. Kellum Department of Critical Care Medicine, The Center for Critical Care Nephology, Take-home message: In critically ill patients, a high serum bicarbonate level and University of Pittsburgh School its duration are associated with a longer of Medicine, Pittsburgh, PA, USA duration of mechanical ventilation, longer ICU length of stay and higher hospital mortality. Abstract Purpose: Although Electronic supplementary material The online version of this article (doi:10.1007/s00134-015-3649-9) contains supplementary material, which is available to authorized users.
A. B. Libo´rio ()) T. T. Leite C. T. de Melo Bezerra Department of Clinical Medicine, Universidade Federal do Ceara´, Av. Abolic¸a˜o, 4043 Ap 1203, Ed. Jangada, Fortaleza, CE CEP 60165-082, Brazil e-mail: [email protected] Tel.: 55 8599987995 D. T. Noritomi Unidade de Terapia Intensiva, Hospital Paulistano, Sa˜o Paulo, SP, Brazil
metabolic alkalosis is a common occurrence, no study has evaluated its prevalence, associated factors or outcomes in critically ill patients. Methods: This is a retrospective study from the Multiparameter Intelligent Monitoring in Intensive Care II database. From 23,529 adult patient records, 18,982 patients met the inclusion criteria. Results: Serum bicarbonate levels demonstrated a U-shaped association with mortality with knots at 25 and 30 mEq/l. Of the total included patients, 5,565 (29.3 %) had at least one serum bicarbonate level measurement [30 mEq/l. The majority were exposed to multiple factors that are classically associated with metabolic
Introduction Metabolic alkalosis can be accompanied by several physiological effects, including hemodynamic consequences as a result of direct effects or by means of ionized calcium concentration reduction, which causes potential
alkalosis (mainly diuretic use, hypernatremia, hypokalemia and high gastric output). Patients with increased serum bicarbonate exhibited increased ICU LOS, more days on mechanical ventilation and higher hospital mortality. After multivariate adjustment, each 5-mEq/l increment in the serum bicarbonate level above 30 mEq/l was associated with an odds ratio of 1.21 for hospital mortality. The association between increased serum bicarbonate levels and mortality occurs independently of its possible etiologies. Conclusion: An increased serum bicarbonate level is common in critically ill patients; this can be attributed to multiple factors in the majority of cases, and its presence and duration negatively influence patient outcomes. Keywords Metabolic alkalosis Mortality Critically ill care Acid-base disorders Electronic database Epidemiology
cardiac arrhythmias and respiratory suppression [1]; hypokalemia, which causes muscle weakness [2]; and difficult mechanical ventilation weaning [3, 4]. Considering the main etiologies [dehydration, diuretic use, renal replacement therapy (RRT), hypokalemia and gastric suctioning], critically ill patients are especially prone to
developing metabolic alkalosis. While metabolic acidosis has long been associated with adverse outcomes and has been a matter of several laboratory and clinical studies [5, 6], relatively little attention has been devoted to metabolic alkalosis. The impact of alkalosis on mortality in general patients has only been evaluated in one unadjusted study of critically and non-critically ill patients, in which the majority of patients had respiratory alkalosis [7]. Given that metabolic alkalosis represents up to half of all acidbase disturbances in hospitalized patients [8] and is often caused by medical interventions, it is concerning that no large studies have been performed in critically ill patients evaluating the prevalence, etiology and clinical consequences of increased serum bicarbonate levels. In the present report, we reported the prevalence rate of increased serum bicarbonate levels and the associated factors during ICU stays. Moreover, we hypothesized that increased serum bicarbonate is associated with the main outcomes of critically ill patients.
Definitions and outcomes Acute kidney injury (AKI) was defined according to the creatinine-based Kidney Disease Improving Global Outcome (KDIGO) criteria [10]. Briefly, only serum creatinine levels were used to classify AKI stage. Given that the MIMIC-II database does not contain previous serum creatinine measurements, the lowest value during the hospital stay was used to determine baseline renal function. We calculated the strong ion difference (SID = Na? ? K? ? Ca2? ? Mg2? - Cl-; all in mEq/l) with electrolytes measured on the same day maximum serum bicarbonate levels were achieved. Recorded outcomes included the number of days on mechanical ventilation per 1,000 patient days of ICU stay, hospital LOS, hospital mortality and post-discharge mortality. Post-discharge mortality was assessed through data from the Social Security Death Index (SSDI) during a 9-month period after hospital discharge. The SSDI is not perfect and may contain incorrect and/or missing data. Only the first ICU admission was considered from each patient.
Methods Study design and setting
Blood gas measurement
The multiparameter intelligent monitoring in intensive care II (MIMIC-II) project is maintained by the Laboratory for Computational Physiology at the Massachusetts Institute of Technology (MIT) and contains de-identified data on patients hospitalized at an ICU at Beth Israel Deaconess Medical Center from 2001 to 2008 [9]. The database is freely available, so any researcher who accepts the data-use agreement and has attended ‘‘protecting human subjects training’’ can apply for permission to access the data. The Institutional Review Boards of the Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center approved the use of the database and granted a waiver of informed consent. A description of MIMIC-II database is detailed in the Supplemental Appendix.
Venous and arterial blood samples were considered, and in patients with abnormal CO2 partial pressure values, the standard serum bicarbonate level was calculated. Each patient had serum bicarbonate levels measured at admission (within 36 h of admission to the ICU). Additionally, patients were classified according to the maximum serum bicarbonate level measured during their ICU stay. Because our objective was to evaluate only the metabolic component of alkalosis, we preferred using the standard bicarbonate level when the pCO2 level was out of the normal range. By using this approach, we could guarantee that variations in pH were due to pCO2 variations only in the normal range. To verify the association between the duration of increased serum bicarbonate levels with the outcome in each subject, we calculated the proportion of days with a high serum bicarbonate level as the number of days with serum bicarbonate \30 mEq/l.
Participants We included all adult patients with an ICU length of stay (LOS) [24 h who had at least one serum bicarbonate measurement within the first 36 h after ICU admission. Patients with serum bicarbonate [28 mEq/l associated with acidemia (serum pH\7.35) and CO2 partial pressure [45 mmHg were considered to have pure respiratory acidosis and were excluded from the study. Additionally, patients with extremely high serum bicarbonate levels ([70 mEq/l) were excluded because a measurement/ archival error was likely.
Statistical analysis First, we used descriptive statistics, including the mean with standard deviation, median and interquartile range or frequencies, to describe the population as appropriate. Next, we investigated the association between the maximum serum bicarbonate level as a continuous variable and in-hospital mortality. All tests were two sided, and p \ 0.05 was considered significant.
Based on the initial exploration of maximum serum bicarbonate levels for hospital mortality, which revealed a U-shaped association, we assessed a cubic spline regression model with serum bicarbonate as a continuous variable and identified two knots at 24 and 31 mEq/l. The values were then categorized as \25 or [30 versus 25–30 mEq/l. This same approach was made using SBE with one knot at -1 and 5 mEq/l. After testing for collinearity, multiple covariate analyses were applied. We adjusted for age, gender, simplified acute physiology score (SAPS-I), sequential organ failure assessment (SOFA), main comorbidities, type of admission (clinical or surgical), diuretic use, either previous to or during the ICU stay, alkali administration, hypo-/hyperkalemia, hypo-/hypernatremia, RRT and gastric output, minimum serum bicarbonate level, partial CO2 pressure [45 mmHg, AKI severity, and mechanical ventilation during ICU stay. For interpretation, we provided odds ratio (OR) values for each 5-mEq/l increase or decrease. Because ICU discharge and mortality represent competing risks, we used the cumulative incidence function to analyze time to hospital discharge and mortality over 28 days. Statistical analyses were performed using SPSS 19.0 for Windows and R-project. A complete statistical analysis description is shown in the supplementary material.
Results Population The MIMIC-II database contains the records of 32,425 patients, of which 24,581 were adults aged C15 years at the time of admission. In total, 5,403 patients were excluded because their ICU LOS was less than 24 h, and another 68 patients were excluded because of insufficient data on the serum bicarbonate levels. In addition, 124 patients with serum bicarbonate levels greater than 28 mEq/l were considered to have pure respiratory acidosis, and 4 other patients were excluded because they had serum bicarbonate levels [70 mEq/l (Fig. 1). The main data regarding demographics, illness severity, acid-base status, and main outcomes of the excluded patients are displayed in the supplementary Table 1. Therefore, the final analytic cohort contained 18,982 patients (80 % of all adult patients admitted to the ICU during the period). The mean age upon admission was 63.8 ± 17.5 years, and 8,159 were females (43.0 %). The mean SOFA and SAPS-I scores on admission were 5.9 ± 4.0 and 13.5 ± 5.9, respectively. The overall ICU and in-hospital mortality were 7.7 and 11.5 %, respectively (Table 1).
Admission age
