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Differences in acid-base behavior between intensive care unit survivors and nonsurvivors using both a physicochemical and a standard base excess approach: A prospective, observational study
Journal of Critical Care (2009) 24, 477–483
Respiration/Ventilation and Tracheostomy
Differences in acid-base behavior between intensive care unit survivors and nonsurvivors using both a physicochemical and a standard base excess approach: A prospective, observational study☆ Alexandre Toledo Maciel MD ⁎, Marcelo Park MD, PhD Intensive Care Unit, Department of Medical Emergencies, Hospital das Clínicas, São Paulo, Brazil
Keywords: Acid-Base; Critically ill patients; Physicochemical approach; Standard base excess; Mortality
Abstract Purpose: This study aimed to test the hypothesis that intensive care unit survivors and nonsurvivors differ with regard to type and severity of acid-base disorders. Materials and Methods: Prospective, observational, cohort study of 107 consecutive patients admitted in a 7-bed intensive care unit during a 6-month period that stayed at least 4 days. All acid-base variables for the first 3 days and the day of discharge were analyzed. Results: Survivors had significant metabolic acidosis upon admission, which was due to hyperlactatemia, an excess of unmeasured anions, and principally, hyperchloremia. A progressive decrease in these anions in the presence of constant hypoalbuminemia led to normal standard base excess at discharge. Nonsurvivors had greater metabolic acidosis upon admission with acidifying variables in similar proportions to that of the survivors. On the day of death, nonsurvivors had a similar degree of metabolic acidosis but a different proportion of the anions (less chloride and more lactate) compared with the day of admission. Unmeasured anions were greater in nonsurvivors both on the day of admission and on the day of death. Conclusions: Intensive care unit survivors and nonsurvivors differed in the severity of metabolic acidosis; however, the proportion of the different anions causing the acidosis on admission was similar between these 2 groups. © 2009 Elsevier Inc. All rights reserved.
1. Introduction Acid-Base disturbances are frequently found in critically ill patients. The severity of these disturbances upon intensive care unit (ICU) admission [1] and also their behavior during ☆ The authors declare that they have no competing interests. ⁎ Corresponding author. E-mail address: [email protected] (A.T. Maciel).
0883-9441/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2009.01.005
ICU stay [2] seem to correlate with prognosis, especially for metabolic acidosis. Standard base excess (SBE) is usually used to quantify the degree of metabolic impairment, but it does not alone reveal the origin of the problem. More recently, the physicochemical approach has improved our understanding of the different mechanisms responsible for the generation of metabolic disorders [3] and has also helped as a prognostic marker based on the main acid in excess in the circulation (chloride, lactate, or unmeasured anions) [4].
478 Gunnerson et al [4] found that lactic acidosis has the worst prognosis and that hyperchloremic acidosis has a better prognosis, similar to patients with no metabolic acidosis. The aim of this observational study was to characterize the progression of the different components of acid-base status during the first 3 days after ICU admission and at the day of discharge or death, using both a physicochemical and a SBE approach. Our hypothesis was that survivors have less metabolic acidosis upon admission, which is corrected during their stay in the ICU; nonsurvivors, however, tend to have more severe metabolic acidosis upon admission and die with a progressive deterioration of their metabolic markers. We also hypothesized that the proportion of the different anions would differ between survivors and nonsurvivors; those who die would have a greater amount of lactate and unmeasured anions, whereas in those who survived, the anion would be predominantly chloride.
2. Materials and methods The study was approved by the local ethics committee. Because all data used here were collected in the process of routine examinations performed for all patients that are admitted to the ICU, the requirement for informed written consent was waived. It is routine in the 7-bed medical ICU to collect a list of laboratory tests from all patients upon admission and then daily around midnight. This list includes an arterial blood gas determination with simultaneous arterial lactate, Na+, K+, Ca2+, Mg2+, Cl−, phosphate, and albumin measurements. All consecutive patients admitted from July 2005 to January 2006 who stayed in the ICU for at least 4 days were included. Acid-Base variables such as pH, pCO2, bicarbonate, SBE, apparent strong ion difference (SIDa), effective strong ion difference (SIDe), and strong ion gap (SIG) were recorded upon admission (day 1), for the next 2 days (days 2 and 3), and at the day of discharge or death. In addition, the SBE was partitioned to clarify the contribution of each one of its components to the SBE evolution (see below). Age, sex, and the APACHE II score were also recorded for all patients, as were ICU and in-hospital mortality. No colloids were used in the management of these patients.
2.1. Laboratory techniques and measurements All samples were analyzed in the central laboratory of the Institution. Na+, K+, Ca2+, and Cl− were measured using the direct ion-selective electrode technique; Mg2+, using a colorimetric technique; and phosphate, by an ultraviolet technique. Albumin was measured with a bromocresol dye colorimetric technique. Arterial blood gas was analyzed, and lactate was measured on the OMNI analyzer (Roche Diagnostics System, F. Hoffmann-La Roche Ltd, Basel, Switzerland). The SBE was calculated from the measured data using the Van Slyke equation (see below) [5].
A.T. Maciel, M. Park
2.2. Quantitative physicochemical analysis The principles of the physicochemical approach to acidbase disturbances proposed by Stewart [6] and then modified by Figge et al [7] have been recently reviewed by other authors [3,8]. Standard formulas used in this study were the following: 1. SBE (Van Slyke equation) (mEq/L) = 0.9287 × (HCO3− (mmol/l) − 24.4 + 14.83 × [pH − 7.4]) 2. SIDa (mEq/L) = Na+ (mEq/L) + K+ (mEq/L) + Ca2+ (mEq/L) + Mg2+ (mEq/L) − [Cl− (mEq/L) + lactate− (mEq/L)] 3. SIDe (mEq/L) = 2.46 × 10−8 × PCO2 / 10−pH + [albumin (g/dL)] × (0.123 × pH − 0.631) + [phosphate (mg/dL) / 3 × (pH − 0.469)] 4. SIG (mEq/L) = SIDa − SIDe To work simultaneously with both the SBE and the physicochemical approach, we partitioned the SBE into 5 distinct components [9,10]: SBE due to sodium, SBE due to chloride, SBE due to albumin, SBE due to unmeasured anions (SIG), and SBE due to lactate. Each component was derived from the following equations (all in mEq/L): • SBE due to sodium (SBENa)
0.3 × ([Na+ (patient)] − 140) (140 mEq/L = normal sodium in our lab)
• SBE due to chloride (SBECl)
102 − [Clcorrected (patient)] (102 mEq/L = normal chloride in our lab) Clcorrected (patient) = Cl (patient) × (140/ Na (patient))
Table 1
General characteristics of the patients (N = 107) ICU survivors ICU nonsurvivors (n = 83) (n = 24)
Sex (male) Age (y), mean ± SD Apache II score, mean ± SD Main diagnosis Severe sepsis/Septic shock Respiratory failure Postoperative Trauma Neurologic syndromes Others COPD Chronic renal failure Mechanical ventilation a Renal replacement therapy a Classic intermittent Sustained low efficiency Continuous Peritoneal In-hospital mortality (%)
42 50 ± 19 13 ± 7
16 56 ± 17 20 ± 8
25 24 12 7 6 9 4 12 45 14 12 2 4 1 20.5
14 3 3 0 1 3 0 5 21 14 5 0 12 0 –
Values are expressed as numbers unless otherwise indicated. a At any time during ICU stay.
Acid base behavior of ICU survivors and non-survivors • SBE due to albumin (SBEalb)
((0.148 × pH) − 0.818) × (45 − albumin (g/L)) (45 g/L = normal albumin in our lab)
• SBE due to lactate (SBElactate)
1 − [lactate (patient)] (1 mEq/L = normal lactate in our lab)
• SBE due to SIG (SBESIG)
SBE − SBENa − SBECl − SBEalb − SBElactate
We considered a value of less than −2 mEq/L of SBE as significant metabolic acidosis [4,11].
479 significant. Means of variation of SBE attributable to SIDa, SIG, lactate, albumin, and phosphate were analyzed by 1way analysis of variance (ANOVA) for repeated measures. Means within group and between groups, as well as the factor × time interaction during evolution over time, were analyzed using 2-way ANOVA. Bonferroni correction for multiple comparisons was used. For all analyses of variance, Tukey test was used in the post hoc analysis. The commercially available SPSS 10.0 (Chicago, Ill) statistical package software was used in the analysis.
2.3. Statistical analysis Data were considered normal using the KolmogorovSmirnov goodness-of-fit model and are shown as means and standard deviations. Single independent means were compared with the Student t test, and a P ≤ .05 was considered
3. Results A total of 159 patients were admitted to the ICU during the study period, and 107 stayed for at least 4 days until death
Fig. 1 General features of acid-base metabolism during the ICU stay of critically ill patients (83 survivors and 24 nonsurvivors). A, The pH evolution (ANOVA 2-way within factor P b .001; between factor, P = .124; and factor × time interaction, P b .001). B, The SBE evolution (ANOVA 2-way within factor P b .001; between factor, P b .001; and factor × time interaction, P = .014). C, The carbon dioxide partial pressure evolution (ANOVA 2-way within factor P = .003; between factor, P = .479; and factor × time interaction, P = .288). #Tukey post hoc analysis P b .05 vs nonsurvivors group. ⁎Tukey post hoc analysis P b .05 vs first day.
480 or discharge. General characteristics of the patients are presented in Table 1. Survivors and nonsurvivors refer to ICU mortality. The pH as well as the pCO2 was not statistically different between survivors and nonsurvivors for all days analyzed (Fig. 1). At the day of discharge, the pH was significantly increased in relation to admission in survivors, and the pCO2 significantly increased in relation to admission in nonsurvivors. The SBE, however, was different between groups at all days and was significantly higher at day 3 and at discharge compared to value at the time of admission in survivors. The SIDa was different and significantly higher in survivors on all days except upon admission (Fig. 2). The higher SIDa in survivors could have been attributed to lower levels of chloride in this group, which is a consistent finding
A.T. Maciel, M. Park for all days, and at day 3 and the last day of ICU stay, differences in lactate levels could have also contributed to this elevation (Table 2). Using the ANOVA 2-way analysis, increases in SIDa in survivors did not reach statistical significance. The SIG was higher in nonsurvivors upon admission and on the day of death but not on days 2 and 3. The total amount of weak acids (albumin and phosphate) was significantly lower in nonsurvivors on all days (Fig. 2). Because SIDa, SIG, and weak acids were not statistically different between admission and discharge in survivors (using the ANOVA 2-way analysis), but there was a significant and progressive increase in SBE during ICU stay, we analyzed the within-group (using ANOVA for repeated measures) metabolic acid-base profile of the patients, partitioning the SBE into its components (see above).
Fig. 2 Metabolic acid-base determinants during the ICU evolution of critically ill patients who survived (n = 83) and those who did not survive (n = 24). A, The SIDa evolution (ANOVA 2-way within factor P = .030; between factor, P b .001; and factor × time interaction, P = .875). B, The plasma lactate evolution (ANOVA 2-way within factor P = .054; between factor, P b .001; and factor × time interaction, P b .001). C, The SIG evolution (ANOVA 2-way within factor P = .815; between factor, P b .001; and factor × time interaction, P = .649). D, The albumin plus phosphate (weak acids) evolution (mEq/L) (ANOVA 2-way within factor P = .541; between factor, P b .001; and factor × time interaction, P = .991). #Tukey post hoc analysis P b .05 vs nonsurvivors group.
Acid base behavior of ICU survivors and non-survivors Table 2
481
Evolution of the components of SIDa during the observation period (mean ± SD) Day 1 Survivors (n = 83)
Day 2 Nonsurvivors Survivors (n = 24) (n = 83)
Na+ (mEq/L) 140 ± 6 142 ± 6 K+ (mEq/L) 4.1 ± 0.8 4.3 ± 1.0 Mg+2 (mEq/L) 1.26 ± 0.27 1.35 ± 0.33 Ca+2 (mEq/L) 2.32 ± 0.21 2.37 ± 0.59 108 ± 9 a 110 ± 9 Cl− (mEq/L) Lactate (mEq/L) 2.6 ± 1.9 3.0 ± 1.9
Day 3
Discharge/Death
Nonsurvivors Survivors (n = 24) (n = 83)
141 ± 5 142 ± 7 4.1 ± 0.7 4.3 ± 0.8 1.25 ± 0.36 1.25 ± 0.32 2.37 ± 0.58 2.28 ± 0.43 108 ± 7 a 111 ± 9 2.1 ± 1.1 2.6 ± 1.5
141 ± 3.9 ± 1.26 ± 2.34 ± 108 ± 1.8 ±
Nonsurvivors Survivors (n = 24) (n = 83)
5 144 ± 7 0.7 4.1 ± 1.1 0.37 1.23 ± 0.34 0.20 2.16 ± 0.40 8a 111 ± 10 0.9 a 3.2 ± 2.1
Nonsurvivors (n = 24)
141 ± 5 142 ± 6 4.0 ± 0.6 a 4.8 ± 1.2 1.35 ± 0.36 1.36 ± 0.35 2.37 ± 0.16 2.18 ± 0.46 106 ± 7 a 109 ± 9 1.7 ± 0.7 a 4.5 ± 4.5
Values are expressed as mean ± SD. a Analysis of variance 2-way P b .013, Tukey post hoc analysis P b .05 vs nonsurvivors. There is no statistical differences in the within group analysis.
Metabolic acidosis (SBE b−2 mEq/L) was present in both survivors and nonsurvivors upon admission, with the acidosis largely being due to hyperchloremia in both groups (Fig. 3). In survivors, SBE was normal (near zero) at the day of discharge because the acidifying component of hyperchloremia and hyperlactatemia decreased significantly until
it reached an equilibrium with the permanent and steady alkalinizing effect of decreased weak acids (mainly hypoalbuminemia) (Fig. 3A). Decreases in SIG between admission and discharge were not statistically significant. In nonsurvivors, there was a non–statistically significant decrease in chloremia and an increase in lactatemia at the day of death;
Fig. 3 Standard base excess and its partitions through the ICU stay in 83 survivors (A) and 24 nonsurvivors (B) and difference of SBE and its partitions between the last and first day of ICU stay in 83 survivors (C) and 24 nonsurvivors (D). The SBE due to sodium, chloride, albumin, SIG, and lactate were calculated as described in the text. §ANOVA 1-way for repeated measures P b .040, P b .05 vs discharge day (Tukey post hoc analysis). ¶ANOVA 1-way for repeated measures P b .001, P b .05 vs discharge day (Turkey post hoc analysis). #ANOVA 1-way for repeated measures P b .001, P b .05 vs day 1 (Turkey post hoc analysis). ⁎ANOVA 1-way for repeated measures (P = .003), Turkey post hoc analysis (P b .05) vs SBECl.
482 SIG was at the same level at admission and on the day of death. Therefore, SBE was similar on the day of death to that at admission with no improvements in any of its acidifying components. In this group, hypoalbuminemia was also responsible for a permanent and steady alkalinizing effect.
4. Discussion The main objective of this study was to characterize the differences in acid-base behavior between ICU survivors and nonsurvivors using both a SBE and a physicochemical approach. It is, to our knowledge, one of the first studies to describe and compare in detail the acid-base status of ICU survivors at the day of discharge and nonsurvivors at the day of their death. Unfortunately, the small sample size and the use of rigorous statistical tests may have generated some type β error, and some real differences between the 2 groups may have been missed. Besides this, our sample was heterogeneous in terms of the main diagnosis, so no definitive conclusions can be drawn for any particular group of critically ill patients. In this study, survival and discharge from the ICU meant, from an acid-base perspective, normalization of SBE. However, this did not mean that all acidifying and alkalinizing variables were completely offset. The most significant alkalinizing variable (hypoalbuminemia) was present at the same level at all days and was not corrected during ICU stay. This is not surprising in the context of a predominantly hyperchloremic metabolic acidosis. The acid-base situation at discharge could be considered a normal physiologic response in critically ill patients (ie, acidifying variables were corrected and a new equilibrium was reached so that SBE was near zero) and not mixed metabolic acidosis/hypoalbuminemic alkalosis [8]. Although no statistically significant changes occurred in the absolute values of SIDa, SIG, and lactate in survivors during their ICU stay, partitioning of the SBE has shown that hyperlactatemia, unmeasured anions, and principally, hyperchloremia all contributed to acidosis generation on admission. Normalization of SBE, however, was mainly attributed to a decrease in lactatemia and chloremia, with statistically significant differences between the values at admission and at discharge (Fig. 3A). Funk et al [12] found changes in chloremia to be mainly responsible for correction of SBE in critically ill patients. This is also suggested by the data presented in Fig. 3C and D. Although SIG and SBESIG were not statistically different between the days of admission and discharge (Figs. 2 and 3A), this could be due to the small sample size, so a possible role for a decreased SIG contributing to an increased SBE could not be discounted. Note that in Fig. 3C, variations in SBECl, SBElactate, and SBESIG were not statistically different. Interestingly, although high values of SIG were found both in survivors and nonsurvivors (Fig. 2), the SBE due to SIG (SBESIG) was comparatively much less significant, suggest-
A.T. Maciel, M. Park ing that the normal expected SIG is greater than zero. Because SIG and SBESIG are not directly measured variables, but rather differences between a collection of other measured variables, small imprecision in each one of these measured variables may lead to great systematic bias in SIG and SBESIG [13] values. Although a large part of the literature assumes a normal SIG to be near zero [14], this is still not the consensus. Some authors have proposed higher normal SIG values [3,13], and others found elevations in SIG of critically ill patients with no apparent acid-base disorder [15,16]. Kaplan [17] also proposed that increased SIG is an appropriate baseline for reduced plasma weak acids in the absence of pathology. Unmeasured anions seem to be a heterogeneous group of different anions that are still not well characterized [18,19], have many possible sources [20,21], and are of unknown significance, except in some specific populations of critically ill patients [22-24]. In fact, a normal value of SIG in critically ill, hypoalbuminemic patients has not been established. Although SIG was different between survivors and nonsurvivors upon ICU admission, its prognostic value is still a matter of controversy, and it was beyond the scope of this study to evaluate its accuracy. In addition, clearance of unmeasured anions has not been proven to be a valuable therapeutic target or marker in the general population of critically ill patients. In our study, there was a tendency for an increase in SBESIG in survivors and decrease in nonsurvivors (Fig. 3). This may suggest that clearance of these anions correlates with outcome. The real impact of this finding is hard to define based on our study. Larger studies are necessary to determine whether this difference in SIG behavior between survivors and nonsurvivors is statistically and clinically important, as is the case for lactate [25]. In disagreement with our initial hypothesis, although nonsurvivors were actually more acidotic upon admission, hyperchloremia was responsible for a large part of the acidosis, and lactate was responsible for a minor part of the metabolic acidosis in both groups. Gunnerson et al [4] demonstrated that the prognosis changes according to the main anion that is responsible for the acidosis, with lactic acidosis being the malady with the worst prognosis. This seems to be useful on an individual basis, but as a group, the proportion of the anions upon admission does not seem to distinguish survivors from nonsurvivors. Antonini et al [26], who studied the profile of acid-base disturbances in the early phase of critical illness, also found a similar proportion of the anions responsible for the metabolic acidosis in survivors and nonsurvivors. In contrast with our study, they found that unmeasured anions account for most metabolic acidosis. This difference may be due to (1) differences in the methodology used for electrolyte measurement and (2) distinct populations of critically ill patients. In nonsurvivors, on the day of death, the SBE was similar to that seen at admission (Figs. 1 and 3B). However, our data suggest that the same degree of metabolic acidosis was kept constant but with proportional, small decreases in chloremia and increases in lactatemia. This emphasizes that attention
Acid base behavior of ICU survivors and non-survivors should be given not only to the degree of metabolic acidosis but also to the anions causing the acidosis. Brill et al [27] have shown that base excess does not predict mortality when it is secondary to hyperchloremic acidosis, so SBE partitioning has the potential to significantly improve outcome prediction. The finding that nonsurvivors were characterized by the absence of correction of the metabolic acidosis is not surprising; the interesting finding is the behavior of the anions, which highlights the relevance of the physicochemical, quantitative acid-base approach. In the work of Gunnerson et al [4], the prognosis was evaluated based on a single quantitative acid-base analysis of patients in which the attending physician asked for a lactate measurement, independent of the time already spent in the ICU. We were able to show a more dynamic and general view of the anions and their possible relationship to the outcome. Lactate, as cited above, although extensively demonstrated in the literature as a good marker of outcome, was not per se a major determinant of metabolic acidosis in our sample. This possibly explains the poor correlation between SBE and lactate found in some studies [28,29]. Lactic acidosis, defined as metabolic acidosis in which lactate is the predominant anion, seems to be present in a few cases, even in the group of nonsurvivors. In conclusion, this study suggests that in clinical practice, daily analysis of the acid-base disturbances using a quantitative approach may be helpful in defining prognosis. Possible benefits of therapeutic interventions to directly change the evolution of any of these acid-base parameters are currently unknown.
References [1] Smith I, Kumar P, Molloy S, et al. Base excess and lactate as prognostic indicators for patients admitted to intensive care. Intensive Care Med 2001;27(1):74-83. [2] Park M, Azevedo LC, Maciel AT, et al. Evolutive standard base excess and serum lactate level in severe sepsis and septic shock patients resuscitated with early goal-directed therapy: still outcome markers? Clinics 2006;61(1):47-52. [3] Fencl V, Jabor A, Kazda A, et al. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 2000; 162(6):2246-51. [4] Gunnerson KJ, Saul M, He S, et al. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients. Crit Care 2006;10(1):R22. [5] Siggaard-Andersen O. The van Slyke equation. Scand J Clin Lab Invest Suppl 1977;37(146):15-20. [6] Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983;61(12):1444-61. [7] Figge J, Rossing TH, Fencl V. The role of serum proteins in acid-base equilibria. J Lab Clin Med 1991;117(6):453-67.
483 [8] Kellum JA. Determinants of blood pH in health and disease. Crit Care 2000;4(1):6-14. [9] Gilfix BM, Bique M, Magder S. A physical chemical approach to the analysis of acid-base balance in the clinical setting. J Crit Care 1993;8 (4):187-97. [10] Funk GC, Doberer D, Kneidinger N, et al. Acid-Base disturbances in critically ill patients with cirrhosis. Liver Int 2007;27(7):901-9. [11] Park M, Taniguchi LU, Noritomi DT, et al. Clinical utility of standard base excess in the diagnosis and interpretation of metabolic acidosis in critically ill patients. Braz J Med Biol Res 2007. [12] Funk GC, Doberer D, Heinze G, et al. Changes of serum chloride and metabolic acid-base state in critical illness. Anaesthesia 2004;59(11): 1111-5. [13] Morgan TJ. What exactly is the strong ion gap, and does anybody care? Crit Care Resusc 2004;6(3):155-9. [14] Kellum JA. Clinical review: reunification of acid-base physiology. Crit Care 2005;9(5):500-7. [15] Cusack RJ, Rhodes A, Lochhead P, et al. The strong ion gap does not have prognostic value in critically ill patients in a mixed medical/ surgical adult ICU. Intensive Care Med 2002;28(7):864-9. [16] Rocktaeschel J, Morimatsu H, Uchino S, et al. Unmeasured anions in critically ill patients: can they predict mortality? Crit Care Med 2003; 31(8):2131-6. [17] Kaplan LJ. Another nail in albumin's coffin. Chest 2007;131(5): 1276-7. [18] Kellum JA. Closing the gap on unmeasured anions. Crit Care 2003;7 (3):219-20. [19] Forni LG, McKinnon W, Hilton PJ. Unmeasured anions in metabolic acidosis: unravelling the mystery. Crit Care 2006;10(4):220. [20] Moviat M, Terpstra AM, Ruitenbeek W, et al. Contribution of various metabolites to the “unmeasured” anions in critically ill patients with metabolic acidosis. Crit Care Med 2008;36(3):752-8. [21] Forni LG, McKinnon W, Lord GA, et al. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care 2005;9(5):R591-5. [22] Kaplan LJ, Kellum JA. Initial pH, base deficit, lactate, anion gap, strong ion difference, and strong ion gap predict outcome from major vascular injury. Crit Care Med 2004;32(5):1120-4. [23] Dondorp AM, Chau TT, Phu NH, et al. Unidentified acids of strong prognostic significance in severe malaria. Crit Care Med 2004;32(8): 1683-8. [24] Balasubramanyan N, Havens PL, Hoffman GM. Unmeasured anions identified by the Fencl-Stewart method predict mortality better than base excess, anion gap, and lactate in patients in the pediatric intensive care unit. Crit Care Med 1999;27(8):1577-81. [25] Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004;32(8):1637-42. [26] Antonini B, Piva S, Paltenghi M, et al. The early phase of critical illness is a progressive acidic state due to unmeasured anions. Eur J Anaesthesiol 2008;25(7):566-71. [27] Brill SA, Stewart TR, Brundage SI, et al. Base deficit does not predict mortality when secondary to hyperchloremic acidosis. Shock 2002;17 (6):459-62. [28] Mikulaschek A, Henry SM, Donovan R, et al. Serum lactate is not predicted by anion gap or base excess after trauma resuscitation. J Trauma 1996;40(2):218-22. [29] Aduen J, Bernstein WK, Miller J, et al. Relationship between blood lactate concentrations and ionized calcium, glucose, and acid-base status in critically ill and noncritically ill patients. Crit Care Med 1995; 23(2):246-52.
Respiration/Ventilation and Tracheostomy
Differences in acid-base behavior between intensive care unit survivors and nonsurvivors using both a physicochemical and a standard base excess approach: A prospective, observational study☆ Alexandre Toledo Maciel MD ⁎, Marcelo Park MD, PhD Intensive Care Unit, Department of Medical Emergencies, Hospital das Clínicas, São Paulo, Brazil
Keywords: Acid-Base; Critically ill patients; Physicochemical approach; Standard base excess; Mortality
Abstract Purpose: This study aimed to test the hypothesis that intensive care unit survivors and nonsurvivors differ with regard to type and severity of acid-base disorders. Materials and Methods: Prospective, observational, cohort study of 107 consecutive patients admitted in a 7-bed intensive care unit during a 6-month period that stayed at least 4 days. All acid-base variables for the first 3 days and the day of discharge were analyzed. Results: Survivors had significant metabolic acidosis upon admission, which was due to hyperlactatemia, an excess of unmeasured anions, and principally, hyperchloremia. A progressive decrease in these anions in the presence of constant hypoalbuminemia led to normal standard base excess at discharge. Nonsurvivors had greater metabolic acidosis upon admission with acidifying variables in similar proportions to that of the survivors. On the day of death, nonsurvivors had a similar degree of metabolic acidosis but a different proportion of the anions (less chloride and more lactate) compared with the day of admission. Unmeasured anions were greater in nonsurvivors both on the day of admission and on the day of death. Conclusions: Intensive care unit survivors and nonsurvivors differed in the severity of metabolic acidosis; however, the proportion of the different anions causing the acidosis on admission was similar between these 2 groups. © 2009 Elsevier Inc. All rights reserved.
1. Introduction Acid-Base disturbances are frequently found in critically ill patients. The severity of these disturbances upon intensive care unit (ICU) admission [1] and also their behavior during ☆ The authors declare that they have no competing interests. ⁎ Corresponding author. E-mail address: [email protected] (A.T. Maciel).
0883-9441/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2009.01.005
ICU stay [2] seem to correlate with prognosis, especially for metabolic acidosis. Standard base excess (SBE) is usually used to quantify the degree of metabolic impairment, but it does not alone reveal the origin of the problem. More recently, the physicochemical approach has improved our understanding of the different mechanisms responsible for the generation of metabolic disorders [3] and has also helped as a prognostic marker based on the main acid in excess in the circulation (chloride, lactate, or unmeasured anions) [4].
478 Gunnerson et al [4] found that lactic acidosis has the worst prognosis and that hyperchloremic acidosis has a better prognosis, similar to patients with no metabolic acidosis. The aim of this observational study was to characterize the progression of the different components of acid-base status during the first 3 days after ICU admission and at the day of discharge or death, using both a physicochemical and a SBE approach. Our hypothesis was that survivors have less metabolic acidosis upon admission, which is corrected during their stay in the ICU; nonsurvivors, however, tend to have more severe metabolic acidosis upon admission and die with a progressive deterioration of their metabolic markers. We also hypothesized that the proportion of the different anions would differ between survivors and nonsurvivors; those who die would have a greater amount of lactate and unmeasured anions, whereas in those who survived, the anion would be predominantly chloride.
2. Materials and methods The study was approved by the local ethics committee. Because all data used here were collected in the process of routine examinations performed for all patients that are admitted to the ICU, the requirement for informed written consent was waived. It is routine in the 7-bed medical ICU to collect a list of laboratory tests from all patients upon admission and then daily around midnight. This list includes an arterial blood gas determination with simultaneous arterial lactate, Na+, K+, Ca2+, Mg2+, Cl−, phosphate, and albumin measurements. All consecutive patients admitted from July 2005 to January 2006 who stayed in the ICU for at least 4 days were included. Acid-Base variables such as pH, pCO2, bicarbonate, SBE, apparent strong ion difference (SIDa), effective strong ion difference (SIDe), and strong ion gap (SIG) were recorded upon admission (day 1), for the next 2 days (days 2 and 3), and at the day of discharge or death. In addition, the SBE was partitioned to clarify the contribution of each one of its components to the SBE evolution (see below). Age, sex, and the APACHE II score were also recorded for all patients, as were ICU and in-hospital mortality. No colloids were used in the management of these patients.
2.1. Laboratory techniques and measurements All samples were analyzed in the central laboratory of the Institution. Na+, K+, Ca2+, and Cl− were measured using the direct ion-selective electrode technique; Mg2+, using a colorimetric technique; and phosphate, by an ultraviolet technique. Albumin was measured with a bromocresol dye colorimetric technique. Arterial blood gas was analyzed, and lactate was measured on the OMNI analyzer (Roche Diagnostics System, F. Hoffmann-La Roche Ltd, Basel, Switzerland). The SBE was calculated from the measured data using the Van Slyke equation (see below) [5].
A.T. Maciel, M. Park
2.2. Quantitative physicochemical analysis The principles of the physicochemical approach to acidbase disturbances proposed by Stewart [6] and then modified by Figge et al [7] have been recently reviewed by other authors [3,8]. Standard formulas used in this study were the following: 1. SBE (Van Slyke equation) (mEq/L) = 0.9287 × (HCO3− (mmol/l) − 24.4 + 14.83 × [pH − 7.4]) 2. SIDa (mEq/L) = Na+ (mEq/L) + K+ (mEq/L) + Ca2+ (mEq/L) + Mg2+ (mEq/L) − [Cl− (mEq/L) + lactate− (mEq/L)] 3. SIDe (mEq/L) = 2.46 × 10−8 × PCO2 / 10−pH + [albumin (g/dL)] × (0.123 × pH − 0.631) + [phosphate (mg/dL) / 3 × (pH − 0.469)] 4. SIG (mEq/L) = SIDa − SIDe To work simultaneously with both the SBE and the physicochemical approach, we partitioned the SBE into 5 distinct components [9,10]: SBE due to sodium, SBE due to chloride, SBE due to albumin, SBE due to unmeasured anions (SIG), and SBE due to lactate. Each component was derived from the following equations (all in mEq/L): • SBE due to sodium (SBENa)
0.3 × ([Na+ (patient)] − 140) (140 mEq/L = normal sodium in our lab)
• SBE due to chloride (SBECl)
102 − [Clcorrected (patient)] (102 mEq/L = normal chloride in our lab) Clcorrected (patient) = Cl (patient) × (140/ Na (patient))
Table 1
General characteristics of the patients (N = 107) ICU survivors ICU nonsurvivors (n = 83) (n = 24)
Sex (male) Age (y), mean ± SD Apache II score, mean ± SD Main diagnosis Severe sepsis/Septic shock Respiratory failure Postoperative Trauma Neurologic syndromes Others COPD Chronic renal failure Mechanical ventilation a Renal replacement therapy a Classic intermittent Sustained low efficiency Continuous Peritoneal In-hospital mortality (%)
42 50 ± 19 13 ± 7
16 56 ± 17 20 ± 8
25 24 12 7 6 9 4 12 45 14 12 2 4 1 20.5
14 3 3 0 1 3 0 5 21 14 5 0 12 0 –
Values are expressed as numbers unless otherwise indicated. a At any time during ICU stay.
Acid base behavior of ICU survivors and non-survivors • SBE due to albumin (SBEalb)
((0.148 × pH) − 0.818) × (45 − albumin (g/L)) (45 g/L = normal albumin in our lab)
• SBE due to lactate (SBElactate)
1 − [lactate (patient)] (1 mEq/L = normal lactate in our lab)
• SBE due to SIG (SBESIG)
SBE − SBENa − SBECl − SBEalb − SBElactate
We considered a value of less than −2 mEq/L of SBE as significant metabolic acidosis [4,11].
479 significant. Means of variation of SBE attributable to SIDa, SIG, lactate, albumin, and phosphate were analyzed by 1way analysis of variance (ANOVA) for repeated measures. Means within group and between groups, as well as the factor × time interaction during evolution over time, were analyzed using 2-way ANOVA. Bonferroni correction for multiple comparisons was used. For all analyses of variance, Tukey test was used in the post hoc analysis. The commercially available SPSS 10.0 (Chicago, Ill) statistical package software was used in the analysis.
2.3. Statistical analysis Data were considered normal using the KolmogorovSmirnov goodness-of-fit model and are shown as means and standard deviations. Single independent means were compared with the Student t test, and a P ≤ .05 was considered
3. Results A total of 159 patients were admitted to the ICU during the study period, and 107 stayed for at least 4 days until death
Fig. 1 General features of acid-base metabolism during the ICU stay of critically ill patients (83 survivors and 24 nonsurvivors). A, The pH evolution (ANOVA 2-way within factor P b .001; between factor, P = .124; and factor × time interaction, P b .001). B, The SBE evolution (ANOVA 2-way within factor P b .001; between factor, P b .001; and factor × time interaction, P = .014). C, The carbon dioxide partial pressure evolution (ANOVA 2-way within factor P = .003; between factor, P = .479; and factor × time interaction, P = .288). #Tukey post hoc analysis P b .05 vs nonsurvivors group. ⁎Tukey post hoc analysis P b .05 vs first day.
480 or discharge. General characteristics of the patients are presented in Table 1. Survivors and nonsurvivors refer to ICU mortality. The pH as well as the pCO2 was not statistically different between survivors and nonsurvivors for all days analyzed (Fig. 1). At the day of discharge, the pH was significantly increased in relation to admission in survivors, and the pCO2 significantly increased in relation to admission in nonsurvivors. The SBE, however, was different between groups at all days and was significantly higher at day 3 and at discharge compared to value at the time of admission in survivors. The SIDa was different and significantly higher in survivors on all days except upon admission (Fig. 2). The higher SIDa in survivors could have been attributed to lower levels of chloride in this group, which is a consistent finding
A.T. Maciel, M. Park for all days, and at day 3 and the last day of ICU stay, differences in lactate levels could have also contributed to this elevation (Table 2). Using the ANOVA 2-way analysis, increases in SIDa in survivors did not reach statistical significance. The SIG was higher in nonsurvivors upon admission and on the day of death but not on days 2 and 3. The total amount of weak acids (albumin and phosphate) was significantly lower in nonsurvivors on all days (Fig. 2). Because SIDa, SIG, and weak acids were not statistically different between admission and discharge in survivors (using the ANOVA 2-way analysis), but there was a significant and progressive increase in SBE during ICU stay, we analyzed the within-group (using ANOVA for repeated measures) metabolic acid-base profile of the patients, partitioning the SBE into its components (see above).
Fig. 2 Metabolic acid-base determinants during the ICU evolution of critically ill patients who survived (n = 83) and those who did not survive (n = 24). A, The SIDa evolution (ANOVA 2-way within factor P = .030; between factor, P b .001; and factor × time interaction, P = .875). B, The plasma lactate evolution (ANOVA 2-way within factor P = .054; between factor, P b .001; and factor × time interaction, P b .001). C, The SIG evolution (ANOVA 2-way within factor P = .815; between factor, P b .001; and factor × time interaction, P = .649). D, The albumin plus phosphate (weak acids) evolution (mEq/L) (ANOVA 2-way within factor P = .541; between factor, P b .001; and factor × time interaction, P = .991). #Tukey post hoc analysis P b .05 vs nonsurvivors group.
Acid base behavior of ICU survivors and non-survivors Table 2
481
Evolution of the components of SIDa during the observation period (mean ± SD) Day 1 Survivors (n = 83)
Day 2 Nonsurvivors Survivors (n = 24) (n = 83)
Na+ (mEq/L) 140 ± 6 142 ± 6 K+ (mEq/L) 4.1 ± 0.8 4.3 ± 1.0 Mg+2 (mEq/L) 1.26 ± 0.27 1.35 ± 0.33 Ca+2 (mEq/L) 2.32 ± 0.21 2.37 ± 0.59 108 ± 9 a 110 ± 9 Cl− (mEq/L) Lactate (mEq/L) 2.6 ± 1.9 3.0 ± 1.9
Day 3
Discharge/Death
Nonsurvivors Survivors (n = 24) (n = 83)
141 ± 5 142 ± 7 4.1 ± 0.7 4.3 ± 0.8 1.25 ± 0.36 1.25 ± 0.32 2.37 ± 0.58 2.28 ± 0.43 108 ± 7 a 111 ± 9 2.1 ± 1.1 2.6 ± 1.5
141 ± 3.9 ± 1.26 ± 2.34 ± 108 ± 1.8 ±
Nonsurvivors Survivors (n = 24) (n = 83)
5 144 ± 7 0.7 4.1 ± 1.1 0.37 1.23 ± 0.34 0.20 2.16 ± 0.40 8a 111 ± 10 0.9 a 3.2 ± 2.1
Nonsurvivors (n = 24)
141 ± 5 142 ± 6 4.0 ± 0.6 a 4.8 ± 1.2 1.35 ± 0.36 1.36 ± 0.35 2.37 ± 0.16 2.18 ± 0.46 106 ± 7 a 109 ± 9 1.7 ± 0.7 a 4.5 ± 4.5
Values are expressed as mean ± SD. a Analysis of variance 2-way P b .013, Tukey post hoc analysis P b .05 vs nonsurvivors. There is no statistical differences in the within group analysis.
Metabolic acidosis (SBE b−2 mEq/L) was present in both survivors and nonsurvivors upon admission, with the acidosis largely being due to hyperchloremia in both groups (Fig. 3). In survivors, SBE was normal (near zero) at the day of discharge because the acidifying component of hyperchloremia and hyperlactatemia decreased significantly until
it reached an equilibrium with the permanent and steady alkalinizing effect of decreased weak acids (mainly hypoalbuminemia) (Fig. 3A). Decreases in SIG between admission and discharge were not statistically significant. In nonsurvivors, there was a non–statistically significant decrease in chloremia and an increase in lactatemia at the day of death;
Fig. 3 Standard base excess and its partitions through the ICU stay in 83 survivors (A) and 24 nonsurvivors (B) and difference of SBE and its partitions between the last and first day of ICU stay in 83 survivors (C) and 24 nonsurvivors (D). The SBE due to sodium, chloride, albumin, SIG, and lactate were calculated as described in the text. §ANOVA 1-way for repeated measures P b .040, P b .05 vs discharge day (Tukey post hoc analysis). ¶ANOVA 1-way for repeated measures P b .001, P b .05 vs discharge day (Turkey post hoc analysis). #ANOVA 1-way for repeated measures P b .001, P b .05 vs day 1 (Turkey post hoc analysis). ⁎ANOVA 1-way for repeated measures (P = .003), Turkey post hoc analysis (P b .05) vs SBECl.
482 SIG was at the same level at admission and on the day of death. Therefore, SBE was similar on the day of death to that at admission with no improvements in any of its acidifying components. In this group, hypoalbuminemia was also responsible for a permanent and steady alkalinizing effect.
4. Discussion The main objective of this study was to characterize the differences in acid-base behavior between ICU survivors and nonsurvivors using both a SBE and a physicochemical approach. It is, to our knowledge, one of the first studies to describe and compare in detail the acid-base status of ICU survivors at the day of discharge and nonsurvivors at the day of their death. Unfortunately, the small sample size and the use of rigorous statistical tests may have generated some type β error, and some real differences between the 2 groups may have been missed. Besides this, our sample was heterogeneous in terms of the main diagnosis, so no definitive conclusions can be drawn for any particular group of critically ill patients. In this study, survival and discharge from the ICU meant, from an acid-base perspective, normalization of SBE. However, this did not mean that all acidifying and alkalinizing variables were completely offset. The most significant alkalinizing variable (hypoalbuminemia) was present at the same level at all days and was not corrected during ICU stay. This is not surprising in the context of a predominantly hyperchloremic metabolic acidosis. The acid-base situation at discharge could be considered a normal physiologic response in critically ill patients (ie, acidifying variables were corrected and a new equilibrium was reached so that SBE was near zero) and not mixed metabolic acidosis/hypoalbuminemic alkalosis [8]. Although no statistically significant changes occurred in the absolute values of SIDa, SIG, and lactate in survivors during their ICU stay, partitioning of the SBE has shown that hyperlactatemia, unmeasured anions, and principally, hyperchloremia all contributed to acidosis generation on admission. Normalization of SBE, however, was mainly attributed to a decrease in lactatemia and chloremia, with statistically significant differences between the values at admission and at discharge (Fig. 3A). Funk et al [12] found changes in chloremia to be mainly responsible for correction of SBE in critically ill patients. This is also suggested by the data presented in Fig. 3C and D. Although SIG and SBESIG were not statistically different between the days of admission and discharge (Figs. 2 and 3A), this could be due to the small sample size, so a possible role for a decreased SIG contributing to an increased SBE could not be discounted. Note that in Fig. 3C, variations in SBECl, SBElactate, and SBESIG were not statistically different. Interestingly, although high values of SIG were found both in survivors and nonsurvivors (Fig. 2), the SBE due to SIG (SBESIG) was comparatively much less significant, suggest-
A.T. Maciel, M. Park ing that the normal expected SIG is greater than zero. Because SIG and SBESIG are not directly measured variables, but rather differences between a collection of other measured variables, small imprecision in each one of these measured variables may lead to great systematic bias in SIG and SBESIG [13] values. Although a large part of the literature assumes a normal SIG to be near zero [14], this is still not the consensus. Some authors have proposed higher normal SIG values [3,13], and others found elevations in SIG of critically ill patients with no apparent acid-base disorder [15,16]. Kaplan [17] also proposed that increased SIG is an appropriate baseline for reduced plasma weak acids in the absence of pathology. Unmeasured anions seem to be a heterogeneous group of different anions that are still not well characterized [18,19], have many possible sources [20,21], and are of unknown significance, except in some specific populations of critically ill patients [22-24]. In fact, a normal value of SIG in critically ill, hypoalbuminemic patients has not been established. Although SIG was different between survivors and nonsurvivors upon ICU admission, its prognostic value is still a matter of controversy, and it was beyond the scope of this study to evaluate its accuracy. In addition, clearance of unmeasured anions has not been proven to be a valuable therapeutic target or marker in the general population of critically ill patients. In our study, there was a tendency for an increase in SBESIG in survivors and decrease in nonsurvivors (Fig. 3). This may suggest that clearance of these anions correlates with outcome. The real impact of this finding is hard to define based on our study. Larger studies are necessary to determine whether this difference in SIG behavior between survivors and nonsurvivors is statistically and clinically important, as is the case for lactate [25]. In disagreement with our initial hypothesis, although nonsurvivors were actually more acidotic upon admission, hyperchloremia was responsible for a large part of the acidosis, and lactate was responsible for a minor part of the metabolic acidosis in both groups. Gunnerson et al [4] demonstrated that the prognosis changes according to the main anion that is responsible for the acidosis, with lactic acidosis being the malady with the worst prognosis. This seems to be useful on an individual basis, but as a group, the proportion of the anions upon admission does not seem to distinguish survivors from nonsurvivors. Antonini et al [26], who studied the profile of acid-base disturbances in the early phase of critical illness, also found a similar proportion of the anions responsible for the metabolic acidosis in survivors and nonsurvivors. In contrast with our study, they found that unmeasured anions account for most metabolic acidosis. This difference may be due to (1) differences in the methodology used for electrolyte measurement and (2) distinct populations of critically ill patients. In nonsurvivors, on the day of death, the SBE was similar to that seen at admission (Figs. 1 and 3B). However, our data suggest that the same degree of metabolic acidosis was kept constant but with proportional, small decreases in chloremia and increases in lactatemia. This emphasizes that attention
Acid base behavior of ICU survivors and non-survivors should be given not only to the degree of metabolic acidosis but also to the anions causing the acidosis. Brill et al [27] have shown that base excess does not predict mortality when it is secondary to hyperchloremic acidosis, so SBE partitioning has the potential to significantly improve outcome prediction. The finding that nonsurvivors were characterized by the absence of correction of the metabolic acidosis is not surprising; the interesting finding is the behavior of the anions, which highlights the relevance of the physicochemical, quantitative acid-base approach. In the work of Gunnerson et al [4], the prognosis was evaluated based on a single quantitative acid-base analysis of patients in which the attending physician asked for a lactate measurement, independent of the time already spent in the ICU. We were able to show a more dynamic and general view of the anions and their possible relationship to the outcome. Lactate, as cited above, although extensively demonstrated in the literature as a good marker of outcome, was not per se a major determinant of metabolic acidosis in our sample. This possibly explains the poor correlation between SBE and lactate found in some studies [28,29]. Lactic acidosis, defined as metabolic acidosis in which lactate is the predominant anion, seems to be present in a few cases, even in the group of nonsurvivors. In conclusion, this study suggests that in clinical practice, daily analysis of the acid-base disturbances using a quantitative approach may be helpful in defining prognosis. Possible benefits of therapeutic interventions to directly change the evolution of any of these acid-base parameters are currently unknown.
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