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35DIAGNOSTIC APPROACHES AND FORECASTING IN THE INTENSIVE CARE
ДИАГНОСТИЧЕСКИЕ ПОДХОДЫ И ПРОГНОЗИРОВАНИЕ В ИТ
Value of combined lactate and central venous oxygen saturation measurement in patients with sepsis: a retrospective cohort study
K. Sitthikool , J.H. Boyd , J.A. Russell , K.R. Walley
St. Paul's Hospital, The University of British Columbia, Vancouver, B C, Canada
Abstract
Introduction. Lactate and central venous oxygen saturation (ScvO2) reflect tissue hypoperfusion but each measure is confounded by many additional factors. These confounding factors differ between lactate and ScvO2. Objectives. We postulated that combined assessment of lactate and ScvO2 may yield information beyond that of each measure alone. Specifically we sought to determine whether lactate has different characteristics and predictive value at different levels of ScvO2. Material and methods. We conducted a retrospective analysis of a Derivation cohort and a Validation Cohort of sepsis patients with lactate and ScvO2 measured within the first 4 hours of intensive care unit admission and 12 hours after resuscitation. Patients were grouped according to: 1) ScvO2 < 60 %; 2) 60 % < ScvO2 < 80 %; 3) ScvO2 > 80 %. Results. Lactate was negatively correlated with ScvO2 in the ScvO2 < 60 % group in both cohorts but was not correlated with ScvO2 in the other ScvO2 groups. Using receiver operator characteristic analysis in the Derivation Cohort, in the ScvO2 > 80 % group lactate was predictive of 28-day mortality with an area under the ROC curve (AUC) of 0.94 and an optimal threshold lactate of 3.0 mmol/L. Using this threshold in the ScvO2 > 80 % groups, 28-day mortality was 32.7 %. Conclusions. Lactate has different characteristics and predictive value at different levels of ScvO2. When ScvO2 < 60 % correlation between lactate and ScvO2 is consistent with a degree of oxygen supply limitation. When ScvO2 > 80 % lactate > 3.0 mmol/L is predictive of mortality.
Keywords: central venous oxygen saturation, oximetry, lactate, sepsis, septic shock, prognosis, mortality
Прогностическое значение комбинации уровня лактата и центральной венозной сатурации кислорода у пациентов с сепсисом: ретроспективное когортное исследование
К. Ситтикул , Дж.Х. Бойд , Дж.А. Рассел , K.P. Велли
Госпиталь Св. Павла, Университет Британской Колумбии, Ванкувер, Канада
Реферат
Актуальность. Уровень лактата и центральная венозная сатурация крови (БстО2) отражают гипоперфузию тканей, но на каждый показатель влияет множество дополнительных факторов. Эти дополнительные факторы различны для лактата и БстО2. Цель исследования. Мы предполагаем, что одновременная оценка уровня лактата и БстО2 может дать более ценную информацию, чем измерения показателей по отдельности. В частности, мы стремились определить, обладает ли лактат различными характеристиками и различной прогностической ценностью при разных уровнях БстО2. Материал и методы. Мы провели ретроспективный анализ экспериментальной и контрольной когорты пациентов с сепсисом, у которых уровень лактата и БстО2 измеряли в течение первых 4 ч после поступления в ОИТ и через 12 ч после реанимации. Пациенты были сгруппированы по критериям: 1) Бст02 < 60 %; 2) 60 % <Бст02 < 80 %; 3) Бст02 > 80 %. Результаты. Уровень лактата отрицательно коррелировал с Бст02 в группе Бст02 < 60 % в обеих когортах, но в других группах Бст02 корреляции выявлено не было. Используя анализ 1ЮС-кривых в экспериментальной когорте, установлено, что в группе БстО2 > 80 % уровень лактата прогнозировал 28-дневную смертность с площадью под кривой 0,94 и оптимальным пороговым значением лактата 3,0 ммоль/л. С учетом этого порога 28-дневная смертность в группе БстО2 > 80 % составила 32,7 %.
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© «Практическая медицина» 2021. Данная статья распространяется на условиях «открытого доступа», в соответствии с лицензией. СС БУ-ЫС-БД 4.0 («АипЬи^оп-ЫопСоттегаа^БИагеАИке» / «Атрибуция-Некоммерчески-СохранениеУсловий» 4.0), которая разрешает неограниченное некоммерческое использование, распространение и воспроизведение на любом носителе при условии указания автора и источника. Чтобы ознакомиться с полными условиями данной лицензии на русском языке, посетите сайт: https://creativecommons.Org/licenses/by-nc-sa/4.0/deed.ru
u For correspondence: Keith R. Walley — MD, Professor, Critical Care Medicine, St. Paul's Hospital, The University of British Columbia, Vancouver, Canada; e-mail: Keith.Walley@ hli.ubc.ca
B For citation: Sitthikool K., Boyd J.H., Russell J.A., Walley K.R. Value of combined lactate and central venous oxygen saturation measurement in patients with sepsis: a retrospective cohort study. Annals of Critical Care. 2021;4:59-68. DOI: 10.21320/1818-474X-2021-4-59-68
О Received: 07.10.2021 В Accepted: 30.11.2021 В Дата онлайн-публикации: 19.01.2022
Introduction
Current guidelines suggest "guiding resuscitation of sepsis and septic shock to decrease lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion" [1]. Earlier guidelines suggested using central venous oxygen saturation (ScvO2) to guide resuscitation of sepsis and septic shock. Yet both lactate and central venous oxygen saturation are highly confounded by factors other than tissue hypoperfusion [2-4] although both share tissue hypoperfusion as one of their underlying determinants. We therefore postulated that the combination of lactate and ScvO2 would provide additional information beyond the individual measurement of lactate or ScvO2.
Lactic acidemia is a biomarker of tissue hypoxia [8-9] and is associated with adverse outcome [9-12]. Regional ischemia (e.g. gut, limb) must be distinguished from inadequate whole body oxygen delivery as the cause of elevated lactate. In the absence or regional ischemia, elevated lactate levels may also be due to accelerated glycolysis driven by sepsis or beta-adrenergic stimulation, reduced entry of pyruvate into the Kreb's cycle due to thiamine deficiency or other causes, increased conversion of pyruvate to lactate in a reducing environment or, not infrequently, due to decreased lactate clearance due to hepatic dysfunction or other causes. The Hour-
Заключение. Уровень лактата имеет разные характеристики и прогностическую ценность при разных уровнях ScvO2. При ScvO2 < 60 % корреляция между уровнем лактата и ScvO2 связана со степенью гипоксии. В группе ScvO2 > 80 % уровень лактата > 3,0 ммоль/л является прогностическим фактором смертности.
Ключевые слова: центральная венозная сатурация кислорода, оксиметрия, лактат, сепсис, септический шок, прогнозирование, смертность
u Для корреспонденции: Кит Р. Велли — д-р медицины, профессор, отдел критической медицины, Больница Святого Павла, Университет Британской Колумбии, Ванкувер, Канада; e-mail: Keith.Walley@hli.ubc.ca
B Для цитирования: Ситтикул К., Бойд Дж.Х., Рассел Дж.А., Велли К.Р. Прогностическое значение комбинации уровня лактата и центральной венозной сатурации кислорода у пациентов с сепсисом: ретроспективное когортное исследование. Вестник интенсивной терапии им. А.И. Салтанова. 2021;4:59-68. DOI: 10.21320/1818-474X-2021-4-59-68
О Поступила: 07.10.2021 В Принята к печати: 30.11.2021 В Published online: 19.01.2022
1 Surviving Sepsis Campaign Bundle of Care recommends measuring a lactate level. If the initial lactate level is more than 2 mmol/L, it should be re-measured [13]. Previous studies suggest a significant reduction in mortality with "lactate-guided" resuscitation [14-15]. However, these conclusions are clouded because, in a key open-label randomized-controlled trial of early lactate-guided therapy, the treatment algorithm also involved interventions guided by ScvO2 [14].
Mixed venous oxygen saturation (SvO2) and its surrogate, ScvO2 measured from a thoracic central line [16], can be used to evaluate oxygen supply/demand adequacy [17] and estimate cardiac output using the Fick equation [18]. Low ScvO2 helps identify inadequate oxygen delivery conditions [17]. High ScvO2 generally indicates adequate oxygen delivery but, importantly, this is not always the case. For example, ScvO2 may be paradoxically high when tissue oxygen extraction is pathologically impaired due to cellular dysfunction involving mitochondria, cofactors, antioxidants, or membrane stabilizers [19]. Early Goal-Directed Therapy targeting ScvO2 as part of the initial resuscitation of septic shock improved outcomes in an early study [20] but failed to improve outcomes in later studies [21-24]. The latter studies are clouded because both the intervention and control groups had already received protocolized initial fluid resuscitation; a key component
DOI: 10.21320/1818-474X-2021-4-59-68
of Early Goal-Directed Therapy, which was the treatment to be tested.
Thus, lactate and ScvO2 both reflect tissue hypoperfusion but each measure is confounded by many additional factors that have not been fully addressed in any study. Importantly, the confounding factors differ between lactate and ScvO2. Thus, it is possible that combined assessment of lactate and ScvO2 may yield information beyond that of each measure alone. Accordingly, we explored the relationship between combined lactate and ScvO2 measurements and clinical outcomes. Specifically, we sought to determine whether serum lactate concentration has different characteristics and predictive value at different levels of central venous oxygen saturation (ScvO2).
Materials and Methods
Statistical analysis
Median (interquartile range) was employed for continuous variables and percentage was used for categorical variables. Chi square tests were utilized for comparison between groups of categorical variables. Kruskal-Wallis tests were used for non-normally distributed continuous data and ANOVA was used for normally distributed continuous data. Group differences associated with a p-value of < 0.05 were considered statistically significant. A linear regression analysis was used to assess the correlation of ScvO2 and lactate. The receiver operator characteristic (ROC) curve with area under the ROC curve (AUC) was used to derived an optimal lactate threshold predictive of 28-day mortality in the Derivation Cohort. This lactate threshold was then tested for prognostic value in the combined cohorts. Statistical analysis was performed using SPSS Version 23 (SPSS Inc., Chicago, IL).
Patient cohorts
Derivation Cohort. All patients admitted to the Intensive Care Unit at St Paul's Hospital (SPH) in Vancouver, British Columbia, Canada, between 2004-2009 were screened for sepsis (n = 754). Sepsis was defined by an acute change in total Sequential Organ Failure Assessment (SOFA) score > 2 points due to infection [25]. Of these, 274 patients who had lactate and ScvO2 measurements within the first 4 hours of study enrollment were included in this analysis as a Derivation Cohort. The study was approved by the University of British Columbia Research Ethics Board (H02-50076-A027).
Validation Cohort. To reduce the possibility of false positive results from the Derivation Cohort we tested for replication of findings in a Validation Cohort. All patients admitted to the Intensive Care Unit at SPH from 2010 to 2018 were screened for sepsis (n = 855). Sepsis was defined using the same consensus definition as above [25]. Of these, 289 patients had lactate and ScvO2 measurements within 4 hours of study enrollment. The study was approved by the University of British Columbia Research Ethics Board (H02-50076-A027).
Measurements in both cohorts. Baseline characteristics and medical comorbidities were assessed at the time of enrollment. Laboratory variables (lactate, ScvO2, hemoglobin, white blood cell count, platelet count, alanine aminotransferase, total bilirubin, creatinine) were measured. Previous studies have used 60 % as a cutoff value for a low ScvO2 and 80 % as a cutoff value for a high ScvO2 [26-27]. Therefore, we classified patients into three groups according to ScvO2 measured within the first 4 hours: 1) ScvO2 < 60 %; 2) 60 %<ScvO2 < 80 %; 3) ScvO2 > 80 %.
Results
Patient characteristics
The Derivation Cohort was comprised of 274 sepsis patients having both lactate and ScvO2 measurements within 4 hours of study enrollment. Baseline characteristics are shown in Table 1 A classified by ScvO2 at time of enrollment: 1) ScvO2 < 60 %; 2) 60 % < ScvO2 < 80 %; 3) ScvO2 > 80 %. Pati2ents in the ScvO2 < 60 2% group had significantly higher baseline lactate levels (2.5 mmol/L) compared with the other groups (ScvO2 > 60 and < 80 % lactate 1.7 mmol/L; ScvO2 > 80 % lactate 1.3 mmol/L, p = 0.01). Patients having ScvO2 > 80 % were younger (p = 0.02) and had significantly higher creatinine concentrations (p = 0.04). Sex, comorbidities, APACHE II score, and other laboratory measurements at presentation were not different between the three groups. There was no significant difference in primary infection sites of sepsis (Table 1 A).
The Validation Cohort was similarly defined and was comprised of 289 sepsis patients. Patients in the ScvO2 < 60 % group had a higher prevalence of ischemic heart disease and had a higher lactate level point estimate, although not statistically significantly higher (Table 1 B). As in the Derivation Cohort, patients having ScvO2 > 80 % were younger (p = 0.04). Again, sex, comorbidities, APACHE II score, and other laboratory measurements at presentation were not different between the three groups. Similarly, primary infection sites were not different between groups (Table 1, B).
IQR is Interquartile range. APACHE II score is Acute physiology and chronic health evaluation II score.
/ \
Table 1. Baseline characteristic in two cohorts of sepsis patients
Derivation Cohort
ScvO2 < 60 % (n = 38) ScvO2 60-80 % (n = 172) ScvO2 > 80 % (n = 64) p
Age, yr, median (IQR) 66.9 (48.7-76.1) 60.4 (48.5-69.8) 56.6 (42.1-68.6) 0.02
Male, n (%) 22 (57.9) 113 (65.7) 44 (68.8) 0.81
Comorbidities, n (%)
Cirrhosis 0 (0) 4 (2.3) 1 (16) 0.61
Other liver disease 3 (7.9) 19 (11.0) 8 (12.5) 0.77
Chronic renal failure 4 (11.1) 23 (13.9) 7 (12.1) 0.87
Hypertension 5 (13.2) 19 (11) 2 (3.1) 0.13
Ischemic heart disease 3 (7.9) 13 (7.6) 8 (12.5) 0.48
Diabetes 1 (2.6) 12 (7.0) 1 (16) 0.4
Chronic obstructive pulmonary disease 4 (10.5) 20 (11.6) 3 (4.7) 0.28
APACHE II score, median (IQR) 23 (16-30) 22 (18-27) 24 (19-27) 0.36
Laboratory variables, median (IQR)
Baseline lactate (mmol/L) 2.5 (1.5-5.1) 1.7 (1.1-4) 1.3 (1-3) 0.01
Baseline ScvO2 (%) 53 (47-57) 72 (67-76) 84 (82-88) <0.001
Creatinine, |imol/L 126 (80.5-202.5) 128.5 (74-234) 210 (93-362) 0.04
White blood cell count, x 103 |L 13.9 (6.8-19.5) 11.6 (5.7-17.7) 11.2 (6.4-16.5) 0.54
Hemoglobin, g/L 99.5 (83-113) 98 (83.5-119.5) 101 (82.5-116.5) 0.77
Platelet count, x 103 |L 196.5 (146-252) 153.5 (73.5-209) 165 (88.5-231.5) 0.2
Total bilirubin, |imol/L 12 (9-15.5) 14 (6-32.5) 15 (7-29) 0.62
Alanine aminotransferease, u//L 50.5 (31-125) 37 (22-74) 33 (16-86) 0.18
Infection sites, n (%)
Lung 24 (63.2) 100 (62.5) 36 (56.3) 0.99
Genitourinary 1 (2.6) 3 (1.7) 1 (16) 0.3
Abdominal 4 (10.5) 19 (11) 11 (17.2) 0.62
Skin and soft tissue 1 (2.6) 8 (4.7) 2 (3.1) 0.95
Others (central venous system, bone, blood) 2 (5.2) 11 (6.3) 3 (4.7) 0.1
between lactate levels and ScvO2 for patients in the 60 %<ScvO2 < 80 % group nor in the ScvO2 > 80 % group (Table 2). Thus, lactate arising from global inadequate oxygen delivery is only evident when ScvO2 < 60 %.
Lactate predicts mortality only when ScvO2 > 80 %
In the Derivation Cohort, lactate was not predictive of 28-day mortality in the ScvO2 < 60 % group (AUC = 0.64, 95 % confidence interval [95% CI], 0.40-0.89,
ScvO2 is correlated with serum lactate only when
ScvO2 < 60 %
In the Derivation cohort we observed a correlation between higher serum lactate at lower ScvO2 (p = 0.01) in the ScvO2 < 60 % group (Table 2). This negative correlation replicated in the Validation Cohort for the ScvO2 < 60 % group (p = 0.004) (Table 2) suggesting that this finding was not a false positive result. In contrast, no correlation was observed in either the Derivation or Validation Cohorts
/• N
Table 1. Continued
Variable Validation Cohort
ScvO2 < 60 % (n = 44) ScvO2 60-80 % (n = 187) ScvO2 > 80 % (n = 58) P
Age, yr, median (IQR) 62.3 (32.5-81.1) 65.0 (52.8-71.1) 59.5 (50.7-64) 0.04*
Male, n (%) 28 (63.6) 118 (63.1) 34 (58.6) 0.81
Comorbidities, n (%)
Cirrhosis 0 (0) 9 (4.8) 5 (8.6) 0.13
Other liver disease 5 (11.4) 27 (14.4) 7 (12.1) 0.81
Chronic renal failure 8 (18.2) 26 (13.9) 6 (10.3) 0.52
Hypertension 10 (22.7) 50 (26.7) 10 (17.2) 0.32
Ischemic heart disease 12 (27.3) 26 (13.9) 4 (6.9) 0.01*
Diabetes 7 (15.9) 33 (17.6) 14 (24.1) 0.4
Chronic obstructive pulmonary disease 7 (15.9) 21 (11.2) 8 (13.8) 0.65
APACHE II score, median (IQR) 20 (17-22) 19 (16-24) 19 (11-25) 0.81
Laboratory variables, median (IQR)
Baseline lactate (mmol/L) 3.8 (1.8-7.7) 2.8 (1.0-5.9) 2.8 (1.5-4.5) 0.2
Baseline ScvO2 (%) 52 (43-56) 71 (67-76) 84 (82-87) < 0.001*
Creatinine, |imol/L 118 (97-139) 98.5 (72-182.5) 120 (86-168) 0.8
White blood cell count, x 103 |L 13 (10-21.4) 14.3 (7.9-19.3) 16.9 (8.6-25.3) 0.57
Hemoglobin, g/L 106 (89-134) 107 (93.5-126) 111 (99-123) 0.65
Platelet count, x 103 |L 152 (108-240) 207 (129-291) 151 (104-256) 0.39
Total bilirubin, |imol/L 25 (11-33) 13 (6-22.5) 14 (6-44) 0.09
Alanine aminotransferease, u//L 43 (26-297) 35 (20-76.5) 28 (20-62) 0.27
Infection sites, n (%)
Lung 11 (25.0) 64 (34.2) 22 (37.9) 0.37
Genitourinary 2 (4.5) 20 (10.7) 8 (13.8) 0.3
Abdominal 6 (13.6) 31 (16.6) 12 (20.7) 0.62
Skin and soft tissue 2 (4.5) 7 (3.7) 2 (3.4) 0.95
Others (central venous system, bone, blood) 5 (11.4) 7 (3.7) 1 (17) 0.4
/" N
Table 2. Correlation of lactate with ScvO2
Derivation cohort Validation cohort
Correlation with lactate P Correlation with lactate P
< 60 % R2 = 0.16 0.01 R2 = 0.098 0.0039
60-80 % R2 < 0.001 0.83 R2 = 0.002 0.56
> 80 % R2 = 0.009 0.45 R2 = 0.005 0.59
Fig 1. Receiver operating characteristic curve of baseline of serum lactate for predicting 28-day mortality in the Derivation Cohort. The area under the curve (AUC) for the ScvO2 < 60 % group is 0.64, for the 60 %<ScvO2 < 80 % is 0.65 and for the ScvO2 > 80 % group is 0.94
p = 0.3) and also not predictive in the 60 % < ScvO2 < 80 % group (AUC = 0.65, 95% CI, 0.56-0.74, p = 0.3). This lack of predictive power was also observed in the Validation Cohort. In contrast, in the ScvO2 > 80 % group from the Derivation Cohort ROC curve analysis showed that the AUC for predicting 28-day mortality was 0.94 (95% CI, 0.88-1.0) (Fig. 1). A lactate level of 3 mmol/L in the group was the optimal threshold in the Derivation Cohort. Using this lactate threshold in the combined Derivation and Validation Cohorts 28-day mortality was 32.7 % when lactate > 3.0 mmol/L while 28-day mortality was 5.6 % when lactate < 3 mmol/L (p = 0.00002) (Fig. 2). Thus, lactate is predictive of 28-day mortality only when ScvO2 > 80 %.
Response to resuscitation
Since lactate arising from global inadequate oxygen delivery is only evident when ScvO2 < 60 % we postulated that lactate clearance in response to resuscitation would be more marked in this group. We further postulated that lactate clearance in response to resuscitation may be less evident at higher ScvO2, which would then suggest that at higher ScvO2, lactate levels may be more heavily influenced by processes other than global tissue hypoxia. To test these hypotheses, we assumed that most resuscitation would have occurred within the first 12 hours after intensive care unit (ICU) admission and we combined Derivation and Validation Cohorts in order to have adequate numbers in subgroups (survivors versus non-survivors in each of three ScvO2 groups). In the ScvO2 < 60 % group lactate clearance was positive (levels decreased from baseline to 12 hours) in survivors but negative in non-survivors. Thus,
Fig 2. In the ScvO2 > 80 % group, a lactate
of 3 mmol/L is the best threshold to predict mortality. Red dots represent non-surviving patients. Blue dots represent surviving patients
for ScvO2 < 60 % the difference in lactate clearance between survivors and non-survivors was 3.2 ± 3.0 mmol/L over 12 hours (p < 0.001). In contrast, no significant difference in lactate clearance was found between survivors and non-survivors in the 60 % < ScvO2 < 80 % group (difference between survivors and non-survivors 1.2 ± 2.1 mmol/L over 12 hours, p = 0.75) nor in the ScvO2 > 80 % group (difference between survivors and non-survivors 1.6 ± 2.4 mmol/L over 12 hours, p = 0.14).
Discussion
In our study, we found a correlation between lactate and ScvO2 only when ScvO2 < 60 %. Since both lactate and ScvO2 are (imperfect) markers of tissue hypoperfusion, this correlation is consistent with elevated lactate reflecting tissue hypoperfusion due to inadequate oxygen delivery when ScvO2 < 60 % (Fig. 3 a). Resuscitation over the first 12 hours of ICU admission in this ScvO2 group resulted in decreasing lactate in survivors while lactate rose in non-survivors. These results suggest that current guidelines may be appropriate for this ScvO2 group of patients. That is, when ScvO2 < 60 % our results support "guiding resuscitation of sepsis and septic shock to decrease serum lactate in patients with elevated lactate level as a marker of tissue hypoperfusion" [1].
In contrast, absence of a correlation between lactate and ScvO2 when ScvO2 > 60 % suggests that lactate may not be particularly reflective of inadequate whole body oxygen delivery for higher values of ScvO2 (Fig. 3 b). Specifically, there is no correlation between lactate and ScvO2 when ScvO2 > 60 % and, furthermore, resuscitation over the first 12 hours of ICU admission does not result in significantly greater lactate clearance in survivors versus non-survivors.
Thus, elevated lactate when ScvO2 > 60 % may be heavily influenced by other processes such as accelerated glycolysis driven by sepsis or beta-adrenergic stimulation, reduced entry of pyruvate into the Kreb's cycle, increased conversion of pyruvate to lactate in a reducing environment or decreased lactate clearance. Thus, when ScvO2 > 60 %, our results question the current guidelines that resuscitation should be guided by lactate clearance.
Notably, lactate appears to convey very different clinical
information when ScvO2 > 80
When ScvO2 > 80 %
elevated lactate is predictive of mortality, possibly by discriminating between surviving patients with adequate oxygen delivery versus non-survivors with mitochondrial or other causes of histotoxic hypoxia. This is an important distinction so lactate measurement is helpful. Yet, lactate levels may not be sufficiently reflective of inadequate oxygen
Fig 3. Postulated explanations for observations
A. ScvO2 < 60 %. Some of the patients in this group have
approximately normal tissue oxygen extraction capacity and, therefore, normal Vo2-Do2 (oxygen consumption — oxygen delivery) relationships (solid line). Pre-resuscitation the problem is that some of these patients have a Vo2-Do2 point that falls below the critical oxygen extraction ratio so that oxygen supply limitation exists (anaerobic metabolism = shock) so that ScvO2 (~1 — Vo2/Do2) is decreased and lactate (dashed line) is increased. Following resuscitation (bold arrow) aerobic meta bolism is restored so that ScvO2 increases and lactate decreases. Thus, lactate correlates with ScvO2 in this group (slope of solid line).
B. 60 < ScvO2 < 80. These patients have a relatively normal
Vo2-Do2 relationship (solid line) and a normal-range ScvO2 but lactate (dashed line) is elevated, dominated by causes other than inadequate whole body oxygen delivery (including regional ischemia) so that lactate is not decreased by resuscitation. Resuscitation may drive Do2 a bit higher but this does not impact tissue oxygenation and lactate may even rise due to factors such as catecholamine-driven increases in glycolysis.
C. ScvO2 > 80. This category may be comprised of two types
of patients with high ScvO2 for different reasons: 1) those with relatively normal oxygen extraction (Vo2-Do2 relationships, solid line) and high oxygen delivery with relatively normal lactate levels and 2) those with very impaired oxygen extraction capacity (dotted line) who have high lactate levels. Resuscitation increases an already high oxygen delivery in 1) with little effect on their relatively normal lactate. However, resuscitation in 2) may further impair tissue oxygen extraction capacity, for example, by worsening tissue edema and oxygen diffusion distances. The key differentiating feature between 1) and 2) is lactate. Using survival versus non-survival as a surrogate marker of 1) versus 2), we found a lactate level of 3 mmol/L as the optimal threshold for distinguishing these two groups.
delivery (tissue hypoperfusion) in these ScvO2 > 80 % patients (Fig. 3 c) to provide a firm guide to resuscitation.
Metabolic acidosis is common in patients with sepsis and septic shock and is a prognostic predictor of poor outcome [5]. For example, negative base excess and lactate measurements are associated with adverse clinical outcome [6-7]. However, normal lactate levels
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in patients with septic shock and lactate alone is not sufficient to judge success or failure of treatment because it can be affected by many factors. For example, an increase in blood lactate following infusion of adrenaline in septic shock was associated with better survival (31-34). Thus, lactate is an imperfect measure. ScvO2 is also imperfect. Low ScvO2 may be a marker for macrocirculatory failure (inadequate whole body oxygen delivery) and high ScvO2 values may reflect microcirculatory or mitochondrial failure. Both abnormally low and high ScvO2 are associated with increased mortality [36]. Thus, ScvO2 is not, by itself, a good predictor of sepsis mortality [28, 37]. Some studies have demonstrated that venous-to-arterial carbon dioxide difference (vaCO2 gap) might be help to identify patients with persistent global hypoperfusion and guide resuscitation process [42]. A vaCO2 > 6 mmHg reflects a low output state with hypoperfusion and a low vaCO2 of < 6 mmHg reflects impaired utilization of oxygen and low CO2 production due to mitochondrial dysfunction [43, 44]. Additionally, central venous-to-arterial carbon dioxide difference (PvaCO2 gap) is associated with lactate clearance since PcvaCO2 gap has moderate accuracy for predicting lactate improvement [45]. Therefore, it is likely that adding vaCO2 gap measurements to the lactate / ScvO2 assessment for provide additional information. We did not have vaCO2 gap measurements consistently measured in these cohorts to address this issue here.
Since lactate and ScvO2 both share the underlying determinant of tissue hypoperfusion, we reasoned that the combination of lactate and ScvO2 may be superior to the single measurement of either lactate or ScvO2. We observed that serum lactate and ScvO2 were negatively correlated when ScvO2 < 60 %. There was no correlation between lactate and ScvO2 for patients with mid-range and high ScvO2. This finding is consistent with a previous study, showing that these variables were correlated when oxygen extraction was high (hence low ScvO2) [38]. Correlation suggests that both parameters share an underlying determinant which, from existing knowledge of the determinants of both lactate and ScvO2, implicates tissue hypoperfusion. Patients who responded to initial resuscitation (survived) had a notably greater decrease in lactate in parallel with an increase in ScvO2, further supporting the notion that the combination of high lactate and low ScvO2 reflected tissue hypoperfusion.
Lactate clearance has been shown to be associated with improved survival in critical ill patients [40]. Previous studies demonstrated that a relative lactate clearance of 10 % and early lactate normalization within 6 hours was associated with decreased mortality rate [30, 41]. Consistent with this, our study revealed that in the ScvO2 < 60 % group lactate levels decreased from baseline to 12 hours in survivors but increased in non-survivors. However, lactate clearance was not as useful in distinguishing survivors from non-
survivors in the groups with higher ScvO2 and, arguably, maybe not as helpful in guiding resuscitation.
We found that when ScvO2 > 80 %, lactate was predictive of 28-day mortality and a lactate level at 3 mmol/L was the optimal discriminatory threshold. However, lactate was not predictive of mortality in the other ScvO2 groups. We postulate that when ScvO2 > 80 %, lactate is predictive of mortality, possibly by discriminating between surviving patients with adequate oxygen delivery versus non-survivors with mitochondrial or other causes of histotoxic hypoxia that led to elevated lactate levels (Fig. 3c). That is, ScvO2 > 70 % (and, hence, ScvO2 > 80 %) generally reflects adequate oxygen delivery and cellular metabolism. On the other hand, in the case of extreme vasodilatory shock where lactate is rising, high ScvO2 suggests severely impaired tissue oxygen extraction ability due to microcirculatory dysfunction or mitochondrial dysfunction [18]. In this setting lactate discriminates between these two physiologic states; normal lactate when oxygen delivery is adequate but elevated lactate when tissue oxygen extraction capacity is impaired. This is consistent with a previous clinical trial which suggested that high ScvO2 levels were associated with increased mortality because high ScvO2 may reflect impaired extraction of oxygen [27]. Patients with high ScvO2 and high lactate levels had significantly higher rates of mortality [36]. Even with adequate resuscitation of the macro-circulation, tissue hypoxia may persist [39].
Limitations to this study are, first, this a retrospective analysis in two cohorts from different time periods. Second, lactate and ScvO2 were not simultaneously measured in all patients sepsis patients admitted to the ICU so that many screened patients were excluded from analysis. This may result in a risk of selection bias. Third, we were unable to fully evaluate clinical factors and therapeutic interventions including amount of fluid resuscitation and doses of vasopressors that might affect levels of ScvO2 and lactate. Finally, this is a single center study, therefore, our findings may not be generalizable to other settings.
Conclusions
Serum lactate concentration has different characteristics and predictive value at different levels of ScvO2. A high lactate when ScvO2 < 60 % suggests inadequate whole body oxygen delivery (tissue hypoperfusion). However, an elevated lactate does not accurately identify tissue hypoperfusion at higher ScvO2. When ScvO2 > 80 % lactate > 3 mmol/L is predictive of mortality. However, an elevated lactate is not a good predictor of mortality for lower values of ScvO2. Serum lactate concentration has different characteristics and predictive value at different levels of central venous oxygen saturation. The combination of lactate and ScvO2 gives insight into the underlying state of shock and potential causes of elevated lactate levels.
Disclosure. The authors declare that they have no competing interests.
Author contribution. All authors according to the ICMJE criteria participated in the development of the concept of the article, obtaining and analyzing factual data, writing and editing the text of the article, checking and approving the text of the article.
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