DOI: https://doi.org/10.21203/rs.3.rs-1717701/v1
Objective: Early lactate clearance was associated with mortality in sepsis patients, but needs further clarification whether it should be adjusted according to the age. Our study aimed to investigate the predictive value of early 6-hour lactate clearance rate with the mortality rate of septic shock patients according to age stratification.
Methods and Results: This was a prospective, single center and observational study. A total of 261 patients with mean age of 69.5 years were enrolled. Male patients accounted for 61.6%, with a total mortality rate of 47.5%. The blood lactate levels (LAC1) of patients showed no significnat differences between Survival Group and Death Group (P=0.767) during ICU admission. However, after 6-hour treatment, the blood lactate levels of patients in Survival Group were significantly lower compared to Death Group (P<0.001), and similar are the results of 6-hour lactate clearance rate (P<0.001).Multivariate Logistic regression indicated that age ( and lactate clearance rate were significantly associated with 28-day mortality rate. The AUC value of ROC curve for lactate clearance rate was 0.800. AUC value of ROC curve for patients >65 years and ≤65 years was 0.778 and 0.845. AUC value of ROC curve for patients >80 years and ≤80 year old was 0.751 and 0.818. However, the lactate clearance rate showed no significant differences between Survival Group patients of different age (P= 0.5413 and P=0.338), respectively.
Conclusion: In clinical practice, The blood lactate levels (LAC1) of patients showed no significnat differences between Survival Group and Death Group,but early 6-hour lactate clearance rate could be used to predict the mortality rate of patients with age stratification, with optimal accuracy.
Lactic acid is the product of anaerobic metabolism,the stored sugars are burned without sufficient oxygen by cells. In patients with sepsis, due to inadequate tissue oxygenation or pyruvate dehydrogenase dysfunction, the blood lactate level could be easily increased, further influencing the homeostasis, and bringing various complications, and even death. The lactic acid levels has been well established as prognostic indicator in sepsis patients [1]. Recently, the lactate levels have been considered as the markers of organism oxygen metabolism and tissue perfusion by guidelines for management of sepsis and septic shock [2]. These guidelines recommended lactate levels as hemodynamic index of fluid resuscitation,and suggested that the levels should be restored to normal range within 6 hours. Previous studies reported that 6-hour lactate clearance rate of at least 10% could significantly improve the survival rate of patients with sepsis [3][4]. However, in critically ill patients, age factor was closelyassociated with various other clinical parameters, such as endogenous creatinine clearance and oxygenation, and all these required age calibration.On the other hand, lactate clearance was closely related to creatinine clearance rate. However, it is still not clear whether there existed any association between 6-hour lactate clearance rate and age for predicting the mortality risk in sepsis patients. Also investigate whehter the influence of 6-hour lactate clearance rate on the prognosis should be distingusished and treated differently acoording to age stratification. This study aimed to investigate the changes of 6-hour lactate clearance rate in septic shock patients who received fluid resuscitation. Logistic model was constructed on the basis of the results of multivariate regression analysis. The receiver operating curve (ROC) was drawn to predict the influence of 6-hour lactate clearance rate on the mortality rate of patients by age stratification to provide effective evidence of the assessment and targeted treatment for critically ill patients clinically.
1.1 Study design: This was a prospective, single center and observational study. Clinical information of patietnts were collected by special personnel, and entered into the database. The data was examined by other researchers, and double checkedby statistical analysis.This study was approved by the medical ethics committee.
1.2 Inclusion criteria: age > 18 years; the definition of sepsis should be referred to the sepsis guidelines of 2016, and the initial arterial blood lactate should be ≥4mmol/ when the sepsis patient was admitted into ICU department [5][6].
1.3 Exclusion criteria: 1) After ICU admission, patients with normal plasma lactate level, and the hospitalization time of the patient was less than 72 hours. 2) Patients who received high doses of catecholamines before ICU admission. 3) Patients with medical history of cirrhosis or hepatic insufficiency. 4) Patients had medical history of chronic renal insufficiency, and a serum endogenous creatinine clearance rate (Ccr) of 50%. 5) Patients who were diagnosed as diabetic and treated with metformin. 6) Patients diagnosed with lymphoma.
1.4 Standard for age stratification: In order to further analyze the interation action between age and lactate clearance rate, this study grouped the enrolled patients with two kinds of age frames. 1) Patients aged 65 was the general definition of the elderly age [7], and therefore adopted this age limit. 2) Patients aged 80 years was considered as another cut off value. Although this age stratification standard had not been applied in the sepsis related researches, it had been reported in some similar studies [7][8].
1.5 Data collection
After ICU admission, clinical informaiton, including gender, age, basic disease, APACHE II score, 6-hour volume of fluid input, lactic acid level before treatment and 6h lactic acid level after treatment were recorded. The prognostic resluts of 28 days were also recorded.
The value of 6-hour lactate clearence rate=( initial lactate concentration- -6-hour lactate concentration) / initial lactate concentration × 100%. The arterial blood was collected to detect the lactic acid, and the blood lactate was measured by GEMpremier -3000 analyzer.
1.6 Statistical analysis
Statitical analysis was conducted by using SPSS 22.0 software. Normal distribution was evaluated using Kolmogorov-Smirnov test. Variables with normal distribution were compared using Student's t-test, and values are presented as means ± standard deviation. Categorical variables are presented as frequencies and analyzed using the chi-square or Fisher's exact test, as appropriate. Univaritate regression was conducted to determine the risk factors for mortality, and the risk factors with p<0.05 entered into multivariate regression analysis. Multivariate analysis was conducted by Logistic model. On the basis of model equation, ROC curve was drawn, and the cut off value was calculated.Area under the curve (AUC) was also calculated to evaluate the predictive power. Two-sided P-values ≤0.05 were considered to be statistically significant.
2.1 In this study, a total of 261 patients were enrolled with a mean age of 69.5, and the total mortality rate was 47.5%. The blood lactate levels of patients showed no significnat differences between the Survival Group and Death Group [5.8 (4.6~7.6) vs. 5.9 (4.9~8.4), p=0.767].However, after 6-hour treatment, the blood lactate levels of patients in the Survival Group were significantly lower than that of patients in the Death Group [4.10 (2.6~5.4) vs. 5.65 (4.6~7.8), p< 0.001]. The 6-hour lactate clearence rate of Survival Group was higher than that of the Death Group [(36.4%(-86.00~86.52) vs. 4.0%(-177.7~53.6), p<0.001]. In addition, compared with patients of Death Group, the patients of Survival Group had less volume of fluid input and lower APACHE II scores (all P <0.001). The results were shown in Table 1.
Table 1 Comparison between 28 days of survival and death
Variables |
Whether or not the 28 day was alive |
Statistics |
P |
|
Yes (n=137) |
No (n=124) |
|||
Age (years old) |
67.28±18.39 |
72.05±14.85 |
t=2.312 |
0.022 |
Sexual (male) |
86 (62.77%) |
75 (60.48%) |
χ2=0.144 |
0.704 |
Rehydration (ml) |
1949.77±132.11 |
2048.50±66.74 |
F=55.873 |
<0.001 |
APACHE IIscores |
13.75±2.86 |
16.01±2.34 |
F=47.981 |
<0.001 |
LAC1{M(Min, Max)} |
5.80 (4.00-15.00) |
5.75 (4.00-15.00) |
Z=0.296 |
0.767 |
LAC2{M(Min, Max)} |
4.10 (0.90-8.10) |
5.65 (1.90-15.00) |
Z=8.061 |
<0.001 |
clearance {M(Min, Max)} |
36.48% (-86.00%-86.52%) |
4.07% (-177.78%-53.66%) |
Z=8.366 |
<0.001 |
2.2 The results of single Logistic regression were shown in Table 2. These results suggested that age (OR=1.02, 95%CI: 1.00-1.03,P=0.025), LAC2 (OR=0.92, 95%CI:0.83-1.02) (OR=1.87,95%CI:1.56- 2.24,P<0.001)and lactate clearance rate (OR=13.30, 95%CI:5.59-31.61)(OR=0.028, 95%CI:0.01–0.08,P<0.001)were significantly correlated with mortality. However, LAC1 showed no significant correlation (OR=0.92, 95%CI: 0.83- 1.02)(OR=1.03,95%CI:0.93- 1.14,P=0.544)with mortality rate. These two variables age and LAC2 were further incorporated into multivariate regression analysis. Results showed that age (OR=1.020, 95%CI:1-1.03, P=0.032) and lactate clearance rate (OR=0.028, 95%CI:0.01-0.07, P<0.001) were significantly correlated with 28-day mortality (Table 2).
Table 2 Logistic regression analysis of 28 days of death
Factors |
Crude OR (95%CI) |
P |
Adjusted OR (95%CI) |
P |
age |
1.017(1.002-1.033) |
0.025 |
1.020(1.002-1.039) |
0.032 |
clearance |
0.028(0.010-0.080) |
<0.001 |
0.028(0.010-0.079) |
<0.001 |
APACHE II |
1.21(1.11-1.32) |
<0.001 |
1.22(1.13-1.33) |
<0.001 |
sexual |
1.101(0.668-1.814) |
0.704 |
|
|
LAC1 |
1.032(0.931-1.141) |
0.544 |
|
|
LAC2 |
1.876(1.567-2.247) |
<0.001 |
|
|
2.3 ROC curve analysis: The ROC curve was conducted to determine the optimal cut off value of lactate clearance rate for 28-day survival. The AUC value was 0.800 (95%CI:0.747-0.853, P<0.001), and the cut off value was 18.93%, with asensitivity of 0.759 and specificity of 0.718. The ROC curve was shown in figure 1.
2.4 Subgroup analysis accorrding to age stratification (age>65 years old or not)
2.4.1 >65 years old: A total of 175 patients were observed with an average age of 78.99±7.70. Among them, 110 cases were male (62.86%), and 65 were female (37.14%). The mean value of lactic acid clearance rate was 19.32% (-177.78%-86.52%), 84 patients achieved 28-day survival, and the mortality rate was about 52.00%. The AUC value was 0.778 (95%CI:0.711-0.845, P<0.001), with a cut-off value of 18.25%, sensitivity of 0.750, and specificity of 0.681. The mean value of lactate clearance rate for survivors was 35.17% (-45.00~86.52), and the mean value of lactate clearance rate fordead patients was 4.44% (-177.78~53.66). The ROC curve results were shown in Figure 2 and comparion of lactate clearance rates and cut-off values between patients with age stratificationwas presented in Table 3.
2.4.2 ≤65 years old: A total of 86 patients were observed with an average age of 50.34±14.11. Among them, 51 cases were male (59.30%), and 35 were female (40.70%). The mean value of lactic acid clearance rate was 25.14% (-87.50%-86.09%), 53 patients achieved 28-day survival, and the mortality rate was about 38.37%. The AUC value was 0.845 (95%CI:0.762-0.927, P<0.001), with a cut-off value of 29.16%, sensitivity of 0.698, and specificity of 0.909.The average lactic acid clearance rate of the patients with survival rate was 37.21% (-85.00~86.09), and the average lactic acid clearance rate of the dead patients was 3.70% (-87.50~41.89).
The ROC curve was shown in Figure 3, and comparion of lactate clearance rates and cut-off values between patients with age stratificationwas presented in Table 3.
2.5 Subgroup analysis accorrding to different age groups (age>80 years old or not)
2.5.1 >80 years old: A total of 77 patients were observed. Thirty four patietns achieved 28-day survival, and the mortality rate was about 55.84%. The AUC value was 0.751 (95%CI: 0.642-0.859, P<0.001), with cut-off value of 18.25%, sensitivity of 0.735, and specificity of 0.651.The average lactic acid clearance rate of the patients with survival was 30.36% (-45.00~86.52), and the average lactic acid clearance rate of the dead patients was 2.27% (-177.78~51.85). The ROC curve was shown in Figure 4, and comparion of lactate clearance rates and cut-off values between patients with age stratificationwas presented in Table 3.
2.5.2 ≤80 years old: A total of 184 patients were observed. One hundred and three patients achieved 28-day survival, and the mortality rate was about 44.02%. The AUC value was 0.818 (95%CI: 0.758-0.879,P<0.001), with a cut-off value of 29.36%, sensitivity of 0.660, and specificity of 0.882. The average lactic acid clearance rate of the patients with survival was 37.21% (-85.00~86.09), and the average lactic acid clearance rate of the dead patients was 3.70% (-87.50~41.89). The ROC curve was shown in Figure 5, and comparion of lactate clearance rates and cut-off values between patients with age stratificationwas presented in Table 3.
2.6 Comparisons of APACHE II score and volume of fluid input between Survival Group and Death Group with age stratification. The APACHE II score showed significant differences between Survival Group and Death Group in patients >65 years old (P=0.004), and similar results were observed in patients >80 years old(P≤0.001). The 6h volume of fluid input also showed significant differences between Survival Group and Death Group at each age stratification (all P≤0.0001). The 6-hour lactate clearance rates were also compared between Survival Group and Death Group: patients≤65 years (37.21 vs.3.70), patients>65 years old (35.17 vs.4.44); patients≤80 years (37.21, vs.4.55); patients >80 years (30.36 vs. 2.27). The results were shown in Table 3.
Table 3 Comparions of lactate clearance rates and cut off values between patients with different age stratifications.
Age |
Group |
Nmuber |
APACHE II score |
6h volume of fluid input |
ml/kg |
Mean 6-hour clearance rate(%) {M(Min, Max)} |
Cut of point (%) |
≤65 years old |
Survival Group |
53 |
15.06±3.01 |
2118.43±301.25 |
28.23±46.56 |
37.21(-85.00, 86.09) |
29.16 |
Death Group |
33 |
15.00±2.53 |
2199.67±291.47 |
29.12±46.56 |
3.70(-87.50, 41.89) |
||
>65 years old |
Survival Group |
84 |
15.40±3.02 |
2134.12±314.84 |
27.81±47.99 |
35.17(-45.00, 86.52) |
18.25 |
Death Group |
91 |
14.80±3.17 |
2117.31±327.07 |
28.49±41.45 |
4.44(-177.78, 53.66) |
||
≤80 years old |
Survival Group |
103 |
13.71±2.70 |
2231.34±327.19 |
28.87±44.10 |
37.21(-85.00, 86.09) |
29.36 |
Death Group |
81 |
14.36±3.08 |
2277.22±356.33 |
29.38±43.84 |
4.55(-109.30, 53.66) |
||
>80 years old |
Survival Group |
34 |
14.66±2.89 |
2189.48±335.74 |
28.87±44.10 |
30.36(-45.00, 86.52) |
18.25 |
Death Group |
43 |
16.02±2.78 |
2318.22±370.65 |
29.38±43.84 |
2.27(-177.78, 51.85) |
2.7 Comparison of lactate clearance rate in survival patients with different age stratifications: According to the stratification of age, the lactate clearance rate of 65-years-old patients showed no signficant difference in survival patients (37.21vs. 35.17, p=0.5413).Similar results were observed in patients of 80 years (37.21vs.30.36, p=0.3338). The results were shown in Table 4.
Table 4 Comparison of lactate clearance rate in survival patients with different age stratifications
Group |
Lactate clearance rate {M(Min, Max)} |
P |
≤65 years old |
37.21 (-85.00, 86.09) |
0.5413 |
>65 years old |
35.17 (-45.00, 86.52) |
|
≤80 years old |
37.21 (-85.00, 86.09) |
0.3338 |
>80 years old |
30.36 (-45.00, 86.52) |
|
Lactic acid is the product of anaerobic glycolysis in human body. It is mainly produced in skeletal muscle, red blood cell and small intestinal mucosa, and eliminated mostly through liver and kidney. When the patient suffers from septic shock, the amount of circulating blood volume was decreased, making the microcirculation abnormal. This in turn increases the anaerobic metabolism, producing and accumulating a large amount of lactic acid. The amount of lactic acid, its oxygen debt and low perfusion degree are closely related to the severity of septic shock [9]. Early lactate clearance is an important parameter for prognosis assessment and therapy control in sepsis [10]. About 30% of lactic acid clearance was eliminated through the kidneys of human body. Bryant et al found that the declination in early lactic acid indicated improvement in the body tissue hypoxia, further associated with decreased mortality rate. The cut-off value of 6-hour lactate clearance rate was <10%, and was considered as the evaluator index for mortality rate of severe sepsis and septic shock patients during hospitalization period, with optimal specificity and sensitivity. About 6 hours after fluid resuscitation, the patients with high lactate clearance rate had better prognosis compared with patients with low lactate clearance rate [2][4]. Early lactate area scores and serial blood lactate levels as prognostic markers for patients with septic shock: a systematic review[11].A previous study has conducted statistical analysis through a large clinical database. The patients were grouped according to different lactic acid levels (low, medium and high), and the mortality rate of patients was 15%, 25%, and 38% in low, medium and high groups, respectively. These results suggested that lactic acid showed a positive correlation with mortality rate, and there existed a direct cause and effect relationship between lactic acid and mortality rate [12]. According to the latest meta-analysis study, the increased lactic acid levels increased the mortality risk. On the contrary, the increased lactic acid clearance rate could also predict the increased survival rate [13].
Previous study [14] indicated that the survival of sepsis patients had significantly higher lactic acid clearance rate compared to the death sepsis patients, suggesting that the low lactate clearance rate was an independent predictive factor of poor prognosis. Its predictive value for prognosis was obviously greater than that of the initial lactic acid level. In this study, the Logistic model and ROC curve were used to investigate the predictive value of 6-hour lactate clearance rate for mortality rate of patients with different age group. This study investigated the relationship between 6-hour lactate clearance rate of septic shock patients and 28-day mortality rate in 261 patients. The results suggested that age and 6-hour lactic acid clearance rate were the risk factors of mortality in these patients. Our study found that the mean lactic acid clearance rate of patients in the Survival Group was 36.48% .37.21% for patients ≤65 years old, and 35.17 for patients >65 years old, 37.2 for patients ≤80 years old, and 30.36% for patients>80 years old. According to a previous study, the average lactate clearance rate was 37.2% in the survival group of septic patients, and the average clearance rate in the death group was 10.5%[15], which was in consistent with our study results. In this study, we performed a subgroup analysis according to the age (65 and 80 years old). Although there were differences in the renal clearance and lactate metabolism among different age groups, the results of this study showed no significant difference among these in different age groups. Previous literature clearly indicated that early lactate clearance rate could be considered as crucial indicator for sepsis treatment [16][17]. Lactate clearance prognosticates outcome in pediatric septic shock during first 24 h of intensive care unit admission. And as a specific indicator of resuscitation outcome, lactate clearance alone is superior to ScvO2 alone during a standard resuscitation paradigm.[18][19]. Arterial Lactate Clearance Rate was considered as Early Resuscitation Goals in Septic Shock[20],A decrease in lactate concentration over time during septic shock is associated with favourable outcomes[21]. Our data suggested showed that the survivors had higher lactate clearance rate, rather than 10% lactate clearance rate. This result was consistent with the results reported by recent similar studies, showing that >30% lactate clearance rate could improve the clinical prognosis of systemic infection related to hyperlactacidemia patients [22] [23]. The 60% lactic acid could be eliminated by liver metabolism, and the 30% lactic acid by kidney metabolism. Therefore, the traditional concept consider that the elderly patients of age more than 65 or 80 years old were required to achieve higher lactate clearance rate than that of adults to obtain the equal survival rate. This might be the reason for the decreased renal clearance ability of elderly patients. However, the actual lactate clearance rate showed no significant difference between the survivors of both the groups, suggesting that elderly patients were not required to obtain higher lactate clearance rate than that of adults to obtain equal survival rate. Our study has some limitations. This was an experimental study conducted in a single center, with small sample size. Hence, the study with larger sample size was required to further confirm these results.
Data Availability
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethical Approval and Consent
The study was approved by the Ethics Committee of the study centers.
Conflict of interes
The authors declare that they have no actual or potential conflicts of interest.
Fund
This study was supported by the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents (2014-108).
Authors' Contributions
Chunhua Jin,Liquan Huang,Ronglin Jiang designed this study. Liquan Huang collected the data. Chunhua Jin were responsible for the statistical analysis. Chunhua Jin finalized this manuscript.Chunhua Jin is the first author.Liquan Huang is the Corresponding Author.
Acknowledgments
All the information get from the case management system in the medical record room of the First Affiliated Hospital of Zhejiang Chinese Medical University,We appreciate the support of them.