Serum lactate level is a major predictor of survival among patients with sepsis (1), and was included in the recent definition of septic shock (2). Furthermore, dynamic lactate indices, such as lactate clearance, have been reported to be useful predictors for survival in patients with septic shock (3). Lactate clearance is also useful to guide the resuscitation of patients with septic shock. A recent meta-analysis reported that early lactate clearance-guided therapy was associated with a lower mortality rate among patients with sepsis (4).
Dexmedetomidine, an alpha 2-adrenergic agonist sedative, has been associated with reduced mortality from sepsis in the subgroup analysis of a number of randomized controlled trials (5, 6). Dexmedetomidine may have beneficial effects on patients with septic shock. Dexmedetomidine has been reported to increase lactate clearance by adrenergic modulation in sheep with experimental septic shock (7). Small, randomized controlled studies have also found that dexmedetomidine decreased lactate levels in surgical patients without sepsis (8, 9). One study suggested that dexmedetomidine may ameliorate liver damage and decrease lactate level (8). However, the effect of dexmedetomidine on lactate clearance in patients with septic shock is currently unknown. The aim of the present study was to determine whether dexmedetomidine could increase lactate clearance in patients with septic shock.
MATERIALS AND METHODS
We conducted a post hoc subgroup analysis of the Dexmedetomidine for Sepsis in Intensive care unit Randomized Evaluation (DESIRE) trial (6), a multicenter randomized controlled trial involving eight intensive care units (ICUs) in Japan. The DESIRE trial enrolled 201 patients with sepsis undergoing ventilation from February 2013 to January 2016. The DESIRE trial was designed to assess the effects of a sedation strategy with dexmedetomidine (DEX group) compared with a sedation strategy without dexmedetomidine (non-DEX group). Patients in the DEX group received dexmedetomidine soon after randomization, and further sedatives were added to achieve the targets of sedation depth, a Richmond Agitation-Sedation Scale (RASS) score of 0 (calm) during the day and the score of –2 (lightly sedated) during the night. Patients in the non-DEX group received sedatives without dexmedetomidine to keep the same target RASS. Description of the intervention, inclusion and exclusion criteria, approval of the institutional review boards, and informed consent have been previously reported (6). The treatment for septic shock was based on the Guidelines for the Management of Sepsis by the Japanese Society of Intensive Care Medicine (10).
Of the 201 randomized patients, this subanalysis included patients with septic shock. Septic shock was defined as three or more cardiovascular components on the Sequential Organ Failure Assessment (i.e., patients requiring moderate or high dose of vasopressors) and a lactate level over 2 mmol/L at admission before randomization.
We collected data on the initial serum lactate level (Lactateinit) at randomization and all subsequent measurements of serum lactate within 48 h of randomization. We evaluated serum lactate levels at 6, 12, 24, and 48 h after randomization. The serum lactate level measured within 6 h was regarded as the serum lactate level at 6 h (Lactate6h). If multiple measurements were performed, the closest time point to 6 h was applied. The serum lactate level measured between 6 and 12 h was regarded as the serum lactate level at 12 h (Lactate12h) and lactate levels at 24 h (Lactate24h) and 48 h (Lactate48h) were similarly evaluated.
The primary outcome was lactate clearance at 6 h (Lactate clearance6h). Lactate clearance6h was calculated as [(Lactateinit − Lactate6h)/Lactateinit] × 100. The secondary outcomes were lactate clearance at 12 h (Lactate clearance12h), 24 h (Lactate clearance24h), 48 h (Lactate clearance48h), heart rate over 48 h, mean blood pressure over 48 h, fluid administration between 0 and 24 h and between 24 and 48 h, length of ICU stay, 28-day mortality, and hospital mortality.
Continuous variables were presented as the mean ± SD or the median and interquartile range (IQR). Categorical variables were presented as numbers and percentages (%). For comparisons between the dexmedetomidine group and the control group, we used the chi-squared test or Fisher exact test for categorical variables and the t test or Wilcoxon rank sum test for continuous variables. Lactate clearance was highly influenced by Lactateinit; therefore, we developed a multiple linear regression model to assess the effect of dexmedetomidine on lactate clearance, adjusting for Lactateinit. Heart rate and mean blood pressure were compared between the groups using two-way repeated measurements analysis of variance. A two-sided P < 0.05 was considered statistically significant, and all analyses were performed using JMP Pro software (version 12.2; SAS Institute Inc., Cary, NC).
Among 201 patients in the DESIRE trial, we identified 112 patients presenting septic shock. One patient in the dexmedetomidine group was excluded due to missing data on the serum lactate level at randomization, and we included 111 patients in analysis (Fig. 1).
Patient characteristics were comparable in both groups, except for the serum lactate level at randomization, which was higher in the non-DEX group than in the DEX group, although the difference was not statistically significant (Table 1). The serum lactate levels were measured after randomization in the DEX and non-DEX groups, respectively, at 5 (4 – 6) h and 5 (4 – 6) h (6 h; P = 0.38), 10 (9 – 11) h and 11 (10 – 12) h (12 h; P = 0.70), 22 (20 – 24) h and 22 (20 – 23) h (24 h; P = 0.99), and 46 (43 – 48) h and 46 (43 – 47) h (48 h; P = 0.22).
The primary outcome, lactate clearance6h could be evaluated in 57 patients (95%) in the DEX group and in 48 patients (94%) in the non-DEX group (Table 2). Lactate clearance6h was not higher in the DEX group (23.3 ± 29.8) than in the non-DEX group (11.1 ± 54.4) (mean difference 12.2; –4.4 to 28.8, P = 0.15), but the adjusted analysis with Lactateinit showed a significant difference (adjusted mean difference 18.5; 2.2–34.9, P = 0.03). Similarly, the adjusted analysis showed absolute changes in serum lactate levels within 6 h were significantly greater in the DEX group than those in the non-DEX group (Additional file 1, http://links.lww.com/SHK/A668, and 2, http://links.lww.com/SHK/A669).
Adjusting for Lactateinit, we also found a significantly higher Lactate clearance12h in the DEX group, whereas there was no difference in Lactate clearance24h and Lactate clearance48h between groups.
In terms of the secondary outcomes, systemic hemodynamics, such as heart rate and mean blood pressure, were not significantly different between the groups (Additional file 3, http://links.lww.com/SHK/A670, 4, http://links.lww.com/SHK/A671, 5, http://links.lww.com/SHK/A672). We also found no significant difference in the dose of fluid administration, length of ICU stay, 28-day mortality, and hospital mortality (Table 3). No significant difference was observed between the two groups in the total SOFA score during the first 8 days. Analysis of the SOFA score for each organ function during first 8 days revealed that the DEX group had lower renal scores than the non-DEX group (renal SOFA score at day 4, 0 [0–1] vs. 1 [0–2], P = 0.18; at day 6, 0 [0–1] vs. 1 [0–2], P = 0.048; and at day 8, 0 [0–1] vs. 1 [0–2], P = 0.016) (Additional file 6, http://links.lww.com/SHK/A673).
We found that dexmedetomidine may increase lactate clearance in patients with septic shock, although dexmedetomidine had no effect on systemic hemodynamics. Dexmedetomidine did not improve mortality rate.
Several observational studies show that lactate clearance was associated with mortality in patients with sepsis (3, 11, 12). However, the increased lactate clearance as such does not provide the survival benefit. The reversal from circulatory failure and protection from organ dysfunction improve survival and result in increased lactate clearance.
Traditionally, lactic acidosis in patients with sepsis is a marker of hypoperfusion, i.e., anaerobic glycolysis due to inadequate oxygen delivery. But a recent study showed that the mechanism of hyperlactatemia was multifactorial (13). The serum lactate level reflects the balance between production and metabolism of lactate. Hyperlactatemia is caused by overproduction, reduced metabolism, or both. In patients with sepsis, the lactate production could be increased anaerobically and aerobically. The sympathetic nerve overstimulation is one of the major contributor to this mechanism. As an example, lactate is produced anaerobically by catecholamine-induced vasoconstriction that results in tissue hypoperfusion (14). Excessive catecholamines can also exacerbate aerobic glycolysis in muscle (15) and results in hyperlactatemia. Conversely, lactate is mainly metabolized in the liver, and partially in the kidney and other organs. In animal models with shock, utilization of lactate by liver is shown to be impaired (16). In addition, sepsis is one of the major risk factors of acute kidney injury in patients with mechanical ventilation (17).
Dexmedetomidine is a highly selective, centrally acting alpha 2-agonist that may provide better sedation than other sedatives in patients with sepsis (6). In addition to the sedative effect, a previous study showed that dexmedetomidine suppressed the release of endogenous catecholamines in healthy humans (18). Dexmedetomidine may alleviate excessive catecholamine-induced lactate overproduction. But the present study was not designed to evaluate the sympathetic nerve overstimulation. So, the markers of sympathetic nerve and lactate overproduction such as serum epinephrine level and muscle lactate were not measured. This mechanism has not been proved and remains as a hypothesis that needs to be attested.
Dexmedetomidine may provide a protective effect against organ dysfunction. A recent study showed that dexmedetomidine attenuated lipopolysaccharide-induced hepatic injury and decreased proinflammatory cytokines in a rat model of sepsis (19). Dexmedetomidine also provided protection from acute kidney injury by decreasing TNF-alpha in a rat model of sepsis (20). A randomized controlled trial in the setting of liver transplantation reported that dexmedetomidine during surgery attenuated liver damage and implied that dexmedetomidine can increase lactate clearance through the amelioration of liver function (8). In addition, meta-analysis in the setting of cardiac surgery reported that dexmedetomidine prevented acute kidney injury after surgery (21). In the present study, the DEX group had lower renal SOFA score during the first 8 days (but not liver SOFA score) and may partly explain the increased lactate clearance.
There is scarce data in current literature about the effect of dexmedetomidine on lactate clearance in septic shock. An animal study using a septic shock model found that dexmedetomidine was associated with lower arterial and portal vein lactate value by adrenergic modulation (7). In a randomized controlled study for patients with conditions other than sepsis, administration of dexmedetomidine during surgery resulted in decreased lactate levels at the end of surgery in patients undergoing liver transplantation (8) and pediatric cardiac surgery (9).
The present study also showed that dexmedetomidine may increase lactate clearance in patients with septic shock. Recently, we have shown an 8% reduction in the 28-day mortality in patients with sepsis treated with dexmedetomidine (6). In this substudy including patients with septic shock, a 13% reduction in 28-day mortality was also demonstrated in the dexmedetomidine group, although the difference was not statistically significant. This survival benefit may be associated with the increased lactate clearance due to dexmedetomidine. The present study indicates that dexmedetomidine can be used for the treatment of sepsis, in addition to sedation.
To the best of our knowledge, this is the first study investigating the effect of dexmedetomidine on lactate clearance in patients with septic shock. It is important to note that dexmedetomidine has a beneficial effect on lactate dynamics, despite unchanging indices of systemic hemodynamics. Inclusion criteria of our study were three or more cardiovascular components on the SOFA score (patients requiring vasopressors), and an elevated lactate level (>2 mmol/L). Therefore, the patients of our study were almost identical to patients with septic shock defined by sepsis 3, which ensured the comparability with future trials conducted on the basis of sepsis 3 definition (1). The present study also has the following strengths: it is a prospective study involving humans, it used a randomized design to compare the use of dexmedetomidine with controls, and there was a low rate of missing data.
Our study has several limitations. First, the initial lactate level was marginally higher in the non-DEX group than in the DEX group. Lactate clearance is strongly influenced by initial lactate value. Therefore, we adjusted for the initial serum lactate level. Second, the sample size was relatively small because our study was a post hoc subgroup analysis. As with the main study, which may have been underpowered for mortality, the assessment of the effect of dexmedetomidine on mortality in the present study may require a larger sample size. Third, the present study did not evaluate the effect of dexmedetomidine on organ protection. We hypothesized that the increase in lactate clearance was a result of suppressed endogenous catecholamines and protection from liver and renal dysfunction. However, the underlying mechanism remains unknown and future studies are needed to test this hypothesis.
Among mechanically ventilated patients with septic shock, sedation using dexmedetomidine resulted in a greater increase in lactate clearance than sedation without dexmedetomidine. However, our study failed to show that dexmedetomidine improved survival rate. It remains unknown whether dexmedetomidine could improve patient outcome. Additional prospective research is needed to evaluate this hypothesis and to determine the effect of dexmedetomidine on mortality.
The authors thank DESIRE Trial Investigators, namely, Masaou Tanaka (Wakayama Medical University); Tomonori Yamamoto (Osaka City University, Osaka, Japan); Akihiro Fuke (Osaka City General Hospital, Osaka, Japan); Atsunori Hashimoto (Hyogo College of Medicine, Nishinomiya, Japan); Hiroyuki Koami (Saga University Hospital, Saga, Japan); Satoru Beppu (National Hospital Organization Kyoto Medical Center, Kyoto, Japan); Yoichi Katayama (Sapporo Medical University, Sapporo, Japan); Makoto Itoh (Yamaguchi Grand Medical Center, Yamaguchi, Japan).
1. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M. Developing a new definition and assessing new clinical criteria for septic shock
: for the Third International Consensus Definitions for Sepsis and Septic Shock
315: 775–787, 2016.
2. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock
315: 801–810, 2016.
3. Nichol A, Bailey M, Egi M, Pettila V, French C, Stachowski E, Reade MC, Cooper DJ, Bellomo R. Dynamic lactate indices as predictors of outcome in critically ill patients. Crit Care
4. Gu WJ, Zhang Z, Bakker J. Early lactate clearance
-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med
41: 1862–1863, 2015.
5. Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, Herr DL, Maze M, Ely EW. Effect of dexmedetomidine
versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care
6. Kawazoe Y, Miyamoto K, Morimoto T, Yamamoto T, Fuke A, Hashimoto A, Koami H, Beppu S, Katayama Y, Itoh M, et al. Effect of dexmedetomidine
on mortality and ventilator-free days in patients requiring mechanical ventilation with sepsis: a randomized clinical trial. JAMA
317: 1321–1328, 2017.
7. Hernandez G, Tapia P, Alegria L, Soto D, Luengo C, Gomez J, Jarufe N, Achurra P, Rebolledo R, Bruhn A, et al. Effects of dexmedetomidine
and esmolol on systemic hemodynamics and exogenous lactate clearance
in early experimental septic shock
. Crit Care
8. Fayed NA, Sayed EI, Saleh SM, Ehsan NA, Elfert AY. Effect of dexmedetomidine
on hepatic ischemia-reperfusion injury in the setting of adult living donor liver transplantation. Clin Transplant
30: 470–482, 2016.
9. Naguib AN, Tobias JD, Hall MW, Cismowski MJ, Miao Y, Barry N, Preston T, Galantowicz M, Hoffman TM. The role of different anesthetic techniques in altering the stress response during cardiac surgery in children: a prospective, double-blinded, and randomized study. Pediatr Crit Care Med
14: 481–490, 2013.
10. Oda S, Aibiki M, Ikeda T, Imaizumi H, Endo S, Ochiai R, Kotani J, Shime N, Nishida O, Noguchi T, et al. The Japanese guidelines for the management of sepsis. J Intensive Care
11. Liu V, Morehouse JW, Soule J, Whippy A, Escobar GJ. Fluid volume, lactate values, and mortality in sepsis patients with intermediate lactate values. Ann Am Thorac Soc
10: 466–473, 2013.
12. Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC, Kline JA, Jones AE. Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock
143: 1548–1553, 2013.
13. Chertoff J, Chisum M, Garcia B, Lascano J. Lactate kinetics in sepsis and septic shock
: a review of the literature and rationale for further research. J Intensive Care
14. Meier-Hellmann A, Reinhart K, Bredle DL, Specht M, Spies CD, Hannemann L. Epinephrine impairs splanchnic perfusion in septic shock
. Crit Care Med
25: 399–404, 1997.
15. Levy B, Desebbe O, Montemont C, Gibot S. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock
30: 417–421, 2008.
16. Arieff AI, Graf H. Pathophysiology of type A hypoxic lactic acidosis in dogs. Am J Physiol
17. Lombardi R, Nin N, Penuelas O, Ferreiro A, Rios F, Marin MC, Raymondos K, Lorente JA, Koh Y, Hurtado J, et al. Acute kidney injury in mechanically ventilated patients: the risk factor profile depends on the timing of AKI onset. Shock
48: 411–417, 2017.
18. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine
in humans. Anesthesiology
93: 382–394, 2000.
19. Chen JH, Yu GF, Jin SY, Zhang WH, Lei DX, Zhou SL, Song XR. Activation of alpha2 adrenoceptor attenuates lipopolysaccharide-induced hepatic injury. Int J Clin Exp Pathol
8: 10752–10759, 2015.
20. Hsing CH, Lin CF, So E, Sun DP, Chen TC, Li CF, Yeh CH. alpha2-Adrenoceptor agonist dexmedetomidine
protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5. Am J Physiol Renal Physiol
21. Shi R, Tie HT. Dexmedetomidine
as a promising prevention strategy for cardiac surgery-associated acute kidney injury: a meta-analysis. Crit Care