Our investigation yielded three major findings: (1) Timely lactate measurement (within 1 h after ICU admission) was associated with lower risk-adjusted in-hospital mortality in patients with hypotension and hyperlactatemia; (2) Survival benefit of the timely lactate measurement was proportional mediated through shortening the time to IVF; (3) Delayed initial lactate measurement showed a positive association with in-hospital mortality.
This is the first investigation to proof the benefit of timely lactate measurement in all patients with unstable hemodynamics (hypotension and hyperlactatemia) rather than just for septic. In our study, despite patients who had initial lactate measurements completed within 1 h had higher SOFA scores, higher initial lactate level and receive more mechanical ventilation and vasopressors, the in-hospital mortality was significantly lower among patients who had initial lactate measurements completed within 1 h after adjustment for confounding. This parallels the findings of previous limited researches, specifically for septic patients. A retrospective study conducted by HC et al.  declared that early lactate measurement (within 1 h after ICU admission) was associated with lower odds of 28-day mortality among septic patients with elevated serum lactate level. Similarly in Han et al.’s study , septic patients with delayed lactate measurements (lactate samples drawn more than 3 h after meeting severe sepsis criteria) demonstrated the highest in-hospital mortality than did patients who had lactate samples drawn within 3 h. On the whole, our results accentuated an essential role of timely lactate measurement for all patients with unstable hemodynamics admitted to ICU.
Interestingly, the definition of “delay” was depend on the length of exposure to severe sepsis in Han’s study, while the actual onset time of severe sepsis is unknown truthfully, which might occurred outside the ICU, moreover, the etiologies for patients with unstable hemodynamics were not always explicit [23, 24]. Although it’s possible that patients would have received timely resuscitation regardless of the etiologies and whether the lactate level was measured or not, identifying patients could delay the lactate measurement and interventions. Thus, the “timely” in present study was beginning with the onset of ICU admission to led clinicians consider lactate draw earlier for all patients with suspected unstable hemodynamics. Additionally, Han et al.  detected a significant relationship between delay in initial lactate measurement and in-hospital death only in patients with an initial lactate value > 2.0 mmol/L, raising the question that the initial lactate level or other clinical parameters associated with the severity of diseases might cause interaction effects between timely lactate measurement and mortality. However, no significant interactions were detected for initial lactate level, SOFA score and minimal MAP in both cohorts. Actually, there was no highly recognized factors that can represent the disease severity, and the mechanism underlying the interaction between these factors and timely lactate measurement is little known. More research is required to develop a deeper understanding of the interaction effects above.
What’s more attractive is to investigate which factors were contribute to the benefit effects of timely lactate measurement in terms of in-hospital mortality. Therapeutic interventions have been shown to mediate this benefit effect in previous studies, including fluid resuscitation, administration of vasoactive agents, both of which were the important components of resuscitation in circulatory shock . According to a randomized controlled trial by Jasen et al. , patients with lactate levels > 3.0 mmol/L in lactate group (with the objective of decreasing their lactate levels by 20% or more per 2 h in the initial 8 h of their ICU stays) received significantly more fluids and more vasodilator therapy during 0-8h and had a lower hospital mortality compared to the control group. Besides, the time to initial therapeutic interventions were equally important. HC et al.  demonstrated that early lactate measurement (within 1 h after ICU admission) was associated with early antibiotic therapy and vasopressors administration in septic patients with lactate levels > 2.0 mmol/L, and further confirmed that the time to initial vasopressors was proportional mediated the survival benefit effect of early lactate measurement. On the contrary, in our study, although patients in Lac-by1 group had a shorter time to IVF and vasopressors in both cohorts, we only found a significant mediation effect of time to IVF in MIMIC using CMA.
Adequate and timely fluid therapy is an essential part of resuscitation of circulatory shock even in cardiogenic shock. A Retrospective cohort study by Kuttab et al.  found that septic patients who were failed to achieving a 30mL/kg crystalloid bolus within 3 hours of sepsis onset was associated with increased odds of in-hospital mortality, irrespective of patients who were elderly, end-stage renal disease, heart failure or documented volume “overload”. Still in Han et al.’s study , patients with lactate levels > 2.0 mmol/L in draw lactate group had a shorter time to IVF and a lower mortality compared with patients in delayed lactates group. Even though we detect no significant mediation effect of time to IVF in eICU, we should not underestimate the value of timely IVF in the management of shock, since our study is a retrospectively study performed on electronic health record data and require further investigate. Studies undertaken so far provide conflicting evidence concerning the impact of time to initial vasopressor on mortality in circulatory shock [28-30], the effectiveness of vasopressor depends on the type and severity of shock, and most patients would have vasopressors administrated prior to ICU admission in two cohorts. These might account for the insignificant mediation effect of time to initial vasopressors administration.
The strength of study was the use of MIMIC-III and eICU databases which contain comprehensive and high-quality data of well-defined and characterized ICU patients in 147 different hospitals from the USA. We also used model of PSM and IPTW to minimize confounding factors and robust our results. It is difficult to elucidate clearly on causality in a retrospective analysis, we apply the CMA to cover this shortage. The present research is also limited by several factors as follows: First, the diagnosis of circulatory shock is based on clinical, hemodynamic and biochemical markers, which summarized into three parts: systemic hypotension, clinical signs of tissue hypoperfusion and hyperlactatemia , it’s impossible to assess the clinical signs of tissue hypoperfusion in our study, hence we only use hypotension and hyperlactatemia to represent the patients with circulatory shock; Second, our study ranging from 2001 till 2015, the versions of the bundles might have changed during the period, and the results may not be adapted to current practice, however, our results were adjusted for the admission period, in MIMIC, since we couldn’t get the exact year of patients’ admission, we divided patients into two groups in terms of admission year (before 2008 and 2008-2012).Third, lactate guiding resuscitation are intricacy in clinical ,more than just fluid and vasoactive agents. The etiologies of shock, the severity of shock and unmeasured confounding factors such the reaction and the decision of the clinicians on duty are all involved in the management of shock and need to be explored in future. Finally, lactate is an imperfect marker of anaerobic metabolism , and lactate cannot be used to guide resuscitation alone, tissue hypoxia should be assessed in a combined analysis including ScvO2 or indices derived from the veno-arterial carbon dioxide pressure gradient.