Several researches have confirmed that LAR is associated with mortality and the development of multiple organ dysfunction syndrome (MODS) in generalized or pediatric sepsis patients [12–14, 16, 17]. A recent study showed that LAR had higher value than single lactate level on predicting neurologic outcomes and survival to discharge in patients suffering out-of-hospital cardiac arrest . We make a reasonable hypothesis that LAR would also be superior to single lactate in predicting mortality in TBI patients.
As a component of LAR, the serum lactate is widely acknowledged as an indicator of inadequate tissue perfusion. And the correlation between serum lactate and mortality has been verified in many clinical settings such as sepsis, shock and trauma [18–21]. However, several studies exploring the association between lactate and outcome in TBI patients showed different conclusions [22–25]. One of these studies even indicated that TBI patients whose serum lactate > 5 mmol/L were likely to have a better survival than those with relatively low lactate level . Furthermore, exogenous supplement of lactate by infusing hypertonic sodium lactate has been verified beneficial for survival and neurologic outcome and cognitive recovery in TBI animal models and patients [26–32]. In our study, serum lactate was higher in non-survivors than survivors, and was useful in predicting mortality in moderate to severe TBI patients with AUC of 0.733. The most key point we think to understand and discuss the relationship between blood lactate and outcome of TBI patients is the different meaning of increased serum lactate between the initial pathophysiological state and exogenous supplement state.
A previous study found that serum lactate would still increase even in normotensive TBI patients . This fact indicated initial increase of serum lactate after TBI could not only caused by peripheral tissue hypoperfusion due to blood loss, but also the worsening tissue oxygenation due to complications such as acute lung injury and neurogenic lung edema. The detailed mechanism of initial increased lactate after TBI deserves further exploration. Initially put forward in 1994, the astrocyte–neuron lactate shuttle has changed the opinion that lactate is only an useless waste during anaerobic metabolism process . It was illustrated that astrocyte would uptake glucose and metabolized it into lactate under the stimulation of much glutamate. Those generated lactate would be transferred to neurons and enter the tricarboxylic acid cycle for energy demand of brain. The increased serum lactate directly penetrating the blood-brain-barrier would also accumulate in neuronal intercellular space and utilized by neurons for energy production [34, 35]. And one study discovered that brain uptake of lactate reflecting by arterio-venous differences for lactate (AVDlac) was higher in more severe TBI patients and non-survivors . Therefore, a reasonable conjecture is that uptake of lactate from neuron after more severe TBI would decrease more serum level of lactate. However, it was confirmed that the magnitude of absorbed lactate by brain was extremely small compared with magnitude of serum lactate level . Therefore, the initial fluctuation of serum lactate level after TBI is mainly attributable to pathophysiological changes of systemic body but not of single brain. This argument might be confirmed by the finding of previous study that blood lactate levels was associated with Sequential Organ Failure Assessment (SOFA) score which reflects systemic organ failure in unspecified ICU patients . In addition, blood lactate level was also verified inversely associated with Glasgow Coma Scale (GCS) in isolated TBI patients . Although higher serum lactate is beneficial for brain energy supplement, the effect of poor pathophysiologic condition indicated by higher serum lactate on outcome could be greater than relatively transient and small effect of energy supplement. Generally, the initial increased serum lactate in natural pathophysiologic condition is inversely associated with favorable outcome in TBI patients by reflecting degree of systemic organ failure and initial brain injury severity.
On the contrary, the continuously increased serum lactate level during exogenous infusion of hypertonic sodium lactate could indicate better survival and recovery after TBI[30, 38, 39]. Because increased serum lactate during exogenous supplement is not a reflection of initial tissue hypoperfusion and organ failure, but only means more alternative energy fuel for injured brain. This is a key point to distinguish the meaning of increased serum lactate under the initial pathophysiological condition and exogenous supplement condition. The beneficial effects of hypertonic sodium lactate on injured brain has been definitely recognized including improving cerebral perfusion and brain glucose availability, reversing impaired brain metabolism and oxygenation, etc. [26–28]. In addition to the function of neuroenergetic material, lactate is actually a crucial signaling molecule which could modulate the production of pentose phosphate, an important molecule to prevent oxidative stress injury in brain [40–43]. It was testified that lactate would provide 60% of the energy source for cerebral metabolism as blood lactate increases to 5 mmol/L [44, 45], To sum up, the elevated serum lactate level during exogenous supplement of lactate is beneficial for neurologic and survival outcome, and cognitive recovery after TBI.
The albumin level of non-survivors was significantly lower than survivors in this study. Produced by hepatocytes, albumin works in multiple way to maintain physiologic function of healthy body including constituting plasma osmotic pressure, transporting insoluble small organic molecules and combining heavy metal ions to eliminate their toxic effects. And low albumin level is also considered as an efficient marker of malnutrition. The causes of hypoalbuminemia after TBI is diversified including initial blood loss due to injury, consumption by secondary oxidative stress injury and physiological hypoalbuminemia resulted from massive crystal liquid infusion. The reduction of serum albumin and its association with mortality after TBI have been confirmed in previous studies [46–49]. The correlation between hypoalbuminemia and poor outcome of TBI patients could be explained by the brain edema and subsequent increased intracranial pressure resulted from insufficient intravascular osmolality. In addition, lower level of albumin could indicate more severe degree of systemic inflammatory response, which was discovered correlated with poor outcome of TBI patients [50, 51]. In our study, the AUC value of single lactate was 0.733. After the incorporation of albumin, the AUC value of LAR was elevated to 0.780. This result indicated that LAR, calculated by the value of lactate and albumin, could more comprehensively reflect tissue injury severity and systemic organ function of TBI patients. The prognostic model constructed by us, which consisted of GCS, glucose, LAR and RDW, is useful in predicting mortality of moderate to severe TBI patients with high discriminative ability and sensitivity.
This study had several limitations. Firstly, this observational study was performed in a single center so that the selection bias was inevitable. A further prospective study with larger sample size in other centers should be conducted to externally validate the predictive value of our prognostic model. Secondly, the long-term neurologic outcome and recovery status were not followed up and recorded so that we could not explore the correlation between LAR and them. Thirdly, the drugs and operations of prehospital emergency medical care which could influence the serum lactate level were not recorded by us. Our results might be confounded by these factors.