Our main finding was the association of delayed 6-hour lactate clearance to hepatosplanchnic hypoperfusion but not to systemic hemodynamics or other perfusion parameters in hyperdynamic septic shock patients undergoing aggressive resuscitation.
The relevance of the concept of lactate clearance has been recently highlighted [4–6, 24]. Therefore, it appears as critical to gain insight into potential pathogenic mechanisms associated to failure to clear lactate, especially in hyperdynamic septic shock patients in whom a low flow state is by definition a less probable mechanism. However, this task may be particularly complex in the setting of septic shock where an easy assumption to make is to attribute persistent hyperlactatemia to inadequate resuscitation. Indeed, although hypoperfusion is the most common cause of hyperlactatemia, increasing evidence for nonhypoxic related mechanisms, such as sustained hyperadrenergia with accelerated aerobic glycolysis, has recently expanded our understanding of the physiological meaning of lactate in sepsis [7–13]. Nevertheless, a limited number of factors, such as persistent global hypoperfusion, microcirculatory dysfunction, impaired hepatosplanchnic perfusion, or liver dysfunction, are more likely involved in a resuscitation scenario. A multimodal perfusion monitoring approach relying on relatively simple or noninvasive clinical tools can identify persistent global hypoperfusion. In our series of hyperdynamic septic shock patients, evolution of metabolic and peripheral perfusion parameters tends to rule out global hypoperfusion as a cause of impaired lactate clearance. In fact, these patients presented a median cardiac index >4 l/min/m2, SvO2 >70%, p(v-a)CO2 <5 mmHg, CRT <4 sec, and a thenar StO2 >80%, which is consistent with an hyperdynamic state.
Videomicroscopic bedside techniques have allowed direct visualization of microvascular flow, especially at the sublingual mucosa . Microcirculatory flow or density abnormalities have been described and linked to bad outcome during septic shock [26, 27]. Microcirculatory dysfunction with microvascular shunting could contribute to the genesis of hyperlactatemia in selected patients . We recently demonstrated a significant correlation between hyperlactatemia and microcirculatory derangements in a large series of septic shock patients . Interestingly, the majority of our patients exhibited significant microcirculatory abnormalities, irrespective of the status of lactate clearance. The median 6-hour values of proportion of perfused vessels, MFI, and PVD among microcirculatory parameters are well beyond the thresholds associated with morbidity or mortality in previous studies [1, 2]. This is consistent with a profoundly abnormal StO2 recovery slope after VOT in our patients with a low lactate clearance, suggesting a persistent microvascular dysfunction.
Splanchnic contribution to hyperlactatemia may be secondary to an increased hypoxic or nonhypoxic gut lactate production, a decreased hepatic lactate clearance secondary to hypoperfusion or dysfunction, or a combination of both [28–31]. In our study, patients with a lactate clearance <10%, increased pCO2 gap, and decreased ICG-PDR to extremely abnormal values (medians of 33 mmHg and 9.7%, respectively) after 6 hours of resuscitation, suggesting the presence of sustained hepatosplanchnic hypoperfusion despite a global hyperdynamic flow status. Moreover, because no difference in liver enzymes between these subgroups was found, it is highly probable that alterations in hepatic flow rather than function were responsible for the low ICG-PDR. Our results confirm and expand previous findings by Friedman et al. that demonstrate a significant association of persistent hyperlactatemia at 24 hours with gastric mucosa hypoperfusion, but without correlation to systemic hemodynamics . Our study, using a more comprehensive and multimodal monitoring approach, supports a relationship between persistent hyperlactatemia and hepatosplanchnic hypoperfusion; the latter is confirmed by an independent technique, such as ICG-PDR.
Several factors theoretically could have contributed to the development of both gut hypoperfusion and hyperlactatemia in our patients. An ischemic bowel may be a source of anaerobic lactate production, which depending on hepatic clearance could result in systemic hyperlactatemia, but only one of these patients was operated on for a nonocclusive colonic ischemia with secondary peritonitis. Some clinical reports have emphasized that intra-abdominal hypertension could induce hyperlactatemia through gut mucosal hypoperfusion and also decrease hepatic lactate clearance [33, 34]. However, no difference in intra-abdominal hypertension between subgroups was observed in our series. Hypovolemia or high doses of vasoconstrictors could hasten hepatosplanchnic hypoperfusion, but this was not the case for our patients, because final pulse pressure variation was 2% (range, 0–5%), with NE doses of only 0.08 (0.05-0.6) mcg/kg/min.
The presence of occult hepatosplanchnic hypoperfusion in the setting of a global hyperdynamic state and with parallel improvements or no change in peripheral perfusion, metabolic, and microcirculatory parameters may appear contradictory. However, regional hepatosplanchnic vasoconstriction is a physiologic and early neurohumoral response to shock that can cause prolonged hypoperfusion and gut ischemia. Persistence of this state as represented by an abnormal gastric tonometry at 24 hours has a strong prognostic significance, irrespective of the status of systemic hemodynamics . Unfortunately, a decline in the availability of gastric tonometry has precluded intensivists to use this valuable physiological monitor. Rather novel techniques, such as transcutaneous assessment of indocyanine green plasma disappearance rate, have become available, offering an opportunity for the early diagnosis of hepatic dysfunction or hypoperfusion . Previous studies demonstrated a strong association between ICG-PDR and outcome in critically ill patients [36, 37]. The ICG-PDR is influenced both by liver function and perfusion, but when evaluated in short periods of time, it mainly reflects hepatosplanchnic perfusion, because the function of liver cells does not change rapidly . Thus, this method could eventually be used as a surrogate for gastric tonometry, and indeed we found a significant correlation between both techniques (Figure 2).
Our study has several limitations. Because it was designed as an acute clinical physiological pilot study, it included a limited number of patients, thus making it difficult to generalize conclusions. Only two sets of measurements were considered, thus precluding the possibility of capturing earlier or late changes of some of these parameters. The majority of patients were of an abdominal source, a factor that eventually could influence the results of the hepatosplanchnic perfusion assessment. We did not address potential nonhypoxic causes for persistent hyperlactatemia. Despite these limitations, we think that our data may be useful to reconsider the approach to persistent hyperlactatemia in hyperdynamic septic shock patients.