Direct assessment of microcirculation in shock: a randomized-controlled multicenter study

Shock is a life-threatening condition defined as a mismatch between oxygen supply and demand in tissue. [1]. The network of microvessels with a diameter < 100 μm is defined as microcirculation and is responsible for tissue supply [2] and homeostasis [3]. Thus, microcirculation is of great importance for clinical routine [4]. Intensive care medicine often tried to optimize systemic blood pressure to improve microcirculation, but several recent studies remained neutral [2, 5]. Indirect methods to assess the microcirculation have been proposed, i.e. serum lactate [6], the capillary refill time [7] or the mottling score [8], that might be suitable resuscitation targets in shock [9]. In parallel, image-based direct visualization with intravital microscopy such as sidestream darkfield-cameras (SDF) have been developed [10]. Several studies showed a correlation between the severity of microcirculatory disturbances and the outcome of critically ill patients [11‐14]. These hand-held devices offer a standardized fast, and non-invasive assessment of the microcirculation at the sublingual mucosa. The obtained results may correlate with the microcirculation of relevant territories such as the gut mucosa and has therefore been suggested as suitable surrogate parameter of whole-body microcirculation [2, 15, 16]. The automated analysis of the video sequences by the AVA 4.3C software should allow a quick objectification of the microcirculatory variables without being dependent on a subjective visual interpretation [17]. However, data on the potential impact of microcirculatory assessment on the decision-making process during shock resuscitation is missing.

The objective of this prospective randomized-controlled trial was to test the hypothesis that considering sublingual microcirculatory perfusion variables in the therapy plan reduces 30-day mortality in patients admitted to the intensive care unit (ICU) with circulatory shock.

The present study represents the largest prospective randomized-controlled trial that investigated the therapeutic impact of real-time knowledge of the status of sublingual microcirculation in patients suffering from different types of shock. The sequential microcirculatory assessment resulted in the decision of treatment changes for fluids or vasopressors in the interventional group, without evidencing any effect on microcirculatory parameters at 24 hours, macrocirculatory and perfusion variables, or 30-day mortality.

In 2002, De Backer et al. described key alterations of the microcirculation in septic [10] and – two years afterwards – in cardiogenic shock [36]. More than 20 years later, DAMIS is the first study that integrated sublingual microcirculatory assessment into the clinical decision-making process in critically ill patients. Our trial demonstrated that real-time knowledge of the microcirculatory status significantly influenced therapeutic decisions of clinicians at the bedside, not only in cardiogenic and septic shock, but in a wide variety of shock patients. The strategy proposed in DAMIS used a multimodal approach to improve tissue perfusion, and provides the clinicians with a microcirculatory consultation that is integrated with standard practice monitoring signals and resuscitation targets, potentially avoiding a reductionist view of the resuscitation process. Apart from this, our study results offer valuable technical data on the use and applicability of real-time microcirculatory assessment in a randomized-controlled clinical trial, in a wide set of patients, such as sepsis, cardiogenic shock, or dehydration [5, 12, 37‐39].

In daily practice, shock resuscitation mainly focuses on normalizing MAP and serum lactate [40]. Nonetheless, achieving a normal MAP does not warrant improvement of microcirculatory flow and tissue perfusion, particularly in patients in which there is a loss of coherence between macro- and microcirculation [5]. Sakr et al. demonstrated in 49 patients suffering from shock that patients with an impaired microcirculation had a significantly worse outcome despite normalizing macrohemodynamic values [37]. On the other hand, persistent hyperlactatemia is not always directly related with tissue hypoperfusion and should be interpreted with caution [41]. Although a high blood-lactate level is associated with an increased odds of death [42, 43], the use of blood-lactate as a single resuscitation target could increase the risk of “over-resuscitation” and induce harm [44, 45]. Therefore, real-time microcirculatory assessment might fill this gap providing valuable information on the status of tissue perfusion, aiding clinicians in the contextual interpretation of standard monitoring signals and in therapeutic decision-making process, namely adjusting fluids and vasopressors. However, in the present study treatment changes after microcirculatory assessment did not improve outcome but showed a trend towards higher mortality compared to the usual care control group.

Early fluid administration in hypovolemic patients may recruit microcirculatory vascular beds and increase overall perfusion parameters [31]. Ospina-Tascon et al. evaluated 60 patients with severe sepsis using SDF microscopy comparing the impact of an early (within 24 h after diagnosing a severe sepsis) to a delayed (more than 48 h) on the sublingual microcirculation [46]. They found that fluid administration enhanced microvascular perfusion in the early, but not late phase of sepsis independently of global hemodynamic effects and of the type of solution. Moreover, in later stages of the disease, fluids could even deteriorate microcirculatory flow by inducing interstitial edema and venous congestion, thus decreasing convective oxygen flow to cells [47]. Vasopressors are often used to increase mean arterial pressure in shock but should be used with caution and considering the microcirculation [13]. Potter et al. collected in their systematic review 6 randomized-controlled trials, 12 interventional, 3 observational, and 1 pilot study with 572 patients [48]. They conclude that there “is no robust evidence to date that any one agent can reproducibly lead to improved microvascular flow” when using mean arterial pressure or cardiac index as target goals. Indeed, as shown by Dubin et al., in patients with abnormal baseline microcirculatory flow, a norepinephrine-induced increase in MAP could recruit perfused vessels [49], while in other patients it could have a detrimental effect, eventually due to excessive precapillary vasoconstriction [50]. Due to these reasons, real-time knowledge of microcirculation emerges as a relevant clinical tool and could further aid physicians to titrate fluids and vasopressors more accurately [51, 52].

In the present study, microcirculatory values were not significantly associated with the outcome. These results are in line with the microSOAP trial (n = 501 ICU patients) that found in a mixed ICU population, lactate levels and several macrohaemodynamic variables, but not microcirculatory variables to be independently associated with hospital mortality [21]. On the contrary, the MicroDAIMON study (n = 97 ICU patients) demonstrated an independent association between baseline MFI < 2.6 and outcome (OR 4.59 95% CI 1.34–15.75, p = 0.015) [53]). In another study with 252 patients suffering from severe sepsis, PPV was normal (≥ 90%) in only 9 (4%) patients and moderately altered (between 80 and 90%) in 35 (15%) patients [54]. In DAMIS, all patients received immediate hemodynamic stabilization before the first SDF measurement. This might explain the relatively high sPPV values, and the lack of association between sPPV and the main outcome.

Microvascular abnormalities differ between different types of shock. Especially septic shock is characterized by typical microvascular inhomogeneous flow [55], while patients with cardiogenic shock suffer – for example—from decreasing vascular density, although heterogeneity also occurs in cardiogenic shock [56, 57]. However, DAMIS considered shock as a clinical syndrome defined by hypoperfusion and consecutive microcirculatory impairment. Capillary refill time and serum lactate are established parameters in septic and cardiogenic shock [7, 58]. Usually, variables of flow rather than variables that represent capillary density are recommended to be used for risk stratification and managing adjustments in – for example – fluid therapy [59]. The most used flow variable is the microvascular flow index (MFI). Especially on the first day of ICU admission, an abnormal and low MFI (defined as < 2.6) is associated with adverse outcomes [53]. MFI needs the manual interpretation of the investigator, but AVA 4.3C does not provide any information about the microcirculatory flow pattern. Other approaches, such as the Point of Care Microcirculation (POEM) score, consider the flow pattern with major attention [60]. The DAMIS study protocol had intentionally omitted a subjective assessment of the flow pattern by the investigator since the software cannot calculate this parameter automatically. Using this automatic algorithm surpasses this individual (subjective) evaluation providing (independent) information about microvascular perfusion (yes/no), density, and the percentage of perfused vessels. Previous studies found a sufficient correspondence between a low PPV and low MFI with a PPV of 88% in the low MFI group and a PPV 94% in the high MFI group [59]. Furthermore, PPV has a low observer variability [61].

The post-hoc sensitivity analyses revealed no significant effects in the different subgroups except for the subgroup with low SOFA score, but the clinical relevance seems negligible. As evolution of microcirculation was similar in all subgroups, the results are probably more a sign for the failure of the selected interventions than the failure of microcirculatory monitoring. The suggested treatment adjustments after microcirculatory counseling did not routinely include inotropic drugs to improve the microcirculation, because the study protocol basically decided to prevent potential heart injury in a mixed population. In the present study, we found a trend towards higher mortality in the interventional group. However, the post-hoc analysis excluding patients with a mismatch between announced and performed treatment changes showed no differences between both groups. It is also possible that treatment consequences of microcirculatory improvement attempts led to a clinical under- or overtreatment resulting in patient harm.

This study opens the road to further analyze the impact of real-time microcirculatory assessment in shock resuscitation. Future studies should explore the best therapeutic interventions to address each pattern of microcirculatory derangement, and its’ relationship with patient-centered outcomes.

Some limitations of this study should be acknowledged. First, there was no additional re-evaluation of the impact of the interventions after 24 hours, which might imply that an ineffective or partially effective treatment was sometimes applied, and no alternative treatment was used in case of failure. Sublingual microcirculation was measured only on two time points. However, previous studies showed that on the first day of ICU admission, an impaired sublingual microcirculation is associated with adverse outcome, while later measurements provided no prognostic information [53]. Measuring on admission might give the opportunity to understand the microcirculation directly after the immediate resuscitation to unmask hemodynamic incoherence. The measurement after 24 hours was meant as control if the treatment changes after the first measurement had been able to improve the microcirculatory values. All patients were hemodynamically stabilized immediately at ICU admission. Consequently, the mean arterial pressure was controlled with vasoactive drugs, which was necessary for inclusion (see supplemental Table 9). A minority of videos evidenced lower technical quality, which might have an impact on the generalizability of the microcirculatory data, although our quality scores obtained are in line with other studies [62], and it must be underlined that videos were performed by experienced trained investigators who were not part of the ICU team. The study protocol was not binding. The counseling in the intervention group was deliberately not binding, as this was neither possible nor reasonable from a scientific point of view with weak evidence, nor for medico-legal reasons. If a mandatory algorithm had been required, this would have decisively changed the character of the study. However, the results clearly show that the consultation had an influence on the therapy adjustments for volume and catecholamine therapy, although there was a not insignificant proportion of patients in whom the announced therapy adjustments were not implemented at all, but in some cases contrary measures were taken. This discrepancy had been identified only a posteriori. The reasons for this are unclear, but the decision about therapy rested exclusively with the intensive care treatment team. We hypothesize that the treating team apparently considered many factors other than microcirculation data, such as serum lactate, organ function, hemodynamics, and other factors, to adjust therapy. We can only speculate that other aspects outweighed microcirculatory advice in some patients during the assessment. Furthermore, the SDF-assessment focused on the sPPV as most promising and reproducible value reflecting the patient’s microcirculatory tissue perfusion. Density values might be important as well, but there exist even less defined cut-off values in the literature, while density parameters are mostly used intra-individually, but not inter-individually. It must be mentioned that, currently, there is no established standard approach for optimizing the microcirculation. Furthermore, there was a considerable percentage of patients with various degrees of limitations for life-sustaining therapy, which are known to be a significant confounder for short-term mortality in critically ill patients [63]. The study provided data about the type and day of the limitation, but not about the cause and motivation for life-sustaining therapy. Of course, the study protocol allowed including different types of shock leading to a certain etiological heterogeneity, but they all lead to an impaired microcirculation. All these factors represent major confounders that could not be adequately adjusted due to the low sample size. Furthermore, the sensitivity analysis did not reveal any difference between the different etiologies. Another limitation is that recruitment occurred competitively resulting in an imbalance of inclusion rates, mostly because the University Hospital of Duesseldorf was the coordinating center with a superior number of trained teams. This distribution did not allow to adjust for any center effects. Furthermore, the randomization process that used blocks of 50 seals. Thus, the other study sites did not used a full block, which might contribute to an imbalanced allocation.

The study protocol anticipated that an early microcirculatory-driven adjustment of catecholamine- and fluid therapy provides a significant benefit for 30-day survival of 19% compared to usual care. However, the result was unable to reject the null hypothesis. Thus even with a less pronounced anticipated effect and – consequently – larger sample size, any positive effect in this study setting cannot be expected. Even after excluding all patients from the interventional group with mismatches regarding the announced and performed adjustments, there was no benefit for the (remaining) interventional compared to the control group. Last, as outlined by Ospina-Tascón et al., choosing mortality as primary endpoint in an intensive care setting might not be the optimal strategy evaluating the effectiveness of interventions [64].

Knowledge of sublingual microcirculatory status resulted in significantly more treatment adjustments during shock resuscitation. However, these adjustments did not impact any microcirculatory variable after 24 hours or patient-centered outcomes although we could not exclude a small reduction in mortality or a large increase in mortality with the integration of microcirculatory assessments in the therapy plan of critically ill patients.