In this prospective observational study, we compare the predictive ability of the macrocirculations (HR, MAP and CVP), microcirculations (CRT, PPI and malting score) and fluid balance, lactate and clearance lactate on the outcomes (mortality, RRT, vasopressors, ICU LOS and MV duration) of patients with septic shock during initial resuscitation. In addition, to have the cumulative effect of the markers, we combined the microcirculation and macrocirculation markers separately at three different time intervals to predict the consequences of septic shock. Our findings showed that the accuracy of the microcirculation markers to predict outcomes were comparable and higher than that of the macrocirculation markers. The three most important predictors of mortality identified in our study were PPI with (AUC: 0.993), CRT with (AUC: 0.990) and lactate with (AUC: 0.984) at 24 h.
Of the microcirculation markers we evaluated, PPI provided the most beneficial prognostic information about mortality in adult patients with septic shock. PPI is an indicator mirroring inadequate perfusion in critical patients 16, and to compare with blood lactate testing, PPI is real-time and non-invasive 24. The plotted ROC curves of PPI and CRT at baseline for predicting mortality showed the AUC 0.837 and 0.695, respectively. These results showed that PPI predicts mortality earlier with better sensitivity and specificity. In the early stages of hypoperfusion, peripheral blood vessels constrict to return enough blood to the heart 25, 26. At this stage, macro vital signs such as HR and blood pressure (BP) are normal. Since the general circulation is stable, blood lactate levels do not rise. However, PPI, an indicator of regional perfusion, decreases as vasoconstriction reduces blood flow in that area. This means that PPI is superior to other micro parameters such as lactate in alerting physicians to hypoperfusion. However, one of the reasons limiting the use of PPI is that it can be easily affected by other factors such as low temperature, vascular diseases, and the position of patients 27, 28.
In this study, there was no significant difference in the accuracy of CRT, and the lactate concentration, and both markers had excellent predictive value for mortality. The ability of the CRT to predict mortality was similar to that of the serum lactate concentration; therefore, measurement of the CRT may be an alternative for invasive measurement of the blood lactate concentration in evaluating patients with septic shock. However, CRT assessment is susceptible to factors that can have a significant impact on results, such as ambient temperature, skin temperature, core temperature, age, ambient light conditions, time of pressure, level, and site of pressure application 29. Some of these conditions can be controlled and the measurements standardized to reduce ambient-related and technical variability 30. Van Genderen et al. 24 investigated the reliability of observers in CRT assessments between different health care workers and showed good overall consensus. Another study showed a good correlation with objective variables of peripheral perfusion 29. Ait-Oufella et al. 19 showed that CRTs were highly reproducible in a prospective cohort of patients with septic shock and showed excellent interracial concordance . However, to optimize CRT reproducibility, teaching, standardizing, and reducing the impact of environmental factors are effective.
Our observational study shows that the fair predictive value (AUC: 0.738 and 0.714) of fluid balance for mortality at 6h and 24h, respectively. These results are consistent with previous studies that showed the higher positive fluid balance in resuscitation over the first two days was associated with increased risk of mortality in septic shock patients 31, 32. Our results also showed a good predictive accuracy value of serum lactate and lactate clearance for mortality and number of vasopressors and also a poor significant predictive value for RRT. Similar to our results, a retrospective study by Ryoo et al. 33 showed that the lactate and lactate clearance levels at 6-hour are more effective tools for the prognosis of septic shock patients who were treated with protocol-driven resuscitation bundle therapy. A study by Mahmoodpoor et al. 34, showed that the serial measurements of serum lactate with special emphasis on its concentration at 24hour after admission remains the most predictive of short-term mortality in the ICU. Another study by Marty et al. 35 reported that lactate clearance was the best parameter associated with the 28-day mortality rate in septic patients during the first 24hr in the ICU. Moreover, a similar study showed that combining lactate levels and its clearance is a reliable predictor of mortality in sepsis 36.
We also found that the mottling score as a non-invasive marker was associated with an increased risk of mortality and RRT in septic patients. Our results confirmed previous studies which reported a strong relation between 14-day mortality and mottling score 22, 23. However, several factors could modify the clinical evaluation of mottling, such as vasopressors dosage 20. An important observation of the present study is the combined models for both macrocirculation and microcirculation markers had a greater AUC and significance with higher accuracy, SN, SP, LR+, PPV, and NPV, and lower values of LR- as compared to the models created with each marker alone; since each of these indicators alone can be influenced by factors that play a role in their accuracy to predict outcomes. While when they are combined, they certainly cover the negative points and highlight the positive points. Therefore, the combination of markers seems to be the most reliable predictor of the septic shock outcome. It seems that the most important variables were microcirculatory variables at 24h, suggesting that clinicians could rely on using microcirculatory parameters to evaluate the adequacy of resuscitation. To support the importance of these variables it would then be appropriate to use the cutoffs identified by the ROC analyses in a multivariable analysis, adjusted for appropriate confounders to identify prognostic value.
Our study has several limitations. It is a single-center study, and results need to be confirmed in a larger population. Our participants were critically ill patients with various pre-existing comorbidities which acute dysfunction precludes a correct interpretation of results. We excluded patients with advanced liver dysfunction and ARDS but cannot rule out some degree of subclinical dysfunction. CRT assessment might be subjected to inter-observer variability, but we used a standardized technique that decreases the likelihood of bias. Nevertheless, while the size of this preliminary study was not very large, it was sufficient to highlight significant results.
In conclusion, microcirculation markers to predict mortality was superior to macrocirculation markers. The three most important predictors of mortality identified in our study were PPI, CRT and serum lactate at 24 h. An important observation of the present study is the combined models for both macrocirculation and microcirculation markers at baseline which had a greater AUCs with higher sensitivity and specificity than the marker alone to predict morbidity and mortality in patients with septic shock.