Yan Chen,Jin-min Peng,Xiao-yun Hu,Shan Li,Xi-xi Wan,Rui-ting Liu,Chun-yao Wang,Wei Jiang,Run Dong,Long-xiang Su,Huai-wu He,Yun Long,Li Weng,Bin Du
Tissue oxygen saturation is predictive of lactate clearance in patients with circulatory shock
Tissue oxygen saturation,Shock,Lactate clearance,Diagnostic accuracy
Background Tissue oxygen saturation (StO2) decrease could appear earlier than lactate alteration. However, the correlation between StO2 and lactate clearance was unknown. Methods This was a prospective observational study. All consecutive patients with circulatory shock and lactate over 3 mmol/L were included. Based on the rule of nines, a BSA (body surface area) weighted StO2 was calculated from four sites of StO2 (masseter, deltoid, thenar and knee). The formulation was as follows: masseter StO2 × 9% + (deltoid StO2 + thenar StO2) × (18% + 27%)/ 2 + knee StO2 × 46%. Vital signs, blood lactate, arterial and central venous blood gas were measured simultaneously within 48 h of ICU admission. The predictive value of BSA-weighted StO2 on 6-hour lactate clearance > 10% since StO2 initially monitored was assessed. Results A total of 34 patients were included, of whom 19 (55.9%) had a lactate clearance higher than 10%. The mean SOFA score was lower in cLac ≥ 10% group compared with cLac < 10% group (11 ± 3 vs. 15 ± 4, p = 0.007). Other baseline characteristics were comparable between groups. Compared to non-clearance group, StO2 in deltoid, thenar and knee were significantly higher in clearance group. The area under the receiver operating curves (AUROC) of BSA-weighted StO2 for prediction of lactate clearance (0.92, 95% CI [Confidence Interval] 0.82-1.00) was significantly higher than StO2 of masseter (0.65, 95% CI 0.45–0.84; p < 0.01), deltoid (0.77, 95% CI 0.60–0.94; p = 0.04), thenar (0.72, 95% CI 0.55–0.90; p = 0.01), and similar to knee (0.87, 0.73-1.00; p = 0.40), mean StO2 (0.85, 0.73–0.98; p = 0.09). Additionally, BSA-weighted StO2 model had continuous net reclassification improvement (NRI) over the knee StO2 and mean StO2 model (continuous NRI 48.1% and 90.2%, respectively). The AUROC of BSA-weighted StO2 was 0.91(95% CI 0.75-1.0) adjusted by mean arterial pressure and norepinephrine dose. Conclusions Our results suggested that BSA-weighted StO2 was a strong predictor of 6-hour lactate clearance in patients with shock. Supplementary Information The online version contains supplementary material available at 10.1186/s12871-023-02139-4.
Tissue oxygen saturation is predictive of lactate clearance in patients with circulatory shock

Tissue oxygen saturation (StO2) decrease could appear earlier than lactate alteration. However, the correlation between StO2 and lactate clearance was unknown.

This was a prospective observational study. All consecutive patients with circulatory shock and lactate over 3 mmol/L were included. Based on the rule of nines, a BSA (body surface area) weighted StO2 was calculated from four sites of StO2 (masseter, deltoid, thenar and knee). The formulation was as follows: masseter StO2 × 9% + (deltoid StO2 + thenar StO2) × (18% + 27%)/ 2 + knee StO2 × 46%. Vital signs, blood lactate, arterial and central venous blood gas were measured simultaneously within 48 h of ICU admission. The predictive value of BSA-weighted StO2 on 6-hour lactate clearance > 10% since StO2 initially monitored was assessed.

A total of 34 patients were included, of whom 19 (55.9%) had a lactate clearance higher than 10%. The mean SOFA score was lower in cLac ≥ 10% group compared with cLac < 10% group (11 ± 3 vs. 15 ± 4, p = 0.007). Other baseline characteristics were comparable between groups. Compared to non-clearance group, StO2 in deltoid, thenar and knee were significantly higher in clearance group. The area under the receiver operating curves (AUROC) of BSA-weighted StO2 for prediction of lactate clearance (0.92, 95% CI [Confidence Interval] 0.82-1.00) was significantly higher than StO2 of masseter (0.65, 95% CI 0.45–0.84; p < 0.01), deltoid (0.77, 95% CI 0.60–0.94; p = 0.04), thenar (0.72, 95% CI 0.55–0.90; p = 0.01), and similar to knee (0.87, 0.73-1.00; p = 0.40), mean StO2 (0.85, 0.73–0.98; p = 0.09). Additionally, BSA-weighted StO2 model had continuous net reclassification improvement (NRI) over the knee StO2 and mean StO2 model (continuous NRI 48.1% and 90.2%, respectively). The AUROC of BSA-weighted StO2 was 0.91(95% CI 0.75-1.0) adjusted by mean arterial pressure and norepinephrine dose.

Our results suggested that BSA-weighted StO2 was a strong predictor of 6-hour lactate clearance in patients with shock.

The online version contains supplementary material available at 10.1186/s12871-023-02139-4.

Circulatory shock is a life-threatening condition affecting about one-third of patients admitted to intensive care unit (ICU) [1]. In such patients, hyperlactatemia has been considered as a signal of tissue hypoperfusion and associated with poor outcome [2, 3]. Meanwhile, the decrease in lactate level is believed to be associated with improved outcome in shock, including septic shock [4] and cardiogenic shock [5]. However, lactate-guided resuscitation might lead to fluid overload with increased risk of morbidity and mortality because of delayed lactate decrease in patients with normalized tissue perfusion [6]. Near-infrared spectroscopy is a technique to determine tissue oxygen saturation (StO2) by identifying oxygenated and deoxygenated hemoglobin with different light abortion patterns. Similarly, a decrease of StO2 level is a reliable indicator for tissue hypoperfusion in trauma patients [7–9]. Furthermore, a recent study showed that StO2 alterations could appear earlier than lactate alteration in a sheep model of peritonitis [10]. The muscle StO2 significantly decreased soon after 8 h from sepsis induction, which was 20 h earlier than the elevation of lactate. Thus, StO2 might have predictive value on lactate decrease, but the clinical implications remained uncertain. Previous prospective observational studies demonstrated the correlation between lactate and StO2 from different anatomical sites including knee [11], cerebral [12] and thenar StO2 [13]. Ait-Oufella et al. observed that knee StO2 was associated with lactate level (R2 = 0.2, P < 0.002) after 6 h of septic shock resuscitation [11]. Tayar et al. showed significant correlation between cerebral regional oxygen saturation and lactate in shock at 8, 24, 48, and 72 h from admission [12]. One previous study aimed to evaluate the predictive value of thenar StO2 for lactate clearance in patients after cardiac surgery without focusing on hypotension [14]. Overall, all the studies failed to show the correlation between StO2 and lactate clearance in shock. This could be partly attributable to redistributes flow preferentially to vital organs during shock [15]. Accordingly, sublingual microcirculation fails to predict gut mucosal microcirculation in septic patients. This means that microcirculation (StO2 included) status at one location can be only used to indicate local perfusion alterations instead of global perfusion [16]. So far, there is no specific method to provide a general evaluation of microcirculation. The most common site of StO2 was thenar [17]. However, it has been suggested that StO2 may have better predictive value in site of masseter [18], deltoid [18], and knee [11]. The rules of nines is known as a tool used to assess the total body surface area involved in burn patients. And it has also been used to evaluate the area of muscle injury for assessment of severity of traumatic rhabdomyolysis in patients with Crush syndrome [19]. Similarly, general StO2 could be estimated according to the rule of nines. Masseter StO2 could represent head, accounting for 9%, deltoid and thenar StO2 represent arms and torso, accounting for 45%, and knee StO2 represent legs, accounting for 46%. We thus hypothesized that BSA (body surface area) -weighted StO2, which was generated from four different sites of StO2 was associated with lactate decrease in patients with shock.

We conducted a prospective observational study in a 15-bed medical ICU in a tertiary teaching hospital. The study protocol was approved by the institutional review board of Peking Union Medical College Hospital. Informed consents were obtained from the patients or relatives.

All consecutive patients admitted for circulatory shock with a serum lactate level of 3.0 mmol/L or more were included. Circulatory shock was defined as systolic blood pressure less than 90 mm Hg or mean arterial pressure was less than 70 mm Hg, patients with evidence of tissue hypoperfusion (including but not limited to oliguria, skin mottling, altered mental status, cool peripheries, hyperlactatemia, etc.) [20]. All patients younger than 18 years old or pregnancy were excluded.

Demographic data, chronic comorbidities, Sequential Organ Failure Assessment (SOFA), shock type, and infection site were recorded on admission. Four sites of StO2 (masseter, deltoid, thenar, and knee), vital signs, blood lactate (arterial), arterial and central venous blood gas were recorded simultaneously within 48 h of ICU admission. And patients were still in state of shock at the moment of measurement after resuscitation was complete according to the Surviving Sepsis Guidelines [21]. Blood lactate concentration was measured repeatedly after 6 h from baseline when StO2 was initially monitored. A central line was placed in internal jugular vein in patients to allow for central venous blood sampling. Radial artery or femoral artery was cannulated in all patients for invasive blood pressure monitoring (IntelliVue Patient Monitor MP 70 (Philips Medical System, Boeblingen, Germany). Arterial and venous blood gases with lactate were measured immediately using GEM Premier 4000 blood gas analyzer (Instrumentation Laboratory, Bedford, Mass). StO2 was measured at right side of the masseter, deltoid, thenar, and knee sites by the Noninvasive cerebral oximetry monitor, BRS-1 with four 40-mm depth infrared probes (Casibrain Techonology Inc, Beijing, CHN). The StO2 values were recorded after 1 min of measurement when the signal was stable. Survival was followed-up during 14 days.

Clearance of Lactate (cLac) was calculated as a change in blood lactate levels (%) after 6 h from baseline when StO2 was initially monitored [22]. The formula is as follows: [(0 h-Lactate − 6 h-Lactate)/ 0 h-Lactate] × 100%. A positive value indicates a decrease in lactate rate. Additionally, patients were divided into lactate clearance group and lactate non-clearance group. Lactate clearance was defined as 6-hour lactate clearance more than 10% [22]. Mean StO2 was the mean value of the four sites StO2. A BSA-weighted StO2 was calculated from four sites of StO2 (masseter, deltoid, thenar and knee), based on the rules of nines, which is a method used to quantify the area of affected skin in burns victims [23]. Masseter StO2 represented head, accounting for 9%, deltoid and thenar StO2 represented arms and torso, accounting for 45%, and knee StO2 represented legs, accounting for 46% (Fig S1). The formulation was as follows: masseter StO2 × 9% + (deltoid StO2 + thenar StO2) × (18% + 27%)/ 2 + knee StO2 × 46% The Septic Shock 3.0 definition was used to define septic shock in the study [24].

On the basis of previous study, area under the receiver operating curves (AUROC) of StO2 for prediction of lactate clearance was expected to be 0.814. Total sample size required was 34 (17 in each group), with a power of 90% and α = 5% (two-sided). Values were presented as the mean (SD) or median (interquartile range (IQR)) for continuous variables as appropriate and as percent for categorical variables. Comparisons between groups were made using the chi-square test or Fisher’s exact test for categorical variables and Student’s t-test or the Mann–Whitney U test for continuous variables, as appropriate. All correlations among parameters were calculated as Spearman’s correlation, including correlation between StO2 in different sites, as well as correlations between StO2 , lactate clearance, MAP and norepinephrine dose. We evaluated correlations of StO2 in different sites using Spearman rank coefficients and visualized the relationships with heatmap. AUROC curves for lactate clearance was computed using the trapezoidal rule. The confidence interval (CI) were determined by the bootstrap technique, and comparison was made as described in DeLong [25]. The analysis of ROC is corrected for confounding factors including norepinephrine dose and mean arterial pressure (MAP). The category-free net reclassification improvement (NRI) was performed to quantify improvement offered by BSA-weighted StO2 [26]. Subgroup analysis was conducted based on patients with septic shock. All statistical analyses were performed using R (version 4.0.0, R studio, Boston, MA). GraphPad Prism 9.0 was used to graph results.

From April 2021 to April 2022, 34 patients were included, of whom 19 (55.9%) had a lactate clearance ≥ 10%. The baseline characteristics of the two groups were shown in Table 1. The most common type of shock was septic shock, followed by cardiogenic shock, and hypovolemic shock. The two main sites of infection were lung (26%) and bloodstream (12%). All of the patients were treated with norepinephrine, median dose 0.5 (interquartile 0.3–1.0) ug/kg/min. Four (12%) patients were treated with epinephrine, median dose 0.3 (interquartile 0.2–0.3) ug/kg/min. The mean SOFA score was lower in cLac ≥ 10% group compared with cLac < 10% group (11 ± 3 vs. 15 ± 4, p = 0.007). Other baseline characteristics were comparable between groups. The 14-day mortality was lower in cLac ≥ 10% group (21% vs. 60%, p = 0.049).

Hemodynamic parameters assessments were showed in Table 2. The 0-hour lactate concentration in cLac ≥ 10% group was 4.9 ± 2.0 mmol/L and 7.7 ± 4.6 mmol/L in cLac < 10% group, with a lactate clearance 39.1 ± 17.4% and − 32.3 ± 38.1%, respectively. For StO2 measurement, there was one aberrant value at knee site (not detectable) and was excluded from analyses. Overall, the StO2 value vary considerably in different anatomical sites. Deltoid and masseter StO2 were higher than knee and thenar (deltoid 74.9 ± 5.5; masseter 73.6 ± 4.3; knee 69.5 ± 7.2; thenar 68.3 ± 6.6). As for comparisons of StO2 between different types of shock, there is a tendency existed toward lower StO2 of thenar, knee and weighted in cardiogenic shock than other types of shock (Table S1). No difference was seen in StO2 sites of masseter and deltoid. Compared to cLac < 10% group, all sites of StO2 except masseter were significantly higher in cLac ≥ 10% group. BSA-weighted of the four sites StO2 was also higher in the cLac ≥ 10% group than cLac ≥ 10% group (73.6 ± 2.8 vs. 67.5 ± 5.1, p < 0.001). Mean arterial pressure, heart rate, vasopressor doses and ScvO2 did not differ between two groups. Fluid balances were lower in cLac ≥ 10% group than in cLac < 10% group 2 and 6 h after StO2 measurement (p = 0.042; p = 0.031) (Fig S2).

No significant correlation exists between five sites of StO2(Fig S3). All sites of StO2 were negatively correlated with MAP, while no correlation was found between StO2 and norepinephrine dose (Table S2). There were significant correlations between lactate clearance and knee, deltoid and BSA-weighted StO2 (Table S3). Hemodynamic indicators include central venous oxygen saturation (ScvO2), mean arterial pressure and masseter StO2 were not predictive of lactate clearance (area under the ROC curve was < 0.7). The area under the receiver operating curves (AUROC) of BSA-weighted StO2 for prediction of lactate clearance (0.92, 95% CI [Confidence Interval] 0.82-1.00) was significantly higher than StO2 of masseter (0.65, 95% CI 0.45–0.84; p < 0.01), deltoid (0.77, 95% CI 0.60–0.94; p = 0.04), thenar (0.72, 95% CI 0.55–0.90; p = 0.01), and similar to knee (0.87, 0.73-1.00; p = 0.40), mean StO2 (0.85, 0.73–0.98; p = 0.09) (Fig. 1; Table 3). Choosing a threshold of BSA-weighted StO2 of at least 72% was associated with a sensitivity of 84% and a specificity of 93% to predict lactate clearance. The predictive positive value was 89% (over 72%, 16/18 patients showed lactate clearance more than 10%), to be compared with 20% (3/15) in patients with BSA-weighted StO2 of lower than 72%. As shown in Fig. 2 and Fig S4, BSA-weighted StO2 had probabilities reclassified upwards over the knee StO2 and mean StO2 model for cLac ≥ 10% group (52.6% and 73.7%, respectively) and for cLac < 10% group (28.6% and 28.6%, respectively). Overall, BSA-weighted StO2 model had continuous net reclassification improvement over the knee StO2 and mean StO2 model (48.1% and 90.2%, respectively). The AUROC for BSA-weighted StO2 was 0.91(95%CI 0.75 -1.0) adjusted by mean arterial pressure and norepinephrine dose (Fig S5). A total of 24 patients were included in the septic shock subgroup. The BSA-weighted StO2 have the largest areas under the curves [0.84, 95%CI (0.67–1.00)] for predicting 6-hour lactate clearance in the septic shock subgroup (Table 3).

In this prospective observational study, BSA-weighted and knee StO2 are predictive of lactate clearance in patients with shock. In addition, BSA-weighted StO2 demonstrated better accuracy to predict lactate clearance than knee StO2. The result remained robust after adjusted by mean arterial pressure and norepinephrine dose and in subgroup analysis of patients with septic shock. BSA-weighted StO2 over 72% indicated a subsequent normalization of lactate within 6 h. StO2 values varied in different sites, with deltoid and masseter higher than knee and thenar. On the other hand, no significant correlation was found between all sites of StO2. This might be attributable to the maldistribution of the blood flow to maintain normal blood flow to the vital organ during shock [27–29]. In a prospective observational study with 22 septic shock patients included, no correlation between basal intestinal or sublingual microcirculation and response to a fluid challenge was found [15]. The study suggested a dissociation between sublingual and intestinal microcirculation during shock. Since there are dissociations between microcirculation, assessment of microcirculatory at certain site can only represent the local microcirculation. Accordingly, the tissue oxygen saturation in any single site might not be considered as an indicator of whole-body perfusion. Two studies suggested forearm StO2 is a more sensitive parameter to hypovolemia than thenar StO2 [30, 31]. Additionally, a systematic review of StO2 monitoring in shock suggested better mortality prediction in sites of knee and brachial muscle, compared to thenar muscle [17]. From this perspective, single site monitoring of microcirculation may limit the predictive value of indicators like StO2. However, most of the studies conducted with single site monitoring of StO2 due to the limited number of probes [17]. Ait-Oufella et al. used simultaneous measurements from thenar and knee only for comparison of two sites of StO2 [11]. Colin et al. monitored masseter, deltoid and thenar StO2 at the same time and mean value of the them was proposed as a surrogate of ScvO218. Authors reported correlations between ScvO2 and masseter, deltoid, thenar StO2, and mean value of StO2 in three sites during 6-hour early resuscitation in patients with severe sepsis. However, knee StO2, which was considered as a good predictor of tissue perfusion, was missed [11]. Furthermore, simple average applied in previous study is lack of sufficient microcirculation representative since StO2 at different sites had considerable heterogeneity. Instead, in our study, the calculated BSA-weighted StO2 had taken weight of four important parts of systemic microcirculation into consideration. Experimental studies found skeletal muscle PO2 monitoring at quadriceps femoris muscle using a polarographic needle electrode was sensitive to the hemodynamic changes during various types of shock [28]. Skeletal muscle PO2 reduced rapidly early before hypotension occurred. This suggested that microcirculation dysfunction could appear earlier than macrocirculation, which gives ground to the consideration of predictive value of StO2 for lactate decrease. Previous observational studies have suggested that dynamic StO2 alteration may be associated with lactate clearance in shock. Lima et al. reported patients with persistent lower thenar StO2 (< 70%) had lower lactate clearance in early resuscitation of septic shock [13]. Ait-Oufella et al. also observed the change of knee StO2 between 6 and 24 h after septic shock initiation was associated with lactate clearance [11]. Besides, the predictive value of StO2 for lactate clearance have been discussed in patients after surgery. Kopp et al. found minimum thenar StO2 is a predictor of lactate clearance in post cardiac surgery patients with an AUROC of 0.83 [14]. This was consistent with our findings that deltoid, thenar, knee and BSA-weighed StO2 were predictive of lactate decrease in patients with circulatory shock. In addition, BSA-weighted StO2 showed greatest AUC than any other single site of StO2. In clinical situation, when patient is still in a state of shock after resuscitation, the changing trends of lactate are unknown at the moment. If BSA-weighted StO2 value is over 72% at the moment, then his lactate level is more likely to decrease over 10% within 6 h. This would be helpful for guiding for following treatment. Different doses of norepinephrine and mean arterial pressure (MAP) might have effects on StO2 despite a considerable interindividual variation [32, 33]. In our study, MAP and vasopressor dose did not differ between two groups. Also, the BSA-weighted StO2 diagnostic performance for lactate clearance was unchanged after controlling for norepinephrine doses and MAP. Fluid was another treatment which might affect StO2 value. However, the lower fluid balance in the lactate clearance group have ruled out the possibility. Our study has strengths. The simultaneously monitoring of microcirculation among multiple sites was performed in the study. Accordingly, BSA-weighted StO2 calculated on four sites StO2 was generated. Unlike single sites StO2 measured in previous studies, BSA-weighted StO2 was a potential indicator of macrocirculation. Our study has limitations. Firstly, this is a single-center study from a tertiary hospital with a relatively small sample size. Secondly, the heterogeneity of patients enrolled may indicate selection bias. However, heterogenous microcirculatory alterations were documented in sepsis [34] as well as in traumatic hemorrhagic shock [35], and cardiogenic shock [36]. Previous study has shown the predictive value of near-infrared spectroscopy derived StO2 for various types of shock [17]. Moreover, subgroup analysis of septic shock patients in our study remained robust. Further investigation for specified population was warranted, though. Thirdly, exclusion of lactate concentration lower than 3mmol/L limits the generalizability of our findings. However, patients in this subgroup might benefit less from serial lactate monitoring [37].

Our results suggest that StO2 was a predictor of lactate clearance in patients with shock. The blood lactate concentrations of patients with a BSA-weighted StO2 over 72% are more likely to decrease in the next 6 h.

Below is the link to the electronic supplementary material. Supplementary Material 1