The peripheral perfusion index and transcutaneous oxygen challenge test are predictive of mortality in septic patients after resuscitation

All the patients needed mechanical ventilation and sedatives. All septic shock patients received broad-spectrum antibiotic coverage. The local hemodynamic support algorithm of septic shock patients: the early goal-directed therapy was as follows: central venous pressure was 8 to 12 mmHg; mean arterial pressure was above 65 mmHg; urine output was above 0.5 ml/kg of body weight (except in the patients with acute renal failure), and the central venous oxygen saturation (ScvO₂) was at 70% or more [13]. The advanced goal of hemodynamic support (after PiCCO catheter placement) was as follows: fluid loading was guided according to pulse pressure variation in ventilated patients (pulse pressure variations below 13% or lack of response to passive leg raising or no respiratory variations of the inferior vena cava diameter (Cx Cart; Phillips Ultrasound, Bothell, WA, USA)); systemic vascular resistance index >1000 dyne/sec/cm⁵; after the macro hemodynamic variables were optimized, if the lactate was not decreasing, sources for the elevation of lactate were sought, and/or maneuvers to lower oxygen consumption were instituted (fever control, increase in sedation/pain medication). The intensivists were blinded for the results of the peripheral perfusion variables.

Information collected at enrollment included demographic characteristics such as age; sex; Acute Physiology and Chronic Health Evaluation II score (APACHE II) [15]; Sequential Organ Failure Assessment (SOFA) score [16]; and primary site and type of infection. The global hemodynamic, traditional metabolic, and PI and OCT variables were measured simultaneously at 24 h after PiCCO catheter insertion.

Simultaneous basic blood gases from the arterial, central venous catheters were obtained (the placement of a central venous catheter in the superior vena cava was confirmed by chest radiography). Blood gas samples were taken anerobically in 3 ml heparinized syringes (PL67BP; BD Diagnostics, Plymouth, UK) and analyzed on blood gas bedside machines (GEM Premier 3000, model 5700; Lexington, MA, USA) or (ABL90: Radiometer, Copenhagen, Denmark). The thermodilution cardiac output was measured by injecting 15 ml of 0.9% saline at 0°C for the PiCCO-Plus (the PiCCO system: Pulsion Medical System, Munich, Germany). Three cardiac outputs, which were within 10% of each other, were obtained and averaged. These global hemodynamic variables were recorded simultaneously.

Transcutaneous sensors (TCM4 Transcutaneous Oxygen/Carbon Dioxide Monitoring System; Radiometer, Copenhagen, Denmark) having previous validation studies were calibrated to known oxygen and carbon dioxide levels according to the manufacturer's guidelines. The sensors were attached to the patients' upper torso below the clavicle in nonbony areas, and skin was prepared with alcohol and shaved when necessary. Areas of injury such as hematomas were avoided. With a total of 15 min equilibration time, heating of the probe to 44°C required 5 min. Baseline PtcO₂ and PtcCO₂ were recorded. The OCTs were performed (FiO₂ was increased to 1.0 for 10 min), and the new PtcO₂ value was recorded every 1 min. The values for PaO₂ were examined on inspired of 1.0 FiO₂. PI and pulse oxygen saturation percentage (SpO₂) were measured in the index finger by using the IntelliVue MP70 monitor (Philips Medical Systems, Boblingen, Germany). The MP70 system calculates the PI as the ratio between the pulsatile component and the nonpulsatile component of the light reaching the light-sensitive cell of the pulse oximetry probe. The ambient temperature of the room was kept constant at approximately 23 to 25°C (climate controlled) during all phases of testing.

The PtcO₂ index is baseline PtcO₂/baseline PaO₂; 10min-OCT is (PtcO₂ after 10 minutes on inspired 1.0 oxygen) - (baseline PtcO₂); the OCI is (10min-OCT)/((PaO₂ on inspired 1.0 oxygen) - (baseline PaO₂)); survival is leaving the ICU alive for that admission.

A descriptive analysis was performed. All data were expressed as mean ± standard deviation, unless otherwise specified. A Mann-Whitney test was used to compare groups on continuous variables, and chi-square and Fisher's exact tests were used to compare categorical variables. Comparisons of two continuous variables were performed using a linear regression. Discrimination of values was assessed with the receiver operating characteristic analysis. All comparisons were two-tailed, and P <0.05 was required to exclude the null hypothesis. The areas under the ROC curves were compared using a Hanley-McNeil test [17]. The statistical analysis was performed by using the software package SPSS version 13.0 (SPSS Inc. Chicago, IL, USA), and MedCalc 11.4.3.0 software (MedCalc, Mariakerke, Belgium).

There were no differences in SpO₂, PtcCO₂, and arterial lactate level between the control patients and the septic patients (Table 2). The control group had a higher baseline PaO₂, baseline PtcO₂, PaO₂ (on FiO₂ 1.0), MAP, 10min-OCT and PI than the septic group (Table 3). There was no difference in PtcO₂ index and OCI between the two groups.

Global, metabolic and peripheral perfusion variables after resuscitation of the septic patients according to survival are shown in Table 3 and Table 4. In this study group, the macro hemodynamic-related parameters, baseline PtcO₂, baseline PtcCO₂, PaO₂ (on FiO₂ 1.0), PtcO₂ index and ScvO₂ showed no differences between survivors and nonsurvivors. Statistically significant variables between the survivors and the nonsurvivors included arterial lactate level (2.3 ± 2 vs. 5.6 ± 4.9mmol/l, P <0.0001), PI (1.95 ± 1.5 vs. 0.6 ± 0.86, P <0.0001), 10min-OCT (186 ± 75 vs. 93 ± 103 mmHg, P = 0.001) and OCI (0.79 ± 0.28 vs. 0.49 ± 0.36, P = 0.01).

There were 26 patients in septic group with ScvO₂ ≥70% after resuscitation, and the mortality was 9/26 (35%) in this subgroup. Statistically significant variables between the survivors and the nonsurvivors included arterial lactate level (2.3 ± 1.5 vs. 5.0 ± 5.2mmol/l, P = 0.034), PI (2.2 ± 1.7 vs. 0.87 ± 1.1, P = 0.013).

In the whole group, the PI was not correlated with the baseline PtcCO₂, PtcO₂ index and ScvO₂. In contrast, the PI was correlated with baseline PtcO₂ (r = 0.298, P = 0.015), 10min-OCT (r = 0.573, P <0.0001), OCI (r = 0.395, P = 0.001), lactate (r = -0.309, P = 0.012). There is a significantly positive relationship between PaCO₂ and PtcCO₂ (r = 0.874, P <0.0001).

The cutoff value and areas under the receiver operating characteristic (ROC) curves for the related variables used for predicting ICU mortality are shown in Table 5. The cutoff of the PI value was ≤0.2 for predicting ICU mortality, resulting in a sensitivity of 65% and a specificity of 92.3%. The PI, 10min-OCT and OCI predicted the ICU mortality with an accuracy that was similar to arterial lactate level, and the PI was significantly better than the difference between central venous and arterial PCO₂ (P(v-a)CO₂) and ScvO₂. In these PtcO₂-related parameters, the 10min-OCT and OCI were significant predictors of lethal outcome, but not baseline PtcO₂ and PtcO₂ index. For predicting ICU mortality, a threshold of 10min-OCT at 66 mmHg was associated with a sensitivity of 65% and a specificity of 96.2%, and a cutoff of OCI at 0.55 was associated with a sensitivity of 60% and a specificity of 88.5%. The ROC curves of baseline PtcO₂, PtcO₂ index, 10min-OCT and OCI are shown in Figure 1, and the ROC curves of PI, lactate, ScvO₂ and Pv-aCO₂ are shown in Figure 2.

Several limitations should be acknowledged. First, the study period may be considered not long enough to evaluate other relevant clinical outcomes and the selected time points are relatively arbitrary. A small number of subjects at a single time point is an important issue and our findings should be confirmed in a larger multicenter study before being translated into regular clinical practice. Second, one can argue that the assessment of these objective parameters requires stability of a number of factors that might affect tissue perfusion and oxygenation. To reduce those uncertainty factors, we strictly stabilized the related parameters (ambient temperature, level of consciousness, hemodynamic status). Third was our failure to directly determine skin microcirculation, local blood flow and subjective peripheral tissue perfusion indicators in this study. Fourth, one can argue that this chest skin circulation is not representative of other site circulations. Recently, some studies have been done to explore the value of evaluating peripheral tissue perfusion of other sites in septic shock patients, such as thenar, deltoid, masseter, and ear sites [40, 41]. Peripheral tissue perfusion monitoring from different parts may have different values. According to previously published studies on critically ill patients [8‐10], we chose the chest site as a relatively standard location for PtcO₂ monitoring. Moreover, the PI could be considered as a method to assess the finger tip circulation in this study. We found that the two site-related parameters were both predictive for outcome, and there was a significant relationship between chest and finger tip site-related parameters. Further studies should be done to test the clinical worth of PtcO₂ in other sites in critically ill patients. Fifth, MAP had been corrected in all the septic shock patients at the measurement stage, but not for ScvO₂. It is difficult for an observational study to guarantee the ScvO₂ ≥70% in clinical practice after resuscitation. In our study, 57% of the septic patients' ScvO₂ were equal or greater than 70% after resuscitation. We excluded nine septic patients in the analysis with low ScvO₂ (<60%) after resuscitation, and these patients had high lactate and poor peripheral perfusion. We acknowledge that the using of ScvO₂ <60% to reveal the imbalance between oxygen delivery and oxygen consumption is relatively arbitrary. According to early goal-directed therapy, ScvO₂ ≥70% is used to reflect the balance between oxygen delivery and oxygen consumption. Therefore, we analyzed a subgroup of septic shock patients with ScvO₂ ≥70%, and we found these peripheral indicators still work. This revealed that peripheral perfusion parameters may provide a specific endpoint of resuscitation after ScvO₂ ≥70%.