Hypoxia-related parameters during septic shock resuscitation: Pathophysiological determinants and potential clinical implications

Introduction

Despite recent advances in septic shock biochemical and clinical understanding, mortality remains around 40% (1). Sepsis-induced hypoperfusion leads to tissue hypoxia, cell and mitochondrial dysfunction, finally leading to multiorgan failure (2). Timely resolution of hypoperfusion through the judicious administration of fluids and vasoactive drugs, among other therapies, may deactivate this vicious cycle and lead to an adequate cellular oxygen delivery and recovery of organ function (3).

Available markers of hypoperfusion in the clinical practice are mere surrogates of deeper physiological phenomena occurring at the tissue and cellular level. Some markers, like central venous oxygen saturation (SvcO₂) or the veno-arterial PCO2 difference reflect global DO₂/VO₂ and flow balances (4-6). Other parameters, like lactate, represent complex interactions between non-aerobic metabolism, hyperadrenergia, and liver lactate clearance (7). On the other side, regional perfusion assessment, like sublingual microcirculation (8) or near infrared spectroscopy (9), can assess specific tissue-derived parameters, which may not reflect other territories of the economy. Recently, capillary refill time (CRT) has emerged as an interesting perfusion monitor, that has a fast kinetics (10,11), and correlates with other perfusion parameters such as hepatosplanchnic indices (12). Furthermore, its behavior also has correlation with severity and mortality (13,14).

The possibility to assess tissue hypoxia at the bedside has been pursued by clinicians and investigators along the years (15,16), but experimental methods have yet to be successfully translated into clinical practice. One proposed alternative is the lactate/pyruvate ratio (LPR). If the electron transport chain of the mitochondria fails due to tissue hypoxia, the cell uses a non-aerobic pathway to synthesize ATP leading to an increase of the LPR. This ratio has been utilized to differentiate hypoxia-related from other causes of hyperlactatemia, such as increased glycolysis without hypoxic stress (17,18). On the other hand, according to the Fick equation (19), the ratio between veno-arterial PCO₂ difference and Ca–vO₂ (ΔPCO₂/Ca–vO₂) represents a clinical surrogate for the respiratory quotient and its increase could signal anaerobic metabolism (20,21). To the best of our knowledge, both parameters have not been yet compared in the clinical scenario.

Recently, the ANDROMEDA-SHOCK trial compared CRT- versus lactate-guided early resuscitation during septic shock, demonstrating benefits in mortality, treatment intensity and organ dysfunction for the CRT arm (13,14,22,23). In a subsequent randomized controlled trial, we assessed both resuscitation strategies in 42 patients, in order to assess the impact of resuscitation strategy on fluid administration, perfusion and deep hypoxia markers during the study protocol, focusing on LPR and ΔPCO₂/Ca–vO₂ (24).

The objective of this study is to perform an assessment of the relationship between LPR and ΔPCO₂/Ca–vO₂, and the relationship between deep hypoxia markers with clinical markers of hypoperfusion during the initial resuscitation of this cohort of septic shock patients. We present the following article/case in accordance with the CONSORT reporting checklist (available at http://dx.doi.org/10.21037/atm-20-2048).

Methods

Patient selection and study protocol

We performed a prospective randomized controlled clinical trial. The design, main outcome and protocolization is detailed in clinicaltrials.gov (NCT03762005). Major outcomes have been previously reported (24). Data for this analysis was obtained from the final study’s database.

This study was conducted during an 18-months period at two intensive care units of teaching hospitals in Santiago de Chile (Hospital Clínico de la Pontificia Universidad Catolica de Chile and Hospital Barros Luco Trudeau). Respective IRBs and Ethics committees approved the study. A signed informed consent was obtained from patients or next of kin before study inclusion.

During the study period, patients equal or older than 18 years old, who fulfilled the following inclusion criteria were considered for randomization:

• Septic shock, defined according to SEPSIS-3 criteria (serum lactate >2 mmol/L, with vasopressor requirements after initial fluid loading of 20–30 mL/kg) (3).
• Positive fluid responsiveness state (25,26).

Exclusion criteria considered the following: >24 hours of septic shock onset, anticipated surgical or dialytic procedure during study period, pregnancy, active bleeding, liver cirrhosis, do-not-resuscitate status or severe ARDS. Randomization was performed through a computerized software, with a permuted block of eight and an allocation of 1:1 into each study arm. Concealment was maintained through centralization of the randomization process. Patients were allocated either into CRT-targeted or Lactate-targeted study arms.

The study protocol lasted 6 hours, and a full set of measurements were performed until hour 24 (see more detailed information in supplementary material 1). Due to the difference in target dynamics, CRT arm was tested every 30 minutes, while lactate arm every 2 hours. If the perfusion target was not met, additional interventions could be initiated at discretion by attending physicians. Other therapies were performed according to current guidelines of septic shock management (3).

Measurements and data collection

Demographic and clinical data were registered at baseline and throughout hospitalization until discharge. Relevant clinical variables, multimodal perfusion assessment, and deep hypoxia makers were registered at baseline (T0), 2 hours (T2), 6 hours (T6) and 24 hours (T24).

Hemodynamic and perfusion variables (see more detailed information in supplementary material 1)

• Macrohemodynamic variables;
• Cardiac output (CO) and derived indices;
• Metabolic-related perfusion variables (11);
• Capillary refill time (13);
• Regional flow:
• Sublingual microcirculation (27);
• Near infrared spectroscopy (NIRS) (8,9,27);
• Liver blood flow by Indocyanine green plasma disappearance rate (PDR-ICG) (27).

Deep hypoxia variables (see more detailed information in supplementary material 1)

To evaluate the presence of tissue hypoxia, we measured the LPR and the ΔPCO₂/Ca–vO₂ ratio. Pyruvate was determined by using pyruvate assay kit Cayman N°700470. ΔPCO₂/Ca–vO₂ ratio was calculated using a validated equation (20,28). In order to ease the interpretation of both markers, data analysis was performed with the percentage of abnormality of each variable, a more intuitive approach for clinicians. For LPR a value of 15 or more was considered abnormal (17). For ΔPCO₂/Ca–vO₂ ratio, a value of 1.4 or more was considered abnormal (29).

In order to assess if derangements in clinical perfusion markers associated with deep hypoxia markers, we assessed the incidence of abnormal hypoxia markers when each clinical parameter presented abnormal values, at any timepoint.

“Target reachers” analysis

Patients of both study arms who attained their prespecified perfusion target at T2 were considered target reachers, while those who did not were considered target non-reachers. We chose this timepoint as it was the first moment at which new measurements were made in both arms after randomization. Both groups were compared according to baseline characteristics and perfusion state. Evolution of deep hypoxia variables represented as percentage of patients with abnormal values, were compared through time in both groups.

Statistical analysis

After discarding normal distribution, non-parametric tests were used. Descriptive statistics are shown as median [interquartile range] or percentage (%) accordingly. Mann-Whitney U, chi-square and Fisher’s exact, were used when appropriate. Data were analyzed with Minitab v17 (Minitab Inc, State College, PA) and GraphPad Prism (GraphPad Softwares, La Joya, CA) softwares. Two-tailed P value <0.05 was considered statistically significant.

Results

Forty-two patients were included in this analysis. Demographic, hemodynamic, and other parameters are shown in Table 1. Main septic foci were abdominal (57%), respiratory (19%) and urinary (12%). Among rescue therapies implemented, 18% used steroids, 18% used epinephrine, and 13% used high-volume hemofiltration.

Table 1 General characteristics of the included population
Full table

One hundred and twenty-five measurements of LPR and 121 measurements of ΔPCO₂/Ca–vO₂ ratio were available during the study period. In 94 occasions both indices were measured simultaneously at specific time-points, and 51 of these measurements corresponded to the first 2 hours. Of these, 22% of LPR and 52% of ΔPCO₂/Ca–vO₂ ratio exhibited abnormal values. Figure 1 shows the lack of correlation between both hypoxia markers, both at early resuscitation (0-2 h, panel A) and the whole study period (0–24 h, panel B).

Figure 1 Concordance between LPR and ΔPCO₂/Ca–vO₂ at initial septic shock resuscitation (0–2 h) and the whole study period (24 h). LPR, lactate/pyruvate ratio; ΔPCO₂/Ca–vO₂: ratio between veno–arterial PCO₂ difference and Ca–vO₂.

Patients with abnormal LPR at baseline (6), compared to those with normal LPR (27) had higher CRT {7 [5–14] vs. 4 [3–6], P=0.02}, but similar APACHE score, lactate levels, NE dose, and 28-day mortality. Patients with abnormal ΔPCO₂/Ca–vO₂ ratio at baseline (19), compared to those with normal ratio (14), presented higher baseline lactate levels {6.1 [3–8.4] vs. 3.4 [2.7–4.1], P=0.049}, but similar severity scores and mortality.

The incidence of abnormal hypoxia markers when different perfusion-related parameters were abnormal at any time point is shown in Table 2. As seen, abnormal values of ΔPCO₂/Ca–vO₂ ratio were significantly more prevalent than LPR alterations in the context of any abnormal perfusion-related parameter.

Table 2 Presence of abnormal hypoxia markers in patients with abnormal perfusion markers
Full table

In 50% of patients cardiac output increased with fluid loading between T0 and T2, while the others it remained constant or decreased. LPR and ΔPCO₂/Ca–vO₂ tended to improve in patients who increased cardiac output [delta LPR: 0.89 (0.15–4) vs. −0.12 (−2–2.2), P=0.12; delta ΔPCO₂/Ca–vO₂ ratio: 0.48 (0.04–1) vs. −0.01 (−0.42–0.3), P=0.11].

Eighteen patients were considered target reachers at 2 hours, while 24 patients were not. Table 3 shows the main clinical, demographic, severity and perfusion characteristics of both subgroups. As shown in Figure 2, target reachers significantly decreased the proportion of abnormal ΔPCO₂/Ca–vO₂ ratio between 0 and 2 hours, while this did not occur in LPR. On the other hand, target non-reachers maintained similar proportions of abnormal deep hypoxia markers.

Table 3 Comparison between demographic, severity scoring, and baseline perfusion variables in target reachers and non-reachers
Full table

Figure 2 Evolution of patients with abnormal hypoxia related parameters between 0–2 hours in target reachers and non-reachers. LPR, lactate/pyruvate ratio; ΔPCO₂/Ca–vO₂, ratio between veno–arterial PCO₂ difference and Ca–vO₂.

Discussion

Our study showed that in a population of fluid responsive patients with septic shock according to SEPSIS-3 (septic patients with hyperlactatemia and vasopressors for arterial hypotension), the presence of concurrent abnormal values of deep tissue hypoxia markers is erratic during early resuscitation. In addition, measured hypoxia markers do not exhibit concordance between them. However, further analysis of our results suggests that both LPR and ΔPCO₂/Ca–vO₂ ratio interrogate different pathways on the hypoxia/hypoperfusion processes of septic shock.

Lactate prognostic value and response to therapy is well established in the literature (30,31), and is still the main resuscitation target recommended by the Surviving Sepsis Campaign for septic shock (3). Its use was primarily advocated under the hypothesis that decreases in tissue blood flow cause tissue hypoxia that increases non-aerobic lactate production due to low mitochondrial oxygen availability (30,32). This latter condition results in tissue injury that leads to organ failure and subsequent morbidity and mortality.

Nevertheless, though by shock definition each patient in our series had hyperlactatemia, only few of them presented a high LPR. We believe that the explanation for these findings can be drawn after reviewing previous reports on the topic:

Levy studied 60 patients with septic shock, lactic acidosis and vasopressor requirements (33). In them, higher lactate levels were closely related with elevated LPRs with a notable direct progression between severity of the septic shock according to norepinephrine requirements, hyperlactatemia levels and LPR. In the subgroup these authors called ‘intractable septic shock’, the APACHE II score was 32 and the norepinephrine dose 2.3 µg/kg/min. The authors concluded their study stating that hyperlactatemia with an elevated LPR is associated with the development of multiple organ failure and death (33).

In the same line, Rimachi studied 17 hyperlactatemic septic patients, and 13 of them (75%) presented high LPR (17). Their APACHE II score was 21±8 and mortality was 58%. Norepinephrine doses were not provided, but the data indicate that these patients were sicker and, consequently, a higher proportion of them presented an elevated LPR as well.

In contrast, Suistomaa studied LPR in 98 patients admitted to the ICU, and 32% of them presented hyperlactatemia (34). Although there were few septic patients (8/98) in this series and data on norepinephrine dose and mortality was not provided, it is specifically mentioned that hyperlactatemia was not associated with LPR elevation. Moreover, their APACHE II score was around 16, indicating that those patients were less severely ill. The no elevation in LPR is concordant with our data.

Considering the previously published evidence, we can speculate that the low prevalence of an elevated LPR may be explained by inclusion of less severe cases of septic shock in our study, which is consistent with the mortality of only 23%.

Regarding ΔPCO₂/Ca–vO₂ ratio, a retrospective study reported a close correlation between blood lactate concentration and the ΔPCO₂/Ca–vO₂ ratio in a cohort of critically ill patients (29). Monnet demonstrated that ΔPCO₂/Ca–vO₂ ratio was able to predict an increase in VO2 in fluid responsive septic shock patients subjected to volume expansion (35), a fact confirmed later by Mallat et al. (36).

Even though we didn’t assess VO₂ systematically, our results are in line with these previous reports. As hypoperfusion resolution is the ultimate goal of VO₂ increase, we expanded the findings to a clinical scenario where hypoperfusion resolution was assessed at the bedside. In practical terms, a ΔPCO₂/Ca–vO₂ ratio normalization could work as a surrogate for an effective rise on DO₂ with a concurrent correction of the oxygen debt, or an effective flow rectification. In other words, in this scenario, fluid responsiveness with ΔPCO₂/Ca–vO₂ ratio improvement after fluid loading could be an indirect marker of VO₂ improvement as evidence of flow responsiveness. This can ultimately explain the reason why LPR and ΔPCO₂/Ca–vO₂ ratio are not concordant as they interrogate different mechanisms and subcellular processes of the pathophysiology of septic shock. Of course, another possibility is that the lack of correlation simply is due to the slower kinetics of recovery of lactate as compared to the rapid changes in O₂ and CO₂ metabolism/production.

Despite the fact that LPR clinical use has been abandoned due to technical complexities and that ΔPCO₂/Ca–vO₂ ratio has not found its place as a functional marker for hypoxia in septic shock, in light of our results, we think that these markers may have a relevant place in the clinical understanding and management of the septic shock patient.

Limitations

This study has several limitations. First, this is a post hoc analysis of a randomized controlled trial. Second, there were some missing values of perfusion variables, mainly due to problems in the preanalytical phase. Third, some technical issues around pyruvate measurements were present. However, our lab personnel have a long-time experience with biologic samples handling and processing. Finally, there is no universal acceptance on the best method to clinically assess the respiratory quotient (i.e., the ratio between VCO₂ and VO₂), including the use of central venous gases over mixed venous gases and the use of CO₂ and O₂ pressures over arterial and venous content (21,37,38). Despite this, recent evidence has provided support for this practical approach (28), which is the one we used in our study.

Conclusions

To our knowledge, this is the first time that the LPR and ΔPCO₂/Ca–vO₂ ratios were compared as hypoxia markers. Despite the huge experimental and theoretical backgrounds, at first, we found no evident correlation between their kinetics. Nevertheless, exploring the contexts for these markers we believe that LPR may help on the assessment of the depth of the dysoxia state and eventually as a prognostic marker, and that the ΔPCO₂/Ca–vO₂ ratio may serve as a more precise signal for flow rectification in previously hypoperfused fluid responsive patients subjected to fluid resuscitation. Undoubtedly, further information on the best scenarios where LPR and ΔPCO₂/Ca–vO₂ ratios may exhibit their full usefulness is still to be gathered.

Supplementary

Study protocol

Each study arm had a specific perfusion target (normalization or 20% decrease of serum lactate levels, or normalization of CRT). When there was an abnormal perfusion target, fluid challenges were performed (500 of crystalloids in 30 minutes) until normalization of target, negativization of fluid responsiveness or pre-defined safety limits were met (i.e., raise in central venous pressure of 5 cmH₂O or more).

Hemodynamic and perfusion variables

Macrohemodynamic variables, including, mean arterial pressure, CV, heart rate, norepinephrine dose (NE dose); fluid responsiveness state; fluid boluses, fluid balance, and outputs.

Cardiac output (CO) and derived indices, measured either with a pulse-contour CO technique (PiCCO device) or a pulmonary artery catheter.

Metabolic-related perfusion variables, such as arterial lactate, central venous-arterial (pCO₂) gradient [P(cv-a)CO₂] (6), and central venous oxygen saturation (ScvO₂) (5).

Capillary refill time measured with a standardized technique (13).

Regional flow

Sublingual microcirculation

Assessed through side dark field (SDF) device. At least five 10–20 second videos were recorded by an expert user and analyzed manually according to recent recommendations. Then, we calculated the microcirculatory flow index (MFI). A value ≤2.5 was considered microcirculatory hypoperfusion (27).

Near infrared spectroscopy (NIRS)

A NIRS probe was placed in the skin of the thenar eminence, in order to assess muscle oxygen saturation (StO₂), with a tissue spectrometer (InSpectra Model 325; Hutchinson Tc, Mn, USA). Values of StO₂ <70% was considered abnormal (8,9,27).

Liver blood flow

Indocyanine green plasma disappearance rate (PDR-ICG) was measured with a transcutaneous assessment if ICG clearance, measured through a finger clip and connected to a liver function monitor (LiMON-Pulsion Medical Systems, Munich, Germany) 0.25 mg/kg of ICG was injected through a central line. Normal ranges described for PDR-ICG is 18% to 25% per minute, and we considered a value <15%/min as categorically abnormal, thus suggesting liver hypoperfusion assuming stable liver function (27).

Deep hypoxia variables

Briefly, plasma from venous blood (using EDTA as an anticoagulant) was obtained by centrifugation of the sample and then deproteinate followed by centrifugation and posterior neutralization with potassium carbonate. The pyruvate level was fluorescently determined by enzymatic reaction coupled to resorufin production. The relationship was then calculated as lactate divided to pyruvate, and a value of 15 or more was considered abnormal (17).

PaCO₂ − PvCO₂/[(SaO₂ − SvO₂) × Hb × 1.36]; whereas PaCO₂ and PvCO₂ are arterial and central venous carbon dioxide, respectively, SaO₂ is arterial saturation of oxygen and Hb is hemoglobin. A value of 1.4 or more was considered abnormal (20,28,29).

Acknowledgments

Funding: ClinicalTrials.gov Identifier: NCT03762005 (Retrospectively registered on December 3^rd 2018). Grant FONDECYT Chile 1170043.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-2048

Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-2048

Provenance and Peer Review: This article was commissioned by the Guest Editors (Glenn Hernández and Guo-wei Tu) for the series “Hemodynamic monitoring in critically ill patients” published in Annals of Translational Medicine. The article was sent for external peer review organized by the Guest Editors and the editorial office.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-2048). The series “Hemodynamic monitoring in critically ill patients” was commissioned by the editorial office without any funding or sponsorship. GH served as the unpaid Guest Editor of the series. The other authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by Respective IRBs and Ethics committees. Informed consent was taken from all individual participants or their next of kin before study inclusion.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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