RESEARCH

 

CO₂ gap changes compared with cardiac output changes in response to intravenous volume expansion and/or vasopressor therapy in septic shock

 

 

F Faris^I; A El-Houfi^II; M El Shahat^III; H Khalid^IV; A Al-Azab^V

^IMSc, MD; Critical Care Medicine Department, Faculty of Medicine, Cairo University, Egypt
^IIMSc, MRCP, FRCP, EDIC; Critical Care Medicine Department, Dubai Hospital, Dubai Health Authority, United Arab Emirates
^IIIMSc, EDIC; Critical Care Medicine Department, Shebin El-Kom Teaching Hospital, Egypt
^IVMSc, PhD; Critical Care Medicine Department, Faculty of Medicine, Cairo University, Egypt
^VMSc, MD; Critical Care Medicine Department, Faculty of Medicine, Cairo University, Egypt

Correspondence

 

 

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ABSTRACT

BACKGROUND. The difference in partial pressure of carbon dioxide (PCO₂) between mixed or central venous blood and arterial blood, known as the ∆PCO₂ or CO₂ gap, has demonstrated a strong relationship with cardiac index during septic shock resuscitation. Early monitoring of the ∆PCO₂ can help assess the cardiac output (CO) adequacy for tissue perfusion.
OBJECTIVES. To investigate the value of ∆PCO₂ changes in early septic shock management compared with CO.
METHODS. This observational prospective study included 76 patients diagnosed with septic shock admitted to Cairo University Hospital's Critical Care Department between December 2020 and March 2022. Patients were categorised by initial resuscitation response, initial ∆PCO₂ and 28-day mortality. The primary outcome was the relationship between the ∆PCO₂ and CO changes before and after initial resuscitation, with secondary outcomes including ICU length of stay (LOS) and 28-day mortality.
RESULTS. Peri-resuscitation ∆PCO₂ changes predicted a >15% change in the cardiac index (CI) (area under the curve (AUC) 0.727; 95% CI 0.614 -0.840) with 66.7% sensitivity and 62.8% specificity. The optimal ∆PCO₂ change cut-off value was <-1.85, corresponding to a <-22% threshold for a 15% cardiac index increase. The PCO₂ gap ratio (gap/gap ratio of T1- PCO₂ gap to T₀-PCO₂ gap) also predicted a >15% change in cardiac index (AUC 745; 95% CI 0.634 - 0.855) with 63.6% sensitivity and 79.1% specificity. The optimal CO₂ gap/gap ratio cut-off value was <0.71. A significant difference in 28-day mortality was noted based on the gap/gap ratio.
CONCLUSION. Peri-resuscitation ∆PCO₂ and the gap/gap ratio are useful non-invasive bedside markers for predicting changes in CO and preload responsiveness.

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The difference in partial pressure of carbon dioxide (PCO2) between mixed or central venous blood and arterial blood. (∆PCO2) is correlated with patient outcome and mortality".^[1] The ∆PCO₂ is correlated with patient outcome and mortality.^[2] Mixed ∆PCO₂ is inversely correlated with the cardiac index. Therefore, substituting central for mixed ∆PCO₂ is an accepted alternative.^[3] One goal of acute circulatory failure treatment is to increase cardiac output.^[4] Measurements of central venous oxygen saturation (S_cvO₂) and ∆PCO₂ are recommended to assess cardiac output adequacy and guide therapy.^[5] A ∆PCO₂ value of >6 mmHg indicates insufficient tissue blood flow, even when S_cvO₂ is >70%.^[1]

This study aimed to investigate the value of ∆PCO₂ changes in early septic shock management compared with cardiac output.

 

Methods

Study design and patients

This observational prospective cohort non-randomised study was conducted on 76 consecutive adult patients admitted to the critical care department of Cairo University Hospital between December 2020 and March 2022. The patients had septic shock and elevated blood lactate levels >2 mmol/L requiring fluid resuscitation and/ or vasopressor drug infusion. The study was approved by the ethical committee of the faculty of medicine, Cairo University (N-194-2019) and registered on clinicaltrials.gov 'NCT05578534]. Written informed consent was obtained from the patient's first-degree relatives.

Inclusion and exclusion criteria

Patients with septic shock were included and were clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mHg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL).^[6] Patients with advanced cardiac (severe and persistent symptoms of heart failure, reduced LVEF <30% or severe valve abnormalities), pulmonary (severe chronic obstructive pulmonary diseases), hepatic (liver cirrhosis with Child-Pugh C) or renal (stages 4 and 5 of the chronic kidney disease) diseases were excluded from the study (Fig. 1).

 

 

Definitions

Sepsis is identified by suspected or confirmed infection and organ dysfunction as defined by the sequential organ failure assessment (SOFA).^[6] Organ dysfunction is defined by an increase in SOFA score of 2 points or more (sepsis-related) from up to 48 hours before to up to 24 hours after the onset of suspected infection.^[7]

Data collection

Patients' demographic data, comorbidities, acute physiology and chronic health evaluation (APACHE) II score upon intensive care unit (ICU) admission, SOFA score (initial and after 48 hours), arterial lactate, ∆PCO₂, blood gases (ABG, cv VBG) and vital signs were collected. Echocardiographic left ventricular outflow tract (LVOT) cardiac output and index data were measured. The microbiological data, source of sepsis, relevant laboratory data, vasopressor/inotropic support and ventilatory support were recorded.

The first set of measurements (T₀) was taken after inserting invasive lines. The second set of measurements (T₁) were obtained after the initial resuscitation, once the mean arterial pressure (MAP) stabilised. This stabilisation occurred either through administering a fluid bolus of up to 30 mL/kg intravenously, initiating vasopressor infusion or after 3 hours, whichever came first.

Lactate clearance was determined by calculating the percentage ratio of (initial arterial lactate level at T - arterial lactate level at 3 hours after treatment)/ arterial lactate level at T₀. The ∆PCO₂ (before and after resuscitation), PCO₂ gap at T₁/PCO₂ gap at T₀ (gap/gap ratio) and cardiac index responsiveness were also calculated.

The patients were classified based on their initial ∆PCO₂, resuscitation response and 28-day mortality into:

a) High gap (P_cv-aCO₂ >6 mmHg) v. normal gap (P_cv-aCO₂ <6 mmHg)^[8,9]

b) Responsive (15% increase in the cardiac index or stable MAP was achieved) v. non-responsive (<15% increase in the cardiac index or a stable MAP was not achieved)^[10,11]

c) Survivors v. non-survivors

d) Positive response to initial resuscitation, defined as an increase in the cardiac index by 15% or a stable MAP (identified by MAP >65 mmHg for 2 hours with no further fluid boluses or vasopressor increments), achieved within or after completion of the first 3 hours post-enrolment. This cut-off value was chosen based on previous studies.^[10-11]

Interventions and study procedures

Our patients were resuscitated according to surviving sepsis campaign recommendations within 1 hour of recognition. The study cohort was included immediately on admission to the ICU and after insertion of invasive lines (T₀).

The resuscitation targets were MAP >65 mmHg, urine output >0.5 mL/ kg/min, S_cvO₂ >70%, normalisation or significant decrease of serum lactate concentration (a decrease of >10% after 3 hours of early resuscitation). Vasopressors were administered during or after fluid resuscitation if MAP could not be maintained.

Additionally, infusion of dobutamine was initiated in cases of myocardial dysfunction or ongoing hypoperfusion despite optimising intravascular volume. Ventilation parameters and sedation drug settings were kept unchanged during the volume expansion (VE).

Outcomes

The primary outcome was to evaluate the response of the ∆PCO₂ to initial resuscitation and its value for assessing fluid responsiveness in the ICU. Secondary outcomes included ICU length of stay (LOS) and 28-day ICU mortality.

Statistical analysis and sample size calculation

Based on the previous studies and using G power software version 3.1.3 (Heinrich-Heine-Universität, Germany) with a power of 0.90 and an alpha error of 0.05, the expected mean difference between low and high ∆PCO₂ patients for the cardiac index was used to calculate a required sample size of 69 patients. Factoring in a withdrawal/non-evaluable participant rate of 10%, 76 patients were recruited.

The analysis of the data was done using SPSS version 25 (IBM Corp, USA). Quantitative variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR), as appropriate. Qualitative variables were presented as count and percentage. A paired-sample Student's t-test was used to compare quantitative variables at two different time points. Student's t-test or Mann-Whitney-U test was used to compare quantitative data between two independent groups. The x² test or Fisher's exact test was used to compare qualitative data between different groups. Pearson's and Spearman's correlation tests were used to measure linear correlation between different quantitative variables. The operating characteristic curve (ROC) analysis was used to measure the predictive ability of different quantitative variables and to identify the best cut-off values. P<0.05 was considered statistically significant.

 

Results

Slightly more than half (53%) of all enrolled patients (n=40/76) responded to resuscitation, while 47% (n=36/76) were non-responsive. In the studied population, the respiratory system was the most common source of sepsis, with pneumonia emerging as the most common diagnosis (Tables 1 and 2).

 

 

Correlation between changes in cardiac index and ∆PCO₂

A statistically significant negative correlation was found between pre and post-resuscitation cardiac index change and corresponding ∆PCO₂ change (r -0.562, p<0.001).

Validity of ∆PCO₂ change to predict 15% or more change in cardiac index

Table 3 provides the predictive characteristics of ∆PCO₂ and gap/gap ratio. The optimal threshold values are also provided.

Comparison between survivors and non-survivors

The post-resuscitation ∆PCO₂ was elevated significantly among non-survivors, while a significant decrease was observed among survivors. The gap/gap ratio was significantly higher and lactate clearance was significantly lower among non-survivors (Table 4).

∆PCO₂ at T1 and gap/gap ratio for predicting mortality at day 28

The best predictor of day 28 mortality was a gap/gap ratio >0.75. The ROC-AUC was 0.855 (95% CI 0.767 - 0.943, p<0.001), with 82.8% sensitivity and 66% specificity. The performance of ∆PCO₂ at T₁ exhibited moderate accuracy (ROC-AUC 0.796; 95% CI 0.672 - 0.920), with a sensitivity of 79.3% and specificity of 72.3%, using a threshold value of 5.85. ∆PC02 at T₀ was found to be non-predictive (p=0.209). The gap/gap ratio was significantly associated with SOFA score, arterial lactate and APACHE II score (Table 5) Fig. 2).

 

 

Discussion

The cardiac output is adequate when it is matched to global metabolic demand. This could be assessed by ∆PCO₂ calculation.^[12] Septic shock patients can remain under-resuscitated despite optimising O₂-derived parameters.^[1,12[

The percentage change in the cardiac index was negatively correlated with the peri-resuscitation changes in ∆PCO₂ and gap/gap ratio (pre or post-resuscitation).

Consistent with our findings, Vallée et al.^[13] demonstrated an inverse correlation between cardiac index, as measured by PiCCO monitor, and P_(cv-a) CO₂ values at the different study times. In contrast, Ospina-Tascon et al.^[8] reported a low agreement between cardiac output, as measured by pulmonary artery catheter (PAC), and P_v-aCO₂ (r²=0.025, p<0.01) at different points of resuscitation. Furthermore, Van Beest et al.^[14]observed a weak relationship between ∆PCO₂ and cardiac index.

In our study, we observed a significant negative correlation between the cardiac output trend and the ∆PCO₂ trend during early septic shock resuscitation.

Our findings indicate that the percentage change in ∆PCO₂ (pre-and post-resuscitation) in cases of septic shock, along with the gap/ gap ratio, serve as reliable parameters for predicting changes in cardiac index (>15% percent increase) and consequently preload (fluid) responsiveness. Interestingly, using ∆PCO₂ to calculate the gap/gap ratio provided the best discrimination for cardiac index responsiveness better than the ∆PCO₂ change. The ROC curve determined a cut-off value of <0.71 for the CO₂ gap/gap ratio to predict preload responsiveness.

Furthermore, based on the mean ∆PCO₂ value observed (8.37 (SD 3.96)), the threshold of ∆PCO₂ decrease corresponding to a 15% increase in the cardiac index is <-22.1% (the cut-off value determined earlier by <-1.85).

Changes in ∆PCO₂ and the gap/gap ratio calculation could be used to predict preload responsiveness non-invasively without the need for specialised skills or expertise.

Similar to our findings, a recent study by Nassar et al.^[15] investigated volume expansion (VE)-induced changes in central venous-to-arterial CO₂ difference (∆-∆PCO₂) and central venous oxygen saturation (∆S_cvO₂) as a reliable parameter of fluid responsiveness in sedated and mechanically ventilated septic patients. Responders were defined as patients with a >10% increase in cardiac index (transpulmonary thermodilution) after VE. ∆-∆PCO₂ and AS_cvO₂ were significantly correlated with Acardiac index after VE (r -0.30, p=0.03 and r 0.42, p=0.003, respectively). The optimal cut-off value (according to Youden index) for ∆-∆PCO₂ was <-23.5%, with a sensitivity of 52% [95% CI 31 - 72%] and specificity of 87% [95% CI 68 - 97%].

Moreover, Pierrakos et al.^[16] conducted a prospective evaluation of the effects of fluid bolus on venous-to-arterial carbon dioxide tension (P_vaCO₂) in critically ill patients with pre-infusion P_vaCO₂ >6 mmHg. Fluid bolus caused a decrease in P_vaCO₂, from 8.7 [7.6 - 10.9] mmHg to 6.9 [5.8 - 8.6] mmHg (p<0.01). This decrease in P_vaCO₂ occurred independently of the pre-infusion cardiac index.

These findings were corroborated by Mecher et al.^[17]who found that the reduction in P_(v-a)CO₂ induced by VE was linked to an increase in cardiac output specifically in patients with elevated P_(v-a)CO₂. Additionally, they noted a correlation between VE-induced changes in cardiac output and changes in P_(va)CO₂ (r -0.46, p<0.01). This confirms that in patients with septic shock, ∆PCO₂ is mainly associated with systemic blood flow rather than tissue hypoxia.

The trend of cardiac output and ∆PCO₂ changes before and after early resuscitation of septic shock could reflect the dynamic nature of the ∆PCO₂ rather than a static parameter. We recommend this approach based on the behaviour of ∆PCO₂ during resuscitation.

Sepsis-induced hypoperfusion may manifest as acute organ dysfunction and/or decreased blood pressure as well as increased serum lactate.^[18] Volume resuscitation is the mainstay in the treatment of shock. To avoid ineffective or even deleterious VE, a resuscitation guided by a reliable volume status evaluation should be ascertained.^[19] Rapid optimisation of volume status has been shown to improve outcomes, whereas extended fluid loading is associated with increased morbidity and mortality.^[20,21]

The 28-day mortality was reported in 10% (n=4) of responsive patients and 69.4% (n=25) of non-responsive patients (p<0.01).

Our results showed that the overall 28-day mortality rate was 38% (n=29), while the survival rate was 62% (n=47).

When we calculated the ratio of ∆PCO₂ at T1/∆PCO₂ at T₀, expressed as the gap/gap ratio, a significant change was observed between low and high-gap patients (p=0.03). The higher ratio among low-gap patients suggests that there was no substantial resuscitation-induced change in ∆PCO₂ in these patients compared with the high-gap patients.

It was proposed that the gap/gap ratio could be classified into three categories: >1 indicating an increase in ∆PCO₂ after initial resuscitation, <1 indicating a decrease in ∆PCO₂ after initial resuscitation and = 1 or static consistent with stable ∆PCO₂ after initial resuscitation.

The gap/gap ratio serves as an indicator of the trend in ∆PCO₂ levels during resuscitation, reflecting prognosis and outcome. Non-survivors exhibited a higher ratio, suggesting less resuscitation-induced change in ∆PCO₂ compared with survivors.

We found that a gap/gap ratio >0.75 could predict 28-day mortality with a sensitivity of 82.8% and specificity of 66%.

Also, there was a significant difference in 28-day mortality among all studied patients based on the gap/gap ratio (p<0.001). Specifically, the mean gap/gap ratio for non-survivors was 1.09 (0.46), whereas for survivors it was 0.67 (0.18).

Similar to our findings, the high ∆PCO₂ correlation with mortality and clinical outcome was reported by a systematic review of 10 prospective studies.^[2]

The cardiac index change was markedly lower in non-survivors. Interestingly, although there was no significant difference in ∆PCO₂ at T₀ between survivors and non-survivors, ∆PCO₂ at T₁ was significantly higher in the non-survivors (p<0.001). This discrepancy highlights the impact of early resuscitation of septic shock on ∆PCO₂ levels. The persistent elevation of ∆PCO₂ despite resuscitation was indicative of poor outcomes. This suggests a more severe disease state with deranged hemodynamic, metabolic and tissue perfusion parameters.

Similarly, Ronflé et al.^[22] found that increased ∆PCO₂ was associated with poor outcomes in the early phase of septic shock, independent of S_cvO₂ or serum lactate concentrations.

In our study, post-resuscitation ∆PCO₂ predicted the 28-day mortality with a sensitivity of 79.3% and specificity of 72.3%, using a cut-off value of 5.85.

Consistent with our findings, previous studies have validated an association between elevated ∆PCO₂ and increased ICU mortality. Ronflé et al.^[22] reported a P_(v-a)CO₂ of 6.5 (3.1) mmHg and 5.3 (2.9) mmHg among ICU non-survivors and survivors (p=0.024), respectively. A threshold of P_(v-a)CO₂ >5.8 mmHg was associated with an increased ICU mortality rate (57% v. 33%, p=0.012). Persistently high P_(v-a)CO₂ was also associated with an increased risk of ICU mortality. Vallée et al.^[13] also demonstrated a higher mortality in patients with high P_(v-a)CO₂ (>6 mmHg).

Ospina-Tascon et al.^[8] conducted a prospective study on ∆PCO₂ in septic shock patients. They found that patients with persistently high and increasing P_v-aCO2 at T₆ exhibited significantly high SOFA scores on day 3 (p<0.001) and increased mortality rates on day 28 (p<0.001), compared with patients with normal P_v-aCO₂ at T₆.

Study limitations

Our study has some limitations. First, this was a single-centre observational study without randomisation. Second, the selection of the cut-off values, indicating an increase in stroke volume >15% with fluid infusion to signify fluid responsiveness, was based on values used in previous studies. However, it is worth noting that the results and predictive effects of resuscitation on ∆PCO₂ might have been different if another cut-off value had been chosen. Similarly, the choice of the cut-off value for ∆PCO₂ (> or <6 mmHg) to indicate high or normal ∆PCO₂ might have impacted the results. Third, central blood samples were chosen for measuring ∆PCO₂ rather than mixed venous samples owing to the simplicity of acquisition and practicality in routine clinical settings. Fourth, the study focused solely on examining the behaviour of ∆PCO₂ without employing it as a therapeutic intervention. Also, patient management and paired blood gas samples were conducted according to the usual ICU practice without intervention from the researchers. Finally, semi-invasive cardiac output measurements like pulse contour analysis catheters were not available at the time of the study. While we aimed to use two methods for cardiac output measurement (non-invasive and semi-invasive), such as echo-Doppler and PiCCO, unfortunately PiCCO catheters or similar methods were not available at the time.

Recommendations

∆PCO₂ is a very useful non-invasive bedside laboratory marker capable of predicting cardiac output changes and guiding therapy during the early resuscitation of septic shock patients.

 

Conclusion

The ∆PCO₂ is an easily measurable method for evaluating fluid responsiveness in the ICU. The PCO₂ gap or peri-resuscitation gap/ gap ratio correlates with changes in cardiac output in septic shock patients during and following early resuscitation. Resuscitation responders showed a significant decrease in ∆PCO₂ after resuscitation.

Declaration. None.

Acknowledgements. None.

Author contributions. None.

Funding. None.

Conflicts of interest. None.

 

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Correspondence:
M Makhlof
dr-mahmoud1978@hotmail.com

Accepted 5 March 2024

 

 

Contribution of the study
The current study provides an insight to the PCO₂ gap changes during and after early resuscitation of septic shock patients, which correlate to cardiac output changes and might also serve as a fluid responsiveness indicator.