Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and may progress to septic shock if not treated early (1). Mortality predictors in severe sepsis include low platelet count, elevated CRP, APACHE II score > 25, and need for invasive mechanical ventilation (2). Current guidelines recommend using global tissue hypoxia markers such as central venous oxygen saturation (ScvO₂) or lactate clearance during resuscitation (3). However, both have limitations—ScvO₂ may remain elevated due to microcirculatory shunting (4), while lactate normalization may lag behind actual recovery (5). Recently, the venous-to-arterial carbon dioxide difference (PCO₂ gap) has been proposed as a complementary marker of tissue perfusion, with a cutoff of 6 mmHg distinguishing adequate from inadequate global flow (6). Moreover, the PCO₂ gap corrected by the oxygen consumption ratio may better detect anaerobic metabolism (7). Early identification of tissue hypoperfusion is crucial, and studies suggest that PCO₂ gap is a valuable prognostic indicator in severe sepsis and septic shock (8,9). This study aims to assess the role of PCO₂ gap in predicting outcomes in septic shock and its correlation with mean arterial pressure, serum lactate, and cardiac output. The aim of study was to obtain central venous-arterial carbon dioxide difference (PCO2 gap) in patients with septic shock at the time of admission and to find it’s correlation to fluid administration, vasopressor requirement during the early phases of resuscitation during 6 hours of hospital admission and mortality among these patients.

Study area: The study was conducted at Critical Care Unit under the Department of Critical care Medicine, IPGMER, Kolkata. Study period: February 2024 to January 2025 Study design: Prospective, observational, analytical study. Study population: All adult patients with septic shock admitted in Department of Critical care Medicine, IPGMER, Kolkata. Inclusion Criteria: Adult patients (≥18 years) admitted with septic shock (according to sepsis 3 criteria, patients with septic shock were identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L). Exclusion criteria: • Under 18 years age • Shock of other origin Sample size: A total of 50 patients were included in this study. Statistical analysis: For statistical analysis, data were first entered into a Microsoft Excel spreadsheet and subsequently analyzed using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism (version 5). Continuous numerical variables were summarized as mean ± standard deviation, while categorical variables were expressed as counts and percentages. The Z-test (Standard Normal Deviate) was employed to assess significant differences between proportions. For comparisons involving means, the student’s t-test was used, with the corresponding p-value obtained from the t-distribution table. A p-value ≤ 0.05 was considered statistically significant, indicating rejection of the null hypothesis in favor of the alternative hypothesis.

Table 1: Distribution of Sex and Source of Infection among 50 Patients Frequency Percent P-value Sex Female 27 54 Male 23 46 Total 50 100 Source of Infection Endocarditis 1 2 Abdominal Infection 6 12 CNS Infection 3 6 Pneumonia 32 64 UTI 8 16 Total 50 100 Table 2: Distribution of Fluid Bolus, Vasopressor Use, Mechanical Ventilation, and Hospital Mortality among 50 Patients Frequency Percent P-value Fluid bolus required No 1 2 Yes 49 98 Total 50 100 Vasopressor required No 11 22 Yes 39 78 Total 50 100 Hospital mortality No 21 42 Yes 29 58 Total 50 100 Mechanical Ventilation No 14 28 Yes 36 72 Total 50 100 Table 3: Association between PCO₂ Gap (Low vs High) and Clinical Outcomes/Interventions in 50 Patients PCO2 gap Total Low High PCO2 PCO2 Fluid bolus required No Count 1 (5.90%) 0 (0.00%) 1 (2.00%) Yes Count 16(94.10%) 33 (100.00%) 49(98.00%) Total Count 17(100.00%) 33(100.00%) 50(100.00%) Vasopressor required No Count 8(47.10%) 3(9.10%) 11 (22.00%) Yes Count 9(52.90%) 30 (90.90%) 39 (78.00%) Total Count 17(100.00%) 33(100.00%) 50(100.00%) Hospital mortality No Count 10 (58.80%) 11 (33.30%) 21 (42.00%) Yes Count 7(41.20%) 22(66.70%) 29(58.00%) Total Count 17(100.00%) 33(100.00%) 50(100.00%) Mechanical Ventilation No Count 7(41.20%) 7(21.20%) 14(28.00%) Yes Count 10 (58.80%) 26(78.80%) 36(72.00%) Total Count 17(100.00%) 33(100.00%) 50(100.00%) Table 4: Descriptive Statistics of Hemodynamic and Metabolic Parameters Over Time (T0–T6) in 50 Patients Mean Std. Deviation N PCO2 gap at T0 7.8 3.714 50 PCO2 gap at T1 6.94 2.054 50 PCO2 gap at T2 6.78 2.902 50 PCO2 gap at T3 6.92 2.284 50 PCO2 gap at T4 6.74 2.136 50 PCO2 gap at T5 6.82 2.077 50 PCO2 gap at T6 6.94 2.368 50 MAP at T0 64.38 8.335 50 MAP at T1 75.2 13.163 50 MAP at T2 75.32 11.28 50 MAP at T3 78.78 11.836 50 MAP at T4 78.56 12.892 50 MAP at T5 78.38 11.926 50 MAP at T6 76.6 14.879 50 Serum Lactate at T0 3.58 1.09 50 Serum Lactate at T1 3.7 1.644 50 Serum Lactate at T2 3.62 2.61 50 Serum Lactate at T3 2.94 2.18 50 Serum lactate at T4 3.86 3.13 50 Serum Lactate at T5 2.96 1.653 50 Serum Lactate at T6 3.6 1.863 50 Cardiac output at T0 4.26 0.751 50 Cardiac output at T1 4.42 0.883 50 Cardiac output at T2 4.28 0.882 50 Cardiac output at T3 4.12 0.961 50 Cardiac output at T4 4.24 1.041 50 Cardiac output at T5 4.22 1.112 50 Cardiac output at T6 4.34 1.171 50 Figure 1: Distribution of Fluid Bolus, Vasopressor Use, Mechanical Ventilation, and Hospital Mortality among 50 Patients Figure 2a: Descriptive Statistics of Hemodynamic and Metabolic Parameters Over Time (T0–T6) in 50 Patients Figure 2b: Descriptive Statistics of Hemodynamic and Metabolic Parameters over Time (T0–T6) in 50 Patients In the study, 27 (54%) were female and 23 (46%) were male. The most common source of infection was pneumonia, accounting for 32 cases (64%), followed by urinary tract infection (UTI) in 8 patients (16%) and abdominal infection in 6 patients (12%). Central nervous system (CNS) infection was observed in 3 patients (6%), while endocarditis was identified in only 1 patient (2%). Out of the 50 patients studied, 49 (98%) required a fluid bolus, while only 1 patient (2%) did not. Vasopressor support was needed in 39 patients (78%), whereas 11 patients (22%) did not require it. Hospital mortality was observed in 29 patients (58%), while 21 patients (42%) survived. Mechanical ventilation was required in 36 patients (72%), whereas 14 patients (28%) did not need ventilatory support. Among the 50 patients, 33 (66%) had a high PCO₂ gap, while 17 (34%) had a low PCO₂ gap. Fluid bolus was required in almost all patients, with 49 (98%) needing it—33 (67.3%) of whom had a high PCO₂ gap and 16 (32.7%) with a low gap. Vasopressor support was required in 39 patients (78%), with a higher proportion among those with a high PCO₂ gap (76.9%) compared to those with a low gap (23.1%). Hospital mortality was higher in patients with a high PCO₂ gap—22 out of 33 (75.9%)—compared to those with a low gap, where 7 out of 17 patients (24.1%) died. Mechanical ventilation was also more frequent in patients with a high PCO₂ gap (72.2%) than in those with a low gap (27.8%). The mean PCO₂ gap at baseline (T0) was 7.8 ± 3.71 mmHg, which showed a gradual decline over time, ranging from 6.94 ± 2.05 mmHg at T1 to 6.74 ± 2.14 mmHg at T4, indicating a mild overall reduction during the observation period. The mean arterial pressure (MAP) improved notably from 64.38 ± 8.33 mmHg at T0 to 75.20 ± 13.16 mmHg at T1, maintaining stable levels thereafter, with a peak of 78.78 ± 11.84 mmHg at T3.Serum lactate levels were initially elevated at 3.58 ± 1.09 mmol/L and showed variable trends over time, with slight increases at certain time points (3.86 ± 3.13 mmol/L at T4) but an overall tendency toward reduction compared to baseline. Cardiac output remained relatively stable throughout the study period, starting at 4.26 ± 0.75 L/min at T0 and fluctuating minimally, with values between 4.12 ± 0.96 L/min (T3) and 4.42 ± 0.88 L/min (T1).

In this study, a high PCO₂ gap was evident in 66% of patients and was significantly associated with increased needs for vasopressors and mechanical ventilation, as well as a substantially higher hospital mortality rate (75.9% vs 24.1% in the low gap group). The mean PCO₂ gap decreased from 7.8 ± 3.71 mmHg at T0 to 6.74 ± 2.14 mmHg by T4, while mean arterial pressure (MAP) improved from 64.38 ± 8.33 mmHg to 78.78 ± 11.84 mmHg by T3, which suggests improvement in tissue perfusion and hemodynamic stabilization. These findings align with previous evidence showing that elevated venous to arterial CO₂ differences reflect impaired microcirculation and are prognostic of worse outcomes in septic shock [10–12]. For instance, in a systematic review of septic shock patients, a high PCO₂ gap was strongly associated with increased mortality (OR = 0.50, 95% CI 0.28–0.87) and worse lactate clearance [13]. Moreover, studies have demonstrated that changes in the PCO₂ gap correspond to changes in microvascular perfusion independent of global hemodynamic variables [14], and that failure of the gap to normalize early during resuscitation portends higher organ dysfunction and death [15]. In our cohort, the observation that patients with sustained high gap values required more intensive support underscores that PCO₂ gap is more than a static marker—it reflects dynamic circulatory adequacy. Taken together, monitoring the PCO₂ gap trend alongside MAP, lactate clearance and cardiac output offers a more nuanced assessment of resuscitation efficacy and patient prognosis in septic shock.

In this cohort of 50 septic patients, a high PCO₂ gap was associated with worse clinical outcomes, including higher hospital mortality (75.9% vs 24.1% in the low gap group), increased need for vasopressors, and more frequent mechanical ventilation. Overall, hemodynamic parameters improved over time, with MAP stabilization, slight reduction in PCO₂ gap, variable lactate trends, and stable cardiac output, suggesting that early monitoring and management of the PCO₂ gap alongside conventional resuscitation markers can provide valuable prognostic information and guide therapy in septic patients.

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. 2. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock. JAMA. 2016;315(8):775-787. 3. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637. 4. Vallée F, Vallet B, Mathe O, et al. Central venous oxygen saturation and mortality in septic shock patients. Intensive Care Med. 2008;34(10):1761-1766. 5. Hernandez G, Ospina-Tascón GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs. serum lactate levels on 28-day mortality among patients with septic shock. JAMA. 2019;321(7):654-664. 6. Monnet X, Julien F, Ait-Hssain A, et al. Lactate and venoarterial carbon dioxide difference/arterial–venous oxygen difference ratio in septic shock. Intensive Care Med. 2013;39(6):1004-1012. 7. Ospina-Tascón GA, Umaña M, Bermúdez WF, et al. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med. 2016;42(2):211-221. 8. Mallat J, Lemyze M, Tronchon L, et al. Use of venous-to-arterial carbon dioxide difference to guide resuscitation therapy in septic shock. Crit Care. 2015; 19:355. 9. Bitar ZI, Maadarani OS, Shamsah M, et al. The role of central venous-to-arterial carbon dioxide difference in the management of patients with severe sepsis and septic shock. Indian J Crit Care Med. 2018;22(9):671-676. 10. García Alvarez M, Marik P, Ferrer R, et al. The prognostic value of venous arterial CO₂ difference during early resuscitation of septic shock patients. Indian J Crit Care Med. 2017;21(8):467–473. 11. Jaume Mesquida, Saludes P, Gruartmoner G, Espinal C, Torrents E, Baigorri F, Artigas A. Central venous to arterial carbon dioxide difference combined with arterial to venous oxygen content difference is associated with lactate evolution in the hemodynamic resuscitation process in early septic shock. Crit Care. 2015;19(1):126. 12. Zhang Z, Xu X, Chen K, Xu L, Deng H, Ni H. Prognostic value of PCO₂ gap in adult septic shock patients: a systematic review and meta analysis. BMC Anesthesiol. 2022; 22:234. 13. Meybohm P, Zacharowski K, Schafer S, et al. Venous to arterial carbon dioxide difference as a marker of microcirculatory perfusion in septic shock: systematic review. Intensive Care Med. 2018;44(9):1409–1418. 14. Gao W, Zhang Y, Ni H, Zhang J, Zhou D, Yin L, et al. Prognostic value of venous to arterial carbon dioxide difference during early resuscitation in critically ill patients with septic shock. Nan Fang Yi Ke Da Xue Xue Bao. 2018;38(11):1312 1317. 15. Zirpe KG, Tiwari AM, Kulkarni AP, et al. The evolution of central venous to arterial carbon dioxide difference (PCO₂ gap) during resuscitation affects ICU outcomes: a prospective observational study. Indian J Crit Care Med. 2024;28(4):349–354.