Anesthesia & Clinical Research
Open Access

The Impact of Early Goal Directed Therapy and PCO₂ Gap Protocol on Outcomes of High-Risk Surgical Patients Admitted to ICU: A Prospective Study

Gad Sayed^{* *}Correspondence: Gad Sayed, Department of Anesthesia, Faculty of Medicine, South Valley University, Qena, Egypt, Tel: +20 01099075675, Email:

Author info »

Introduction

Impaired tissue oxygenation in critically ill patients may be due to multiple factors could progressively lead to adverse outcomes such as organ dysfunction, organ failure, prolonged stay in Intensive Care Unit (ICU) and in hospital and increased mortality [1]. Early detection of tissue hypoxia and maintenance of adequate tissue oxygenation are considered the key elements in the care of critically ill patients. Optimization of hemodynamics and improvement of both metabolic status and tissue oxygenation are primarily addressed via “goal-directed” therapies [2,3]. Unfortunately, the adequacy of tissue perfusion remains difficult to assess. A broad use of monitoring tools and parameters has been reported to help clinicians in resuscitation of critically ill patients, but their non-specificity to tissue hypoxia exploited the need for additional markers to be investigated [4]. The difference between venous carbon dioxide and arterial carbon dioxide pressure (pCO₂ gap) has been described as a parameter reflecting tissue hypo perfusion in critically ill patients who are insufficiently resuscitated. The pCO₂ gap/CavO₂ ratio has also been introduced as an indicator of the respiratory quotient, thus the relationship between DO₂ and VO₂ [5,6].

Most of the knowledge about the pCO₂ gap and the pCO₂ gap/ CavO₂ ratio has come from studies in the literature on animal models or Intensive Care Unit (ICU) patients. To date, publications pertaining to the operative setting are sparse, specifically the ability of hemodynamic protocols based on the pCO₂ gap measurement to decrease postoperative adverse outcomes including ICU days and length of hospital stay LOS [7]. With that thought in mind, this study was designed to compare the impact of goal directed therapy and PCO₂ gap algorithm application on outcomes of high risk patients undergoing major abdominal surgery regarding ICU stay and LOS.

Patients and Methods

This was single blinded prospective randomized clinical trial that was conducted between Jan. 2020 and Mar. 2021. After approval from ethical committee of Qena University Hospitals, Qena, Egypt 85163. Eighty high-risk surgical patients who underwent major abdominal surgeries and admitted postoperatively to ICU were included in the research after obtaining written informed consent from the patients or from the patient’s legal representative. The criteria for inclusion are that of Shoemacker criteria summarized (Table 1) [8].

Table 1: Demographic, surgical and intensive care inclusion criteria.

The participants were randomly assigned into two groups. Group (A) (n=40) ScvO₂-CVa CO₂ gap-guided protocol (PCO₂ gap protocol) applied with 12 h postoperative (Figure 1). End point PCO₂ gap aiming to keep pCO₂ below 6 mmHg. When needed, readings of ScvO₂, PCO₂ gap, Hct, SpO₂, Cardiac Index (CI) were taken every 4 hours postoperative.

Figure 1: The ScvO₂-cvaCO₂ gap-guided protocol. ScvO₂ : venous central O₂ saturation; cvCO₂ gap: central venous-to-arterial pCO₂ difference; SaO₂: arterial O₂ saturation; CI: Cardiac Index; SVV: Stroke Volume Variability; PPV: Pulse Pressure Variability.

Group (B) (n=40): Early goal-directed therapy treatment flowchart, Kaiser Permanente Northern California, was applied 12 h postoperatively targeting MAP>65 mmHg, CVP between 8-12 cmH₂O, Haematocrite value more than 30, Svo₂ >75% and urine output more than >0.5 ml/kg/hr (Figure 2). Readings of ScvO₂ , Hct, UOP, CVP and MAP were taken every 4 hours postoperative. All patients were admitted to ICU immediately postoperative. Monitoring included electrocardiography, noninvasive blood pressure end tidal CO₂ pulse oximetry and urine output determined by insertion of urinary catheter (Foley’scatheter). for central venous pressure and mixed venous oxygen saturation monitoring during major surgery, all patients from both groups catheterized by standard three-lumen catheter central line (Certofix trio, B Braun, Germany) in the right internal jugular vein, catheter tip positioned within the superior vena cava, and correct positioning were verified by chest radiograph. For arterial sampling arterial catheters (Arteriofix, B Braun, and Germany) were placed. All patients were managed according to their allocated group. Data concerning ventilator dependency days, duration of stay in ICU and LOS were recorded.

Figure 2: Early goal directed therapy treatment flowchart kaiser permanente Northern California. RBC: Red Blood Cells; ScvO₂ : Venous Central O₂ Saturation..

Statistical analysis

Mean and standard deviations were calculated for all quantitative variables using IBM SPSS 23.0 statistical software, P <0.05 were considered significant. All data are presented as absolute value (%), as mean ± standard. Student’s t-test was used to assess the differences between both groups in the case of a normal distribution. The chi- square test or Fisher’s exact test was used for categorical data.

The sample size was composed of 80 patients divided into 2 groups of 40. They constituted the total of consecutive high risk surgical patients in a period of 14 months. Calculations indicated a minimum sample size of 80 patients [confidence level (1-a) 95%, power level (1-b) 80%].

Results

Regarding demographic data among study groups: Table 2 shows that the mean age of patients with GDT was 56.67 ± 12.35 years and means body mass index was 27.51 ± 7.56 kg/m2 while mean age of PCO2 group was 51.56 ± 13.67 years with mean body mass index was 27.93 ± 4.11 kg/m². Majority (80% of GDT group and of PCO2 of enrolled patients were males. Regarding type of surgical intervention of enrolled patients, they are summarized (Table 3). The most frequent surgical interventions were exploration and resection and anastomosis. Regarding duration of ventilator dependency, it was lower in group A (0.07 ± .2) than group B (1.3 ± 2.4). ICU stay was lower in group A (2.9 ± 2.3) than group B (4.1 ± 3.8). As for Length of hospital stay it was also lower in group A (8.3 ± 3.7) compare to group B (9.9 ± 3.8). Although all these variables were lower in group A than group B, the differences were Figure 2: Early goal directed therapy treatment flowchart kaiser permanente Northern California. statistically insignificant as shown (Table 4).

Table 2: Baseline data of enrolled patients.

Table 3: Type of surgery of enrolled patients.

Table 4: Ventilation days, ICU stay, and hospital stay among study groups

Discussion

The widely practiced and critically acclaimed protocols of GDT have been well received in the critical care settings. Yet, questions have been raised if their adequacy could be improved by introducing additional markers [9,10]. PCO₂ gap has been proposed to better describe the correlation between systemic blood flow and global metabolic demand as it provides information that is not provided by other parameters [11,12]. The recent studies including this study have adopted this hypothesis and put it under research. The main finding of our study is that PCO₂ directed resuscitation approach can decrease ICU stay, ventilator dependency days and LOS in high-risk patients who undergone major abdominal settings as effectively as conventional GDT protocol with no statistical difference between both protocols.

Robin et al. supported these results through prospective single- center observational study in a 1-year period, which included 150 high risk surgical patients total [7]. They observed that a high PCO₂ gap (≥ 6 mmHg) was associated with more organ failure, longer duration of mechanical ventilation and LOS. In April 2021, Ehab Saeed Abdalazeem, conducted a study on 100 adult patients diagnosed with severe sepsis or septic shock and were divided in two groups according to ΔPCO₂ [13]. The high ΔPCO₂ group was associated with higher incidence of complication and organ failure than normal ΔPCO₂ group. As regard the length of ICU stay and days of mechanical ventilation, they were also longer in high ΔPCO₂ group although the difference was statistically insignificant.

Although these studies have demonstrated that targeting PCO₂ in management of critically ill patients has an impact on lowering morbidity with hemodynamic stability, the results of a study conducted by (Pierre-Grégoire Guinot) in 2017 came in disagreement with the above findings [14]. They ran the study on 393 patients who undergone cardiac surgery with Cardio Pulmonary Bypass (CPB) and their results did not support an association between PCO₂ gap and postoperative outcomes (morbidity, mortality, SOFA scores, ICU length of stay) [15]. This contradiction could be explained by the change in physiopathology of the cardiac surgical population included in Guinot study. Most relevant publications have highlighted the significant impact of CO on PCO₂ gap that the PCO₂ gaps represent an indicator for CO meeting the global metabolic demand, i.e. Elimination of CO₂ produced by peripheral tissues [7,11,16-19]. The impact of CPB on CO₂ production and acid-base balance could change the balance between partial CO₂ tension and CO₂ content by changing metabolic conditions, blood flow, body temperature, and alveolar ventilation.

The conflict between results could well suggest that it may be not sufficient to direct resuscitation towards PCO₂ gap only. The use of PCO₂ gap in conjunction with ScvO₂ has also been investigated and has been shown to predict the patient's outcome better than using ScvO₂ alone [20]. In a Study by Vallee 2008 it was suggested that ICU resuscitated patients, targeting only ScvO₂ may not be sufficient to guide therapy [15]. They proposed that even if the target value of 70% ScvO₂ is met, a P (cv-a) CO₂ more than 6 mmHg could be a useful marker for inadequately resuscitated patients.

In 2020, Philippe Portran designed an original pilot study for patients who had undergone standard cardiac surgery to investigate the value of ΔPCO₂ as aprognostic tool and comparing that with an existing algorithm that involves targeting values of ΔPCO₂, ERO₂ and lactate [21]. High ΔPCO₂ (≥6 mmHg) was observed on ICU admission and on POD1 tat also failed to predict prolonged duration of stay in ICU. However, a significant increase in both ICU and hospital LOS was noted in the group of patients who were managed by the algorithm. The association between POD1 values of ΔPCO₂, and POD1 variations for ΔPCO₂ and ERO₂ or lactate were inconclusive or absent at best, suggesting that an approach combining the ICU admission values of ΔPCO2, ERO₂ and lactate could predict outcomes regarding ICU and hospital stays more effectively than ΔPCO₂ alone. Recent studies published in 2019 proposed that ratio of PCO₂ gap to the arterial- venous oxygen content difference also may be useful as a target for resuscitation they concluded that Pcv-aCO₂/Ca-vO₂ is an important predictor of postoperative major organ morbidity and mortality in patients undergoing cardiac surgery [22]. In our study, we opted for drawing samples from central venous catheter rather than PAC. Results may be different if PAC was used, but choice was in favor of feasibility and partly because PAC is not routinely used in management of high-risk patients in our ICU. Finally, PCo₂ gap and the conventional markers in GDT (serum lactate, mixed venous oxygen saturation) all have different physiological kinetics and taking all these physiological differences into account may alter results but also it would be very difficult. Part of our choice of methodology was to provide practitioners with feasible simple bedside tool that according to our findings may lead to avoid longer ICU and hospital stays.

Conclusion

We conclude that, for high-risk surgical patients admitted to ICU, it is possible that rapid resuscitation targeting PCO2 value is as effective as early GDT resuscitation protocol, regarding the impact on duration of ICU days, ventilator days and LOS. We recommend further studies to be directed towards evaluation of the role Pco2 gap plays as a part of the different resuscitation protocols currently applied in the critical care settings, and not as a sole target for resuscitation.

References

1. Routsi C, Vincent JL, Bakker J, De Backer D, Lejeune P, d'Hollander A, et al. Relation Between Oxygen Consumption and Oxygen Delivery in Patients After Cardiac Surgery. Anesthesia and analgesia. 1993;77(6):1104-1110
2. Carl M, Alms A, Braun J, Dongas A, Erb J, Goetz A, et al. S3 Guidelines For Intensive Care in Cardiac Surgery Patients: Hemodynamic Monitoring and Cardiocirculary System. GMS German Medical Science. 2010;8(1):1102-1110.
3. Kapoor PM, Magoon R, Rawat R, Mehta Y. Perioperative Utility of Goal-Directed Therapy in High-Risk Cardiac Patients Undergoing Coronary Artery Bypass Grafting:“A Clinical Outcome and Biomarker-Based Study”. Annals of cardiac anaesthesia. 2016;19(4):630-638.
4. Vincent JL, Rhodes A, Perel A, Martin GS, Della Rocca G, Vallet B, Pinsky MR, Hofer CK, Teboul JL, de Boode WP, Scolletta S. Clinical review: Update on hemodynamic monitoring-a consensus of 16. Critical Care. 2011;15(4):1-8.
5. Ospina-Tascón GA, Hernández G, Cecconi M. Understanding The Venous–Arterial CO2 to Arterial–Venous O2 Content Difference Ratio. Intensive care medicine. 2016;42(11):1801-1804.
6. Zanier ER, Nicolini R, Canavesi K, Conte V, Protti A, Gattinoni L, et al. Combination of venoarterial pCO2 difference with arterovenous O2 content difference to detect anaerobic metabolism during progression to brain death. InInternational Neurotrauma Symposium. 2004;10(5):20-32.
7. Robin E, Futier E, Pires O, Fleyfel M, Tavernier B, et al. Central venous-to-arterial carbon dioxide difference as a prognostic tool in high-risk surgical patients. Critical Care. 2015;19(1):1-10.
8. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective Trial of Supranormal Values of Survivors As Therapeutic Goals in High-Risk Surgical Patients. Chest. 1988;94(6):1176-1186.
9. Mecher CE, Rackow EC, Astiz ME, Weil MH. Venous Hypercarbia Associated with Severe Sepsis and Systemic Hypoperfusion. Critical care medicine. 1990;18(6):580-589.
10. Teboul JL, Mercat A, Lenique F, Berton C, Richard C. Value of The Venous-Arterial PCO2 Gradient to Reflect The Oxygen Supply to Demand in Humans: Effects of Dobutamine. Critical care medicine. 1998;26(6):1007-1010.
11. Bakker J, Vincent JL, Gris P, Leon M, Coffernils M, Kahn RJ. Veno-Arterial Carbon Dioxide Gradient in Human Septic Shock. Chest. 1992 ;101(2):509-515
12. Lamia B, Monnet X, Teboul J. Meaning of arterio-venous PCO2 difference in circulatory shock. Minerva Anestesiol. 2006;6(72):597-604
13. Abdalazeem ES, Abdelgawad B, El-Rahman AH. Role of Central Venous-Arterial PCO2 Difference In Prediction of Clinical Outcome in ICU Septic Patients. Egyptian Journal of Anaesthesia. 2021;37(1):189-195.
14. Guinot PG, Badoux L, Bernard E, Abou-Arab O, Lorne E, Dupont H. Central Venous-to-Arterial Carbon Dioxide Partial Pressure Difference in Patients Undergoing Cardiac Surgery is Not Related to Postoperative Outcomes. J Cardiothorac Vasc Anesth. 2017;31(4):1190-1196
15. Exarchopoulos T, Charitidou E, Dedeilias P, Charitos C, Routsi C. Scoring Systems for Outcome Prediction in A Cardiac Surgical Intensive Care Unit: A Comparative Study. American Journal of Critical Care. 2015;24(4):327-334.
16. Vallée F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, et al. Central venous-to-arterial carbon dioxide difference: An additional target for goal-directed therapy in septic shock?  Intensive Care Med. 2008;34(12):2218-2225.
17. Cuschieri J, Rivers EP, Donnino MW, Katilius M, Jacobsen G, Nguyen HB, et al. Central Venous-Arterial Carbon Dioxide Difference as an Indicator of Cardiac Index. Intensive Care Med. 2005;31(6):818-822.
18. Futier E, Robin E, Jabaudon M, Guerin R, Petit A, Bazin JE, et al. Central venous O2 saturation and venous-to-arterial CO2 difference as complementary tools for goal-directed therapy during high-risk surgery. Critical care. 2010;14(5):1-10
19. Ospina-Tascón GA, Bautista-Rincón DF, Umaña M, Tafur JD, Gutiérrez A, García AF, et al. Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock. Critical care. 2013;17(6):1-10
20. Du W, Liu DW, Wang XT, Long Y, Chai WZ, Zhou X, et al. Combining central venous-to-arterial partial pressure of carbon dioxide difference and central venous oxygen saturation to guide resuscitation in septic shock. Journal of critical care. 2013;28(6):1110-1115.
21. Portran P, Jacquet-Lagreze M, Schweizer R, Fornier W, Chardonnal L, Pozzi M, et al. Improving The Prognostic Value Of∆ PCO2 Following Cardiac Surgery: A Prospective Pilot Study. Journal of clinical monitoring and computing. 2020;34(3):515-523.
22. Mukai A, Suehiro K, Kimura A, Funai Y, Matsuura T, Tanaka K, et al. Comparison of the venous–arterial CO 2 to arterial–venous O2 content difference ratio with the venous–arterial CO2 gradient for the predictability of adverse outcomes after cardiac surgery. Journal of clinical monitoring and computing. 2020;34(1):41-53.