There exists a potential link between baseline PaO₂/FiO₂ ratio and postoperative outcome in the group of patients undergoing elective coronary artery bypass grafting.

Background: Oxygen saturation and the PaO₂ are the direct risk factors for post -operative respiratory outcome in patients undergoing prolonged surgery under general anaesthesia. However the effect of preoperative PaO₂ and PaO₂/FiO₂ ratio on the postoperative course of the patient undergoing coronary artery bypass grafting is not known.

Hypothesis: Pre-operative PaO₂ and PaO₂/FiO₂ ratio have a significant effect on the postoperative outcome among the patients undergoing coronary artery bypass grafting.

Study design: Prospective clinical study
Setting: Tertiary health care centre

Materials and Methods: One hundred and fifty eight consecutive patients with a EURO Score of < 6 undergoing routine first time coronary artery bypass grafting were selected for this study. Patients with ventricular dysfunction, Chronic Obstructive Pulmonary Disease (COPD), renal or hepatic dysfunction, patients on mechanical ventilation, on preoperative Intra Aortic Ballon Pump (IABP) and those who had to undergo emergency surgery were excluded from the study. All patients were managed by the same anaesthesia and surgical team and the anaesthesia management protocol was similar for all the patients.

The pre-operative PaO₂/FiO₂ ratio (base line) for all patients was noted before anaesthesia induction in room air. The primary outcome measures were duration of mechanical ventilation, ICU stay and hospital stay. The secondary outcome measures were requirement of inotropes, arrhythmias, requirement of IABP, cardiogenic shock, perioperative myocardial infarction, sepsis, respiratory failure , any other organ dysfunction and death .The total duration of follow up period was one month.

Statistical analysis: Seventeen subjects were subsequently dropped because of incomplete data. Consequently, the data for 141 subjects were used for the analysis. The various methods used were Student T test, Spearman’s coefficient correlation, bi-variate and univariate logistic regression analysis. In each case a p value of < 0.05 was considered to be significant.

Results: There exists a positive correlation between preoperative PaO₂/FiO₂ ratio and duration of intubation (r = -0.5607, p = 0.001) as well as Intensive Care Unit (ICU) stay (r = -0.2564, p = 0.002). PaO_2/FiO2 ratio also has a positive correlation with the use of inotropes (p=0.03) and frequency of death (p=0.014) in the patients undergoing CABG .

Conclusion: Low pre-operative PaO₂/FiO₂ ratio has a direct impact on the in-hospital outcome among the patients undergoing coronary arterybypass grafting.

Keywords: Coronary artery disease; PaO_2/FiO2; In-hospital outcome

Coronary Artery Bypass Grafting Surgery (CABG) contributes to a major proportion of cardiac surgery. Different determinants of postoperative morbidity and mortality had been studied widely [1]. Altered pulmonary function is one among the components that significantly contributes to the thirty days mortality. However the feasibility of pulmonary function test is a concern when patient load is maximum. It has been shown that oxygen saturation and the PaO₂ are the direct risk factors for the post-operative respiratory outcome in high risk patients undergoing prolonged surgery under general anaesthesi [2, 3]. PaO₂/FiO₂ ratio has been considered as an indicator of pulmonary gas exchange. As pulmonary function test is a relatively invasive preoperative screening procedure we thought of taking PaO₂/ FiO₂ ratio as a screening test to determine adverse postoperative outcome in patients undergoing CABG under Cardiopulmonary Bypass (CPB).

Pre-operative PaO₂ and PaO₂/FiO₂ ratio have a significant effect on the postoperative outcome among the patients undergoing CABG under CPB.

After hospital ethic committee approval and written informed consent from the patients, 158 patients with a Euro score of >6 who underwent first time CABG procedure at our institution between June 2010 and October 2014 were included in the study. Patients with ventricular dysfunction, COPD, renal/hepatic dysfunction, on mechanical ventilation, preoperative IABP and those who had to undergo emergency/redo surgery were excluded from the study. Seventeen subjects were subsequently dropped because of incomplete data. Consequently, the data for 141 subjects were used for the analysis.

The patients were premedicated with oral diazepam 10mg at night before and 5 mg in the morning on the day of surgery. In addition they received injection morphine 0.1mg^-1kg and injection phenergan 0.5mg^-1kg intramuscularly one hour before being shifted to the operation theatre. Arterial blood gas was taken with room air during the preoperative visit and before administration of any sedative agents. Anaesthesia was induced with intravenous thiopentone sodium 5mgkg^-1, fentanyl 5μgm- ¹ kg and ₁ mg kg_-1 rocuronium bromide was used for muscle relaxation. Anaesthesia was maintained with midazolam, fentanyl and vecuronium bromide. All the patients were mechanically ventilated with 50% air-oxygen mixture with a tidal volume of 7-8 ml kg^-1. The plateau airway pressure was kept below 30cm of H₂O and end tidal carbon dioxide was maintained between 35-40 mmHg.

The surgery was performed by the same group of surgeons and anaesthesiologist. Patients underwent a median sternotomy, with harvesting of saphenous veins and internal mammary arteries as conduits. Myocardial protection was obtained with crystalloid and cold blood cardioplegia via the antegrade route, and moderate hypothermia (33°C). Haematocrit was maintained between 20% and 25%, and Cardiopulmonary Bypass (CPB) flow was maintained between 2.0 and 2.5 l ^-1 min ^-1 m². The mean perfusion pressure was kept at 70-90 mmHg by adjusting the pump flow, hematocrit, nitroglycerin or phenylephrine infusion.

After arriving at the ICU patients were ventilated mechanically with pressure regulated volume control mode. Systolic blood pressure was maintained between 100-130 mmHg and mean arterial pressure > 60 mmHg. Weaning was started as soon as the awake and alert with cerebral function adequate for cooperation. The criteria for weaning from mechanical ventilation were as follows: spontaneous tidal volume >6mlkg^{- 1}, no significant vasoactive infusions, chest tube drainage < 100mlhr^-1, stable hemodynamic without any evidence of low cardiac output syndrome, haemoglobin > 10mg dl^-1, endotracheal suctioning < once hr^-1, PO₂ of > 150 mmHg with an FiO₂ of < 0.5 and PaCO₂ between 35-45 mmHg, SaO₂ > 95% and absence of life threatening arrhythmias, IABP or open chest. Throughout the weaning process and after extubation, arterial blood gas analysis and pulse oximetry were monitored closely. All the patients were monitored for the primary outcome measures that included the duration of mechanical ventilation, ICU stay and hospital stay as well as the secondary outcome measures like, requirement of inotropes, arrhythmias, requirement of IABP, cardiogenic shock, perioperative myocardial infarction, sepsis, respiratory failure , and death.

Before analyzing the association between different perioperative variables which could affect postoperative outcome, we divided the patients into two groups on the basis of PaO₂/FiO₂ ratio. As the normal PaO₂/FiO₂ ratio ranges between 300-500, we have taken the lower limit as the cut-off point to divide the groups (Group I, PaO₂/FiO₂ ratio < 300 and Group II, PaO₂/FiO₂ ratio ≥ 300.Difference between two groups were assessed by t-test for continuous or ordinary variables and by the Chi-square test for dichotomous variables. A univariate analysis was performed to demonstrate the association between the perioperative predictors for adverse postoperative outcome in between the groups. The relationship between the PaO₂/ FiO₂ ratio and period of intubation and length of ICU stay was determined by plotting a scatter plot and the calculation of Spearman’s correlation coefficient. In each setting a p value of < 0.05 was considered to be significant.

The summary statistics of the patients are provided in Table 1 and 2. For further analysis of the primary and secondary outcome measures, patients were divided in two groups based on the PaO₂/FiO₂ ratio [Group 1, n=34(24.11%) and Group II, n=107(n=75.89%)].Both the groups were comparable in demographics and preoperative clinical parameters (Table 3). No difference was observed for the duration of surgery, CPB time and aortic cross clamp time (Table 4).

The characteristics of 141 CABG patients are shown in Table 1. Patients were divided into two groups. Group1: PaO₂/FiO₂ ratio<300, Group 2:PaO2/FiO2 ratio >300.Group 1 constituted of 34 patients and Group 2 constituted of 107 patients. A significant positive correlation was found between PaO₂/FiO₂ ratio and intubation period (r = -0.5607, p = 0.001) (Figure 1, Table 4) and ICU stay period (r = -0.2564, p = 0.002) , (Figure 2, Table 4) .Furthermore, the PaO₂/FiO₂ ratio also correlated with the use of inotropes (dopamine and noradrenaline ) and the frequency of death in patients undergoing CABG (Table 3 and Table 4)

Pulmonary dysfunction after CPB may be the result of multiple insults [4]. These include extra-CPB factors (ie, general anesthesia, sternotomy, and breach of pleura) and intra-CPB factors (ie, blood contact with artificial material, administration of heparinprotamine, hypothermia, cardiopulmonary ischemia, and ventilatory arrest) [5, 6]. There are various factors responsible for decreased postoperative pulmonary oxygen transfer after CABG. It has been shown that preoperative pulmonary function tests do not predict the outcome of the patient after CABG [7]. Arterial blood gas analysis is used in most institutions for management of patients undergoing cardiac surgery. Aim of this study was to find out the relationship between the PaO₂/FiO₂ ratio and perioperative outcomes of the patients undergoing CABG as the PaO₂ / FiO₂ ratio is easier to calculate, and may be more valuable in clinical situations.

In 1983, Covelli, et al demonstrated that oxygen tensionbased indices, including both (a/A) PO₂, and PaO₂ /FiO₂, were highly reliable, even in critically ill patients [8]. In a recent study to determine the effects of diabetes on pulmonary gas exchange in patients undergoing CABG, Seki, et al [5,9] concluded that the PaO₂ / FiO₂ ratio was a reliable predictor of the (a / A) PO₂ ratio during early postoperative management. In the present study,

the PaO₂ / FiO₂ratio was well correlated with intubation period and length of ICU stay.

Postoperative ventilation of patients undergoing cardiac surgery is justified because the incidence of respiratory insufficiency or low cardiac output after cardiac surgery is relatively high. However, there are many adverse effects of mechanical ventilation. Prolonged mechanical ventilation increases hospital costs, nursing dependency, airway and lung trauma, as well as stress and discomfort of endotracheal suctioning and weaning from ventilation [10]. More recently, a combination of modified anesthetia techniques, and advances in surgical procedures including myocardial protection and postoperative management has resulted in a marked decrease in postoperative intubation period [11-13]. Higgins and colleagues demonstrated that early extubation could be performed safely and did not increase perioperative morbidity [13].

The PaO₂/FiO₂ ratio has been recognized as a good index for predicting mortality and the need for endotracheal intubation in patients suffering from trauma [14]. It has also been suggested to be a reliable predictor of the arterial/alveolar oxygen tension ratio and of pulmonary dysfunction in patients undergoing CABG [15]. In addition, arterial blood gas analysis is routinely performed just after returning to the ICU in most hospitals and the PaO₂/ FiO₂ ratio is the simplest of the oxygen tension-based indices to calculate. The normal range of PaO₂/FiO₂ ratio is 350–500. In the

patients in our study who had a prolonged intubation period and ICU stay the PaO₂/FiO₂ ratio was < 350 .This result suggests that the PaO₂/FiO₂ ratio may be a good postoperative predictor of early extubation. Suematsu et al, demonstrated that PaO₂/FiO₂ ratio as one of the main risk factors for pulmonary oxygen transfer in patients undergoing coronary artery bypass grafting [4]. The result of the present study also proves that there exists a significant relationship between the duration of ventilation, ICU stay and the PaO₂/FiO₂ ratio. The patients with PaO₂/FiO₂< 350 needed significantly longer duration of intubation and ICU stay. The effect of PaO₂ on the control and regulation of mitochondrial as well as cellular respiration has been well described by several authors [16, 17]. In an cell culture model of pediatric cardiac myocyte, Merante F et al observed that chronically hypoxic cells exhibited significantly reduced activities of pyruvate dehydrogenase, cytochrome C oxidase and other enzymes involved in mitochondrial metabolism. This transcriptional down regulation of the key mitochondrial enzyme system leads to insufficient aerobic metabolism,production of lactic acidosis and high incidence of myocardial failure[18]. This may indirectly explain the high use of inotrope as well as percentage of death due to myocardial failure in our group I patients.

The number of inotropes administered during the immediate postoperative period (a gross index of myocardial function) has also been found by previous investigators [19-21] to be an independent determinant of outcome in patients undergoing CABG. According to Michalopoulos and colleague the combination of inotropic drug therapy and excessive blood transfusions is significantly associated with hospital death following CABG[18]. Results of our present study also suggest that the incidence of death was higher in the group with PaO₂/FiO₂ ratio < 350 which also had a higher requirement of inotropes.

Based on our findings, we conclude that patients with low preoperative PaO₂/FiO₂ ratio may need more careful perioperative management as these patients may have increased risk of perioperative complications.

1. Michalopoulos A, George Tzelepis, Urania Dafni,  Geroulanos S. Determinants of hospital mortality after Coronary Artery Bypass Grafting. Chest. 1999;115(6):1598-1603.
2. Rosenberg J, Ullstad T, Rasmussen J, Hjørne FP, Poulsen NJ, Goldman MD. Time course of postoperative hypoxaemia. Eur J Surg. 1994;160:137-143.
3. Zibrak JD, O'Donnell CR. Indications for preoperative pulmonary function testing. Clin Chest Med. 1993;14(2):227-236.
4. Suematsu Y, Sato H, Ohtsuka T, Kotsuka Y, Araki S, Takamoto S. Predictive risk factors for pulmonary oxygen transfer in patients undergoing coronary artery bypass grafting. Jpn Heart J. 2001;42(2):143-153.
5. Seki S, Yoshida H, Ooba O, Teramoto S, Komoto Y. Pulmonary oxygen transfer deficits of diabetic origin in patients undergoing coronary artery bypass grafting. Surg Today. 1993;23(7):592-597.
6. Shapiro BA, Lichtenthal PR. Inhalation-based anesthetic techniques are the key to early extubation of the car- diac surgical patient. Cardiothorac Vasc Anesth. 1993;7:135-136. DOI: 10.1016/1053-0770(93)90204-X.
7. Jacob B, Amoateng-Adjepong Y, Rasakulasuriar S, Manthous CA, Haddad R. Preoperative pulmonary func- tion tests do not predict outcome after coronary artery bypass. Conn Med 1997;61:327-32.
8. Covelli HD, Nessan VJ, Tuttle WK. Oxygen derived variables in acute respiratory failure. Crit Care Med 1983; 11:646-49.
9. Seki S, Yoshida H, Momoki Y, Ooba O, Teramoto S, Komoto Y. Impaired pulmonary oxygenation of diabetic origin in patients undergoing coronary artery bypass grafting. Cardiovasc Surg. 1993;1(1):72-78.
10. Lefemine AA, Harken DE. Postoperative care following open-heart operations: routine use of controlled venti- lation. J Thorac Cardiovasc Surg 1966;52(2):207-16.
11. Chong JL, Pillai R, Fisher A, Grebenik C, Sinclair M, Westaby S. Cardiac surgery: moving away from inten- sive care. Br Heart J 1992;68:430-433.
12. Quasha AL, Loeber N, Feeley TW, Ullyot DJ, Roizen MF. Postoperative respiratory care: a controlled trial of early and late extubation following coronary-artery bypasses grafting. Anesthesiology 1980;52:135-41.
13. Higgins TL. Pro:early endotracheal extubation is preferable to late extubation in patients following coronary artery surgery. J Cardiothorac Vasc Anesth. 1992;6(4):488-493.
14.  Horovitz JH, Carrico CJ, Shires GT. Pulmonary response to major injury. Arch Surg. 1974;108:349–355.
15. Butler J, Chong GL, Pillai R, Westaby S, Rocker GM. Early extubation after coronary artery bypass surgery: effects on oxygen flux and haemodynamic variables. J Cardiovasc Surg (Torino). 1992;33:276-280.
16. Gnaiger E, Steinlechner-Maran R, Mendez G, Eberl T, Margretler R. Control of mitochondrial and cellular respiration by oxygen. J Bioenerng Biomembr. 1995;27(6):583-596.
17. Rumsey WL, Schlosser C, Nuttiner EM, Robiolio M, Wilson DF. Cellular energetic and the oxygen dependence of respiration in cardiac myocytes isolated from adult rat. J Biol Chem. 1990;265(26):15392-402.
18. Merante F, Mickle DA, Weisel RD, Li RK, Tumialti LC, Rao V, et al. Myocardial aerobic metabolism is impaired in cellular model of cyanotic heart disease. Am J Physiol. 1998;275(5):H1673-1681.
19. Turner JS, Morgan CJ, Thakrar B, Pepper JR. Difficulties in predicting outcome in cardiac surgery patients. Crit Care Med. 1995;23:1843–1850.
20. Thompson MJ, Elton RA, Sturgeon KR,  Manclark SL, Fraser AK, Walker WS, et al. The Edinburgh cardiac surgery score survival prediction in the long-stay ICU cardiac surgical patient. Eur J Cardiothorac Surg. 1995;9(8):419-425.
21.  Michalopoulos A, George Tzelepis , Urania Dafni , Geroulanos S. Determinants of hospital mortality after Coronary Artery Bypass Grafting. Chest. 1999;115(6):1598-1603.