Early Outcomes of a High PaO₂/FiO₂ Ratio during Cardiopulmonary Bypass

Abstract

Background: In cardiac surgery, supraphysiological oxygen levels are frequently applied perioperatively. In this study, we examined the postoperative effect of perioperative hyperoxemia in cardiac surgery.

Methods: All patients who underwent mitral valve replacement via the standard sternotomy method between 2010 and 2021 were analyzed by scanning the hospital data system. The patients were divided into 2 groups: the hyperoxemic group (partial pressure of oxygen/fraction of inspired oxygen [PaO₂/FiO₂] > 500 mmHg) (Group I) and the normoxemic group (300 mmHg < PaO₂/FiO₂ < 500 mmHg) (Group II) according to the mean of 3 PaO₂/FiO₂ values calculated by using 3 PaO₂ and 3 FiO₂ levels. Postoperative complications, the mechanical ventilation time, the need for noninvasive mechanical ventilator support, the length of intensive care unit (ICU) stay, the hospitalization period, and the mortality rate of the groups were compared.

Results: A total of 78 patients were included in the study, and 53 of the patients (67.9%) were female. The mean age of the patients was 58.89±12.60 years. The total mechanical ventilation time was significantly higher in the hyperoxemic group than in Group II (P<0.001) (18.18±12.90 h and 11.45±7.85 h, respectively). The amount of postoperative bleeding was significantly higher in Group I (P=0.003) (539.47±201.74 mL and 417.50±186.93 mL, respectively). The total amount of blood products administered during surgery and ICU stay was higher in Group I (P=0.041) (3.55±1.59 units and 2.87±1.89 units, respectively).

Conclusion: We observed that the group with hyperoxemia during cardiopulmonary bypass had a higher amount of postoperative bleeding and the need for transfusion, as well as a longer duration of mechanical ventilation and intensive care.

Introduction

Although oxygen plays an important role in the synthesis of adenosine triphosphate, the energy source of cells, it also causes oxidation, which can lead to damage to the cells. This situation raises the paradox of oxygen toxicity.¹ While oxygen administration is a necessity in hypoxemia, there are concerns about the potentially harmful effects of excess oxygen administration such as absorption atelectasis, inflammatory cytokine release, central nervous system toxicity, and a decrease in cardiac output.^{2, 3}

Thus far, supraphysiological levels of oxygen have been frequently administered in cardiac surgery patients perioperatively to protect against the non-physiological nature of the surgery and the risk of hypoxia induced by cardiopulmonary bypass (CPB), which can result in elevated levels of reactive oxygen species (ROS).^{4, 5} High levels of ROS cause cellular damage and cardiac myocyte dysfunction, increased necrosis and apoptosis in myocytes, and vascular dysfunction. “Oxygen toxicity” caused by increased ROS formation can cause serious side effects, especially in ischemia/reperfusion situations such as in cardiovascular surgery.⁶

Despite technological advances in both surgical techniques and CPB equipment in cardiac surgery, mortality and morbidity remain high. It is common practice to deliver high levels of oxygen to the arterial blood, as blood gas sampling is usually done intermittently during the CPB procedure.⁷ However, although the risks associated with hypoxemia are well known, the possible harmful effects of hyperoxemia are not fully considered.⁸

A partial pressure level of oxygen above 100 mmHg/13.3 kPa is defined as hyperoxemia.⁹ In our study, we used the Horovitz index, which is more commonly used to evaluate pulmonary gas exchange. The normal value of this index is a partial pressure of oxygen/fraction of inspired oxygen (PaO₂/FiO₂) ratio exceeding 47 kPa (350 mmHg).¹⁰ Although its definition is not completely clear, a PaO₂/FiO₂ value greater than 500 mmHg is considered hyperoxemia.¹¹

In this study, we hypothesized that hyperoxemia would be associated with higher perioperative and postoperative mortality and morbidity, as well as longer mechanical ventilation (MV) and intensive care unit (ICU) stay.

Methods

Our study was conducted at Istanbul University-Cerrahpaşa, Institute of Cardiology after the approval of the Istanbul University-Cerrahpaşa Clinical Research Ethics Committee (Date: 02.06.2021 Number: 103415). All patients who underwent mitral valve replacement via the standard sternotomy method between 2010 and2021 were analyzed by scanning the hospital data system.

The inclusion criteria consisted of age between 18 and 80 years, an ejection fraction (EF) of greater than 40%, undergoing elective conditions within the standard surgery period (> 6 h), and not experiencing any serious complications related to perioperative surgery or anesthesia. The exclusion criteria were composed of undergoing emergency surgeries, age over 80 years, an EF below 40%, undergoing additional surgical procedures (eg, aortic valve replacement, CPB graft surgery, and atrial septal defect closure), having pulmonary edema due to mitral or tricuspid insufficiency, having a history of chronic renal failure, having uncontrolled diabetes, having hypertension, suffering cerebrovascular events, experiencing serious surgical complications in the perioperative period, a surgical time longer than the standard surgery period (> 6 h) due to these complications, and death during the perioperative period.

The anesthesia procedure varied according to the preference of the anesthesiologist. Nonetheless, induction was started with an FiO₂ level of 0.8 in all the patients as this is the standard practice in our clinic. The FiO₂ level was reduced to 0.6 and ventilated with the pressure control mode such that the tidal volume was 6 to 8 mL/kg and the positive end-expiratory pressure (PEEP) was 3 to 5 cm/ H₂O. The standard sternotomy procedure was performed on all the patients. Heparin was administered at a dose of 3 to 4 mg/kg, with an activated clotting time (ACT) of over 400 seconds. CPB was started normothermically with 100% oxygen. Hypothermia was applied at 30 °C to 32 °C. The blood flow was adjusted at 2.4 L min-1 m² according to the body surface, and the mean arterial pressure was kept between 60 and 80 mmHg. Blood cardioplegia was applied at 20-minute intervals in all the patients. Blood gas was taken after each cardioplegia. Blood transfusion (erythrocyte suspension) was applied to the patients whose hematocrit level was below 20% during CPB and below 28% after CPB. All the patients were taken to the ICU and connected to MV. The patients were followed up in the ICU for at least 36 hours.

The hospital database, anesthesia and perfusion observation forms, and patient files were examined. Additionally, the patients’ demographic characteristics, previous diseases, preoperative echocardiographic values, blood gas values taken during the perioperative period, and inotropic agents administered after CPB were recorded.

The study population was divided into 2 groups: the hyperoxemic group (PaO₂/FiO₂>500 mmHg) (Group I) and the normoxemic group (300 mmHg<PaO₂/FiO₂ <500 mmHg) (Group II) according to the mean of 3 PaO₂/FiO₂ values calculated by using the 3 PaO₂ values based on blood gas measurements obtained during CPB (at the beginning of CPB [T₁], during CPB [T₂], and at the termination of CPB [T₃]) and 3 FiO₂ levels. The EF (%) and pulmonary artery pressure (PAP) in the postoperative echocardiography results; postoperative complications including cerebrovascular events, infection, atrial fibrillation, and acute renal failure; the MV time; the need for noninvasive mechanical ventilator (NIMV) support, the length of ICU stay, the hospitalization period, and the mortality rate the groups were compared.

Statistical data analysis was performed using the IBM SPSS 21 Statistics (Armonk, NY). All the values are given as the mean with the standard deviation. The Kolmogorov–Smirnov and Shapiro–Wilk tests were used to determine the distribution of the data set. Two independent groups were compared in the study. The Pearson χ² and Fisher exact tests were employed to compare categorical data. The results of a multiple regression analysis, conducted to identify the possible confounding effects of age and sex, revealed that neither had any potentially confounding effects.¹² Comparison of quantitative variables between the 2 study groups was done using the Student t test and the Mann–Whitney U test. Mixed-design ANOVA was conducted to find statistical differences between the 2 groups in repeated measurements (PaO₂, FiO₂, mean arterial pressure [MAP], and lactate) at 3 time points. The Mauchly test of sphericity was used to test the sphericity assumption, and the test result was not significant. The sphericity assumption was met, and no correction was used. A P value of less than 0.05 was considered statistically significant.

Results

Through scanning the hospital database, 114 patients who underwent isolated mitral valve replacement were identified out of 189 patients who underwent mitral valve replacement via the standard sternotomy method between 2010 and 2021. A total of 78 patients were included in the study. Fifty-three patients (67.9%) were female and 25 (32.1%) male. The mean age of the patients was 58.89±12.60 years. The mean cross-clamp time was 101.76±35.34 minutes, and the total CPB time was 156.78±58.66 minutes. The length of ICU stay of the patients was 4.19±4.62 days, and the hospitalization period was 7.41±3.16 days. While the total amount of bleeding in the first 24 hours postoperatively was 476.92±202.53 mL, the total amount of blood products (ie, red blood cells, fresh frozen plasma, and platelets) administered to the patients during the surgery and in the ICU was 3.21±1.77 units. A single inotropic agent was mostly used (48.7%) in case of a need for inotropic support after CPB. Dopamine, an inotropic agent, was used in all the patients (100%) at CPB termination. After CPB, 7.7% of the patients (n=6) needed a pacemaker, and 3.8% of these patients (n=3) needed a permanent pacemaker.

Moreover, 21.8% (n=17) of the patients required postoperative NIMV in the ICU. The mean duration of MV was 14.73±11.13 hours. In addition, 10.3% (n=8) of the patients were reintubated after extubation. Complications during the postoperative period are shown in Table 1. Six patients (7.7%) were readmitted to the ICU after being discharged from the ICU, and 8 patients (10.3%) died during the postoperative period.

Table 1.

Comparison of postoperative complications and measurements between the groups^*

	Group I (PaO2/FiO2 >500 mmHg) (n=38)	Group II (300 mmHg< PaO2/FiO2 <500 mmHg) (n=40)	P
Sex			0.193
Female	29 (76.3)	24 (60.0)
Male	9 (23.7)	16 (40.0)
Age (y)	64.71±10.70	55.25±12.70	0.001
Duration of CPB (min)	169.61±74.88	144.58±34.06	0.285
Cross-clamp duration (min)	105.95±40.08	97.78±30.14	0.478
Postoperative AF	23 (60.5)	18 (45.0)	0.252
Need for pacemakers	5 (13.2)	1 (2.5)	0.104
Need for permanent pacemakers	2 (5.3)	1 (2.5)	0.610
Postoperative PAP (mmHg)	37.25±7.30	37.88±9.24	0.943
Postoperative EF (%)	58.55±4.64	57.75±7.42	0.993
Total vasopressor requirement (NO)			0.187
1	15 (39.5)	23 (57.5)
2	14 (36.5)	11 (27.5)
3	4 (10.5)	5 (12.5)
4	5 (13.2)	1 (2.5)
Dopamine	38 (100)	40 (100)	n/a
Adrenaline	21 (55.3)	16 (40.0)	0.262
Noradrenaline	7 (18.4)	1 (2.5)	0.027
Dobutamine	9 (23.9)	7 (17.5)	0.692
Postoperative complications
NIMV requirement	8 (21.1)	9 (22.5)	1.000
Duration of MV (h)	18.18±12.90	11.45±7.85	<0.001
Reintubation	3 (7.9)	5 (12.5)	0.712
ARF	7 (18.4)	7 (17.5)	1.000
CVVHDF	1 (2.6)	1 (2.5)	1.000
CVE	2 (5.3)	1 (2.5)	0.610
Amount of bleeding (mL)	539.47±201.74	417.50±186.93	0.003
Transfusion (units)	3.55±1.59	2.87±1.89	0.041
SSI	5 (13.2)	6 (15)	1.000
Duration of ICU stay (d)	4.68±4.69	3.73±4.55	0.082
Duration of hospitalization (d)	8.00±3.60	6.85±2.59	0.033
Readmission to hospital	3 (7.9)	3 (7.5)	1.000
Mortality	3 (7.9)	5 (12.5)	0.712
Measurements taken during CPB
T1 PaO2 (mmHg)	306.03±42.51	260.75±55.40	0.001
T1 FiO2 (%)	0.51±0.09	0.55±0.09	0.038
T1 MAP (mmHg)	68.13±7.02	66.73±6.45	0.359
T1 lactate (mmol/L)	1.02±0.30	1.24±0.71	0.349
T2 PaO2 (mmHg)	265.92±26.67	235.03±36.09	<0.001
T2 FiO2 (%)	0.45±0.05	0.50±0.05	<0.001
T2 MAP (mmHg)	72.53±7.60	73.33±7.38	0.718
T2 lactate (mmol/L)	1.10±0.38	1.43±0.76	0.042
T3 PaO2 (mmHg)	252.82±42.40	239.3±35.70	0.131
T3 FiO2 (%)	0.50±0.10	0.58±0.10	0.001
T3 MAP (mmHg)	72.58±7.88	74.15±7.21	0.312
T3 lactate (mmol/L)	1.22±0.39	1.75±0.99	0.015
T1 PaO2/FiO2 (mm/Hg)	615.35±91.77	474.52±77.18	<0.001
T2 PaO2/FiO2 (mm/Hg)	599.04±68.06	474.10±58.90	<0.001
T3 PaO2/FiO2 (mm/Hg)	517.16±112.98	418.09±75.10	<0.001
Mean PO2/FiO2 (mm/Hg)	577.18±75.72	455.47±34.02	<0.001

CPB, Cardiopulmonary bypass; AF, Atrial fibrillation; PAP, Pulmonary artery pressure; EF, Ejection fraction; NIMV, Noninvasive mechanical ventilator; MV, Mechanical ventilation; ARF, Acute renal failure; CVVHDF, Continuous venovenous hemodiafiltration; CVE, Cerebrovascular event; SSI, Surgical site infection; ICU, Intensive care unit; PaO₂, Partial pressure of oxygen; FiO₂, Fraction of inspired oxygen; MAP, Mean arterial pressure; T_1, At the beginning of cardiopulmonary bypass; T_2, During cardiopulmonary bypass; T_3, At the termination of cardiopulmonary bypass

^* Data are presented as mean±SD or n (%).

The mean age was significantly higher in Group I (P=0.001). Measurement of the PaO₂/FiO₂ ratio at 3 different time points during CPB (ie, T₁, T₂, and T₃) was significantly higher in Group I (mean±SE=577.19±9.43, 95% CI: 558.39–595.98) than in Group II (mean±SE=455.57±9.20, 95% CI: 437.24–473.89) (Figure 1) (F(2,152)=27.663, P<0.001 η²_p=0.267). There was no significant difference in terms of EF and PAP values in the preoperative period echocardiographic measurements between the groups (P=0.322 and P=0.202, respectively). No differences were noted between the groups concerning the total CPB and cross-clamp times (P=0.285 and P=0.478, respectively). The total MV time was significantly higher in the hyperoxemic group than in Group II (P<0.001). The amount of postoperative bleeding was significantly higher in Group I (P=0.003) (539.47±201.74 mL and 417.50±186.93 mL, respectively). The total amount of blood products administered during surgery and the ICU length of stay were higher in Group I (3.55±1.59 units and 2.87±1.89 units, respectively; P=0.041). While the length of stay in the ICU was similar when the 2 groups were compared (P=0.082), the total length of hospital stay was significantly higher in Group I (8.00±3.60 d and 6.85±2.59 d, respectively; P=0.033). No significant difference was found in the mortality rate between the groups (P=0.712) (Table 1).

Figure 1.

Variations of the PaO₂/FiO₂ ratio with time during cardiopulmonary bypass

Group 1: PaO₂/FiO₂ > 500 mmHg

Group 2: 300 mmHg < PaO₂/FiO₂ < 500 mmHg

PaO₂, Partial pressure of oxygen; FiO₂, Fraction of inspired oxygen; T_1, At the beginning of cardiopulmonary bypass; T_2, During cardiopulmonary bypass; T_3, At the termination of cardiopulmonary bypass

EF and PAP measurements during the postoperative period were similar in both groups (P=0.993 and P=0.943, respectively). The lactate value measured at 3 different time points increased significantly more in Group II than in Group I (P<0.001).

Discussion

The current study is one of the rare cardiac surgery studies with a methodology in which perioperative hyperoxemia was defined using the PaO₂/FiO₂ ratio. In this retrospective study, hyperoxemia during CPB in mitral valve repair had negative effects on morbidity. In addition, we observed that hyperoxemia during CPB increased the amount of postoperative bleeding and blood transfusion requirement. Although the length of ICU stay was not affected, the duration of MV was prolonged in hyperoxemic patients, and the total length of hospital stay increased. However, the mortality rate did not differ between the groups.

Pulmonary toxicity due to hyperoxemia was initially described by Smith.¹³ In addition to the direct toxic effect of oxygen on the lungs due to elevated ROS, increased alveolar oxygen concentrations also lead to absorption atelectasis. Non-ventilated but perfused areas of the lung increase the intrapulmonary shunt and decrease the arterial oxygen fraction. Hypoxic pulmonary vasoconstriction is a physiological response against increased intrapulmonary shunts, but it is inhibited by elevated oxygen levels. For the mitigation of this situation, high postoperative oxygen administration constantly leads to elevated absorption atelectasis conditions, resulting in a vicious circle.

Prolonged MV duration is one of the most important complications of cardiac surgery.¹⁴ Various strategies have been performed to shorten the duration of MV, including the performance of reaching a low tidal volume and trying new ventilator modes.¹⁵ It was observed that liberal oxygen therapy (PO₂=190–300 mmHg) was associated with prolonged MV duration compared with conservative oxygen therapy (PO₂=75–112 mmHg).¹⁶ In a more recent study, Jakutis et al¹⁶ showed that the duration of MV was longer in patients with severe hyperoxemia (PO₂>300 mmHg) during CPB. Various studies have also indicated that hypoxemia affects the duration of MV in cardiac surgery.^{7, 17, 18} As a significant result, in our study, we found that the duration of MV was longer in hyperoxemic patients.

It is noteworthy that various studies have reported different values of hyperoxemia. Different studies have used PaO₂, FiO₂, or FiO₂/PO₂, similar to our study. In addition to these different values, the baseline values were also different. The FiO₂ and PaO₂ values that should be used during the perioperative or postoperative period in CPB have not been fully clarified, except for a study that recommended keeping FiO₂ at 35% during CPB.¹⁹

The World Health Organization (WHO) in 2016 recommended high FiO₂ (80%) for 2 to 6 hours during the peri- and postoperative periods to prevent surgical site infection (SSI). However, the results of studies on this subject are contradictory.²⁰ Although several studies have shown that high oxygen prevents SSI, larger studies have shown that there is no association between high oxygen levels and SSI.^{16, 21-23} In a study by Pryor et al²⁴ on general surgery patients, it was shown that the use of high perioperative FiO₂ did not reduce the overall incidence of SSI, but it could have harmful effects (bleeding and increased need for transfusion). In this study, no positive effect of hyperoxemia on SSI was observed.

Hyperlactatemia has been widely accepted as a marker of tissue hypoxia/hypoperfusion. It is thought that hyperlactatemia may result not only from tissue hypoxia or anaerobic glycolysis but also from increased or accelerated aerobic glycolysis while responding to stress conditions.²⁵ In a study on female runners, it was observed that hyperoxemia decreased lactate levels. Sevuk et al²⁶ reported lower lactate levels in patients with hyperoxemia during CPB and suggested that it could be used to prevent tissue hypoxia. Similarly, in our study, lactate levels of hyperoxemic patients during CPB were lower than those of Group II.

Hyperoxemia causes a direct vasoconstrictive effect and increases coronary vascular resistance, as well as systemic vascular resistance.²⁷ It also leads to the deterioration of diastolic dysfunction by altering the calcium balance of myocytes.^{28, 29} These conditions may lead to the deterioration of coronary and systemic perfusion during cardiac surgery. Studies on patients with cardiac disease have reported that those with hyperoxemia have higher cardiac enzymes than normoxemic patients.^{30, 31} Although cardiac enzymes were not measured in our study, similar results were observed in both groups in terms of EF and PAP measured during the pre- and postoperative periods to evaluate cardiac function. In addition, the higher requirement for noradrenaline and pacemakers at the end of CPB in the hyperoxemic group in our study can be considered an indicator of myocardial dysfunction.

Cardiac ICUs are special units that provide care to patients after cardiac surgery or those who are critically ill. The maintenance provided in these units requires a great deal of effort and cost. Therefore, both short ICU stays (<24 h) and early discharges (<5 d) are recommended after cardiac surgery.³² In a study by Sutton et al³³ conducted on cardiac surgery patients, an increase in both ICU and hospital stays was observed in hyperoxemic patients. Similar to our study, in a study by Jakutis et al,¹⁶ while the duration of ICU stay was not affected by hyperoxemia, the length of hospital stay was prolonged. In our study, the length of stay in the ICU was not affected despite the prolongation of the MV period with the routine postoperative ICU stay of at least 36 hours in the cardiac surgery protocols applied in our clinic.

Studies in the literature regarding the effect of hyperoxemia on bleeding and transfusion need are limited. Hyperoxemia is also associated with alterations in blood flow, capillary damage, intravascular hemolysis, and platelet dysfunction.³⁴ In our study, consistent with a study by Belbour et al, more postoperative bleeding and need for transfusion were observed in hyperoxemic patients. Both the amount of bleeding and the increase in the need for transfusion were the factors that significantly affected morbidity and mortality in cardiac surgery patients. Nonetheless, more studies are required to evaluate the relationship between hyperoxemia and the amount of bleeding.

Cardiac surgery is a type of surgery with a high mortality rate compared with many other surgical fields. Whereas there are studies showing that hyperoxemia increases mortality, several other studies have reported that it has no effect.^35-38 In our study, the mortality rates of hyperoxemic and normoxemic patients were similar.

Although our study was retrospective and the number of patients was relatively small, uncomplicated isolated mitral valve patients selected for the study represent a very specific group with many exclusion criteria. Sex (men) and age (older) are among the most important non-modifiable risk factors for coronary artery diseases.³⁹ Moreover, women carry a higher risk of events and mortality after CPB at a young age.⁴⁰ As a limitation of our study, the patients in Group I were older than those in Group II. Still, the large number of women in Group I may clear up the confusion.

Conclusion

The results of the present study showed that the group with hyperoxemia during cardiopulmonary bypass had a higher amount of postoperative bleeding and the need for transfusion. In addition, the duration of mechanical ventilation and ICU stay was longer. Hyperoxemia, which is almost routinely applied to prevent hypoxia in cardiac surgery, may increase postoperative morbidity. Therefore, conservative oxygen treatments may be preferred in cardiac surgery protocols, especially during cardiopulmonary bypass.

Notes:

This paper should be cited as: Yilmaz Ak H, ÖzşahinY, Yeşiltaş MA, Sandal B, Salihoglu Z, Erkalp K. Early Outcomes of a High PaO₂/FiO₂ Ratio during Cardiopulmonary Bypass. J Teh Univ Heart Ctr 2022;17(2):41-47.