Effect of desflurane-remifentanil vs. Propofol-remifentanil anesthesia on arterial oxygenation during one-lung ventilation for thoracoscopic surgery: a prospective randomized trial

One-lung ventilation (OLV) during thoracic surgery can rapidly result in impaired systemic oxygenation. The grade of hypoxemia during OLV is mainly influenced by an increase in shunt and dead space. Hypoxic pulmonary vasoconstriction (HPV) is a physiological protective mechanism that diverts pulmonary perfusion from the non-ventilated to the ventilated area of the lung, thereby decreasing the shunt of unsaturated blood and ameliorating the degree of hypoxemia. This physiologic modulation is influenced by numerous factors such as various drugs, temperature, acid–base status, airway pressure, patient position, and cardiac output [1]. In numerous animal studies and in studies of isolated lungs, HPV has been shown to be modulated by volatile anesthetics [1‐5]. However, human studies have yielded inconsistent results regarding the effects of different anesthetics on systemic oxygenation during OLV [6‐10]. Moreover, the effects of desflurane-remifentanil balanced anesthesia have not been evaluated in a clinical study.

Most halogenated inhaled anesthetics are characterized by its dose-dependent systemic vasodilatory effect [11‐14]. We hypothesized that the vasodilatory effect of desflurane may affect any protective role of HPV, thus impair oxygenation during OLV, even when it is used as a balanced anesthesia, compared with total intravenous anesthesia (TIVA). To evaluate this hypothesis, we compared the effects of two commonly used modern anesthetics, desflurane and propofol, with concomitant remifentanil continuous infusion in both arms, on systemic oxygenation during OLV for video-assisted thoracoscopic surgery.

The Institutional Review Board of Seoul National University Hospital approved this study (reference # 1406-052-587; approval date, July 7, 2014). All patients provided written informed consent, and the study was performed according to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki (ClinicalTrials.gov identifier: NCT02191371; principal investigator, Yunseok Jeon; registered on July 7, 2014).

Patient recruitment and data collection was performed between July and December 2014. Among the 183 patients with lung cancer screened for eligibility, 104 patients were randomized to either desflurane (n = 52) or propofol group (n = 52; Fig. 1). After completion of protocol, 103 patients (52 in the desflurane and 51 in the propofol group) were analyzed. One patient in the propofol group was excluded from the primary analysis, as her baseline PaO₂ was lower than the exclusion criteria (70 mmHg). The characteristics of the patients included in this study were well balanced between the groups (Table 1). There was no difference in underlying diseases and current medications between groups. We included patients scheduled for a lobectomy at enrolment, but several patients required procedures other than pre-planned lobectomy during surgery (Table 1). The distribution of operation types was comparable between the groups (p = 0.428). The right lung was ventilated during OLV in 32/52 and 34/51 patients in the desflurane and propofol groups, respectively (p = 0.682).

Intraoperative blood gas and anesthetic variables at each time point in each group are shown in Table 2. Preoperative and pre-OLV (during TLV before initiation of OLV) PaO₂ were comparable between the groups (92 ± 14 vs. 93 ± 11 mmHg and 217 ± 35 vs. 231 ± 60 mmHg in the desflurane vs. propofol group, respectively). Three pre-OLV PaO₂ data (2 in the propofol group and 1 in the desflurane group) were excluded from analysis, as F_IO₂ (0.5) was not maintained during the period. The primary endpoint, PaO₂ at 30 min of OLV was lower in the desflurane group than the propofol group (170 ± 72 vs. 202 ± 82 mmHg in desflurane vs. propofol group, respectively; p = 0.039). For other time points during OLV, PaO₂ was lower in the desflurane group compared to the propofol group [180 ± 75 vs. 226 ± 84 mmHg (p = 0.004), 179 ± 85 vs. 214 ± 82 mmHg (p = 0.043), and 198 ± 90 vs. 258 ± 122 mmHg (p = 0.009) in desflurane vs. propofol group at 15, 45, and 60 min of OLV, respectively; Fig. 2]. The lowest PaO₂ during the OLV period was lower in the desflurane group than the propofol group (133 ± 50 vs. 162 ± 63 mmHg, respectively; p = 0.010). The serial changes in PaO₂ during 60 min of OLV revealed a lower PaO₂ in the desflurane group compared to that in the propofol group (mean difference, 45 [95% CI, 16–75] mmHg; p = 0.003). The interaction between group and time was not significant during OLV (p = 0.098). Compared to the pre-OLV state, PaO₂ at 15, 30, and 45 min of OLV were significantly lower in the desflurane group (217 ± 35 vs. 180 ± 75, 170 ± 72, and 179 ± 85 mmHg; adjusted p = 0.003, p < 0.001, and p = 0.002, respectively), but not in the propofol group at any time point (Fig. 2).

After 30 min of OLV, mean arterial pressure (MAP) was lower in the desflurane group, and accordingly, lesser remifentanil was used in the desflurane group than propofol group (Table 2). The total amounts of remifentanil administered during surgery were 911 ± 337 μg in the desflurane group and 1407 ± 638 μg in the propofol group, respectively (p <0.001). BIS was maintained within the target range (30–50) throughout the surgery in both groups.

Two patients in the desflurane group received continuous infusion of a vasoactive drug (noradrenaline and phenylephrine, respectively) to maintain adequate hemodynamics. None of the patients received transfusion peri-operatively. Three cases in the desflurane group (p = 0.243) required lung recruitment strategies during OLV to maintain an adequate oxygenation profile, and therefore subsequent data were excluded from comparison of PaO₂ in these patients after the recruitment maneuvers. The rescue maneuvers were performed after 30 min of OLV in all three cases. After alveolar recruitment, hypoxemia was improved and no changes in the anesthetic protocol were required.

In this study, oxygenation under desflurane-remifentanil balanced anesthesia was lower than that under propofol-remifentanil TIVA during OLV for video-assisted thoracoscopic surgery. This is the first reported clinical trial in which desflurane was shown to impair oxygenation during OLV compared to TIVA in lung cancer patients undergoing thoracoscopic lung surgery.

Recently, many surgical procedures have been performed using less-invasive approaches. Large percentages of thoracic operations for lung resection are performed through video-assisted thoracoscopic surgery. Thus, the durations of both the operation and postoperative recovery period have been shortened. Both desflurane and propofol are relatively new anesthetics with short-acting properties characterized by rapid onset and offset due to their low blood gas partition coefficient and low context-sensitive half time, respectively. Therefore, they are highly attractive and offer fast-track anesthesia and earlier recovery for postoperative rehabilitation in minimal invasive thoracic surgery. However, the roles of these modern anesthetics in management of oxygenation during OLV remain unclear in humans.

In animal studies, inhalational anesthetics are known to inhibit the protective role of HPV during alveolar hypoxia combined with OLV both in vitro and in vivo [2]. Halothane, enflurane, isoflurane, sevoflurane, and desflurane depressed HPV in a dose-dependent manner in isolated rat or rabbit lung [4, 22, 23]. Isoflurane or desflurane impaired oxygenation during OLV, while intravenous anesthetics, such as propofol or pentobarbital, had no detrimental impact on HPV in animal studies [3, 5, 24, 25]. However, in clinical investigations, results regarding the effects of anesthetics on oxygenation and HPV during OLV have been inconsistent [6‐10, 26, 27]. Propofol improved oxygenation and shunt fraction during OLV compared to sevoflurane anesthesia in patients undergoing esophagectomy [6] or thoracotomy pulmonary lobectomy [27]. In other studies, propofol anesthesia did not differ in changes in shunt fraction or oxygenation during OLV for thoracic surgery in comparison with sevoflurane or isoflurane [7‐10]. Moreover, arterial oxygenation was not different between propofol-alfentanil vs. isoflurane anesthesia during OLV in patients undergoing thoracoscopic pulmonary surgery or esophageal surgery [26]. Above all, there have been no previous reports comparing the effects of the two commonly used anesthetics, desflurane and propofol, on arterial oxygenation during OLV in thoracic surgical patients.

In accordance with previous reports [21, 28], our data demonstrated a decrease in PaO₂ during the first 30 min of OLV and gradual improvement thereafter in both groups (Fig. 2). During desflurane anesthesia, PaO₂ decreased significantly after 15 min of OLV compared to the pre-OLV state, and then recovered gradually to pre-OLV levels at 60 min. On the other hand, arterial oxygenation was relatively well maintained during propofol anesthesia throughout the study. None of the time points during OLV indicated a lower PaO₂ compared to pre-OLV state in the propofol group.

One explanation for our results is that more vasodilation induced by desflurane anesthesia would have attenuated any protective effect of HPV during alveolar hypoxemia, thus decreased systemic PaO₂ in the desflurane group compared to the propofol group. This is partially supported by significantly lower arterial blood pressure despite the lesser use in remifentanil during desflurane anesthesia compared to propofol anesthesia in the present study (Table 2). Significant drop in MAP during desflurane anesthesia compared to propofol anesthesia also has been reported in previous animal study (66 vs. 103 mmHg), in which the effect of anesthetics (desflurane vs. propofol) on arterial oxygenation during OLV was evaluated [3].

Previously, an attempt to inhibit HPV by infusing the potent vasodilator sodium nitroprusside (SNP) during OLV has failed to show significant changes in pulmonary vascular resistance (PVR), shunt fraction, or arterial oxygenation [29]. However, only seven patients were used to evaluate the effect of administering SNP on HPV, by measuring related parameters only once during OLV, before the surgery commenced. Moreover, there was no time window from drug administration to measurement of the variables, or duration of drug infusion to reach the predefined goal (25% decrease in MAP), as presented by the authors. Although vasodilation induced by SNP decreased PVR (166 ± 23–131 ± 22 dynes/s/cm⁵) and PaO₂ (285 ± 42–225 ± 47 mmHg) in that study, the decreases were not significant. Therefore, further investigations may be needed.

Decreases in PaO₂ and use of lung recruitment maneuvers during OLV were observed in three patients that received desflurane, while no cases were observed in the propofol group. During the events, the lowest PaO₂ levels under F_IO₂ of 1.0 were 60, 69, and 87 mmHg, respectively. All episodes occurred after 30 min following initiation of OLV. In the last case, the degree of hypoxemia was not severe; however, the attending anesthesiologist decided to provide rescue treatment and proceed with OLV for the remainder of the surgical procedure. Similar events have been reported in previous animal studies comparing desflurane and propofol during in vivo OLV [3]. In this previous study, 3 of 10 pigs showed oxygen desaturation < 90% during OLV with desflurane anesthesia, while no cases were observed in the group receiving propofol. Although there were no further complications after desaturation in our study, these results suggest that desflurane anesthesia for OLV could result in deterioration of oxygenation especially in subjects with under-reserved pulmonary function.

In the current study, blood pressure was managed using adjustment of remifentanil infusion according to the hemodynamic changes during the surgical procedure. We tried to use anesthetic techniques relevant to real clinical practice. It is clearly reflected in the lower use of remifentanil in the desflurane group mainly due to the sustained lower blood pressure in this group compared to the propofol group. In a previous study investigated the effects of different concentrations of remifentanil during OLV, no differences in PaO₂ were observed despite the significantly different blood pressures [30]. Therefore, we considered that the observed difference in PaO₂ may not the consequence of the difference in remifentanil use between the two groups in this study.

Although a significant difference in PaO₂ was detected between the groups (170 vs. 202 mmHg at 30 min of OLV in the desflurane vs. propofol group, respectively; p = 0.039), the difference may be clinically irrelevant to the anesthesiologist who is managing oxygenation in patients undergoing OLV. In this trial, we used a F_IO₂ of 1.0 throughout the OLV period with the expectation that it would better distinguish the difference in oxygenation between the groups [31]. A clinically significant difference in PaO₂ may have been found between the two groups if a lower F_IO₂ had been used.

In some studies, desflurane showed relatively conserved vascular resistance compared to sevoflurane [32]. In other studies, desflurane has shown more vasodilatory effect among inhalational anesthetics [11‐14]. Although no differences were observed in oxygenation between sevoflurane and propofol anesthesia during OLV in several previous studies [8‐10], desflurane, even as balanced anesthesia, showed more impaired oxygenation during OLV compared with propofol anesthesia in the present study. However, we did not compare the two popular inhales, sevoflurane vs. desflurane, in the present trial. Further studies are required for comparison of effects of two commonly used volatile anesthetics.

The following limitations should be considered when interpreting our results. First, we did not measure the pulmonary shunt fraction, perfusion or the extent of pulmonary vasoconstriction in each isolated lung during surgery, which could have explained the effects of the anesthetic on pulmonary circulation, arteriovenous shunt fraction, or the degree of ventilation/perfusion mismatch. Therefore, it is difficult to conclude that there were any effects of the anesthetics on the role of HPV during OLV from these results. Second, we did not fix the dose of desflurane, propofol, or remifentanil during this study. Instead, they were titrated by attending anesthesiologists in charge according to anesthetic depth (BIS) or hemodynamic values. Therefore, our results do not reflect the effect of any specific anesthetic dose. Third, although we fixed F_IO₂ at 1.0 during OLV in both groups, minimal loss of inspired oxygen in the desflurane group was inevitable due to the volume of inhaled anesthetic. However, the present anesthetic protocol was based on the general practice of the institution. Thus, these results should be interpreted in the context of a thoracic surgery anesthesia practice using inhalational and/or intravenous anesthetics. The F_IO₂ or concentration of inhalational anesthetics could be adjusted according to the clinical setting. Fourth, the cardiac index used in this study was calculated based on non-externally calibrated pulse contour analysis, which may be less precise than pulmonary or transpulmonary thermodilution methods. Therefore, this may have obscured the interpretation of the effects of cardiac output on HPV. Finally, the dose of desflurane administered during the study was 1.0–1.1 MAC. This dosage may seem rather high for a balanced anesthesia protocol, reflecting the lower MAP and less use of remifentanil in the desflurane group compared to those in the propofol group. However, in real clinical situation, anesthesiologist continuously changes the dose of anesthetics according to the patient’s responses, and we believe that the results of our study may be more useful in the clinical practice.

In conclusion, oxygenation under desflurane-remifentanil balanced anesthesia was lower than that under propofol-remifentanil TIVA during OLV for video-assisted thoracoscopic surgery. In patients who develop hypoxemia during OLV with inhalational anesthetics, change anesthetics to an intravenous agent should be considered.