Thoracic epidural anaesthesia is widely used for intra- and postoperative analgesia in patients undergoing major thoracic surgery. It results in better pain control and less respiratory depression after surgery as compared to the use of intravenous (i.v.) opioids [1,2]. A reduced incidence of pulmonary morbidity has also been reported .
Inhalational agents are known to produce dose-dependent inhibition of the hypoxic pulmonary vasoconstriction (HPV) reflex . Thus, reducing end-tidal concentration of a volatile anaesthetic by using a thoracic epidural blockade could theoretically improve intraoperative oxygenation during one-lung ventilation. Sympathetic blockade induced by thoracic epidural anaesthesia may potentially affect patient oxygenation through several other mechanisms. Epidural anaesthesia reduces the minimum alveolar concentration (MAC) of inhalational anaesthetics , and the potentiation of these agents could lead to increased inhibition of the HPV reflex . On the other hand, thoracic epidural anaesthesia may affect the ventilation/perfusion ratio by modifying pulmonary blood flow. Cardiovascular effects induced by sympathetic blockade may enhance the HPV reflex by decreasing the mixed venous partial pressure of oxygen .
The aim of this prospective, randomized, controlled clinical study was to evaluate the effects of thoracic epidural anaesthesia used in combination with isoflurane/nitrous oxide anaesthesia on intraoperative oxygenation during one-lung ventilation for lung resection surgery.
With approval of the institutional Ethics Committee and patient's written informed consent, 40 patients undergoing open-chest one-lung ventilation in the lateral decubitus position were included in the study. The same team of surgeons performed all surgical procedures (pneumonectomy, lobectomy and atypical lung resections). Patients with severe cardiovascular or respiratory diseases or ASA Grade >III, as well as patients with contraindications to the placement of an epidural catheter or to the use of a double-lumen endobronchial tube were excluded. Routine pulmonary function tests and arterial blood- gas analysis were performed preoperatively. Patients with a predicted postoperative FEV1 <40% also underwent pulmonary perfusion scintigraphy to verify a predicted postoperative FEV1 >35%.
Premedication was given 30 min before arrival in the operating room with diazepam 0.1 mg kg−1 orally and atropine 0.01 mg kg−1 intramuscularly. A thoracic epidural catheter was placed at the T5-6 or T6-7 interspace. Using a computer-generated sequence of numbers and a sealed envelope technique, patients were randomly allocated to two groups. In the control group the epidural catheter was not used until the completion of the study (group General, n = 20). In the treatment group, after an initial test dose with 2 mL of lidocaine 2%, an epidural block was induced with 5 mL of lidocaine 1% and fentanyl 1 μg kg−1. The epidural blockade was maintained with 5 mL boluses of lidocaine 1% every 60 min (group Integrated, n = 20). General anaesthesia was induced after loss of pinprick sensation had been observed at the T2-9 dermatomes.
Intraoperative monitoring included continuous electrocardiogram (leads II and V5), heart rate (HR), invasive arterial pressure, arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) (IL BGM 1312, Instrumentation Lab., Lexington, MA, USA), pulse oximetry (SPO2), inspired oxygen fraction (FiO2), end-tidal carbon dioxide (EtCO2) and isoflurane concentrations, peak airway pressure, and minute ventilation.
General anaesthesia was induced with sodium thiopental 5 mg kg−1 and fentanyl 1 μg kg−1 i.v. After adequate muscle relaxation with atracurium 0.6 mg kg−1 i.v., a double-lumen endobronchial tube was placed. According to our routine practice we used a left-sided endobronchial tube for both right- and left-sided thoracic procedures. Adequate position of the endobronchial tube was confirmed with fibreoptic bronchoscopy before and after turning the patient to the lateral decubitus position. In case of unstable or very high airway pressure, the correct position of the endobronchial tube was checked again with fibreoptic bronchoscopy.
The patients were mechanically ventilated with nitrous oxide in oxygen (FiO2 = 0.5) with a Cato volume cycled ventilator (Dräger, Lübeck, Germany), using a tidal volume of 9 mL kg−1, an inspiratory-to-expiratory time ratio of 1:1, and an inspiratory pause of 10%. The respiratory rate was adjusted to maintain an arterial CO2 partial pressure ranging between 4.6 and 5.6 kPa. The same parameters were maintained also during one-lung ventilation . No positive end-expiratory pressure was applied during the study.
General anaesthesia was maintained with isoflurane (end-tidal concentration 0.5-1.5%), titrated to maintain systolic arterial pressure and HR within ±20% of baseline values. Hypotension (decrease of systolic arterial pressure >30% from baseline values) was treated with i.v. infusion of gelatin solution 500 mL. Muscle relaxation was maintained with a continuous i.v. infusion of atracurium 0.01 mg kg−1 min−1.
Arterial blood-gas analyses were performed as follows: after induction of general anaesthesia during two-lung ventilation with the patient supine (Baseline); after 10, 30, 45 and 60 min of open-chest one-lung ventilation; at the end of surgery with two-lung ventilation and the patient in lateral decubitus position; in the post-anaesthesia care unit (PACU) with the patient supine and receiving oxygen by facemask. The PaO2/FiO2 was calculated at each time point.
If intraoperative desaturation (SPO2 < 92%) occurred, the position of the endobronchial tube was first verified with fibreoptic bronchoscopy, and then the FiO2 was increased to 100% until SPO2 recovered to ≥92%. If this was ineffective, surgery was temporarily interrupted and the non-dependent lung was re-inflated manually with 100% oxygen. Positive end-expiratory pressure (PEEP) or continuous positive airways pressure (CPAP) was not applied to the non-ventilated operated lung at any time . When SPO2 had recovered to 98% for 15 min, ventilation was resumed with FiO2 0.5 in nitrous oxide. The need for at least one episode of ventilation with 100% oxygen and/or manual re-inflation of the operated lung was recorded.
The infusion of atracurium was stopped approximately 20 min before the last skin suture. When surgery was finished, the volatile anaesthetic agents were discontinued and residual neuromuscular block was antagonized with neostigmine 2 mg and atropine 1 mg i.v. The lungs were ventilated manually with 100% oxygen until spontaneous ventilation resumed. Extubation was performed when the patient was judged to be awake, breathing regularly with adequate oxygenation (SPO2 > 92% breathing room air). In the PACU, after the study was completed, patients in group General received an epidural test dose followed by the epidural injection of 5 mL of lidocaine 1% and fentanyl 1 μg kg−1. Postoperative analgesia consisted of a continuous epidural infusion of ropivacaine 0.2% with fentanyl 2 μg mL−1 (infusion rate 4-6 mL h−1) and proparacetamol 2 g i.v. every 8 h. Rescue analgesia with tramadol 100 mg i.v. was available if required .
To calculate the required sample size we took into account the mean and standard deviation (SD) of arterial partial pressure of oxygen reported during one-lung ventilation in a previous study performed in our Institution with the same clinical setting . Twenty patients per group were required to detect a difference in the PaO2/FiO2 ratio of 5.9 kPa between the two groups at the 30 min observation time (with an effect size to SD ratio of 0.8), accepting a two-tailed α error of 5% and a β error of 20% . Statistical analysis was performed using the program Systat 7.0 (SPSS Inc, Chicago, IL, USA). The U-test was used to compare continuous variables, while categorical data were analysed using the contingency table analysis with the Fisher's exact test. Unless otherwise indicated, results are mean (±SD) or numbers (%). P ≤ 0.05 was considered as significant.
All surgical procedures were successfully completed. There were no differences in anthropometric variables, preoperative pulmonary function tests, duration of surgery, intraoperative blood loss and total amount of fluid volume infused during surgery between the two groups (Table 1).
In patients receiving epidural anaesthesia, the HR had decreased at 10 min of open-chest one-lung ventilation compared to baseline (supine, two-lung ventilation). In that group, HR remained significantly lower than in group General throughout the study period (Fig. 1). No significant differences were observed in mean arterial pressure, or incidence of clinically relevant hypotension, between the two groups at any time point (Fig. 1). In group General, the mean arterial pressure after 10 min of open-chest one-lung ventilation was higher than at baseline. No further deviations from baseline were observed. The end-tidal concentrations of isoflurane required to maintain cardiovascular stability were lower in group Integrated than in group General (Fig. 2).
The PaO2/FiO2 ratio decreased in both groups during one-lung ventilation as compared to baseline (Fig. 3). It recovered to baseline during spontaneous breathing in the PACU. No differences were observed at any observation time between the two study groups. The gradient between arterial and end-tidal PCO2 did not differ between the two groups at any time. Ventilation with 100% oxygen because of SPO2 ≤ 92% was required in nine patients of group General (45%) and in eight patients of group Integrated (40%) (P = 0.64). Manual re-inflation of the operated lung was required in one patient of group General only (P = 0.99).
The anaesthesia technique is one of several factors that can affect oxygenation during one-lung ventilation for lung surgery. The literature provides controversial information about the effects of epidural block on patient oxygenation during one-lung ventilation [9,10]. This prospective, randomized, controlled study demonstrated that epidural block does not result in clinically relevant deterioration of oxygenation during one-lung ventilation in patients anaesthetized with isoflurane.
The innervation of the pulmonary vasculature is provided by the autonomic nervous system. Thus, sympathetic blockade induced by epidural anaesthesia can theoretically affect vascular tone of the pulmonary vessels during one-lung ventilation. In a study on intact instrumented dogs, Brimioulle and colleagues  demonstrated that epidural block increased the HPV reflex by more than 25%. This effect disappeared after α- and β-adrenergic blockade, suggesting that the effects of epidural block on pulmonary circulation were related to the sympathetic blockade . On the other hand, Ishibe and colleagues  evaluated the effects of epidural block on HPV in dogs using an analysis of the pressure-flow curve. They demonstrated that thoracic epidural anaesthesia had no influence on the primary hypoxia-induced increase in vascular tone, but enhanced blood flow diversion from the hypoxic lobe, thus improving arterial blood oxygenation. Moreover, it should also be considered that sympathetic blockade induced by epidural anaesthesia affects cardiac output and arterial pressure , with potential effects on both the HPV reflex and patient oxygenation . Accordingly, epidural blockade can lead to different and to some extent contrasting effects on patient oxygenation during one-lung ventilation. This might finally result in a clinically insignificant net effect.
In patients undergoing lung resection with total i.v. anaesthesia, Garutti and colleagues  observed worse arterial oxygenation and shunt fraction in patients who also had thoracic epidural block. On the contrary, in a very similar clinical setting, von Dossow and colleagues  reported that thoracic epidural block combined with light isoflurane anaesthesia did not impair arterial oxygenation to the same extent as total i.v. anaesthesia. This was attributed to less marked effects on cardiac output and enhanced cardiovascular stability when switching from two-lung to one-lung ventilation. Like von Dossow and colleagues, we maintained general anaesthesia with isoflurane, which has more marked depressant effects on the HPV reflex than propofol . This might have partially masked the effects of epidural blockade.
Several major limitations can be outlined in this investigation. We only measured patient oxygenation and simple cardiovascular variables, while other important factors, like cardiac output and shunt fraction, were not directly determined. However, this was a clinical study and our aim was mainly focused on the evaluation of crude clinical effects of epidural anaesthesia on intraoperative oxygenation during one-lung ventilation. Furthermore, considering the information already available in the literature on this matter, we did not find monitoring with pulmonary artery catheters ethically or economically justifiable.
Another pitfall of this study is related to the relatively small sample size, which may increase the risk for a type-two error. Our power calculation was aimed at detecting a difference in PaO2/FiO2 ratio of 5.9 kPa (that corresponded in our clinical setting to a difference in arterial PO2 between the two groups of about 2.6 kPa), and was based on results of a previous investigation . However, when making a ‘post hoc’ power calculation from the data collected in the present investigation, 20 patients per group would allow detection of a difference in PaO2 between the two groups of 4 kPa, with α and β errors of 5%. This means that our results allow us to exclude, with a 95% power, that thoracic epidural blockade can produce changes in arterial oxygenation ≥4 kPa during one-lung ventilation in patients anaesthetized with isoflurane.
In conclusion, this clinical investigation demonstrates that adding a thoracic epidural block to isoflurane anaesthesia during one-lung ventilation for lung resection surgery does not result in clinically relevant detrimental effects on intraoperative oxygenation as compared to the use of isoflurane alone.
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