Discussion
Main Findings
The main findings of this study are:
Low tidal-volume ventilation during hepatectomy induced an increase in the concentration of IL-8 in the ELF collected during hepatectomy.
Low tidal-volume ventilation during hepatectomy resulted in a lower P/F ratio after surgery.
These were contrary to our hypothesis that low VTventilation would reduce lung inflammation and preserve physiological lung functions following major surgery, compared to conventional ventilation.
The Mechanism of Lung Injury
Our hypothesis was based on studies that showed the benefits of low VT ventilation in ARDS patients.[1] A considerable number of ARDS cases originate from extra-pulmonary complications including pan-peritonitis, cholecystitis, multiple injury, and massive transfusion. Severe systemic inflammation is a common occurrence in these conditions. Ischemia-reperfusion of organs or other parts of the body are the leading causes of systemic inflammation. The liver is one of the largest organs in the human body; approximately 25 % of the entire blood flows into the liver. Therefore, repeated hepatic ischemia-reperfusion may be a major cause of systemic inflammation. Takeuchi and colleagues showed polymorphonuculear cell (PMN) recruitment in the lungs, proinflammatory cytokine elevation in the blood and lung homogenates, and pulmonary edema in mice after 90 min of liver ischemia and reperfusion.[10] Our previous study showed that lung injury occurs following repeated hepatic ischemia and reperfusion with high VT ventilation in rats.[11] Taken together, hepatic surgeries performed with the Pringle maneuver is a potential leading cause of lung injury; therefore, reducing VT during hepatectomy is a reasonable strategy to prevent lung injury.
Protective Ventilation During Surgery
Recently, several studies have been conducted regarding VT and lung functions during surgery. Michelet and colleagues showed that concentrations of IL-8, IL-6, and TNF-α in the plasma were lower in patients who underwent esophagectomy with lower VT ventilation (5 mL·kg−1, PEEP 5 cm H2O) than in those who underwent esophagectomy with higher VT ventilation (9 mL·kg−1, PEEP 0 cm H2O) during one-lung ventilation.[12] Wolthuis and colleagues showed that the concentration of IL-8 in broncho-alveolar lavage (BAL) fluid was significantly lower in patients ventilated with a low VT (6 mL·kg−1, PEEP 10 cm H2O) than in those ventilated with a large VT (12 mL·kg−1, PEEP 0 cm H2O) during elective surgery.[13] Severgnini and colleagues reported that low VT ventilation (6–8 mL·kg−1, PEEP 6–8 cm H2O) during abdominal surgery improved postoperative pulmonary function and reduced the modified Clinical Pulmonary Infection Score as compared with a standard ventilation strategy (10–12 mL·kg−1, PEEP 0 cm H2O).[14] A recent, randomized controlled trial showed that ventilation with a VT of 6 to 8 mL per kg of predicted body weight with a PEEP of 6 to 8 cm of H2O and a recruitment maneuver reduced major pulmonary complications after abdominal surgery compared to ventilation with a VT of 10–12 mL per kg of predicted body weight with no PEEP and no recruitment maneuver.[15] These studies reported that low VT ventilation during surgery results in reduced inflammation or better lung functions after the surgery as compared with relatively higher VT ventilation. We should note that relatively higher PEEP and/or lung recruitment maneuver were applied to the groups that are ventilated with lower VT in those papers.[12–15]
The results of the present study were in contrast to those of previous studies in terms of the correlation between the level of VT and the post-surgical lung function. The most plausible reason for the discrepancy is the level of PEEP that was applied in the present study. We used relatively low PEEP (3 cmH2O) in both the groups, which may have influenced the results. Recently, there are a few papers that focused on the relationship between PEEP level during surgery and postoperative pulmonary complications in otherwise healthy patients. Ladha et al. retrieved anesthesia records and compared ventilation settings with respiratory complications.[16] Protective ventilation defined as a median PEEP of 5 cmH2O or more, a median tidal volume of less than 10 mL·kg−1 of predicted body weight, and a median plateau pressure of less than 30 cmH2O was associated with a decreased risk of postoperative respiratory complications. de Jong et al. retrieved anesthesia records and compared median PEEP of < 5 cmH2O, = 5 cmH2O, or > 5 cmH2O with respiratory outcome.[17] Application of PEEP > 5 cmH2O was associated with a significant lower odds of respiratory complications and decreased hospital length of stay in patients undergoing major abdominal surgery but not in patients undergoing craniotomy. These findings suggest that special consideration such as application of PEEP of 5 cmH2O or higher is necessary especially when abdominal surgery is undergone. More recently, a meta-analysis revealed that a protective lung ventilation, low VT ventilation concomitant with PEEP and intermittent recruitment maneuver, showed a significant reduction in incidences of postoperative lung infection, atelectasis, acute lung injury, and length of hospital stay; whereas, low VT alone failed to reduce some of the incidences.[18] In the present study, low VT ventilation with low PEEP applied to patients undergoing hepatectomy failed to improve pulmonary function, which is consistent with the previous findings.[16–18] Moreover, it is important to understand that optimal VT or PEEP for otherwise healthy patients undergoing surgery could be different from those for ARDS patients with a baby lung.
Mechanism of Deteriorated Lung Function
After 6 h of ventilation, we found that IL-8 in the ELF was higher in the TV6 group than in the TV12 group. Previous studies have shown an increase in IL-8 levels in atelectatic lungs. Lung collapse results in increased IL-8 levels in BAL fluid and the re-expansion of the lungs further increases IL-8 levels in rabbits.[19] One-lung ventilation resulted in an IL-8 increase in the ELF of the non-ventilated lungs.[20] These observations suggest that the increase in IL-8 levels in the ELF in the low VT group in the present study was due to a repeated lung collapse and re-opening of the lungs (atelectrauma) during surgery due to low VT ventilation concomitant with low PEEP. ICAM-1 in the plasma was significantly higher in the TV6 group than in the TV12 group. Plasma ICAM-1 is associated with poor clinical outcomes in patients with acute lung injury.[21] In that study, however, plasma ICAM-1 level is also elevated in the patients with hydrostatic pulmonary edema, who basically have minimal lung injury. In the present study, mean plasma ICAM-1 concentrations in the TV12 and TV6 were from 107 to 117 ng/mL and from 133 to 196 ng/mL, respectively. These values were identical to that for the patients with hydrostatic pulmonary edema in the previous study (median 177 ng/mL),[21] suggesting that the effects of plasma ICAM-1 in the present study on lung injury are minimal in both groups.
Advantages of BMS Method Over BAL Collection
Historically, BAL fluid has been used to assess the biochemical status of the airway; however, we collected bronchial ELF using the BMS method to assess lung inflammation in this study. There are a few advantages of BMS method over BAL collection. First, concerns have been raised related to patient safety during BAL collection, including desaturation during the procedure, surfactant breakdown, and a spreading of localized pathology. In fact, Bauer and colleagues showed a decrease in the PaO2/FIO2 ratio after BAL collection, regardless of the BAL volume used.[22] Second, it is not possible to quantitate the concentration of biomarkers in the airway because the exact dilution factor may not be obtained in this way. Lastly, it is inappropriate to obtain repeated BAL measurements within a short period of time because the biomarkers are washed out. In the BMS method, ELF is collected using an absorptive probe guided by a fiberoptic scope; thus, we were able to safely and repeatedly collect biochemical markers from the patients' airways. In contrast to BAL, BMS has the following advantages when used to determine the biochemical status of the airway: oxygenation can be maintained during and after the procedure; alveolar surfactant is preserved; quantification of the biochemical markers is possible; and samples can be repeatedly obtained within a short duration.[9]
Limitations of the Study
The present study has a few limitations. First, we did not find a relevant paper to refer to in terms of the standard deviations of the two groups and thus we did not perform power analysis. Accordingly, there may be type-two error in the results of the study. Second, a steroid was administered prior to the Pringle maneuver. It is mandatory to administer a steroid for hepatectomy at our institute, regardless of the study; however, this may have limited systemic inflammation in both of the groups. In fact, in both groups, TNF-α levels in the plasma were below the detection limit, and IL-8 levels in the plasma during the surgery were similar to that of baseline values. Third, in the previous paper, the median plasma sICAM-1 concentrations for survivor and non-survivor among patients with ARDS were 338 ng/mL and 737 ng/mL, respectively,[21] whereas the plasma ICAM-1 values of our patients in each group were far fewer than those values in the previous paper namely those of survivors. This fact suggests that although there was significant difference in plasma ICAM-1 in two groups in our study, the extent of the increase in ICAM-1 may not have clinical or biological significance. However we have not proven this and slightly elevated plasma ICAM-1 in the TV6 group may be the cause of lower P/F ratio after the surgery. Lastly, postoperative oxygenation difference was the only clinical outcome between the groups. No patient experienced hypoxia postoperatively because each patient received supplemental oxygen at the PACU. However, the data suggest some patients, especially those in the TV6 group (mean P/F ratio of about 300), may have experienced hypoxia unless supplemental oxygen was applied. We may consider this as clinically significant.
BMC Anesthesiol. 2016;16(47) © 2016 BioMed Central, Ltd.
