High peak airway pressure (Ppeak) and high end-tidal carbon dioxide tension (PETCO2) are the common problems encountered in the obese patients undergoing gynecological laparoscopy with conventional volume-controlled ventilation. This study was designed to investigate whether volume-controlled inverse ratio ventilation (IRV) with inspiratory to expiratory (I:E) ratio of 2:1 could reduce Ppeak or the plateau pressure (Pplat), improve oxygenation, and alleviate lung injury in patients with normal lungs.
Sixty obese patients undergoing gynecological laparoscopy were enrolled in this study. After tracheal intubation, the patients were randomly divided into the IRV group (n = 30) and control group (n = 30). They were ventilated with an actual tidal volume of 8 mL/kg, respiratory rate of 12 breaths/min, zero positive end-expiratory pressure and I:E of 1:2 or 2:1. Arterial blood samples, hemodynamic parameters, and respiratory mechanics were recorded before and during pneumoperitoneum. The concentrations of
Volume-controlled IRV not only reduces Ppeak, Pplat, and the release of inflammatory cytokines, but also increases mean airway pressure, and improves oxygenation and dynamic compliance of respiratory system in obese patients undergoing gynecologic laparoscopy without adverse respiratory and hemodynamic effects. It is superior to conventional ratio ventilation in terms of oxygenation, respiratory mechanics and inflammatory cytokine in obese patients undergoing gynecologic laparoscopy.
gynecologic laparoscopyinflammatory cytokineinverse ratio ventilationlung injury;
Laparoscopy is associated with increases peak airway pressure (Ppeak) and high end-tidal carbon dioxide tension (PETCO2) with conventional ratio ventilation mode, especially in obese patients. Laparoscopic gynecologic surgery usually requires steep lithotomy or Trendelenburg position, demanding additional ventilatory adjustments to maintain oxygenation and normocapnia.1, 2 It is difficult to improve the hypercapnia by increasing the respiratory rate or tidal volume, as the high airway pressure may not allow a further increase in tidal volume, and increasing respiratory rate sometimes fails to correct hypercapnia. Applying positive end-expiratory pressure (PEEP) might improve oxygenation and be accompanied with an increase in Ppeak. Furthermore, high tidal volume and high airway pressure may lead to lung barotrauma and volutrauma. It is reported that pressure-controlled inverse ratio ventilation (IRV) can successfully recruit collapsed alveoli and has improved oxygenation at lower Ppeak.3, 4, 5, 6, 7 However, its use is sometimes limited by the significant elevation in Ppeak with increasing the risk of barotrauma3, 4 and a decrease in tidal volume. Prolonging inspiratory time with inspiratory to expiratory (I:E) ratio more than 3:1 might affect cardiac output, and the optimal I:E of IRV is 2:1,8 so we investigated whether volume-controlled IRV (I:E = 2:1) was superior to conventional ratio ventilation in terms of oxygenation and respiratory mechanics in obese patients undergoing laparoscopic gynecologic surgery.
This study was approved by the Hospital Ethics Committee of Jinxing maternity and child health care hospital and registered in the protocol registration system (www.chictr.org.cn, registration number:ChiCTR-IPC-15006522). Informed consent was signed by the patients. From May 2014 to June 2015 we chose a total of 60 obese patients of elective major gynecologic laparoscopy, ASA grade I or II, age 34–61 years, body mass index 30–35 kg/m2 (weight 71–87 kg), and expected duration of surgery > 1 hour. We excluded patients with cardiopulmonary disease and age > 65 years or < 18 years. The 60 patients were randomly divided into the IRV group (n = 30) and control group (n = 30), based on a computer-generated randomization list.
All patients were premedicated with 5 mg midazolam and 0.5 mg atropine intramuscularly 30 minutes before arrival at the operating room. After entering the operating room, monitoring, including electrocardiogram, noninvasive blood pressure, heart rate, cardiac output, stroke volume index, systemic vascular resistance, and other indicators, was applied with BioZ.com noninvasive hemodynamic (Cardio Dynamics company, USA) and venous access was established. After preoxygenation, anesthesia was induced with intravenous fentanyl 4 μg/kg, propofol 2 mg/kg given over 15 s, and cis-atracurium 0.15 mg/kg. After tracheal intubation using direct laryngoscope, the patients were randomly divided into of two groups with volume-controlled ventilation mode. Lungs were ventilated with Datex-Ohmeda Aspire anesthesia ventilator. Respiratory parameters were set as: actual tidal volume 8 mL/kg actual body weight, respiratory rate 12 breaths/min, PEEP of zero, oxygen flow 1 L/min, fraction inspired oxygen (FiO2) 1.0, and I:E ratio of 2:1 (in the IRV group) or 1:2 (in control group).
Anesthesia was maintained with propofol 4–6 mg/kg/h and 1.5–2.5% end-tidal sevoflurane to keep the bispectral index value between 45 and 55 (BIS monitor Model A2000; Aspect, USA) and control the hemodynamic response to the surgical procedure within a 20% range of the preoperative value. Muscle relaxation was monitored by the train-of-four (TOF) stimulation on the ulnar nerve (Type TOF-Watch SX; Organon, Oss, The Netherlands). Continuous infusion of cis-atracurium (0.08–0.1 mg/kg/h) was performed to keep TOF value below 5%. Respiratory parameters were kept constant if PETCO2 was <50 mmHg. When PETCO2 exceeded 50 mmHg, respiratory rate or tidal volume was adjusted to maintain PETCO2 below 50 mmHg. Spirometry readings included Ppeak, plateau pressure (Pplat), mean airway pressure (Pmean), PEEP (auto-PEEP), and dynamic compliance of the respiratory system (CL) using a side-stream spirometry device (Anesthesia Monitor D-FPD15-00; GE, Taipei, Taiwan). CO2 pneumoperitoneum tension was set at 15 mmHg. Throughout the study period, lactated Ringer's solution was infused at rate of 6–8 mL/kg/h.
The patients were put in a 30° Trendelenburg position after trocars were placed and in the supine position again at the end of pneumoperitoneum. Hemodynamic parameters were monitored at 5 minutes before anesthesia induction (T0), immediately before onset of pneumoperitoneum (T1), 60 minutes after onset of pneumoperitoneum (T2), and the end of surgery (T3). Arterial blood gas was analyzed using a blood gas analyzer (ABL8000A; Denmark) at T1 and T2. Postoperative complications were observed, such as discharge time in the postanesthesia care unit (PACU), hypoxemia [defined as arterial partial pressure of oxygen (PaO2) < 80 mmHg], and other pulmonary complications. The patients could be discharged from PACU when modified Aldrete score was 9 or above.
Before and during pneumoperitoneum, we collected respectively right bronchoalveolar lavage fluid soaked in 20 mL normal saline for 5 minutes with a fiber bronchoscope (Olympus, Tokyo, Japan), and 20–30% of this fluid was recovered. The samples were centrifuged (3000 r/min, r = 16 cm) for 15 minutes at 4°C and the supernatant stored at 70°C. Tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 levels were detected with enzyme-linked immunosorbent assays (Boshide Biotechnology, China), using a microplate reader (Hyperion MRIII, USA) according to the manufacturer's instruction.
2.1. Statistical analysis
All data were analyzed with SPSS 19.0 statistical software (SPSS Inc, Chicago, IL, USA). Descriptive statics and compliance with normal distribution was examined with one-sample Kolmogorov–Smirnov test. Between the two groups, two-tailed Student t test and Mann–Whitney U test were used. Categorical variables were evaluated with the Chi-square test. All quantitative data were expressed as mean ± standard deviation. A value of p < 0.05 was considered statistically significant.
The sample sizes of this study were determined based on the following considerations. The main variable was PaO2 in this study, which had a standard deviation of 38.6 from the pilot study done in 10 patients. A priori power analysis using two-sided analysis with α error of 0.05 and a power of 1.1 showed that 54 patients were needed for this study.
Sixty patients were recruited into the study. No patient was excluded for any reason. All the patients were adult women with a mean age of 55.6 ± 5.8 years and a mean body mass index of 33.1 ± 1.9 kg/m2. The mean duration of surgery was 118.5 ± 26.8 minutes. No significant differences were found in age, body mass index, or duration of surgery between groups (p > 0.05; Table 1). PaO2 increased significantly at T2 than at T1 in both groups, and PaO2 was higher in the IRV group than those in the control group at T2 (502.73 ± 52.54 vs. 466.51 ± 45.37; p < 0.05; Table 2). . PetCO2values were all < 50 mmHg before T2, and PaCO2 was increased obviously at T2 than at T1 in both groups, but there was no statistically significant difference between the two groups at T2. On comparison of pH, PaCO2, HCO3− and SaO2 at T1 or T2 in both groups, there were no statistical significance (p > 0.05). The patients were showed a moderate hypercapnia (defined as PaCO2 > 45 mmHg) during pneumoperitoneum in both groups. At T2, the Ppeak and Pplat were lower in the IRV group than those in control group (28.8 ± 2.3 vs. 32.3 ± 2.9, 27.5 ± 1.9 vs. 30.7 ± 2.2, respectively; p < 0.001), but the Pmean and auto-PEEP were higher in the IRV group than in the control group. There were statistically significant differences in Pmean and auto-PEEP (17.1 ± 1.8 vs. 12.3 ± 1.6, 4.3 ± 1.1 vs. 2.9 ± 0.8, respectively; p < 0.01), and CL was improved significantly compared to the control group (21.2 ± 1.5 vs. 19.6 ± 1.2; p < 0.001; Table 2).
Table 1. Data of patients in the two groups immediately before onset of pneumoperitoneum (baseline).
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BioZ.com noninvasive hemodynamic monitoring reflected the hemodynamic changes in the two groups. In the condition of anesthesia and pneumoperitoneum, mean arterial blood pressure fell, and gradually increased after the end of pneumoperitoneum. Intragroup comparison indicated that the blood pressure, heart rate, cardiac output, stroke volume index, and systemic vascular resistance were higher at T2 than T1, (p < 0.05), but comparison of hemodynamic parameters between the two groups found no statistical significance (p > 0.05; Figure 1). The levels of TNF-α, IL-6, and IL-8 were increased significantly 60 minutes after onset of pneumoperitoneum in both groups. At T2, the concentrations of TNF-α, IL-6, and IL-8 were lower in the IRV group than in the control group (p < 0.05; Table 2). No postoperative hypoxemia was observed and there was no statistical significance in incidence of hypercapnia and PACU discharge time between the two groups (p > 0.05; Table 2). There were no cases of respiratory complications during the hospital stays of all patients.
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Figure 1. (A) Mean arterial pressure, (B) heart rate, (C) cardiac output, (D) stroke volume index, and (E) peripheral vascular resistance. The hemodynamic data were similar in both groups (p > 0.05). T0: 5 minutes before anesthetic induction, T1: immediately before onset of pneumoperitoneum, T2: 60 minutes after onset of pneumoperitoneum, T3: at the end of surgery. IRV = inverse ratio ventilation.
The present study compared volume-controlled IRV with I:E ratio of 2:1 and conventional volume-controlled ventilation with I:E ratio of 1:2 in obese patients undergoing gynecologic laparoscopy. This study demonstrated significant increases in PaO2, Pmean, and CL during volume-controlled IRV, whereas significant decreases in Ppeak, Pplat, and the concentrations of TNF-α, IL-6, and IL-8 compared with conventional ratio ventilation. So far, there have been few studies of IRV in patients with normal lungs undergoing gynecologic laparoscopy.
Obese patients are susceptible to high Ppeak due to the reduction of CL and functional residual capacity.9 Ppeak increased and CL decreased during pneumoperitonium in the obese patients undergoing gynecologic laparoscopy. On the one hand, CO2 insufflation elevated the abdominal pressure, pushed the diaphragm into the thorax, raised pleural pressure and compressed lung, which would result in the reduction in CL and diminution of lung volumes. On the other hand, due to the weight of abdominal contents, the steep Trendelenburg position has great effect on cephalad shift of the diaphragm, lung volumes, and pulmonary functional residual capacity10, 11; the steep Trendelenburg position and CO2pneumoperitonium elevated the Ppeak and reduced functional residual capacity in patients undergoing laparoscopic gynecologic surgeries.
The lower peak airway pressure in the IRV group was possibly due to slowing inspiratory flow and prolonging inspiratory time of IRV. Higher mean airway pressure might be achieved by prolongation of I:E ratio. A previous study proved that IRV could improve oxygenation and reduce Ppeak and Pplat compared to volume-controlled ventilation in gynecologic laparoscopy.12
It is well known that IRV can improve arterial oxygenation in acute respiratory distress syndrome, and elevates Pmean, recruits atelectatic alveoli, reduces intrapulmonary shunt, improves ventilation and decreases dead space ventilation. Prolongation of the inspiratory time allows enough time to gas exchange. Meanwhile, as the expiratory time is short, IRV might lead to trapped air in the lungs with generation of intrinsic PEEP or auto-PEEP. Mechanical ventilation also generated auto-PEEP in conventional ratio ventilation possibly because of hyperinflation and high airway pressure in present study. In addition, PEEP could improve oxygenation for elevating Pmean. Hence IRV would contribute to improving oxygenation. IRV may lead to intrinsic PEEP5 and it is thought to improve oxygenation and have advantageous effects on pulmonary mechanics.13
In the IRV group, although PaCO2 was slightly higher than the control group, there was no significantly different between two groups. Prolonged inspiratory time of IRV increased the mean distribution time to facilitate inspired gas for distribution and diffusive mixing within the lungs and thereby enhance CO2 elimination. It is a reasonable explanation that prolonging the inspiratory time did not affect elimination of CO2, probably due to the CO2 absorption into blood.14 A previous study demonstrated that a prolonged inspiratory time increased the mean distribution time in the lung and improved CO2 removal.15 This study also shows that IRV has no effect on elimination of CO2.
In this study, CO2 pneumoperitoneum and steep Trendelenburg position might lead to an increase in SVR in circulatory system, and reduce venous return and cardiac output because of the compression of inferior vena cava, but there were no significant differences in hemodynamic parameters between groups in this study. IRV with I:E of 2:1 might reduce cardiac output with minimal effect on mean arterial pressure, and this meant that IRV did not hamper venous return with possible consequent hemodynamic derangement. This was consistent with the previous statement that increasing the percentage of inspiratory time had no demonstrable changes in hemodynamics during mechanical ventilation.16, 17 IRV might reduce cardiac output only I:E ratio beyond 2:1.18
In this experiment, the levels of TNF-α, IL-6, and IL -8 were significantly lower in the IRV group than in the control group at 60 minutes after CO2 insufflation. Not only mechanical ventilation, but also operation wound and CO2 pneumoperitonium might provoke the release of inflammatory factors. Acute lung injury involves a series of inflammatory response in the lungs, with accumulation of both pro- and anti-inflammatory cytokines in bronchoalveolar lavage fluid.19 Inflammatory factors play an important role in the stress response. TNF-α and IL-6 are important inflammatory factors. TNF-α is mainly secreted by activated macrophages, and is a proinflammatory cytokine and the initial factor in the inflammatory response; other inflammatory cytokines can be induced to produce TNF-α. IL-6 is one of the most important inflammatory mediators—the damage degree of lung is positively correlated with its concentration.20 Not only are large tidal volume and high Pplat the main factors of ventilator-induced lung injury,21 but obesity is also a great risk for lung injury, which is associated with increased inflammation cytokines, indicated by the increases of TNF-α and IL-6, through activation of toll-like receptor and nuclear factor light chain-κB signaling pathways.22 Conventional ratio ventilation mode caused higher cytokine levels compared with IRV. Therefore IRV can alleviate inflammation response.
In general, lung-protective ventilation strategies consist of small tidal volume with optimal PEEP and limited Pplat during mechanical ventilation. It is well known that ventilation at a low tidal volume can result in atelectasis, but IRV can reduce atelectasis and intrapulmonary shunt fraction because of higher mean airway pressure. High peak airway pressure is thought to contribute to barotrauma and lung injury through the generation of elevated alveolar shear forces.
The limitations of our study are: (1) auto-PEEP was not measured accurately because of instrumentation; (2) second, hemodynamic parameters are noninvasive; and (3) further studies are needed to determine the optimal ventilatory mode that could reduce Ppeak or Pplat and maintain normocapnia without adverse respiratory and hemodynamic effects.
In conclusion, IRV not only reduces Ppeak, Pplat, and the release of inflammatory cytokine, but also increases Pmean, and improves oxygenation and CL in obese patients undergoing gynecologic laparoscopy without adverse respiratory and hemodynamic effects. It is superior to conventional ratio ventilation in terms of oxygenation and respiratory mechanics and inflammation response in obese patients undergoing gynecological laparoscopy.
We are indebted to Dr Zhu Sheng for providing editorial review for manuscript preparation.