Inverse Ratio Ventilation for Preventing IntraOperative Hypercapnia in Children Undergoing Laparoscopic Surgery

Background High end-tidal carbon dioxide tension (P ET CO 2 ) and respiratory acidosis occurs frequently in patients undergoing laparoscopic surgery. The aim of this study is to be investigate the effect of pressure-controlled inverse ratio ventilation (IRV) with inspiratory to expiratory ratio (I: E) of 2:1 on children undergoing laparoscopic surgery. Methods Eighty children undergoing elective laparoscopic surgery were allocated randomly to the IRV group (1: E=2:1) and the control group (I: E=1:2). Children received pressure-controlled ventilation with I: E ratio of 2:1 or 1:2. Hemodynamic parameters and respiratory mechanics were recorded. Side effects were also recorded. was lower (25% vs. 42.5%, P= 0.03).


Introduction
At present, laparoscopic technology is widely used for pediatric surgery. Insu ation of carbon dioxide (CO 2 ) could result in hypercapnia and acidemia in the patients undergoing laparoscopic surgery. [1] We are confronted with di culty in maintaining end-tidal carbon dioxide tension (P ET CO 2 ) in normal range without lung injury. It is di cult to improve the hypercapnia by increasing the respiratory frequency under pressure control ventilation mode. Pressure control ventilation with positive end-expiratory pressure (PEEP) would improve oxygenation accompanied with a decrease in tidal volume (Vt). However, pressure control ventilation with higher airway pressure would increase Vt, but high airway pressure might lead to lung barotrauma and volutrauma. The documents indicated that inverse ratio ventilation (IRV) could improve oxygenation and reduce peak airway pressure compared with conventional ventilation mode. [2][3][4][5][6] Moreover, it was reported that the optimal I: E ratio was 2:1 when using IRV. [7] So we investigated the effect of pressure-controlled IRV (PC-IRV) with inspiratory/expiratory (I: E) ratio of 2:1 on respiratory function in children undergoing laparoscopic surgery. PC-IRV has been used extensively in the past to improve oxygenation in patients with acute hypoxemic respiratory failure. The aim of this study was to investigate whether PC-IRV might have the bene t of also improving ventilation without increasing the peak airway pressure. We hypothesized that pressure-controlled IRV with I: E ratio of 2:1 could increase Vt, improve gas exchange and promote CO 2 elimination in the children undergoing laparoscopic surgery.

Methods
This study was approved by the Jiaxing Hospital's Institutional Review Board. Written informed consent was obtained from the children's guardians. The trial was registered at www.chictr.org.cn (Registration number: ChiCTR2000035589). From August 10 to October 9, 2020, we recruited a total of 82 children undergoing elective laparoscopy (appendectomy or herniorrhaphy). Inclusion criteria: ASA grade I or II, age 2-6 years, weight 10-25 kg and expected duration of surgery lasted more than 30 min. The children with cardiopulmonary disease, obesity (index body mass ≥ 30kg/m 2 ) and airway hyper-response were excluded from the study. Eighty children were randomly divided into the IRV groups (I: E = 2:1) and the control group (I: E = 1:2), based on a computer-generated randomization table.
All children had no premedication. On arrival at operating room, monitoring including electrocardiogram, noninvasive blood pressure (BP), heart rate (HR) and pulse oxygen saturation (SpO 2 ) was applied with anesthesia monitor, and venous access was established. Anesthesia was induced with inhalation of 5%-7% sevo urane, intravenous fentanyl 4 ug/kg, propofol 2 mg/kg, and tracheal intubation was facilitated with intravenous cis-atracurium 0.1 mg/kg. Anesthesia was maintained with inhalation of sevo urane. The lungs were mechanically ventilated with pressure-controlled mode and respiratory parameters of anesthesia ventilator were set as follows: driving pressure of 15 cmH 2 O, respiratory rate of 20 breaths/min, PEEP of zero, oxygen ow of 1 L /min, fraction of inspired oxygen of 1.0 and I: E ratio of 1:2. When establishing CO 2 pneumoperitoneum, the driving pressure value was adjusted to 18 cmH 2 O in both groups, and I: E ratio was set as 2:1 in the IRV groups and I: E ratio was still 2:1 in control group, other respiratory parameters were constant.
Anesthesia was maintained with 2-3% end-tidal sevo urane to keep the bispectral index (BIS) value between 40 and 55 (BIS monitor Model A2000, 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 (Organon Corporation, type: TOF-Watch SX, Holland). Cis-atracurium was infused at a rate of 0.1 mg. kg − 1 .h − 1 to keep TOF value below 5%. The driving pressure was increased to maintain P ET CO 2 below 50 mmHg if the value of the end-tidal carbon dioxide tension (P ET CO 2 ) exceeded 50 mmHg. Spirometry readings included inspiratory V T , mean airway pressure (Pmean), P ET CO and total PEEP (PEEPtot) using a side-stream spirometry device (Type: D-FPD15-00, GE company, Taipei, China).
During the study period, lactated Ringer's solution was infused at a rate of 5-6 ml.kg − 1 .h − 1 . CO 2 pneumoperitoneum tension value was set at the level of 8 mmHg during operation. Immediately after establishing CO 2 pneumoperitoneum, the children were turned to a supine position with head down at 10 degrees below horizon. Noninvasive systolic blood pressure (SBP) and diastolic blood pressure (DBP) and HR were recorded at baseline or before anesthesia (T0), 2 minutes before establishing CO 2 pneumoperitoneum (T1), 30 min after initiation of CO 2 pneumoperitoneum (T2) and the end of surgery (T3). Respiratory mechanics were recorded at T1 and T2. Arterial blood was drawn and analyzed using a blood gas analyzer (Type: ABL8000, Denmark) at T1 and T2 respectively. Hypercapnia was de ned as PaCO 2 > 45 mmHg. The time to extubation and discharge time from post-anesthesia care unit (PACU) were recorded. Post-operative complications, if any, were also recorded, such as post-operative hypoxemia (post-operative hypoxemia was de ned as SpO 2 below 91% while receiving air), pneumothorax and other pulmonary complications. The children could be discharged from PACU when Modi ed Aldrete Score was 9 or above. [8] Statistical analysis Data were analyzed with a SPSS 17.0 statistical software (SPSS Inc.,Chicago USA). Quantitative variables with normal distribution were compared with t test and one-side analysis of variance. Data with non-normal distribution were used two-side Mann-Whitney U-test in both groups. Categorical variables were evaluated with the Chi-square test. All quantitative data were expressed as mean ± standard deviation. A P < 0.05 was considered statistically signi cant.
The sample sizes were determined based on the primary outcome. The primary variable was V T in this study. A priori power analysis using two-sided analysis with α error of 0.05 and a power of 0.8 showed that 32 patients were needed to detect a 7 ml increase in V t from the mean value in each group for this study. Sample size was increased to 40 to allow for dropout in each group in this study.

Results
Eighty-two children were enrolled into the study (Fig. 1). Eighty children nished this study and two patients were excluded for hesitations in participation. No signi cant differences in terms of age, weight and duration of surgery between the groups (Table 1) (P > 0.05). At T1, there were no signi cant differences in PaO 2 , PaCO 2 and pH in both groups (P > 0.05). At T2, PaO 2 and pH were greater in the IRV group than in the control group (282.7 ± 45.6 vs. 246.5 ± 35.5 mmHg, 7.34 ± 0.03 vs. 7.32 ± 0.03) ( Table 2) (P < 0.01), while PaCO 2 was lower in the IRV group than in the control group (43.9 ± 4.65 vs. 46.7 ± 4.90 mmHg) (P = 0.013), there were signi cant differences in PaO 2 , PaCO 2 and pH at T2. SaO 2 were similar in both groups (P < 0.05).   Fig. 2, there were no statistical signi cances in blood pressure and HR between the 2 groups at T2 (P > 0.05).
Eight cases of hypercapnia occurred in IRV group within 30 minutes after initiation of CO 2 pneumoperitoneum and 17 cases of hypercapnia occurred in the control group, there were statistical signi cances in the incidence of intra-operative hypercapnia between the 2 groups (P = 0.03). No postoperative hypoxemia was observed and there was no statistical signi cance in incidence of hypercapnia, extubation time and PACU discharge time between the 2 groups (P > 0.05) ( Table 1). There were no respiratory complications observed during the hospital stays.

Discussion
Longer inspiratory time with ongoing ow will increase the tidal volumes. Larger tidal volume at the same rate will lead to higher minute ventilation and peak airway pressure. Ventilation with PEEP may improve oxygenation, but increase peak airway pressure. Hypercapnia is the most common complication in the patients undergoing laparoscopic surgery, and anesthesiologists face challenges in maintaining P ET CO 2 without increasing obviously the peak airway pressure. In view of the above mentioned, we didn't use PEEP in this study.
In this study, we discussed the respiratory effects of pressure-controlled IRV (I: E = 2) ventilation in children undergoing laparoscopy, and found that pressure-controlled IRV could signi cant decreases P ET CO 2 , improve oxygenation and gas exchange in children undergoing laparoscopy compared to conventional ratio ventilation.
IRV is different from the conventional ventilation mode. Prolonging inspiratory time can increase the alveolar ventilation volume and functional residual capacity and expand the collapsed alveolar. Besides, IRV may reduce dead-space, which is contributed to the gas distribution in the lungs. At present, the studies on IRV are fewer in children undergoing laparoscopy. Under the pressure-controlled mode, the Vt and Pmean will be higher in IRV group than those in the control group. As inspiratory time was prolonged and inspiratory ow velocity slowed down, the airway resistance decreased, which brought about an increase in Vt. Moreover, IRV could generate auto-PEEP (endogenous PEEP), [9] which was bene cial to oxygenation. Besides, it was reported that arterial blood oxygenation is directly related to mean airway pressure, [6,10] so higher Pmean was also contribute to oxygenation and gas exchange in a certain range. [11] As inspiratory time is prolonged, the expiratory time is relatively short under pressure-controlled IRV mode, IRV may generate endogenous PEEP. IRV could lead to an increase in Pmean and reduce venous return. In our study, blood pressure and heart rate had no statistical differences in both groups. It meant that IRV with I: E of 2:1 didn't affect venous return. IRV might reduce cardiac output only I: E ratio beyond 2:1. [3,12] Only when inspiratory time was excessive prolonged and Pmean reached a certain high level, IRV would result in a decrease in cardiac output, and have an effect on hemodynamics. [3,13] IRV could bring about an increase in the Pmean and PaO 2 , as was agree with the study of Mercat A, et al. [5] However, Pmean has an important effect on hemodynamics. Although the Pmean was signi cantly higher in the IRV group than conventional ventilation group, there were no signi cant differences in hemodynamic parameters between the 2 groups. Hence, Pmean has no effect on hemodynamics in a certain range, it was similar to the results of Movassagi R, et al. [13] PaO 2 was signi cantly higher in the IRV group than conventional ventilation group at 30 min after initiation of CO 2 pneumoperitoneum. It indicated that IRV could obviously increase the oxygen content, and promote oxygenation. PaCO 2 was lower in IRV group than the control group, there was signi cantly different between the 2 groups. PaCO 2 increased obviously in both groups 30 min after initiation of CO 2 pneumoperitoneum. The main reason was caused by the CO 2 absorption in blood, [14] IRV did not affect the discharge of CO 2 . PaCO 2 fell down 5.3 mmHg in patient with normal weight during mechanical ventilation when tidal volumes decrease per 100 ml, PaCO 2 fell 3.6 mmHg in morbidly obese patients. [15] So the tidal volume was the main factor that determined CO 2 discharge during mechanical ventilation.
Moreover, CO 2 pneumoperatoneum might affect hemodynamics during laparoscopic surgery. [16] The limitations of our study are as following: IRV is different from the conventional ventilation mode, it may have some potential risks: the long-term complications of respiratory system remain to be studied. The large sample sizes are needed to investigate the adverse respiratory and hemodynamic effects.

Conclusion
Pressure controlled IRV may reduce the incidence of intra-operative hypercapnia as well as increasing Vt and thus improving CO 2 elimination in children undergoing laparoscopy compared to conventional ventilation. It is superior to conventional ratio ventilation in terms of gas exchange and respiratory mechanics in children undergoing laparoscopy.

Declarations
Ethics approval and consent to participate: This study was approved by the Ethics Committee of Jiaxing hospital and written informed consent was obtained from the children's guardians.

Consent for publication: Yes
Availability of data and material: Authors will allow sharing the data, such as blood pressure, heart rate and respiratory parameters. The data will be accessible 6 months after publication.