The Effect of Volume Controlled and Pressure Controlled Ventilation Modes on Cerebral Oximetry and Blood Gas Status in Laparoscopic Cholecystectomy, A Randomized Controlled Trial

Emre Badur Anesthesiology and Reanimation Department, Sisli Hamidiye Etfal Training and Researche Hospital, University of Health Sciences, Istanbul, Turkey Mustafa Altınay (  m_altinay@yahoo.com ) Anesthesiology and Reanimation Department, Sisli Hamidiye Etfal Training and Researche Hospital, University of Health Sciences, Istanbul, Turkey Pınar Sayın Anesthesiology and Reanimation Department, Sisli Hamidiye Etfal Training and Researche Hospital, University of Health Sciences, Istanbul, Turkey Ayşe Surhan Çınar Anesthesiology and Reanimation Department, Sisli Hamidiye Etfal Training and Researche Hospital, University of Health Sciences, Istanbul, Turkey leyla türkoğlu Anesthesiology and Reanimation Department, Sisli Hamidiye Etfal Training and Researche Hospital, University of Health Sciences, Istanbul, Turkey tuğba yücel Anesthesiology and Reanimation Department, Dr.Sadi KONUK Training and Researche Hospital, University of Health Sciences, Istanbul, Turkey


Background
Since the laparoscopic methods have been introduced to the surgical operations, laparoscopic cholecystectomy has become the golden standard in cholelithiasis surgery. 1 For laparoscopic surgery, carbon dioxide (CO 2 ) insu ation is used which increase the intra-abdominal pressure. The arterial oxygenation, the functional residual capacity and the lung compliance will be affected and may be resulted with cardiovascular events. 2,3 Volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) are two mechanical ventilation modes that can be used along with their own advantages and disadvantages. 3 The VCV needed a pre-determined tidal volume (TV). The risk of lung damage is the main concern. In contrast the PCV avoid from excess respiratory tract pressure which applied to the lung. However TV may become unstable. Both techniques previously evaluated if one provide lower respiratory work and better tissue oxygenation. Some studies indicated that PCV is better for arterial and tissue oxygenation. 4 Along with the arterial gas results, near infrared spectroscopy (NIRS) is used to evaluate the depth of anesthesia by measuring the oxygenation change at the tissue level in the prefrontal cortex. 5 Although NIRS was used in different surgeries, their use in laparoscopic abdominal surgery is extremely limited. 5,6 In the available literature we could not be able to nd a study which evaluates the effectiveness of perioperative ventilation modes with the NIRS method.
The aim of present study was to compare VCV and PCV modes with NIRS cerebral oximetry and arterial gas results in laparoscopic cholecystectomy

A prospective, randomized study was conducted in the Sisli Hamidiye Etfal Training and Research
Hospital between March and July 2020. Study was started after obtaining approval from the local ethics committee with the approval number: 1496. Registration of study at ClinicalTrials.gov was made at 25/01/2021 with the NCT04723043 number. Informed consent was taken from all patients. All procedures that performed in our study were made in accordance with the ethical standards of the Helsinki declaration (2008).

Sample size calculation and randomization
Considering the difference in large effect size (effect size=0.8) between the groups, the sample size was calculated as 70 cases in total for 95% Power, alpha signi cance level 0.05. Randomization was done with closed envelopes before the procedure.

Inclusion and exclusion criteria
For the study period patients that underwent elective laparoscopic cholecystectomy were enrolled for the study. Patients aged between 18 and 65, with American Society of Anesthesiology (ASA) score 1 and 2, body mass index (BMI) <30 kg / m2, were included.
Patients who did not give informed consent, patients who underwent previous thoracic/abdominal surgery, patients who underwent emergency laparoscopic cholecystectomy, patients who have ASA score ≥3, hematocrit value ≤ 30 and, BMI> 30 kg / m2 were excluded. Patients with a history of cardiac, neuromuscular, hepato-renal, endocrine, major pulmonary disease (de ned as a decrease in capacity or ow rates below 70% in pulmonary function tests) were also excluded. Patients who returned to laparotomy for surgical reasons after starting laparoscopically, who developed perioperative hemodynamic instability and who used respiratory mechanics outside the study protocol were excluded from the study.

Primary-Secondary Outcomes
The primary outcomes of the study were the cerebral oxygenation measured with NIRS, peak pressure and plateau pressure of the patients in both groups, the secondary ndings were the patients' SpO 2 , endtidal carbon dioxide and partial oxygen pressure in arterial blood gases.

Preoperative care
All patients underwent standard anesthesia evaluation for the procedure. Premedication was done with 0,07 mg/kg intravenous midazolam.

Intraoperative care
Single derivation electrocardiogram, pulse-oximetry, noninvasive arterial pressure and EtCO 2 parameters were monitored. NIRS monitoring was performed using a Masimo (Irvine, CA, USA) device. NIRS cerebral probes were placed in the right and left frontal regions. A 20-gauge cannula was inserted into the radial artery. Anesthesia induction is by intravenous administration of 2 mg/kg propofol, 1 mg/kg lidocaine, 1.5 mcg/kg fentanyl and 0.6 mg/kg rocuronium bromide. Anesthesia maintenance was done with sevo urane %2 and remifentanil 0.15-0.25 mcg/kg/hour. During the maintenance process, the oxygen-air ow was set to 4 lit/min and the FiO 2 set to 40%. During anesthesia, mechanical ventilation was applied to the patients with a Drager (Medical, Lübeck, Germany) brand device.
Mechanical ventilation settings applied to all patients were adjusted according to ideal body weight. In the P group, inspiratory pressure (P insp ) was set to create a tidal volume of 8 ml / kg in pressurecontrolled mode, while in the V group, the tidal volume was set as 8 ml / kg in the volume-controlled mode. In both groups, the initial respiratory frequency was 12 breaths/minutes, the inspiration/expiration time ratio was 1/2, FiO 2 was 40%, and positive end expiratory pressure (PEEP) was 5cm/H 2 O. While applying mechanical ventilation in all patients, it was aimed to keep the EtCO 2 value between 33-35 mmHg. If the EtCO 2 was above 35 mmhg, the respiratory frequency was primarily increased by 2 units every ve minutes in both groups. In this increase, the frequency was accepted as the upper limit of 18 breaths/minute. If the EtCO 2 values did not decrease under 35 mmHg at the 5th minute after reaching 18 breaths per minute, the P insp value of the patients in the P group was increased by 2 cm/H2O every ve minutes as needed. In the V group, the volume settings were increased by 1 ml/kg every ve minutes as needed. The upper limit was determined as 30 cm/H2O for the P group and 10 ml/kg for the V group. Patients whose CO 2 values did not decrease under 35mmhg despite mechanical ventilation with all these upper limit values were excluded from the study by making more complicated changes in mechanical ventilation and insu ation pressures. If EtCO 2 values were below 33 mmHg, in both groups, it was rst reduced to 10 breaths/min, and if there was no increase after ve minutes, P insp values were decreased by 2 cm/H2O every ve minutes in the P group, while the tidal volume was decreased by 1 ml/kg in the V group. However, tidal volume was not allowed to fall below 6 ml/kg in both groups.
Demographic data (gender, age, height, weight, and ASA score) as well as operative data (anesthesia, operation, and insu ation duration) were recorded in both groups, T0 was de ned as T0 before anesthesia, T1 after intubation, T2 5 minutes after insu ation, T3 just before desu ation, and T4 5 minutes after desu ation. Heart rate, systolic/diastolic arterial pressure values, saturation of pulseoximetry (SpO 2 ) and NIRS values were recorded at all time points. Additionally, EtCO 2 in T1, T2, T3 and T4; arterial blood gas results for pH, pO 2 , pCO 2 , HCO 3 , BE and Lactate; Tidal volume, respiratory frequency, peak pressure (P peak ), plateau pressure (P plateau ) and, PEEP was recorded.
Statistical analysis SPSS 15.0 for Windows program was used for statistical analysis. Descriptive statistics; numbers and percentages for categorical variables, mean, standard deviation, minimum and maximum for numerical variables were given. Comparisons of numerical variables in two independent groups were made using the Student t-Test (when the normal distribution exists), the Mann Whitney U test (when the normal distribution condition was not exist). The rates in the groups were compared with Chi-Square Analysis. Statistical alpha signi cance level was accepted as p<0.05.

Results
CONSORT diagram of the study was presented in gure 1. In total 70 patients were evaluated in the study between March and July 2020. Groups did not differ for age, BMI, operative time, anesthesia duration and insu ation duration (p>0.05 for all comparisons) ( Table 1).  Hemodynamic parameters were presented in Table 3. The systolic, diastolic and, mean arterial pressures did not differ between groups (p>0.05 for all comparisons). The heart rate at T0, T2 and T3 was signi cantly high in group P (p=0,017 p=0,043 p=0,020 respectively). The SpO 2 levels was signi cantly lower in group P at T0 (p=0,006). The EtCO 2 levels was signi cantly higher in group P at T2 time point (p=0,008). Other comparisons for hemodynamic parameters were not signi cant. The comparisons for blood gas parameters were not signi cant as well (p>0.05 for all comparisons) ( Table 4).

Discussion
In a randomized controlled setting, our results indicate that cerebral oxygenation was better in patients ventilated with PCV mode due to higher NIRS values and lower P peak and P plateau values.
The laparoscopic surgery improves the quality of life by avoiding abdominal incisions, extensive dissection and related comorbidities. 1 However pneumoperitoneum causes an increase in intra-abdominal pressure and indirectly a decrease in lung volumes, functional residual capacity and pulmonary compliance. An increase in airway resistance may be resulted with development of atelectasis in the basal parts of the lung and ventilation-perfusion mismatch can occur. 1,3 The VCV mode increases P peak and P plateau values which are directly related with the lung damage. In a randomized controlled setting, Sen et al. compared VCV and PCV on 40 patients who underwent laparoscopic cholecystectomy.
The results indicate that P peak and P plateau pressures were higher in patients who underwent VCV after pneumoperitoneum. 7 Netthra et al. compared VCV and PCV on 60 laparoscopic cholecystectomy patients. Their results indicate that PCV resulted with lower P mean and Ppeak values. Our study is also consistent with the studies which resulted in favor of PCV in laparoscopic cholecystectomy. Our results indicate that P peak and P plateau values were found to be signi cantly higher in the VCV group, especially after insu ation. Literary data indicate that VCV may decrease the safety index by increasing the risk of volu-trauma and barotrauma in the VCV mode in laparoscopic cases. To stop the increase in P peak pressure and decrease lung injury, applications such as changing the respiratory rate and tidal volume or switching to PCV mode are performed. 9 Although the PCV mode is a good method in the management of elevated P peak values, its effects on ventilation dynamics and hemodynamic parameters did not clearly de ne.
The high P peak values in VCV mode may also resulted with decrease in partial oxygen pressure. However, the effect of VCV and PCV modes on tissue oxygenation are contradictory. Balick-Weber et al. examined the respiratory effects of laparoscopic surgery on 21 patients. No change was shown on partial oxygen pressures after insu ation. 10 Hans et al. also reported no signi cant difference between PO2 pressures on 40 obese patients who underwent laparoscopic by-pass operation. 11 However, in two other studies conducted in obese patients, partial oxygen pressures were shown to be higher in patients ventilated with PCV mode. 12,13 In our study, partial oxygen pressure values were higher in PCV mode, however no signi cant difference was found for blood gas parameters between groups.
Tissue oxygenation measurements have been used frequently in perioperative patient management in recent years. Different methods such as bispectral index electroencephalography or auditory evoke potentials are used to measure anesthetic depth. The NIRS is another method which used to evaluate the depth of anesthesia by measuring the oxygenation change at the tissue level in the prefrontal cortex. 14 We could not be able to nd a study that evaluates the cerebral oxygenation with NIRS in laparoscopic surgery. However, NIRS was used in different surgeries previously. Green et al. 6 in their study with 46 patients who underwent major abdominal surgery, detected low tissue oxygenation using the NIRS method, which could not be detected by conventional monitoring methods.
Gibson et al. 15 compared NIRS values before and after insu ation in 70 patients who had undergone laparoscopic abdominal surgery and showed that NIRS values decreased statistically after insu ation.
Although there was no signi cant difference between SpO 2 and PaO 2 pressures in our study, the NIRS values of patients who underwent PCV were found to be signi cantly higher during pneumoperitoneum compared to the VCV group. This may be an evidence that oxygenation disorder occurs at the tissue level, although the resulting oxygenation change is not re ected in conventional monitoring parameters and arterial blood gas analysis.
Kurukahvecioğlu et al. 16 in their study with 60 patients who had undergone laparoscopic abdominal surgery showed that insu ation pressure caused blood to pool in the lower extremities, which decreased cerebral NIRS values. This decrease is a mechanical result of the high pressure created by insu ation in the abdomen. This mechanical condition occurs not only in the abdomen, but also in the thorax, with the high P peak created by the VCV mode, as demonstrated in our study. Increased intrathoracic pressure reduces preload and indirectly cardiac output, and consequently explains the signi cantly lower NIRS values in the VCV group in our study.
The limitation of our study is that we had to use P peak and P plateau instead of trans-pulmonary pressure to evaluate the safety of controlled mechanical ventilation modes. Because transpulmonary pressure is the most objective parameter in the evaluation of ventilator induced lung injuries. However, it was not preferred because it is measured by invasive methods.

Conclusion
In laparoscopic cholecystectomy operations, tissue oxygenation with PCV mode is higher than with VCV mode. In PCV mode, the risk of lung barotrauma, which is likely due to high P peak and P plateau values, is lower. NIRS can be used in laparoscopic cholecystectomy cases because it is more sensitive, noninvasive and easy to use than arterial blood gas analysis in measuring tissue oxygenation. Availability of data and materials: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.