Intraoperative lung-protective ventilation adjusting tidal volume to a plateau pressure restriction in elderly patients: A randomized controlled clinical trial

2.1 Study design

This was a single-center, randomized clinical trial performed at the Third Affiliated Hospital of Anhui Medical University, China. Patients were enrolled from November 2015 to October 2017. The study was approved by the Ethics Committee of the Third Affiliated Hospital of Anhui Medical University for Human Studies (ethical committee number HFYY 2015016) in September 2015, and written informed consent was obtained from all patients. The study was registered in the Chinese Clinical Trial Registry (no. ChiCTR 1800014578). The study protocol complied with the 1975 Declaration of Helsinki.

2.2 Patient and public involvement

Patients were randomly assigned to study group or control group by automatic number. People who had access to the randomization information were not involved with any experimental trial procedure. Patients in this trial were not involved in the design, recruitment, and conduction of the study. Once allocated to a group, the surveillance data of each patient was collected and collated, and personal data collected during the study was kept confidential and stored securely at the study site in a locked cabinet accessible only to the data analyst members. The results of this study were not disseminated directly to study participants.

2.3 Participants

Patients who met the following criteria were included: (I) older than 65 years; (II) of either sex; (III) with physical status I to III according to the American Society of Anesthesiologists; (IV) with normal preoperative pulmonary function; (V) scheduled for elective open abdominal surgery with an expected duration of general anesthesia between 1.5 and 3.0 hours. Patients who met the following criteria were excluded: (I) with a history of asthma or chronic obstructive lung diseases; (II) with bronchial infection in three weeks; (III) with sleep apnea syndrome; (IV) with a body mass index (BMI) ⩾ 35 kg/m 2 ; (V) with a history of benzodiazepine use; (VI) with intracranial hypertension; (VII) lack of cooperative or cognitive learning; (VIII) with uncontrolled severe hypertension and cardiovascular diseases; (IV) with liver or kidney dysfunction; history of second- or third-degree heart block or ischemic heart diseases; (X) who were unable to maintain an appropriate peripheral oxygen saturation by pulse oximetry (SpO 2 ), those presenting with anemia (hemoglobin 9 g/dL), or distorted anatomy of the tracheobronchial tree on chest radiographs.

2.4 Study protocol

Patient randomization was accomplished through our Division of Biostatistics using a computerized random number generator. Group assignment was concealed in a sealed envelope until surgery began. All patients were anesthetized by an anesthetist responsible for the intraoperative patient care who did not participate in the investigation. An anesthetist resident collected the intraoperative data and was blinded to the study, and this process continued until the end. All patients were fully informed about the study and blinded to their groups. Patients were confirmed with inclusion or exclusion criteria and randomly divided into two groups: the conventional MV with V T of 8 ml/kg - 1 and no PEEP (CV group), and LPV with adjusting V T levels and 9 cm H 2 O levels of PEEP (LPV group). However, the proper PEEP level was set as a variable based on a prior study in anesthetized patients [2]. For an initial period of five minutes after the start of surgery, PEEP was applied using the ventilator settings described below. Before starting the PEEP setting, arterial blood gases were measured. Concerning the LPV, the V T was determined in the following manner. The MV was started with an initial V T of 8 ml/kg - 1 with no PEEP for five minutes, and at this point, the airway Pplat remained relatively stable. Then, we set the PEEP at 9 cm H 2 O, and the Pplat was elevated to a higher level than the previous PEEP setting. Based on this situation, we only needed to adjust the V T to obtain a decreased Pplat. V T adjustment was initiated five minutes after stabilized PEEP, and the V T was incrementally reduced with a manual adjusting knob approximately every two minutes until a targeted Pplat less than 20 cm H 2 O was maintained as an expected criterion for individualized V T levels of LPV. However, LPV was established without repeated recruitment maneuvers, and stable levels of Pplat and V T were maintained during the study period. Figure 1 show the protocol procedure and incremental PEEP, Pplat, and decremental V T phases. However, the respiratory rate was regulated at any time according to arterial carbon dioxide partial pressure (PaCO 2 ), which was limited to a maximum of 8 kPa (60 mm Hg), again assuring pH values between 7.25 and 7.45 [9]. Additionally, the V T was readjusted according to the above method if the respiratory rate was modified for excessive PaCO 2 and once Pplat changed.

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All patients were brought to the operating room without premedication. Peripheral intravenous access was established with an infusion of 37 ∘ C solution to maintain a positive daily fluid balance and an adequate urine output. After three minutes of administration of pure oxygen, general anesthesia was induced as a sequential anesthetic to facilitate tracheal intubation with an appropriate size tube, using F 28–30 in females and F 30–32 in males. Anesthesia was maintained with a target-controlled anesthetic infusion (TCI) (Sims Graseby Ltd., Watford, UK) and sevoflurane at 1%. A 4 mg bolus of cisatracurium was administered every 30 to 45 minutes according to clinical need.

The lungs were ventilated by adjusting the Datex Ohmeda Aspire 7100 Anesthesia Machine (GE Healthcare, Helsinki, Finland) in a volume-controlled ventilation mode with an inspired oxygen fraction (FiO 2 ) of 60%, and the ventilator delivered a square waveform flow with an inspiratory/expiratory (I/E) ratio of 1:2 and no PEEP. Ventilation was started without PEEP and Pplat between 14 and 20 cm H 2 O. The respiratory rate was set at 12 breaths/min, and V T was maintained at 8 ml/kg - 1 . Following stabilization of the hemodynamic parameters after general anesthesia, the ventilation strategies were changed according to the group allocation described in Section 2.4.

Heart rate (HR), invasive systolic, diastolic, and mean arterial blood pressure (MAP), and SpO 2 were measured by the Datex Ohmeda S/5 monitor (Datex-Ohmeda Division, Instrumentarium Corp., Helsinki, Finland) during the entire anesthesia period. A Narcotrend monitor (Narcotrend index: NI) was attached to each patient for continuous measurement to obtain the appropriate anesthesia depth, and the partial pressure of CO 2 at the end of expiration (PetCO 2 ) was measured by introducing a capnography side stream sampler attached at the elbow between the endotracheal tube and the anesthesia circuit (D-Fend TM , E-CAiO-OO, GE Healthcare, Finland Oy Helsinki, Finland). The core body temperature ( T 𝑐𝑜𝑟𝑒 , ∘ C) was monitored continuously via a unilateral earhole using a novel temperature measuring instrument (Braun Ltd., IRT, Germany). Additionally, an indwelling bladder catheter was inserted, and the location of the endotracheal tube was further identified by fiberoptic bronchoscopy. The ambient temperature of the operating room was maintained at approximately 24 ∘ C, which did not involve the other appropriate intraoperative warming method for each patient.

However, in the LPV group, the protocol was only started if patients were hemodynamically stable, characterized by two necessary conditions: a good intraoperative hemodynamic state (MAP ⩾ 70 mmHg) and optimized oxygen saturation (SpO 2 ⩾ 95%). In the case of interruption because of hemodynamics or oxygen saturation concerns, the LPV was re-established after five minutes of stabilization. Intraoperative hypotension ( $>$ 20% decrease in baseline blood pressure) was treated with 10 mg intravenous ephedrine or 40 μ g phenylephrine, while bradycardia was treated with 0.5 mg intravenous atropine and/or aided lung expansion with positive pressure mask ventilation, applied whenever signals of hypoxemia plus abundant airway secretions were presented.

In both groups, following peritoneal cavity cleaning, the patients were administered 1 mg/kg - 1 of tramadol and 8 mg of ondansetron; the administration of sevoflurane was stopped, and the maintenance of anesthesia was supplemented by TCI with propofol, and remifentanil titrated according to clinical need. After incision closure, the administration of remifentanil and propofol was stopped. In the LPV group, at 10 minutes before the end of surgery, ventilation was switched to CV ( V T of 8 ml/kg - 1 without PEEP).

2.6 Perioperative measurements

MAP, HR, and NI were recorded at five time points: T1, 5 minutes after intubation; T2, just before the commencement of surgery following the stabilization of hemodynamic parameters; T3, 1 hour after the beginning of surgery; T4, 10 minutes before the end of surgery; T5, immediately after extubation. Intraoperative blood loss, liquid input, urine output, and MV and surgery duration were also recorded.

Intraoperative Pplat and V T were monitored continuously and recorded at T1, T2, and T4. These values were used to calculate the overall percentage of the decreases in V T and Pplat.

SpO 2 , PetCO 2 , and T 𝑐𝑜𝑟𝑒 ( ∘ C) were recorded at T2 and T4. At this time, arterial blood gas was analyzed at T2 and T4, and arterial oxygen partial pressure (PaO 2 ) and pH were determined using an ABI-30 analyzer (Radiometer, Copenhagen, DEN).

The dynamic lung compliance (CLdyn) of the respiratory system was calculated using the following standard formula: CLdyn = V T /peak airway pressure (Paw) – PEEP [10]; oxygen index (OI) = PaO 2 /FiO 2 ; respiratory index (RI) = P (A-a) O 2 /PaO 2 = ([PB – PH 2 O × FiO 2 – PaCO 2 ] – PaO ) 2 /PaO 2 [11]. The alveolar dead space/ V T ratio ( V 𝐷𝑎𝑙𝑣 / V T ) = 1.14 (PaCO 2 – PetCO 2 )/PaCO 2 – 0.005 [12]. Here, P (A-a) O 2 indicated the alveolar-arterial gradient; PB, atmospheric pressure; PH 2 O, saturated vapor pressure; FiO 2 , inhaled oxygen concentration (%); PaCO 2 , arterial carbon dioxide partial pressure; V 𝐷𝑎𝑙𝑣 , alveolar dead space; V T , tidal volume; PetCO 2 , partial pressure of end-expiratory CO 2 .

The start of spontaneous breathing was observed by the fluctuation of the breathing bag on the anesthesia machine without automated driving, and the return of spontaneous breathing was facilitated by allowing a full recovery of the upper airway reflexes and return of sufficient spontaneous breathing rate $>$ 8 breaths/min - 1 , spontaneous V T ⩾ 6 ml/kg - 1 , or oxygen saturation (SpO 2 $>$ 93% at FiO 2 100%), and the tracheal tubes were extubated. Additionally, patient responses to language and orientation, including naming, repetition, listening, place, and time, provided a rough evaluation of the recovery of conscious state or cognitive function.

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A power calculation was performed based on the respiratory index. A pilot study involving six patients at our center indicated that we needed to study a minimum of 25 individuals in each group to detect a 20% difference in the mean RI before and after ventilation was switched to lung-protective mode at both 0.95 (SD 0.28) and 0.80 (SD 0.34) at a power of 95% and a two-sided significance level of 0.05. To compensate for the possibility of dropout, we added 20% more patients for a final sample size of 61 patients.

All data collected in this study were analyzed using SPSS 22.0 software (IBM Inc., Chicago, IL, USA). Normally distributed measurement data were expressed as mean ± standard deviation (SD), while non-normally distributed measurement data were expressed as median (interquartil range), and the comparisons were examined by Student- t test. The Mann-Whitney U test was employed for intergroup comparisons, and the Wilcoxon signed-rank test was used for comparisons between different time points within the same group. The categorical data were expressed as n(%), and the differences between the two groups were examined by chi-square analysis or Fisher’s exact test. 0.05 was considered statistically significant.