Feasibility and Safety of an Over-pressure wash-in Method Using Fresh Gas Flow 0.5 L and Sevoflurane 8% During Initiation of Low-flow Anaesthesia: a Prospective, Randomised, Description Study
Conditions: Inhalation; Gas
Sponsor: Royal Hospital, Oman

COVER PAGE 
 
 
 
Official Title: 
“Feasibility and safety of an over-pressure wash-in method using fresh gas flow 0.5 L and Sevoflurane 
8% during initiation of low-flow anaesthesia: a prospective, randomised, descriptional study”. 
 
 
Proposal ID: MoH/CSR/23/27624  
The study proposal was approved by the Health Studies and Research Approval Committee (HSRAC), 
Ministry of Health, Sultanate of Oman dated 26/12/2023. 
 
 
Date: 01-01-2024           
 
 
 
 
 
 
 
 
 
 
 

 
Title  
Feasibility and safety of an over-pressure wash-in method using fresh gas flow 0.5 L and Sevoflurane 
8% during initiation of low-flow anaesthesia: a prospective, randomised, descriptional study 
Introduction and review of literature  
Low-flow anaesthesia (LFA) with fresh gas flow (FGF) ≤ 1 L/min has advantages due to relatively 
lower cost, less environmental burden, and increased humidity and temperature of inspired gas leading 
to improved mucociliary function of the patient.1  Any technique that employs a fresh gas flow that is 
less than the alveolar ventilation can be classified as LFA. The development of modern anaesthetic 
machines, gas analyser monitors, precision vaporisers and introduction of more potent volatile agents 
with minimal uptake were some of the breakthroughs encouraging LFA enthusiasts.2 The staggering 
amount of environmental pollution due to anaesthetic gases during the present-day practice virtually 
mandates every anaesthesia provider to take that extra bit of effort to use the available facilities to 
implement LFA.3 The idea of LFA is to replenish the consumed gases with as minimum fresh gas as 
possible while making sure to remove CO2 before recirculating. This minimises the loss of anaesthetic 
agents into the environment.4 The merits of reducing flow must not overrule safety, by maintaining 
adequate oxygen content in the circle and avoiding hypoxic gas mixture, inadequate anaesthesia control 
and too light anaesthesia with risk for awareness.2, 5  
Volatile anaesthetic agents are unique in that it is possible to significantly reduce the mass of drug 
delivered to the circuit (by lowering FGFs) without altering the amount that actually enters the patient.6 
Studies have shown that 1 L/min change in FGF with Sevoflurane results in a change of between 4 and 
18 ml/hour consumption of sevoflurane.7 The challenge is to control the dynamic equilibrium of FG 
composition as the uptake and metabolism are time-sensitive and many factors influence the 
consumption and production of gaseous components. This can be achieved only through frequent 
adjustments in the gas flow controls.1  
LFA requires flow meters calibrated to low flow down to 50 ml/min, leak-proof circle breathing system 
and airway devices like cuffed endotracheal tube (ETT), gas monitoring system providing inspired and 
end-tidal concentrations of agent, vapourisers capable of delivering high concentrations and calibrated 
to be accurate at low FGF. Since low FGFs are added to significantly large reserve volume 
(approximately 9-10 litres), consisting of breathing tubing, reservoir bag, anaesthetic ventilator, 
intergranular space, etc., in addition to functional residual capacity (FRC) of the patient, it requires 3-
time constants (calculated by reserve volume divided by FGF) to effect 95% change in gas composition 
to occur. However, once steady state is achieved, LFA provides the most economic use of anaesthetic 
agents. Sevoflurane when used with strong base-free CO2 absorbent is suitable for use in LFA because 
it has low blood-gas solubility. The minimum alveolar concentration (MAC) of Sevoflurane varies with 

patient age, from 1.4% at age 80 years to 2.3% at age 1 year.8 The optimal alveolar concentration of 
Sevoflurane (FAS) to prevent motor movement and autonomic response during anaesthesia is MAC-Bar 
which approximates 1.5 MAC. Thus, the target of FAS during anaesthesia in daily practice varies 
between 1 to 3.5%, depending on the adjuvant drugs used.  
Since use of low FGF leads to a long time constant, a wash-in phase using a high FGF and high 
vapouriser concentration (FV) of volatile anaesthetic is warranted in order to rapidly achieve the required 
concentration of inhalation anaesthetic in the breathing system.8 Conventionally LFA is administered 
using high flows initially up to 4-10 L/min for 3-time constants (approximately 3 minutes) with 
Sevoflurane dial setting of 0.8-2.5% to bring the circuit to the desired concentration, then the flows are 
reduced for maintenance of anaesthesia. In this method of initial high flows, there is risk of delivering 
high anaesthetic concentrations during induction of anaesthesia and wastage of volatile agents when the 
total consumption of anaesthetic agent (AA) is calculated at the end of surgery.  
Wash-in is the time taken to reach 1 MAC concentration. Sevoflurane wash-in schemes lack simplicity, 
target coverage and applicability. Various studies have demonstrated that the time to reach 1 MAC 
decreased at higher flow rates (1-2-4) but plateaued at 4-4.8 L/min. Lindqvist et. al.9 reported a 2-step 
wash-in technique to achieve a FAS of 1.2%; starting with FGF 1 L·min− 1 and FVS 8% for 1 min, then 
reducing FGF to 1, 0.7, 0.5, and 0.3 L·min− 1. They found that the respective time to achieve the target 
FAS was 1.8, 1.5, 2.5 and 3.6 min. Horwitz et. al.10 reported that by using a FGF of 1.0 or 0.5 L·min− 1 
with a FVS 6% during the wash-in, the respective time to reach 1 MAC was 6.2 ± 1.3 and 15.2 ± 2.4 
min and up to 1.5 MAC at 7.5 ± 2.5 and 19 ± 4.4 min. Shin et al.11 performed a wash-in study using a 
Primus anaesthetic machine connected to a test-lung, using a FGF of 0.5, 1, and 3 L·min− 1 and setting 
the FVS to 6%. The respective mean time to reach a FAS of 4% for each FGF was 1165, 534, and 155 s. 
Nel MR et. al.12 have shown while using FGF=6 L (Nitrous Oxide 4L + O2 2L) and Sevoflurane 
vapouriser dial set at 2.5% that equilibration point defined as FE /FI=0.8 (corresponding to FAS=2%) 
can be reached in a mean (standard deviation) of 8.2 ± 2.1 min. Tribuddharat S et. al.8 studied the 1-1-
8 wash-in scheme with FGF=2L (O2 1 L + Air 1 L) and FVS 8% which yielded a respective FAS of 1, 
1.5, 2, 2.5, 3, and 3.5% at 1, 1.5, 2, 3, 3.5, and 4.5 min when used with N2O and at 1, 1.5, 2, 3, 4, and 5 
min when used with air.  
In a test lung model study Jakobsson et. al.4 reported wash-in with a respective FGF of 0.3 and 4 L·min− 
1 and a FVS of 8%. They found that the FAS reached 1 MAC (2.1%) at 547 ± 83 and 38 ± 6 s, respectively. 
It was possible to increase the AA concentration from 0 to 1 MAC value in around one minute by using 
a FGF of 4–4.8 L/min using a fixed dial setting of 3 MAC, but raising the FGF further did not result in 
shorter wash-in times. Wash-in times were significantly faster with higher flow rates for FGF spanning 
from 1, 2 and 4 L/min, however a plateau started at FGF 4–4.8 L/min, where increasing the FGF further 
up to 6 or 8 L/min did not shorten the time to reach 1 MAC significantly.13  
The conventional method which uses initial high FGF during the wash-in phase defeats the purpose of 
LFA such as conservation of gases, reduced environmental pollution and economical savings even 

though it provides a more stable gas composition within the breathing system. Beginning of anaesthesia 
is also a task-intense phase requiring multiple tasks to be performed to ensure the patient safety. Any 
additional tasks during this phase may have high chances of being forgotten with a potential for 
compromised patient safety. Therefore, the technique has to be simple to execute. We wish to evaluate 
a technique of initiating Sevoflurane LFA which is simple, has a quick wash-in and minimises gas 
consumption without compromising the safety when compared to conventional method of attaining 
LFA using initial high flows.  
 
Methods  
After obtaining the approval from the Institutional Ethics Committee of The Royal Hospital, Muscat, 
we will register this prospective, randomised, descriptive study in an appropriate online clinical trial 
registry. A written informed consent will be obtained from all the patients. Forty-eight patients of either 
gender aged 18-65 years, with American Society of Anesthesiologists (ASA) physical status of 1-2, 
undergoing elective surgery with the expected duration more than 1 hour under general anaesthesia 
requiring endotracheal intubation will be included. Pregnant women, smokers, patients with a body 
mass index (BMI) ≥30 kg/m2, cardiac/pulmonary/renal or liver impairments, upper or lower respiratory 
infections within the past 6 weeks and anticipated difficult airway will be excluded.  
Age, gender, height and weight of the patients will be recorded. All the patients will follow the standard 
fasting requirements and receive no sedative premedication. They will be randomised before entering 
the operating room into one of the two groups, ‘conventional group’ (Group C) and ‘over-pressure 
group’ (Group OP), using block randomisation technique with varying block sizes. An appropriate 
intravenous cannula will be secured in the operating room and Ringer’s Lactate 500 ml will be started. 
The patients will receive standard anaesthetic care and intra-operative monitoring with 
electrocardiogram, pulse oximeter (SpO2), non-invasive blood pressure (NIBP) and capnography. 
Avance CS2 anaesthesia workstation (GE Healthcare, Madison, WI, USA) which has an integrated 
anaesthetic gas analyser, displays age-adjusted MAC according to the internal algorithm and returns 
sampled gas to the breathing system will be used in this study. The breathing system will consist of a 2 
L reservoir bag, disposable breathing circuit, heat-moisture exchanger and standard circle system with 
Sodalime as the CO2 absorbent. The workstation will be tested to ensure no leak in the system and 
vapourisers are calibrated.  
Ideal Body Weight (IBW) of the patient will be calculated based on the following formula: IBW 
(kg)=50 + 0.91 (height in cm – 152.4) for Men and 45.5 + 0.91 (height in cm – 152.4) for Women. The 
ventilator will be preset in Pressure Control-Volume Guarantee (PCV-VG) mode with a tidal volume 
of 8 ml/kg of IBW, respiratory rate=14 breaths/min, positive end-expiratory pressure (PEEP)=5 cmH2O 
and an inspiratory:expiratory ratio of 1:2. The set minute volume will be noted. The alarm for end-tidal 
Sevoflurane (FAS) will be set at 2% to alert the clinician.  

Heart rate (HR), blood pressure (BP) and peripheral oxygen saturation will be recorded before induction 
of anaesthesia, every minute until 5 min after induction and every 5 min intervals thereafter. The FGF 
will be set at 6 L/min with 100% O2 during pre-oxygenation and manual ventilation. Following pre-
oxygenation for 3 min, general anaesthesia will be induced with intravenous Fentanyl 2 μg/kg followed 
by Propofol 2 mg/kg administered over 30 seconds and Rocuronium 1 mg/kg for neuromuscular 
blockade. Lungs will be ventilated manually and propofol 20 mg every minute will be administered 
until tracheal intubation. Tracheal intubation with an appropriate size ETT will be performed 90 seconds 
later, the cuff inflated to 25-30 cmH2O using a cuff-pressure monitor device and ETT secured with an 
adhesive tape. The correct ETT position will be confirmed by auscultation and square-wave 
capnograph. FGF will be paused during intubation and restarted after inflating the ETT cuff. The FGF 
hereafter will consist of O2 and Air with a set FIO2=0.6. FGF and Sevoflurane vapouriser dial (FVS) will 
be set as per the group allocation and mechanical ventilation will begin. The time of opening of 
vapouriser will be considered Tzero.  
Following will be the steps during wash-in for achieving LFA:  
The ‘conventional’ group (Group C): FGF will be set to 6 L/min and the FVS 3% at Tzero. The FGF will 
be reduced to 0.5 L/min upon reaching FAS 2%. Hereafter, the FVS will be set to 4% and maintained till 
15 min (T15) from Tzero.  
The ‘over-pressure’ group (Group OP): FGF will be set to 0.5 L/min and FVS 8% at Tzero. Subsequently, 
the FVS will be set to 4% upon reaching FAS 2% and maintained till 15 min (T15) from Tzero.  
The time of reaching FAS=2% will be noted in both the groups. The time taken in seconds from Tzero to 
reach FAS 2% (Ttarget) will be calculated. Inspired concentration of Sevoflurane (FIS), FAS, and age-
adjusted MAC will be retrieved from the automatically recorded ‘trend’ of parameters. FIS, FAS and 
age-adjusted MAC will be noted every 30 sec. starting from Tzero, till T5 and every minute thereafter 
until T15.  
Consumption of gases (Oxygen, Air and Sevoflurane) from the beginning until T15 will be retrieved. 
Any reduction in mean BP >20% from the baseline will be treated with intravenous Ephedrine 12 mg 
bolus and consumption of Ephedrine will be noted. Expired minute volume (MVE) at Ttarget and T15 will 
be noted. The study period will end at T15 in both the groups. Painting the surgical parts and draping 
will be permitted during the study period. Care will be taken to avoid any activity which risks ETT 
disconnection during the study period. Subsequent management of anaesthesia will be left to the 
discretion of the attending Anaesthesiologist.  
For both the groups, ‘stability of Sevoflurane concentration’, defined as FAS in the target range of 1.6- 
2.4% during the time interval from Ttarget till T15 will be assessed. The investigator will be allowed during 
this period to increase or decrease if needed the vapouriser dial by 1% at a time every 2 min to keep the 
FAS in the target range. The number of times the vapouriser dial is adjusted will be noted. The system 
will be considered ‘stable’ if the FAS is maintained in the target range without the need for dial 
adjustment and ‘unstable’ if vapouriser dial adjustment is needed at any time during this period. 

Delivery of Oxygen will be monitored to ensure at least 300 ml/min and delivered FIO2 at least 0.3 at 
all time. The investigator will be allowed to increase if needed the set FIO2 by 0.1 at a time every 2 min 
to keep the delivered FIO2>0.3. The number of times the set FIO2 is adjusted will be noted. End-tidal 
carbon dioxide (ETCO2) will be maintained between 30 and 40.  
The aim of the study is to assess during the wash-in phase of LFA the feasibility of the method, stability 
of the system and consumption of gases. The primary outcome will be the time required to achieve FAS 
2%. Secondary outcomes will be the stability of the system assessed by the number of times vapouriser 
dial and the set FIO2 adjusted, consumption of gases and of ephedrine.  
 
Statistical analysis  
Sample size is calculated based on a previous study8 which showed the 1-1-8 wash-in scheme with 
FGF=2L (O2 1 L + Air 1 L) and Sevoflurane dial at 8% yielded an FAS of 2% at 2 ± 0.5 min. Hence, we 
assume that with our wash-in technique using FGF=0.5 L (O2 + Air) and FVS 8% the time needed to 
reach FAS=2% will be around 8 min. To detect a difference of 2 min (25%) with standard deviation 
(SD) of 2 using an alpha level of 0.05 and a power of 0.90 the sample size needed is 22 per group. For 
a possible 10% dropouts, it is decided to include 24 patients per group.  
Statistical analysis will be carried out using an appropriate statistical software. Data will be presented 
as mean ± SD or median (range). Intergroup differences will be assessed for significance using 
Student’s t, Kruskal-Wallis, chi-squared or Fisher exact tests, as appropriate. P < 0.05 will be considered 
statistically significant.  
Study duration: Approximately 8 months (from December 2023 to July 2024). Data collection: 
December 2023-May 2024, statistical analysis and writing manuscript: June-July 2024.  
How will the expenses be met with? :  Does not involve any additional expenditure.  
Department associated in the study: Department of Anaesthesia and Intensive Care, Royal Hospital, 
Muscat.  
 
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