Low Flow Anaesthesia; Cost-effectiveness of the Flow-I Anaesthesia Machine, a Comparison to Established Anaesthesia Delivery Unit
Phase: NA
Conditions: General Anaesthesia
Sponsor: Jan Jakobsson

 
 
 
 
Low flow anaesthesia; cost-effectiveness of the Flow-I anaesthesia machine, 
a comparison to established anaesthesia delivery unit  
 
 
 
  
 
 
 
 
 
 
 
VERSION V1.0 
 
November 17th 2013 

 
Chief Investigator: 
Jan Jakobsson,  
Adjunct Professor,  
Department of Clinical Science,  
Karolinska Institutet 
Danderyds University Hospital 
182 88 Stockholm 
Sweden 
Jan.jakobsson@ki.se 
 
Study Investigators: 
Jan Jakobsson 
Dr Oliver Smith,  
Department of Anesthesia,  
Charlotte Maxeke Johanessburg Academic Hospital,  
South Africa 
 
R. Ryan Field, MD 
Neuroanesthesiology Liaison 
CA3 Curriculum Co-Director 
Assistant Clinical Professor 
Department of Anesthesiology 
Department of Neurosurgery 
UC Irvine – Health 
USA 
 
 

Content 
 
1. 
Protocol Summary .............................................................................................................. 4 
2. 
Background ......................................................................................................................... 5 
3. 
Objective ............................................................................................................................. 7 
4. 
Inclusion and Exclusion Criteria ......................................................................................... 8 
5. 
Ethics Committee Approval and Patient Informed Consent ............................................... 9 
6. 
Randomisation .................................................................................................................. 10 
7. 
Anaesthesia Protocol ......................................................................................................... 11 
8. 
Outcome Variables ............................................................................................................ 12 
9. 
Statistics ............................................................................................................................ 13 
10. 
Study Timelines ............................................................................................................. 14 
11. 
Insurance ....................................................................................................................... 15 
12. 
Confidentiality ............................................................................................................... 16 
13. 
Adverse Event Reporting .............................................................................................. 17 
14. 
References ..................................................................................................................... 18 
 

1. 
Protocol Summary  
 
Title of study:  Low fresh gas flow during elective general anaesthesia -  
A study comparing the Flow-I and a conventional anaesthetic machine with a circle 
system including a bellow reservoir. 
 
 
Institution:  Department of Anaesthesia & Intensive Care Danderyds University 
Hospital, Institution for Clinical Science, Karolinska Institutet, Stockholm, SWEDEN 
 
Study time-lines: Patients inclusion in 8 month, study report in 12 month, from 
initiation of patient into study.  
 
Objective: To test the hypothesis that the Flow I patient circle and fresh gas 
generation provides a faster and less gas consuming equilibrium and maintenance of 
general anaesthesia as compared to a conventional anaesthetic machine including a 
breathing circle with a below reservoir.  
The study will compare Flow I to a conventional anaesthetic machine during routine 
elective general surgery in ASA 1-2 patients under general anaesthesia based on 
desflurane at a fresh gas flow of 1 L/min.  
Study design: prospective, randomized study. 
 
Participants: one hundred ASA 1-2 patients aged 20 – 60 years scheduled for elective 
general anaesthesia will be recruited. Patients will be randomized to Flow I or a 
conventional anaesthetic machine having general desflurane anaesthesia at a fresh gas 
flow of 1 l/min fresh gas flow. 
 
Duration of treatment: Study protocol covers 72 hours after end of anaesthesia 
(follow-up of quality of recovery until day 3)  .  
 
Main measurements: 
Time to go from 1 to 1.5 MAC end-tidal concentration during controlled ventilation 
with a tidal volume of 6 ml/kg and a respiratory rate of 12 breaths per minutes. 
Amount anaesthesia agent consumed; Gram inhaled anaesthetic per minute 
anaesthesia. 
 
 

2. 
Background 
Desflurane, one of the third generation of inhaled halogenated anaesthetics has 
physiochemical properties promoting its use in low flow anaesthesia. The low blood and 
tissue solubility promotes its rapid equilibration and thus potential benefit when used in 
conjunction with lowering of the fresh gas flow. It has been shown superior to isoflurane for 
control of haemodynamic also at flow rates of 1 L/min. 
Bennett et al  compared desflurane and isoflurane for control of haemodynamic response. 
They found that Desflurane allowed for more rapid control of blood pressure response to 
surgical stimulus median 2 minutes (range 1 to 12 minutes) for desflurane versus 6 minutes 
(range 1 to 12 minutes, p = 0.011). The desflurane group required fewer 30% incremental 
anaesthetic increases than the isoflurane group (1.8 versus 2.5, p = 0.016) to control increased 
systolic blood pressure. End tidal/inspired drug concentration ratios were closer to unity in the 
desflurane patients both before (0.94 versus 0.80) and after (0.86 versus 0.70) changes in drug 
concentration to treat increased systolic blood pressure.  
Avramov et al evaluated the effect of the fresh gas flow (FGF) rate and the anesthetic 
technique on the ability to control the acute hyperdynamic response to a specific surgical 
stimulus during surgery in 90 consenting ASA physical status I-III patients undergoing lower 
abdominal procedures. The patients were initially maintained with desflurane or isoflurane, 
0.7 minimum alveolar anaesthetic concentrations, at total FGF rates of either 1 or 3 L/min. In 
response to the surgical stimulation of skin incision and retropubic dissection, an increase in 
mean arterial pressure (MAP) ~20% above the pre-incision baseline MAP value provoked a 
stepwise increase in the inspired concentration of the volatile anaesthetic or the IV 
administration of a variable-rate infusion of esmolol. They found that desflurane was 
significantly faster in controlling haemodynamic response to painful stimulation also at low, 1 
L/min fresh gas flow. At 1 L/min, the average time to control the mean arterial pressure was 
significantly shorter with desflurane (17 ± 12 min) compared with isoflurane (29 ± 16 min), 
with 60% of the patients in the isoflurane group requiring rescue therapy.   
Low blood gas solubility promotes in theory the use of the third generation inhaled 
anaesthetics for use during general anaesthesia with low fresh gas flow. The benefits of low 
blood and tissue solubility during low and minimal flow are not yet studied. 
Reducing the fresh gas flow has many benefits, it reduces the risk for unnecessary work place 
contamination, it reduces the environmental pollution and it is cost-effective . Many 
institutions are therefore adopting low flow technique. Inhaled anaesthesia with low flow 
technique may also have benefits as compared to the intravenous anaesthetic technique, 
propofol based anaesthesia that has become increasingly popular. The low flow inhaled 
anaesthesia technique would assumingly become cost-effective also with the availability of 
generic low prize propofol   . The easiness to start and continuously monitor end-tidal 
concentration should also be recognised.  
Choi et al compared two fresh gas flows techniques and the time to effect: control of a blood 
pressure increase during surgery with sevoflurane. They compared the ability of the Zeus 

multifunctional anaesthesia system to control haemodynamic response to surgical stimulation 
in semi-closed anaesthesia (SCA) or closed circuit anaesthesia (CCA) modes. Fifty patients 
undergoing gynaecological surgery were randomly assigned to SCA or CCA. Anaesthesia 
was induced with 2 mg/kg propofol and paralysis was achieved with 0.9 mg/kg rocuronium, 
i.v. and maintenance was with sevoflurane (minimum alveolar concentration [MAC], 1.0) 
using 2 l/min oxygen plus 2 l/min nitrous oxide (SCA 4 l/min group) or 50% oxygen plus 
50% nitrous oxide (CCA group). An increase in mean arterial pressure (MAP) > 20% above 
baseline in response to surgical stimulation provoked a stepwise increase in sevoflurane (1.3 
MAC and then 1.6 MAC), followed by fentanyl 1 pg/kg intravenously (rescue drug). The time 
required for MAP to return to within 10% of baseline was significantly shorter in the CCA 
group (6.4 +/- 3.6 min) compared with the SCA 4 l/min group (10.2 +/- 6.0 min). It seems 
reasonable to conclude that time to onset of effect of sevoflurane is rapid and dependent on 
the dose administered. 
The breathing circle should ascertain an adequate gas mixture inhaled; oxygen and inhaled 
agent as well as absence of carbon dioxide. The anaesthetic machine provide the fresh gas 
entering the breathing circle. There are technical developments. The delivery of fresh gas 
differs between devices.  

Objective 
To test the hypothesis that the Flow I breathing circle system without a below reservoir 
provides a faster and less anaesthetic vapour consuming wash-in and maintenance of 
Etdesflurane  
The aim of the study is to compare gas kinetics, time needed in order to change the end-tidal 
concentration, and vapour consumption (and associated cost) between the novel Flow-I circle 
system and the standard anaesthesia equipment/machine at the centre (multi-centre study; 3 
centres) during general anaesthesia for routine elective surgery in ASA 1-2 patients. 
The study will compare The Flow I to a conventional anaesthetic machine including a 
breathing circle based on a below reservoir during routine desflurane with a fresh gas flow of 
1 L/min in ASA 1-2 patients having elective surgery.  
 

3. 
Inclusion and Exclusion Criteria 
 
100 ASA 1-2 patients aged 20 – 60 years scheduled for elective general anaesthesia will be 
recruited. 
 
Inclusion criteria 
 Age 20 to 60 years  
 BMI 20-30 
 ASA 1-2 
 
Exclusion criteria 
 COPD 
 BMI > 30 
 ASA >2 
 Sever cardiovascular disease ASA >2 
 Renal disease 
 Diabetes 
 Hepatic disease 
 Psychiatric disease or any psychoactive medication 
 
 
All patients will receive all treatment and care in accordance to the routines of the department 
apart from the volatile anaesthetic and fresh-gas flow that the patient is randomised to. 
All study specific data will be recorded and collected on a Case Record Form coded in 
accordance to randomisation.  

4. 
Ethics Committee Approval and Patient Informed Consent 
 
The study will be reviewed by regional Ethics Review Board. The protocol will be reviewed 
by registered in Clinical Trial Data bases in accordance to National Regulations 
The study will not be initiated before approval has been received from the Ethics Review 
Board and reviewed by National drug authority as needed. 
All patients will receive verbal and written information and signed informed consent will be 
required before any patients are entered into the study. 
 

5. 
Randomisation  
 
Patients will be randomised on entering the operating theatre. The anaesthetist responsible for 
the patient will open an envelope in which the group will be noted. Each patient will have an 
inclusion number and each inclusion number will correspond to attribution to a treatment 
group in accordance with a randomization list pre-established by the envelope technique. The 
envelopes will be created from 2 random lists.  
Patients will be randomised to  
 Flow I 
 Conventional anaesthetic machine 
for maintenance of anaesthesia. 
 and subsequently to a fresh gas flow of 
 1 L/min FiO2 0.5 oxygen in air 
 
 

6. 
Anaesthesia Protocol 
All patients will follow the routines of the department expect for the randomisation of 
anaesthetic machine 
All patients will receive general anaesthesia in accordance to local practice expect for the 
randomisation of anaesthetic machine and maintenance of a fresh gas flow of 1 L/min during 
anaesthesia. 
 Establishment of intravenous access, 1000 ml Ringeractetat.  
 All patients will have preoxygenation FiO2 0.8 for 60 seconds including 3 “deep 
breath” prior to propofol (2.5 mg/kg) fentanyl (2 microgr/kg) co-induction will be 
administered until adequately anaesthetised. 
  Intravenous continuous infusion remifentanil will be administered in a dose 3 µg/ml  
 Muscle relaxation will be administer in accordance to local practice  
 Patients will be ventilated with oxygen for 3 minutes and thereafter intubated. 
 
No surgery will commence until a 1.5 MAC is reached.  
The vaporizer will be weighed before and after each patient anaesthetised and gram inhaled 
anaesthesia per minute anaesthesia will be calculated  
The fresh gas flow is increased to 4 L/min oxygen and 2 L/min air when last stitch is made. 
 Time to extubation 
 Time to state name and date of birth 
 Time to discharge from the PACU 
 
All patients will receive PONV prophylaxis in accordance to local routines. 
 PONV during the first 24 hours after surgery 
 Patients satisfaction 
 
 

7. 
Outcome Variables 
Primary study variable, amount of gas vaporized halogenated anaesthetic per minute 
anaesthesia.  
Secondary study variables; 
1. Time needed to increase from Etaa 1 to Etaa 1.5 age adjusted MAC with a constant 1 
L/min. and a dialled 3 MAC, the vaporiser set at 18 %, in conjunction to start of 
surgery 
a. When the 1.5 Etaa has been achieved the gas setting should be adjusted in 
accordance to clinical needs throughout the surgery. 
2. Time needed during wash-out, time from cessation of administration until reaching 0.2 
MAC 
a. Time from cessation of administration to awakening; extubation and able to 
state name and date of birth 
a. Time to reach Aldrete > 8 
b. Pain and need for analgesics and anti-emetics during the PACU stay 
c. Follow-up of quality of recovery PQRS 
 

8. 
Statistics 
 
As this is an explorative pilot study thus no formal sample size will be determined. 
Power calculation 
Based on the experience from pilot study a vaporizer consumption of 0.28 gr/min with a SD 
of 0.07 and the Flow-I being more efficient vapor injection providing an estimated 0.03 
gr/min reduction of vapor a group size of 43 patients would be required in order to verify a 
significant difference p < 0.05 at a power of 80%. A total of 2 x 43 in all 86 and a drop out / 
lost for follow-up of about 10-14 patients 100 patients will be recruited. 
Comparison of normally distributed variables will be done by Student’s t-test, of variables not 
following a normal distribution by Wilcoxon Test. 
 

9. 
Study Timelines 
 
Total duration of the study: Estimated 12 months from start of patient inclusion until study 
report 
. 
 

10. 
Insurance 
 
All treatments except randomisation will be given in accordance to the routines of the 
department. No extra insurance is therefore required. The National Patient Safety Insurance 
will cover potential insurance claims.  

11. 
Confidentiality 
 
All retrieved data will be compiled on CRFs identified by the randomisation code. Patient 
identity will only be available in case of adverse effect or required by any other reason for the 
medical care. The patient code list will be stored in a dedicated storage place, patient record 
storage and available 24 hours 7 days a week after contact with Principal Investigator.  
 
 
 
 
 
 

12. 
Adverse Event Reporting 
All serious adverse effects and adverse effects or risks with respect to the study material will 
be reported in accordance with the applicable local and European Union laws and regulations. 
Regulatory Authorities, Ethics Committees and all participating investigators are informed in 
accordance with the given timelines set out in the applicable laws and regulations.  
The investigator will also notify all serious adverse events or other significant safety concerns 
irrespective of causality that arise to Maquet within 24 hours,  
 

13. 
References 
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Anaesthesiol Scand. 2012 Apr;56(4):420-32. 
 
Brattwall M, Warrén-Stomberg M, Hesselvik F, Jakobsson J. Brief review: theory and 
practice of minimal fresh gas flow anesthesia. Can J Anaesth. 2012 Aug;59(8):785-97. doi: 
10.1007/s12630-012-9736-2.  
 
Bennett JA, Mahadeviah A, Stewart J, Lingaraju N, Keykhah MM. Desflurane controls the 
hemodynamic response to surgical stimulation more rapidly than isoflurane. J Clin Anesth. 
1995 Jun;7(4):288-91. 
 
Avramov MN, Griffin JD, White PF. The effect of fresh gas flow and anesthetic technique on 
the ability to control acute hemodynamic responses during surgery. Anesth Analg. 1998 
Sep;87(3):666-70. 
 
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Mortier EP. Optimization of desflurane administration in morbidly obese patients: a 
comparison with sevoflurane using an 'inhalation bolus' technique. Br J Anaesth. 2003 
Nov;91(5):638-50. 
 
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A, Henke JA, Rust M, Hipp RF. Experiences with the new inhalational agents in low-flow 
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Cardiopulm Pathophysiol. 1995;5 Suppl 2:47-57. 
 
Hargasser S, Hipp R, Breinbauer B, Mielke L, Entholzner E, Rust M. A lower solubility 
recommends the use of desflurane more than isoflurane, halothane, and enflurane under low-
flow conditions. J Clin Anesth. 1995 Feb;7(1):49-53. 
 
Ekbom K, Assareh H, Anderson RE, Jakobsson JG. The effects of fresh gas flow on the 
amount of sevoflurane vaporized during 1 minimum alveolar concentration anaesthesia for 
day surgery: a clinical study. Acta Anaesthesiol Scand. 2007 Mar;51(3):290-3. 
 
Dolk A, Cannerfelt R, Anderson RE, Jakobsson J. Inhalation anaesthesia is cost-effective for 
ambulatory surgery: a clinical comparison with propofol during elective knee arthroscopy. 
Eur J Anaesthesiol. 2002 Feb;19(2):88-92. 
 
Heidvall M, Hein A, Davidson S, Jakobsson J. Cost comparison between three different 
general anaesthetic techniques for elective arthroscopy of the knee. Acta Anaesthesiol Scand. 
2000 Feb;44(2):157-62. 
 
Choi SU, Shin HW, Jung HI, Park JY, Yoon SZ, Lee YS, Kim WY, Chang SH. Control of the 
haemodynamic response to surgical stimuli in semi-closed circuit or closed circuit anaesthesia 
using a multifunctional anaesthesia system. J Int Med Res. 2010; 38: 1637-44.