York 1999
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In many western countries the cost and availability of anaesthetic agents are rarely taken into consideration when an anaesthetic proceedure is being planned. This is in marked contrast to the situation in many developing countries where, not only is cost a prime consideration but even more so is the availability of the anaesthetic agents which may indeed be the decisive factor as to whether an anaesthetic can take place at all.

In situations where the supply of cylinders of oxygen and nitrous oxide fails inhalational anaesthesia can still be administered by utilization of the draw-over system, preferably combined with an oxygen concentrator to supplement the percent of oxygen inspired. This has proved to be extremely effective, but has the disadvantage of utilizing expensive volatile agents at a rapid rate.

If soda lime is available the amount of volatile agent required can be greatly reduced by
utilization of low flows of fresh gas with a circle system. The greatest possible savings occur when the fresh gas flow is reduced to the patients basal oxygen requirement of about 250ml of oxygen per minute. In this system the expiratory valve on the circle is closed so that all expired gases are recycled and there is no wastage of expensive volatile agents.

Without compressed gases a high resistance TEC vaporizer cannot be used and the volatile agents must be introduced into the circle system either by direct injection or by
use of a low resistance vaporizer within the circuit (VIC).

The Goldman vaporizer has been extensively used in this way for many years but is no longer manufactured in the UK and is difficult to obtain. The Komesaroff vaporizer however, is readily obtainable in the UK and is similar in design to the Goldman. It is an uncalibrated vaporizer consisting of a small glass bowl with a simple control dial, with three divisions between the fully on and fully off position.

A study was carried out to assess the performance of the Komesaroff vaporizer when situated within the circle (VIC) using halothane and basal oxygen delivered by an oxygen concentrator. The aim of the study was to determine if anaesthesia could be administered both safely and economically in the absence of compressed gases.

Patients and methods

Twenty unselected adult patients (ASA 1 or 2) scheduled for elective surgery not requiring muscle relaxation were studied. Patients in whom halothane was contraindicated were excluded from the study. Before commencing anaesthesia the anaesthetic circuit was confirmed as leakproof by closing the expiratory valve, plugging the outlet at the airway and inflating to 20mmHg. The circuit was then flushed with oxygen from the DeVibiss OV50 concentrator.

No pre-medication was given to the patients. Immediately prior to induction a 20G intravenous cannula was inserted and morphine 0.1mg/kg was administered Following induction of anaesthesia with propofol 2.5mg/kg. a laryngeal mask was inserted and connected to the circle system. Oxygen was introduced into the circle via
the oxygen concentrator and the flow rate adjusted to match the level of the patients basal requirements as determined by the degree of distension of the reservoir bag.

Anaesthesia was maintained with halothane administered via the Komesaroff vaporizer situated on the inspiratory limb of the circle system. The vaporizer dial was set at the second division for 10 minutes after which the setting was reduced to a position mid-way between the first and second divisions. Following the inital bolus of morphine given prior to induction further analgesia was provided by additional increments of morphine as clinically indicated.

The inspired and expired gases were analyzed continuously at the patients airway and the results recorded every minute for 15 minutes thereafter every 5 minutes. After analysis the sample gases returned to the circuit. Measurements were also made of the patients minute volume, respiratory rate, pulse rate and blood pressure and oxygen saturation. The temperature of the halothane was recorded continuously by means of an oesophageal thermometer inserted through the dial of the vaporizer with its tip lying under the surface of the halothane. The interval between induction and incision was recorded At the conclusion of surgery the vaporizer was turned off, the circuit flushed with oxygen and the amount of halothane remaining in the vaporizer was measured and the volume used during the anaesthetic calculated.

Results

The age of the patients ranged from 20 - 80 years and their weights from 50 - 110 kg. The duration of surgery ranged from 15 minutes to two hours and 30minutes. Satisfactory anaesthesia was provided in all patients. The Fi02 remained above 50% and the oxygen concentration remained between 95-100% at all times. A pilot study had previously demonstrated the importance of administering the first injection of morphine, prior to induction to provide a sufficient degree of analgesia at the begining of surgery. The interval between induction and incision ranged from 4 to 15 minutes. No patients reacted to the initial incision. Whenever anaesthesia lightened as indicated by increased respiratory rate or tidal volume increments of morphine were administered and this, together with the increased rate of vaporization, was enough to prevent movement. The average quantity of morphine given was 10mg in the first hour and 4mg per hour thereafter.

The anaesthetics was remarkably stable throughout. It was not found necessary to alter the dial setting for halothane once surgery commenced. The setting of the dial midway between the first and second division was found to produce an expired concentration of halothane in the region of 1.5%.

The quantity of halothane vapourized ranged between 2-8ml per hour, according to the patients age and physical condition.

The temperature of the halothane fell by the rate of about 10C every minute for the first
five minutes until it reached approximately 150C and thereafter remained fairly constant.

Discussion

Halothane was chosen as the volatile agent as it is inexpensive and commonly available in developing countries. The anaesthetic component was provided by morphine rather than nitrous oxide which is expensive and frequently unavailable.

Basal flow rates of oxygen were used from the outset, sufficient halothane being vaporized from the Komesaroff vaporizer when set at the second division, to achieve surgical anaesthesia by the time the incision was made.

The avoidance of nitrous oxide not only reduced cost but provided an additional safety
factor since a hypoxic mixture could not be administered with the technique used.

Although an agent monitor was used during the study, the percentage of halothane within the circuit was reasonably predictable and safety was enhanced by the built it self regulation due to the direct relationship between the rate of vaporisation and the patient's minute volume.

Provided the anaesthetist is familiar with the vaporizer and the control dial does not exceed the second division any increase in concentration that occurs does so slowly and is reflected in cardiovascular and respiratory depression. For this reason the system could be used safely without agent monitoring by an experienced anaesthetist who had no cylinders of oxygen or nitrous oxide and only a limited supply of halothane.

Romania is a republic of 23 million inhabitants, situated in south-eastern part of the Central Europe. The country’s history extends back 2,000 years when the Kingdom of Dacia was conquered by the Romans, and a new nation was born, the Romanians, a Latin people surrounded mainly by Slavic nations. On the north by Ukraine; on the east by Moldavia; on the south-east by Black Sea; on the south by Bulgaria; on the south-west by Serbia, and on the west by Hungary. The total area of Romania is about 91,700 sq. mi. (237,500 sq. km) and forests cover approximately 29 per cent of the total land area. Bucharest is Romania’s capital and largest city.

Romanians constitute 89 per cent of the total population. Important ethnic minorities are Hungarians, Germans and Gypsies. Romania also has small numbers of Ukrainians, Jews, Russians, Serbs, Croats, Greeks, Turks, Bulgarians, Tatars and Slovaks. Population density is about 249 people per sq. mi. The population is about 56 per cent urban. The country is divided into 40 counties and the municipality of Bucharest.

Primary education in Romania is free and compulsory for children between the ages of 6 and 15, and the most students choose to continue their education beyond the age of 16. The literacy rate is more than 97 per cent. The educational system emphasizes practical and technical studies. In 1995 statistic shown that some 255,000 students annually attended institutions of higher education. Romania has seven general universities, all of them include Medical Universities and Colleges. The most important Universities are the University of Bucharest (founded 1864), the University of Cluj-Napoca (founded 1919) and the University of Iasi (founded 1860). In addition Romania has four technological universities.

In Romania the medical specialty of Anaesthesia and Intensive Therapy was validated as an independent specialty in 1957. Three years later, in 1960 the ITU’s started to work as a part of the surgical wards and departments. Only in 1972 were independent departments of Anaesthesia and Intensive Therapy established in every big hospital. In 1973 the Romanian Society of Anaethesia and Intensive Therapy was established as an independent body affiliated to the WFSA.

At present a number of 226 ITU’s are working with 3,674 beds ( approximately 2 ITU beds per 100 general hospital beds. In Romania the anaesthesiologists are mostly in charge of ITU management, only 10 per cent are managed by cardiologists and 5 per cent by pediatricians. For example in 1995 there were 206,998 admissions on ITU’s, with a mean stay of 4.37 days and mortality rate of 5.83 per cent. Most of the ITU’s are large, with more than 20 beds and serve also as high dependency units for postoperative care. That could explain the short mean stay and the low mortality.

In Romania there are 10 Academic Units of Anaesthesia and Intensive Therapy. At the undergraduate level anesthesia and intensive therapy is taught during one semester in the fourth year of study, and consists of 16 hours courses and two hours/student/week practical training. The postgraduate education is accomplished in 5 years of training. In order to obtain the Romanian diploma of specialist in Anaesthesia and Intensive Therapy the trainees must pass two part examination. The final part of the examination consists of a written exam with 10 topics, two vivas and performance of an anaesthetic technique in the operating theatre.

The research activities are mainly clinical and have developed mostly during the last nine years. Romanian Society of Anesthesia and Intensive Therapy has organized annually a symposium or a congress since 1974. Only recently, with the help of the WFSA, it started to organize refresher courses and to edit two quarterly journals.

All anaesthetics are given by anaesthesiologists, assisted by a nurse-anaesthetist who is not allowed to give anaesthetics alone. In Romania there are about 1,000 anaesthetists, 2 per cent of medical doctors. 17 per cent are Registrars, 48 per cent are Specialist Anesthetists, which requires a further examination after five years of practice to became a consultant. The remaining 35 per cent are Consultants.

The induction of anaesthesia is carried out in the operating theatre, and each operating theatre is equipped with an anaesthetic machine, but most of them are old. About 60 per cent of anaesthetic machines are more than 10 years old and 30 per cent more than 20 years old. In general there are big differences between a limited number of big hospitals, mainly teaching hospitals, where modern anaesthesia equipment is provided, and small district hospitals where the anaesthetic machines are old and monitors are insufficient. Only 60 per cent of anaesthetic machines are equipped with a ventilator, the central oxygen supply is available in 80 per cent of operating theatres and ECG monitoring in about 56 per cent of operating theaters. The anaesthetic circuits in use are mostly circles and Bain circuits. In Romania in 1995 were carried out 842, 000 anesthetics, of which 60 per cent were inhalational, 13 per cent total intravenous and 27 per cent were regional anaesthetics.

Older anaesthetic machines of the Spiromat 650 and 656 type (Drager) and machines equipped with anaesthetic ventilators of Pulmomat type are not designed for low flow anaesthesia . Gas leakage is tolerated in technical tests which would cause problems if the flow is reduced to below 2l/min. Conventional anaesthetic machines, with a suspended bellows and continuous flow of fresh gas into the breathing system ( Sulla 19 or Sulla 800V and 808V)(Drager) can be operated with a fresh gas flow of 1 l/min if they have been properly maintained. However, because of the way these machines are designed and constructed, special attention would have to be paid to monitoring the volume of gas in circulation so that any changes in the character of ventilation could be detected and corrected at an early stage. This matter is limiting the use of low flow anaesthesia, mainly due to the lack of monitoring of airway pressure, minute volume and concentration of anaesthetic agent in the breathing gas. Use of conventional anaesthetic machines and low flow anesthesia can be achieved by modifying them with an FGE-valve (fresh gas decoupling valve) or a Ventilog 3. Minimal flow anesthesia with flow of 0.5 l/min for routine clinical use is possible only in a few, mainly cardiac surgery centers and transplant centers which are equipped with new generation anaesthetic machines such as AV1, Cato and Cicero (Drager).

Low Flow Anesthesia in Pakistan

Dr A M Siddiqui

Leeds

The practice of Anesthesia in developing world means provision of Anesthetic service for four fifth of the world's population where the problems, environment and issues are different from the developed world but the goal remains the same "let there be no morbidity".

Pakistan is a land of many splendors from one thousand Kilometers long coastal beaches on Indian Ocean to golden deserts of Thar, desolate plateaus, fertile plains and world's highest peaks like K 2,Gashabrum, Trihmir and Rakaposhi are all in Pakistan.

The total population of Pakistan is 135 million while the per capita expenditure by the Government on health is 12 US$. Due to this state the private sector also provides much services and large foreign companies, various local entrepreneurs, philanthropists and welfare organizations have established modern hospitals apart from small privately owned hospitals of doctors which tend to do less and earn more. Therefore the practice of Anesthesia is quite variable from modern, up to date to old-fashioned style.

The major limitations in the ideal or good practice of Anesthetics are the Non availability of required Equipment and training of Human Resource due to monetary constraints. There are approximately Four Hundred Qualified Anesthetists in Pakistan as compared to 8400 in Great Britain. A large number of unqualified and semi trained doctors practice Anesthetics while there is no continuous medical education system. There fore the understanding and application of knowledge of Ipw flow anesthesia is deficient among those who practice Anesthetics.

The practice of low flow Anesthesia is restricted to the larger cities teaching hospitals whereas the usual practice of Anesthesia in general involves high flows through the Magill's circuits, Bains and Ayre's T Piece and some times" the no flow " which is although a misnomer means that patient breaths ambient air through an Anesthetic equipment which has a draw over sort of vaporizer on one end of a corrugated black rubber tube and an expiratory Ambu E valve on the Patient's end.

This results into waste of Anesthetic gases and agent, loss of humidity and heat and above all pollution of whole atmosphere especially when there is no Gas Scavenging System and no Department of Occupational Health for screening.

This state of Anesthetic Practice is due to high cost of essential monitoring equipment, like end tidal C02 monitors, Oxygen sensors and volatile analyzers. Therefore the Anesthetist has to rely on various observations, like the dial reading of the vaporizers, which poorly depict the end tidal volatile concentrations while using low flows. The vaporizers are also not reliable because of lack of servicing facilities. It's a common observation to notice the damaged dial of Halothane Vaporizer .When these get stuck due to Thymol accumulation , are freed by hitting them with gas cylinder keys.

The practice of Low Flow Anesthesia is limited by

1. The Anesthetist's apprehension of hypoxic gas mixture delivery.

2. Slow change to the depth of Anesthesia especially when no continuous IN techniques are used and induction surgery time is minimum due to induction of Anesthetics in operating theatre instead of Anesthetic rooms.

3. The Anesthetist's apprehension of

A. Increased resistance to breathing B   

B. Unknown composition of inspired gas mixtures.

C. Accumulation of Anesthetic metabolites

D. Leaks through many joints in the system

E. Dependency on inaccurate Rotameters.

4. Complexity of equipment for the user.

The advantages of adopting Low Flow Anesthesia would be

1.Economy

2. Pollution free environment

3.Conservation of heat and humidity

4. Reservoir of about 5 liters of breathing gases' in case of gas supply failures 5.Closer monitoring of the patient.

All these provide sound logic to opt for low flow Anesthesia in Pakistan if the other problems mentioned above are also solved.

I have been working on the PHDC System now for nearly 2 years, starting out as a means to save the tread on my back tyres when I went out of area while diving with colleagues. It has now developed into a complete system for emergency oxygen resuscitation and completely closed anaesthesia. There are 4 main areas of use that have now been identified, which will greatly benefit from the PHDC System. These are: -

1. Emergency Resuscitation
2. Transportation
3. Out of areas operations
4. Exotic gas environments

Emergency Resuscitation:
As we all know, every patient is dying for oxygen, regardless of mechanism of injury, in both cardiac and traumatic injuries. The PHDC System can provide 100% Oxygen to a patient regardless of respiratory state or effort. O2 can be administered via a B.I.B.S. mask if the patient is spontaneously breathing or by mask for the unconscious patient with no airway adjunct in place; ultimately the system can be connected to an ET tube via a standard 15mm connector.

Transportation:
The whole PHDC system is lightweight and man carriable and can be stored or used in places such as ambulances, helicopters, Aeromed equipped planes and the like. It should be noted that the RAF, when evacuating a patient from the Falkland Isles for example, require 7 'J' Size Oxygen cylinders per patient. The PHDC system can be used for long periods without re-supply thus making it ideal for medium to long distance patient transportation.

Out of areas operations:
This heading encompasses a lot of uses and is used very broadly. 'Out of areas' simply means in an environment where transportation to an in-patient facility is not readily available or in an environment where definitive care of high standard could not normally be achieved, for example in 3rd World countries, off-shore installations, expeditions and so forth. Because the PHDC system can stand alone for in excess of 7 days in the field without re-supplies it makes it the ideal choice for this working environment.

Exotic gas environments:
Exotic gas is a term used to describe the increased ambient partial pressures of normal gases that we would take for granted in everyday use. As we all know, even oxygen can become poisonous to the CNS and pulmonary systems if the partial pressure exceeds 1.6 ATA. Can you imagine working out the MAC of halothane at a depths of 30msw in a hyperbaric chamber whilst trying to maintain life support of an injured diver as well?
As I have previously mentioned, the PHDC system was originally designed for use in diving emergencies and so therefore had to be able to work in a hyperbaric environment. By definition then, it will also work in a hypobaric environment such as Aeromed evacuation.
The entire system utilises standard diving computers with 16 compartment tissue tables to monitor the on and off loading of saturated gases in the patients tissues. It will also work out the equivalent percentages for any anaesthetic agent that you use within the system.

As well as providing high percentages of oxygen to emergent patients, the PHDC system also utilises the low-flow technology often found in advanced diving systems for the provision of anaesthesia using either Halothane or Isoflurane through an OMV type device. The use of Xenon is also being looked at as the principle induction and maintenance gas for anaesthesia within the PHDC system.

The main advantages of the PHDC system are: -
· Lightweight and man carriable
· User friendly at all levels
· Stand alone capability in excess of a week
· The ability to extend the life of a standard 'D' size cylinder to over 208 hours in an anaesthesiology role and 32 hours in an emergent role

In conclusion, the PHDC system has a lot to offer in many areas of use, primarily though in 3rd world use, out of area operations and in a military role. A clinical model for use in Bosnia next year is planned to be ready by March 2000.

A machine resembling a conventional circle breathing system attached to a vertical bellows-in-bottle and mechanical ventilator is described. With no fresh gas flow it becomes totally closed and oxygen is automatically added to match uptake by a mechanical valve arrangement. Oxygenation of the patient is therefore not dependent on electronic systems. As a closed breathing system, it is suitable for use in research involving inhaled xenon, as it allows minimum wastage of this very expensive gas. It can also be used as a conventional circle system driven by a bag in bottle arrangement, as it will spill excess gas if a high fresh gas flow is supplied to it from an anaesthetic machine.

Several versions of the machine have been built over the last five years and improvements have been made on each occasion. These will be described in the lecture:
1) Original version with to and fro absorber incorporated into it. This was built by a retired automotive engineer in Denmark for Intensive Care Unit studies involving uptake of tracer gases.
2) Home made version for use in laboratory studies. Designed specifically for use with xenon. Build quality was inferior to previous version but performance and ease of use much improved. Oxygen addition was achieved with a straightforward mechanical device. Xenon was then added under computer control with feedback from the oxygen concentration in the breathing system. Xenon analysis was not necessary for the functioning of this automatic system but for added safety it was measured using an ultrasonic analyser. The apparatus functioned correctly allowing economy of xenon usage, to reduce running costs. The design of the machine was shown to be sound in concept but a better build quality would be required for any human studies.
3) New version of machine in (2) above, designed for xenon research studies in human subjects. Built to very high standard by Penlon Ltd. Attaches to a reusable Penlon circle. Oxygen is still added by an automatic mechanical arrangement, but xenon is now added manually. This avoids use of non-licensed computer control software in human study. Manual xenon delivery to circle has been made as user friendly as possible. The machine warns the operator when the decision to give or not give a xenon bolus needs to be made. This is done by means of a warning light on a remote control handset. If the operator decides to deliver a xenon bolus to the circle, they press a button on this handset. Xenon is delivered through a rotameter flowmeter at a set flow rate whilst this button is held down. This machine will be on display at the ALFA 99 meeting. It has been assembled on a mobile stand for research in the Intensive Care Unit as a xenon sedation delivery device. It can however also be assembled as part of an anaesthetic machine. The attraction of xenon as a sedative is that it may have fewer haemodynamic depressant effects than agents in current use.

Click for a JPG image (73k) of John's breathing system

Our experience on xenon-anaesthesia covers human and animal studies. The former have been performed to obtain a FA/FI curve, to evaluate Xe expenditure and to validate a Xe recycling system; the latter on rats to evaluate the effects of the subchronic exposure to Xenon in the main organs, and the modifications of the ryanodine binding in skeletal muscle. Moreover the intravenous administration of Xe has been evaluated in pigs.
Human studies: 3 volunteers in spontaneous breathing by face mask, after 10 min. of denitrogenation received a gas mixture Xenon/oxygen 70:30. Because of Xe low partition coefficient, we expected to reach the steady state very quickly, and to obtain a quick wash-out with a fast and complete awakening. This was expressed with a FA/FI curve that shows a rapid onset of the anaesthetic concentration, correlated with the clinical time of unconsciousness.
15 patients undergoing abdominal surgery received a low flow or a totally closed circuit anaesthesia with a gas mixture Xenon/oxygen 70:30, in order to determine Xenon expenditure and to validate a recycling system of the gas. The patients received on average a dose of fentanyl about 40-45% less than that described in the literature for a gas mixture of nitrous oxide/oxygen 70:30, as a result of some analgesic effect of Xenon. Xenon expenditure data showed a low consumption after the filling of the circuit: the mean value of Xenon expenditure during the filling of the circuit was 749.8 ± 56.9 ml/min., which progressively reduced in the first hour of anesthesia until about 60 ml/min. and then stayed stable for the remaining time. The percentage recovered was about 60% of pure Xenon and more than 90% of Xenon in a gas mixture Xenon-oxygen 70:30. Xenon anaesthesia cost is now acceptable.
Animal studies: the effect of subchronic exposure to Xenon on the morphology of main extraneuronal organs and in blood chemistry was evaluated in 30 rats divided in 3 groups (Xenon exposed, sham exposed, controls). G1 (10 rats, mixture Xe/O2 70:30 for 2.5 h/day for a week), G2 (10 rats, mixture Nytrogen/ O2 70:30 for 2.5 h/day for a week), G3 (controls). The results showed no significant alterations in main organs (lung, liver, kidney), and only slight changes in adrenal gland, due to stress of exposure. Blood analysis resulted within normal ranges in all groups.
The effects of Xe vs halogenated (isoflurane and halothane) on ryanodine binding in skeletal muscle of rats. At low ionic strength (physiologic) isoflurane stimulated ryanodine binding with a bell-shaped dose response curve (6 mM, theoretical gas conc. 1.1%). Halothane slightly stimulated it at 2-4 mM (2 mM, theoretical gas conc. 2.2%). 1 MAC Xenon (70% ) inhibited it by 10%, and this different effect might have clinical importance in patients susceptible to malignant hyperthermia.
Pharmacokinetics of Xenon during intravenous and inhaled administration was studied in 4 pigs. The results suggest that the i.v. administration helps to obtain quickly useful arterial and venous concentrations of Xe: this could be important during the induction of anaesthesia. Anyway, considering the low concentration of Xenon in the solution now available (12-12.50%), a totally intravenous Xenon anaesthesia could have no practical use for the great volume needed.

References
1. Lachmann B, Armbruster S, Schairer W, Landstra M, Trouwborst A, Van Daal G-J, Kusuma A, Erdmann W. Safety and efficacy of Xenon in routine use as inhalational anaesthetic. Lancet 1990; 335:1413-5.
2. Giunta F, Natale G, Del Turco M, Del Tacca M. Xenon: a review of its anaesthetic and pharmacological properties. Applied Cardiopulmonary Pathophysiology 1996; 6 (2): 95-103.
3. Ferrari A, Giunta F: Xenon anaesthesia in humans: expenditure and recycling. Br J Anaesth 1998, 80 (1): 27.
4. Giunta F, Ferrari A, Del Turco M, Ferrari E, Santini L: Caratteristiche anestetiche del gas Xenon. Minerva Anestesiol 1997, 63 (1) n.9: 355-366.
5. Ferrari A, Erdmann W, Del Tacca M, Formichi B, Volta CA, Ferrari E, Bissolotti G, Giunta F: Xenon anesthesia: clinical results and recycling of gas. Applied Cardiopulmonary Pathophysiology 1998; 7 (3): 153-155.
6. Natale G, Ferrari E, Pellegrini A, Formichi B, Del Turco M, Soldani P, Paparelli A, Giunta F: Main organ morphology and blood analysis after subchronic exposure to Xenon in rats. Applied Cardiopulmonary Pathophysiology 1998; 7 (4): 227-233.
7. Zucchi R, Ronca-Testoni S, Giunta F, Ronca G: Effects of volatile anestheticson ryanodine binding in skeletal muscle. Applied Cardiopulmonary Pathophysiology 1998; 7 (4): 223-226.

Mike Holder to go here.

Volatile anaesthetic agents, in keeping with most chemicals, are not entirely stable substances; this fact has been long appreciated. Toxic compounds can be produced either by the body’s metabolism (production of inorganic fluoride) or by external forces (the effect of soda lime on trichloroethylene). Virtually all the volatile anaesthetics are influenced to some extent by their passage through a carbon dioxide absorber; the precise effect and significance will vary from drug to drug with the breakdown products ranging from the quite innocuous to the potentially lethal. For many of the older agents, the presence of such degradation products is only just being appreciated and, although potentially dangerous, the agents have provided excellent ‘clinical service’ over the years. Against this background, it is perhaps puzzling that the introduction of sevoflurane into clinical practice should have caused such a stir over the production of a single breakdown product – the ubiquitous Compound A!

Compound A is one of several chemicals produced when sevoflurane reacts with a carbon dioxide absorbent. It has long been known to cause renal damage in rats with a threshold for damage of about 100ppm, though recently a dose-duration threshold of 300ppm-h has been proposed as more appropriate. The mechanism for the damage has been postulated as being mediated by the renal uptake of Compound A S-conjugates and subsequent metabolism by beta-lyase (though some recent work has questioned this). The accepted mechanism seems reasonable as drugs that influence beta-lyase activity (such as probenecid) have been shown to alter the renal threshold for Compound A damage in rats. However, there is confusion, and controversy, as to whether this effect in rats is also true in humans. There is evidence that beta-lyase activity is different in the two species and hence the potential for Compound A toxicity is also likely to be different.

Different research groups have shown conflicting findings in studies of volunteers anaesthetised with sevoflurane for several hours using circle systems. Dr Eger’s group in San Francisco has shown that there is proximal and distal renal tubule damage in subjects exposed to 1.25 MAC at 2L/min for up to 8 hours. Conversely, Ebert (Wisconsin), Kharasch (Seattle) and Ikeda (Hamamatsu) have been unable to show any effect on renal function in studies almost identical to those of Dr Eger. Between these two extremes of opinion, others have shown a mild transient proteinuria (Higuchi, Tokyo) or have proposed a ppm-h threshold of 240 (30ppm for 8 hours) for Compound A (Goldberg, New Jersey). It would seem to an ‘outsider’ that the weight of evidence suggests that, under normal circumstances, either there is no effect on renal function after prolonged use or any effect is mild and transient (perhaps little more than that caused by imprecise perioperative fluid balance).

Whilst the above groups have looked at the effect of sevoflurane exposure on Compound A production and renal damage, other groups have looked at the factors within the circle system that will influence the production of Compound A. The overall view of a number of groups is that Compound A production is greatest at lower fresh gas flow, higher inspired sevoflurane concentration, higher absorbent temperature and drier absorbent. Baralyme (as more commonly used in the USA) has been shown to produce more Compound A than soda lime and the potassium content of the absorbent would seem to be critical. Certainly, using the factors above, it is possible to reduce the amount of Compound A produced in a circle system and hence reduce the ‘challenge’ to the kidney. One key factor has been the fresh gas flow to the circle when using sevoflurane. Much of the early work on the clinical use of sevoflurane and the production of Compound A was conducted with gas flows of 6l/min. However, more recent work, particularly by Ebert, has used flows of 1l/min and has shown that the maximum concentration of Compound A produced has been less than 40ppm. Assuming the proposed ppm-h threshold of 240, this would suggest that renal damage is unlikely in exposures times of less than 6 hours (i.e. within the duration of the majority of surgery).

Although there remains uncertainty about the Compound A situation, the evidence suggests that only one group (Dr Eger’s) has been able to demonstrate any real problem with the use of sevoflurane. Whether the simultaneous development and launch of desflurane had any effect on the research into sevoflurane and its potential problems must remain a matter of speculation but in an analogy to boxing, ‘in the blue corner (?desflurane), we have Dr Eger and his team, whilst in the red corner, we have virtually the rest of the research world’.

The fact that sevoflurane has been used in millions of patients world-wide with no reports of sevoflurane-induced renal failure and that the vast majority of countries have not placed any flow restriction on its use must suggest that Compound A does not pose a significant risk.

Prof. Dr G. ROLLY, University Hospital Gent (Belgium)

 

1. A) Past

   It is generally admitted that it is Ralph Waters of Madison-Wisconsin who introduced the closed circuit rebreathing technique in anaesthesia in 1924, by developing the to-and-fro system. It is really a milestone. Nevertheless, already earlier several rebreathing systems have been described, such as that rescue system developed by Hales in 1727, a rebreathing system designed by Kuhn in 1906 and a N20 economising apparatus developed by Coleman, which could be used only for very short anaesthesias. A circle rebreathing system was, after initial studies, designed by the Drager Company in 1925.

   The high cost of cyclopropane and the flammability, made the rebreathing technique constantly develop. Important steps were also the description of the Revell circulator and the use of a special canister with active charcoal to absorb the potent inhalation anaesthetic at the end of anaesthesia.

   Time going on, circle systems with improvements in design surpassed the to-and-fro administration. The concept of injecting liquid anaesthetic opened new areas. It was scientifically approached by Lowe, by describing the square root of time uptake and administration, which was argued last year by Lin, Servo-controlled liquid injection was described in 1983 by Ross and in 1986 by Westernskow and proved to be important steps. Description and definition of low-flow and minimal flow anaesthesia was done by Foldes in 1952 and Virtue in 1974.

   Scientific activities related to closed circuit and low flow anaesthesia occurred as well in the USA, important steps being creation of CLASS in 1983 and the publication of The Circular in 1984. In Europe after successful national and European meetings with dedicated closed circuit, low flow symposia, the creation of ALFA was done, which has actually its official 4th Annual Symposium in York.

    

    B) Present

    

   Although the denomination closed circuit is clear, still some semantic confusion can exist with the meaning of low flow anaesthesia. This term should be applicable to patients of all ages. The proposition ofBaum that the term should not be linked to a defined fresh gas flow rate, but to the proportion of rebreathing, makes good sense. According to Baum low flow should be that flow rate whereby at least 50 % of the exhaled gas volume is rebreathed.

   Despite the scientific considerations and theoretical and economic advantages, low flow and certainly closed circuit are only clinically practised to a small extent, even in the USA, where economic pressures are tremendous. What are the barriers that exist to make anaesthesia practitioners less enthusiastic or even afraid of using these techniques?

   Of course in the immediate past, particularly in the USA anaesthesia respirators were available whereby the selected tidal volume was no longer obtained after reducing the fresh gas flow and the respirator had to be adjusted. Nevertheless since then new respirators became available and particularly in Europe all current respirators have an almost constant volume, independent of fresh gas flow. Recently in some respirators automatic compensation is made for eventual leaks.

   In the immediate past, it was shown that hypoxic gas mixtures could be obtained after some time, in the presence of N₂O. After the present day standard requirements for oxygen concentration monitoring in the inspired gas mixture and the lesser use of N₂O, this can be completely prevented.

   The important difference between the set fractional anaesthetic concentration at the vaporiser (F_D) and the finally obtained inspired (Fi) and alveolar (fa) concentrations were probably not assessed in full and the high F_D concentrations were also difficult to obtain with the older inhalation anaesthetics. Again the present day availability of anaesthetic gas monitoring and even legal requirements to standard use it, give even a better insight in the kinetic process occurring in the breathing system.

   Accumulation of foreign gases, such as methane, acetone, ethanol, hydrogen and the normal body constituent nitrogen, has been given in the immediate past maybe too much scientific and theoretic evidence. The accumulation is however fresh gas flow dependent and even in closed circuit conditions, by intermittent flush of the system, they do not present any harm. Presence of the dangerous substance CO is more an induced situation provoked by negligence, allowing the sodalime to dry out. This "Monday" disease is furthermore not linked to low flow or closed circuit anaesthesia and can completely be prevented.

   If we now turn to European practice, all the modern apparatus can be used for low flow anaesthesia, provided the system is made airtight. The rotameters and certainly the modem technical approach of measuring gas flow by electronic means, permit an exact control and give a perfect feedback control for the anaesthesiologist. The modern design of respirators, particularly with fresh gasflow decoupling, allow fresh gas flow independent ventilation. Closed circuit anaesthesia in rigid terms, and particularly quantitative closed circuit, can actually only is provided with one particular apparatus, the PhysioFlex.

   All inhalational anaesthetics can be used for low flow and closed circuit application. From a technical point of view the modem vaporisers are precise enough to allow reliable output at very low gas flows. New concepts of vapour administration in the fresh gas flow or injection direct in the circuit is reliable and is practised.

   Of course the kinetic particularities of the inhalation anaesthetics have to be considered and the important fd/fa differences of the older ones (e.g. halothane) have to be acknowledged, making an initial period of high flow necessary. This is less the case for the more recent ones, like desflurane and sevoflurane, whereby low flow conditions can be realised much sooner. This is an important aspect for shorter duration anaesthesias, particularly for one-day surgery.

   The concern for the development of eventually toxic breakdown products generated during low flow/closed circuit anaesthesia, has forced the FDA to restrict the technique to minimum 2 I/ min fresh gas flow for sevoflurane. This was however not followed in several European countries. Comp A formation may be less than initially reported and may be also depend on the design of the anaesthetic circuit. New absorbents for CO₂ are since short available, to lessen or even hinder the generation of Comp A.

   C) Future

   Although very difficult to predict the future, it can be assumed that new drugs and new apparatus and techniques will be available in the next century.   After the successful application of inhalation anaesthetics currently known, a new “futurane” will be developed. Taking into account the high pressure of environmental aspects and the pressure of "green" groups, this drug must be more environmentally friendly than the present ones, should be free of any organ toxicity and should certainly have a fast onset of action and recovery. Xenon may be a candidate, but certainly for the expensive drug, low flow or even closed circuit application seems to be mandatory.

   Highly sophisticated administration will be available, electronically computer controlled, with electronic gas flow meters. Liquid anaesthetic via micropump administration will be common. Manual control of computer administration, effect site controlled, as is presently available for intravenous anaesthetics, will be done. The ultimate step will probably be brain activity controlled closed loop/closed circuit anaesthesia, which will certainly for research purposes, be available within some years.

   
    

    

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