1. Short history of the rebreathing technique in anaesthesiology

As early as in 1850 John Snow recognized that a considerable amount of inhalation anaesthetics were exhaled  unchanged in the expired air of anaesthetized patients. He concluded and could proof  that the narcotic effect really could be markedly prolonged by reinhaling these unused vapours (1). About 75 years later, in 1924, rebreathing systems equipped with carbon dioxide absorbers were introduced into anaesthetic practice. While Ralph Waters used a to-and-fro system (2), the German gynecologist Carl J. Gauss and the chemist Hermann D. Wieland did advocate the use of  a circle system for application of purified acetylene as an inhalation anaesthetic (3). The introduction of the highly combustible anaesthetic gas cyclopropane in 1933 urged anaesthetists to use fresh gas flows as low as possible to reduce pollution of  the operating room and, thus, to minimize the risk of inadvertent explosions (4).

In 1954 halothane was introduced, a new volatile anaesthetic characterized by high anaesthetic potency yet narrow therapeutical width. To ensure patients safety, the use of this anaesthetic was bound to the knowledge of the applied vapour concentration. Its estimation, however, only was simple and easy if a high fresh gas flow was used and the proportion of rebreathing was kept rather low. The more, as the vaporizers, available at that time, didn´t work sufficiently reliably and precisely in the low flow range. Thus, although nearly all anaesthetic machines were already equipped with sophisticated rebreathing circle systems, paradoxically, it became clinical routine to use fresh gas flows as high as 4 to 6 l/min, completely excluding any significant rebreathing (4). In many countries this is still the routine way to execute inhalational anaesthesia (5). However, due to the development of modern anaesthetic apparatus, the availability of comprehensive gas monitoring, an increasing environmental awareness, the introduction of new advantageous but expensive inhalational anaesthetics, and the world wide restriction of economical ressources in medical care, since about fifteen years an increasingly strong  recollection towards low flow techniques can be observed - and should be encouraged (6).
 

2. Low flow anaesthesia - the theory

Rebreathing systems can be used in different ways: If used with a fresh gas flow equal to the minute volume of the patient, the share of rebreathing will be neglectible. Nearly completely the expired air will vented out off the system as excess gas via the APL-valve. The patient gets nearly pure fresh gas. If a flow of 4.0 l/min is used, the share of rebreathing will increase to about 20%. The patient inhales a gas the composition of which still resembling that of the fresh gas. Only if the flow is reduced to at least 2.0 l/min or lower values, the share of rebreathing will reach 50% or more. Thus, only when low fresh gas flows are used the share of rebreathing will become significant, and judicious use is made frome the rebreathig technique (7).

According to the literature two different low flow techniques can be distinguished. The term Low Flow Anaesthesia was introduced by F. Foldes, inaugurating an anaesthetic technique performed with a fresh gas flow of 1.0 l/min (8).  R. Virtue introduced the term Minimal Flow Anaesthesia by recommending the use of an even lower flow of 0.5 l/min (9). As emphasized beforhand, the lower the fresh gas flow the lower is the amount of gas vented out of the breathing system as waste and the higher is the proportion of rebreathing. The general term - low flow anaesthesia - should be restricted to defining an anaesthetic technique in which a semiclosed rebreathing system is used recirculating at least 50% of the exhaled air back to the patient after CO2 absorption. Using modern rebreathing systems this will be achieved only if the fresh gas flow is reduced to at least 2 l/min (10).

However, there is a limit for reducing the fresh gas flow: To prevent from gas volume deficiency at least that gas volume has to be delivered into the breathing system, which is definitely taken up by the patient (Fig.1).

During the course of anaesthesia oxygen is taken up constantly by the patient in the range of the basal metabolic needs. It can be calculated by applying a simplified version of Brody´s formula (11):

The uptake of nitrous oxide and the volatile anaesthetic, however, follows a power function. Nitrous oxide uptake of a normal body weight adult patient can be roughly estimated by applying Severinghaus´ formula (12)

and the uptake of inhalational anaesthetics may be calculated by H. Lowe´s formula (13):

Thus, assuming a constant gas composition circulating within the breathing system, the total gas uptake, the sum of oxygen, nitrous oxide and inhalational anaesthetic uptake, is following a power function. Initially it is high and declines sharply during the first 30 minutes, but is comparatively low and decreases only delayed during the following time course of anaesthesia. This exponential characteristic of the gas uptake results from the fact that the partial pressure difference of anaesthetic gases between the alveolar space and the blood, being initially high, decreases continuously with increasing saturation of the blood and the tissues. If the anaesthetist, by frequent alterations of the settings at the gas controls, could succeed to approximate the total gas uptake, anaesthesia with closed rebreathing system would be realized. In clinical practice, however, continuous adaptations of the fresh gas flow according to the continuously changing individual gas uptake will be impossible. Whereas, applying very simple and safe standardized dosing schemes, low flow techniques like Minimal Flow and Low Flow Anaesthesia can be performed safely with already available anaesthetic equipment in routine clinical work (7,14).

 
3. Low flow anaesthesia - the practice
 
3.1 Induction

Premedication and induction of low flow anaesthesia is performed according to the usual induction scheme. Preoxigenation by applying pure oxygen via a face mask is followed by intravenous injection of a hypnotic. After neuromuscular relaxation and endotracheal intubation or insertion of a laryngeal mask the patient is connected to the breathing system. In about 85% of all cases the gas tightness of the laryngeal mask will allow the fresh gas flow to be reduced to 0.5 l/min, even if controlled ventilation is performed (7,15).  There are no procedure specific requirements for premedication and induction.
 

3.2  Initial high flow phase

According to the guidelines given by Foldes or Virtue, during the first initial phase lasting 10 to 15 minutes a high fresh gas flow has to be used. The author himself (7,16) recommends to set the oxygen flow to 1.4 l/min and the nitrous oxide flow to 3.0 l/min. This fresh gas composition guarantees in most of all patients an inspired oxygen concentration of at least 30%, meeting the recommendations of Barton and Nunn (17,18). The following settings of the vaporizers are used routinely during the initial phase: enflurane 2.5 Vol%, isoflurane 1.5 Vol%, sevoflurane 2.5 Vol%, and desflurane 4.0 to 6.0%. If these settings are used over the first 10 to 15 minutes an expired concentration of about 0.7 to 0.8 times the MAC of the respective volatile agent will be gained. In addition to a nitrous oxide MAC of about 0.6, corresponding to a nitrous oxide concentration of 60%, this will result in a common MAC of 1.3 representing the AD95, the anaesthetic gas concentration guaranteeing a sufficient anaesthetic depth for 95% of all patients to tolerate the skin incision without any movement. To initially use a high fresh gas flow is furthermore indispensable for sufficient denitrogenation and wash in of the aspired gas composition into the whole gas containing space. Last but not least, if the flow to early would be reduced to too low values, inevitably gas volume deficiency would result compromizing adequate ventilation (7,16).
 

3.3  Flow reduction

If Low Flow Anaesthesia is to be performed, the fresh gas flow can be reduced to 1.0 l/min already after 10 minutes. Flow reduction will lead to a significant increase of rebreathing. The inspired gas, thus, contains a markedly increased proportion of the exhaled gas which already had passed the patient´s lung and contains less oxygen. The resulting decrease of oxygen content in the gas mixture has to be compensated by increasing the fresh gas oxygen content, which must be the higher the lower is the flow. Thus, to maintain a safe inspired oxygen concentration of about 30 % in Low Flow Anaesthesia, the fresh gas oxigen concentration has to be increased to 50%, but at least to 40%. With the fresh gas flow reduction, furthermore, the amount of anaesthetic vapour delivered into the system is markedly reduced. This has to be compensated by a corresponding significant increase of the agent´s concentration in the fresh gas. Only in this way the aspired anaesthetic concentration within the breathing system can be kept constant. In Low Flow Anaesthesia the fresh gas enflurane concentration is increased to 3.0 Vol%, isoflurane to 2.0 Vol% and sevoflurane to 3.0 Vol% (7,16,19). Due to its specific pharmacokinetic properties, only the fresh gas desflurane concentration can be maintained unchanged (20).  Executing these standardized schemes,  the expired anaesthetic concentrations will be maintained in the aspired range of 0.7 to 0.8 times the MAC.

If Minimal Flow Anaesthesia is to be performed, the initial high flow phase should last about 15 minutes. A sufficiently long initial high flow phase will prevent from accidental gas volume deficiency, which always will result whenever the gas loss via individual uptake and leakages is higher than the gas volume delivered into the system. To maintain a safe inspired oxygen concentration of at least 30%, oxygen fresh gas concentration has to be increased to 60%, but at least to 50%, when the flow is reduced to 0.5 l/min.  Simultaneously  the anaesthetic concentration of the fresh gas has to be increased: When enflurane is used to 3.5 Vol%, isoflurane to 2.5 Vol%, sevoflurane to 3.5 Vol%, and the Desflurane concentration standardizedly is raised by 1 Vol%. By applying this dosing scheme again an expired agent's concentration in the range of 0.7 to 0.8 times of the respective MAC will be maintained too (7,16,19,20).

 
3.3.1  Inspired oxygen and nitrous oxide concentration

After flow reduction from 4.4 to 0.5 l/min an initial increase of the FIO2 over the following period of 30 to 45 minutes can be observed. It will be more pronounced in small or elderly patients with low oxygen uptake than in strong young and athletic patients. This initial increase is followed by a slow but continuous decline of the inspired oxygen concentration to lower values, on its part being the more pronounced the higher is the oxygen uptake of the patient (Fig.2). Whenever the lower alarm limit of the oxygen monitoring is reached, which carefully must be adjusted to 30%, the oxigen flow has to be increased by 10% of the total fresh gas flow, whereas the nitrous oxide flow must be decreased by the same amount. Thus, in Minimal Flow Anaesthesia, the oxygen flow has to be increased by 50 ml/min  and the nitrous oxide flow to be reduced by 50 ml/min likewise. After these adjustments, again, first a slow increase of the FIO2  will be followed by its slow but continuous decrease. Whenever the lower alarm threshold is reached anew, the oxygen flow again has to be increased by 10% of the total fresh gas flow and the nitrous oxide flow to be reduced by the same amount. In Low and Minimal Flow Anaesthesia the oxygen concentration within the breathing system is changing slowly but continuously during the course of the anaesthetic procedure (7,16).
 

3.3.2  Concentration of inhalational anaesthetics

If, with reduction of the flow, the fresh gas concentration of the volatile anaesthetic is increased according to the given standardized schemes, a slight decrease of the inspired and expired anaesthetic concentration can be observed. The vaporizers of all modern anesthetic apparatus are switched into the fresh gas line (VOC). Thus, the reduction of the flow results in a corresponding significant decrease of the amount of anaesthetic vapour delivered into the system. In all the different anaesthesia machines, likewise, the breathing system, the ventilator, the connecting hoses and the patient hose assembly contain a gas volume of about 5 to 6 liter. This, in addition to the gas volume of about 2.5 liter contained in the lung of an adult patient, is the distribution space for the anaesthetic vapour delivered into the system (7). A fresh gas flow as low as 500 ml/min assumed, a change of the vaporizer's setting from zero to 5 Vol% only will raise the amount of vapour from 0 to 25 ml/min, a considerably small volume if compared with the distribution space. Thus, in low flow anaesthesia there is a marked difference between the  anaesthetic´s fresh gas concentration and its concentration within the breathing system, and this difference is the higher the lower is the fresh gas flow, but the lower the less soluble is the anaesthetic agent (19-21) (Fig.3). If the concentration of the volatile anaesthetic shall be changed, the vaporizer has to be adjusted to a concentration considerably exceeding the aspired nominal value.
 

3.3.3  Time constant

The time constant is a measure for the time it takes, that alterations of the fresh gas composition will lead to corresponding alterations of the gas composition within the breathing system. According to a formula given by Conway (22) the time constant (T) can be calculated by the division of the system's volume (VS) by the difference between the amount of anaesthetic agent delivered into the system with the fresh gas (VD) and the individual gas uptake (VU):

A given volume of the system and a given individual gas uptake assumed, the time constant is reversely proportional to the fresh gas flow. The marked increase of the time constant has to be taken into account when switching from high to low fresh gas flows (Fig. 4). Whenever the gas composition within the breathing system needs to be changed rapidly, the fresh gas flow has to be increased for adequately accelerating the wash in of the newly aspired gas composition. If low flow anaesthesia is performed with the newer volatiles, characterized by low anaesthetic potency and solubility like sevoflurane and desflurane, the time constants will be significantly shorter as VD can be raised considerably and VU is extremely low (19-21,23).
 

3.4  Recovery phase

According to the long time constant, the vaporizer can be closed about 15 to 20 minutes before the definite end of the surgical procedure. If the low flow is maintained, the decrease of the anaesthetic's concentration is delayed and slow. During that time recovery of spontaneous breathing can be induced by using the SIMV ventilation mode or by manual assistance of the ventilation. Not until about five minutes before extubation the anaesthetic gases are washed out by switching to high flow of pure oxigen. Care is taken of the recovering patient in the usual manner (7,16).
 

3.4.5 Characteristics of low flow anaesthesia

If commercially available anaesthetic machines are used, with Low and Minimal Flow Anaesthesia the maximum of flow reduction is reached which can be gained in routine clincal practice. Both techniques are extreme variants of semiclosed use of rebreathing systems, as still a small amount of excess gas is used.
The performance of Low and Minimal Flow Anaesthesia becomes very simple if standardized schemes are used to controll the fresh gas flow and its composition. This schemes require only rare adjustments at the gas flow controls and vaporizers. The anaesthetist, however, must accept that the gas concentrations within the breathing system not will remain constant at the aspired values, but rather will change slowly but continuously during the course of anaesthesia.

Last but not least, standardized schemes for the performance of low flow anaesthesia only can be guidelines. The fresh gas flow and its composition always must be adapted to the individual patient's reaction and the current requirements of the surgical procedure.

 
4. Technical preconditions for safe performance of low flow anaesthesia

4.1. Monitoring and alarm thresholds

Due to its specific characteristics following monitoring is essential for safe performance of low flow anaesthesia (6,7,16): As the difference between the gas concentrations in the breathing system and the fresh gas increases with the extend of flow reduction, the anaesthetic gas composition can't be reliably assessed from the composition of the fresh gas. Thus, continuous monitoring of the inspired oxigen concentration is absolutely indispensable. The same applies for the concentration of volatile anaesthetics, if a fresh gas flow lower than 1 l/min is used. The lower threshold for the inspired oxigen concentration should be set to 30%, and the upper alarm limit of inspired anaesthetic concentration to 2.0-3.0 Vol% for Halothane, Enflurane and Isoflurane likewise, to 5.0 Vol% for Sevoflurane and 8.0 Vol% for Desflurane. Always the fresh gas volume must be as large as to sufficiently compensate the gas loss via individual uptake and leakages. Otherwise gas volume deficiency will occure, inevitably leading to an alteration of the ventilation. Continuous monitoring of the air way pressure or, alternatively, the minute volume therefore also is indispensable. The disconnect alarm should be set to a value 5 mbar lower than the peak pressure, the lower alarm limit of the minute volume monitoring to 0.5 l/min lower than the aspired minute volume. If low flow techniques are performed consistently the soda lime consumption will increase fourfold. By continuous monitoring of the inspired carbon dioxide concentration soda lime exhaustion reliably can be detected. If this monitoring is not available jumbo or double absorber canisters should be used and the soda lime changed after each day of work (7,24).
 

4.2. Anaesthetic apparatus

The technical features of the anaesthetic apparatus have to comply with following requirements (7,10):

The flow control system must feature needle valves and flow meter tubes calibrated and reliably working even in the low flow range, the vaporizers must be fresh gas flow compensated. The rebreathing system has to be sufficiently gas tight: The leackage must not exceed 100 ml/min at a pressure of 20 mbar to meet the requirements for Minimal Flow Anaesthesia. The performance of low flow techniques is significantly facilitated by the availability of an anaesthetic gas reservoir, by which small accidental gas volume deficiencies can be balanced. Such gas reservoir can be, alternatively, the endinspiratory volume contained in the bag of a bag-in-bottle ventilator, or the bellows of a ventilator with standing or hanging „floating“ bellows, or the manual ventilation bag in machines equipped with a fresh gas decoupling valve. If an anaesthetic apparatus is used, featuring continuous flow of the fresh gas into the breathing system, furthermore, it has to be considered that each alteration of the fresh gas flow will lead to a corresponding alteration of the tidal volume. Only if an anaesthetic ventilator is used, featuring fresh gas flow compensation, the preset tidal volume will be delivered independently from the fresh gas flow range. Fresh gas flow compensation can be realized, alternatively, by discontinuous delivery of the fresh gas into the breathing system, or by automatic electronical control of the ventilator´s performance corresponding to the fresh gas flow rate.

Using modern anaesthetic equipment even in pediatric anaesthesia low flow techniques are advantageous and can be executed safely (7,25,26).
 

5.  Advantages of low flow anaesthesia

The advantages of low flow anaesthesia are obvious and indisputable and were already comprehensively listed in Waters´ paper (2): the reduction of anaesthetic gas and vapour consumption, the decrease of atmospheric pollution with inhalation anaesthetics, the improvement of anaesthetic gas climate, and the significant reduction of costs.

Comparing two hours of continuous high flow (4.5 l/min) with minimal flow (0.5 l/min) isoflurane anaesthesia, the consumption of oxygen is reduced by 115 l, that of nitrous oxide by 300 l, and that of isoflurane vapour by 5.6 l (7). If high flow techniques, using fresh gas flows of about 4.5 l/min, would be replaced consistently by low flow anaesthesia, in Germany and the UK the resulting reduction in gas and anaesthetic vapour consumption were projected to be about 350 million liters of oxygen, 1000 million liters of nitrous oxide, 33500 liters of fluid isoflurane and 46250 liters of fluid enflurane (10). The conclusion is very simple and obvious: The lower the flow the less the gas consumption (27,28).

Anaesthetists also have to deal with increasingly stringent official regulations on the maximum acceptable workplace concentrations of anaesthetic gases (29). Careful maintenance of the anaesthetic apparatus and scrupulous attention on leaks from breathing systems provided, even the extremely low anaesthetic gas concentrations stipulated by the US National Institute of Occupational Safety and Health can be achieved easily only by the use of low flow techniques (30,31). Most operating theatres, however, are equipped with central gas-scavenging systems, and it is possible to stay within the defined limits even if high fresh gas flows are used. Nevertheless, high flow anaesthesia will inevitably result in pollution of the atmosphere beyond the operating theatre. Both, nitrous oxide and the volatile anaesthetics contribute to the destruction of the ozone layer and to the greenhouse effect. The ozone destructive potential of the volatile anaesthetics halothane, enflurane and isoflurane, which are partially halogenated chlorofluorocarbons (CFCs), is assumed to be only 0.1-1 % of all fully substituted CFCs. Furthermore, the proportion of nitrous oxide, emitted from hospitals, is only about 1 % of the total amount of nitrous oxide polluting the atmosphere. Most is derived from bacterial metabolism in fertilised soil. Nevertheless, even if the emission of anaesthetic gases is a comparatively small fraction of the total polluting gases, anaesthetists are morally obliged to minimize pollution in an age of increasing environmental awareness, and it is their duty to use all technical facilities available to achieve this (32-36). Desflurane and sevoflurane, which are halogenated only with fluorine, are assumed to have nearly no ozone depleting potential but may contribute considerably to the greenhouse effect.

Appropriate humidification and warming of anaesthetic gases have significant impact on the function and the integrity of the ciliated epithelium of the respiratory tract. During anaesthesia, the absolute humidity of the inspired gas should range preferably between 17-30 mgH2O/l, and its temperature between 28-32 °C.  After an initial period of 30-45 minutes in an actively heated compact breathing system, the values referred to above can be achieved solely by the use of a low flow technique (37-41).
 
Cost savings directly result from the decrease of gas and anaesthetic consumption. They are related to the duration of the anaesthetic procedure, the price of the respective anaesthetic agent and the extend of flow reduction (42-44). Comparing high flow (4.5 l/min) with a minimal flow (0.5 l/min) technique lasting 2 hours, assuming the inspired anaesthetic concentration at MAC, savings of about US$ 15 can be gained if enflurane, about US$ 21 if isoflurane and about US$ 47 if desflurane is used (16). By comparison, the additional cost of about US$ 0.60 resulting from increased consumption of soda lime during 2 hours is negligible (7). Relating to the beforehand mentioned projection, the annual financial savings resulting from reduced gas and anaesthetic consumption in Germany and UK are assumed to total more than US$ 65,36 million if low flow anaesthetic techniques would be performed consistently (10). It seems to be realistic to assume a cost saving in the range of 50 - 75% if low flow techniques would be used consistently in clinical routine practice (7,45,46).  Even the more costly anaesthetics like desflurane could be used without significant increase in costs (47).
 

5.1  Efficiency of inhalation anaesthetic techniques

One of the most striking aguments in favour for low flow anaesthesia is the marked increase in efficiency of inhalational anaesthesia (48). The efficiency (Eff) can be calculated by dividing the amount of agent taken up by the patient (VU) by the amount of agent delivered into the breathing system (VD):
 

Considering this algorithm it becomes obvious that an inhalation anaesthetic technique is the less efficient, the lower is the individual uptake and the higher is the amount of agent which is delivered into the breathing system. As the amount of agent delivered into the system directly is bound to the fresh gas flow, the anaesthetic technique will be the less efficient the higher is the fresh gas flow. And this, especially, holds for anaesthetic agents featuring low solubility and anaesthetic potency (Fig. 5). If desflurane, for instance, is used with a flow of 4.5 l/min at an inspired concentration of 6.0 % over a period of 2 hours,  the overall efficiency will decline to 0.07: Only 7 % of the total amount of agent delivered into the system is really needed and taken up by the patient, whereas 93 % are wasted with the excess gas escaping from the breathing system (7). Only if this agent is applied with low fresh gas flow rates, the efficiency can be increased to an acceptable range of about 30%. The use of anaesthetic agents featuring likeweise low solubility and anaesthetic potency, like Sevoflurane and Desflurane, for economic and ecologic reasons only can be justified if judicious use is made of rebreathing techniques (47,49,50).
 

6. Trace gas accumulation

A matter of concern remains the accumulation of trace gases resulting from the diminution of the wash out of foreign gases, which is the less the lower is the fresh gas flow. Foreign gases may decrease the concentration of nitrous oxide and oxygen. That may, for instance, be the case if nitrogen accumulates due to insufficient denitrogenation, or the argon concentration may rise due to the use of an oxygen concentrator (51,52). Methan, physiologically exhaled by the patient, in high concentrations may compromise the measurement and monitoring of halothane concentration (53). Accumulation of acetone may prolong  the emergence from anaesthesia and provoke nausea or vomiting. However, only in the very rare cases of severely ketoacidotic patients this really may become clinically relevant (54). Accumulation of these trace gases even in prolonged low flow anaesthesia, up to now, have not been shown to be of real clinical importance (55).

All inhalational anaesthetics react with carbon dioxide absorbents by absorption and degradation, most eagerly if the absorbent is desiccated (56). The new volatiles desflurane and sevoflurane are more liable to react with the alkaline absorbents  than the older anaesthetics halothane, enflurane or isoflurane. Desflurane more than enflurane and isoflurane react with absolutely dry carbon dioxide absorbents by generating carbon monoxide. Only partial wetting markedly reduces this chemical reaction, and if soda lime contains only 4.8% and Baralyme only 9.5% water, carbon monoxide generation is suppressed completely (57). It had been concluded, consistently not to use fresh gas flows lower than 5 l/min to safely avoid accidental carbon monoxide intoxication resulting from trace gas accumulation (58). This conclusion, however, strongly must be rejected, as just high fresh gas flows are liable to dry out the absorbents. Contrarily, low flow anaesthesia, preserving the moisture content of the absorbents, just can be taken as a measure preventing from carbon monoxide generation (59). Sevoflurane more eagerly than halothane reacts with dry absorbents too (60,61). Both agents, however, also react with normally wet carbon dioxide absorbents by generating haloalkenes: Halothane by forming BCDFE = 1,bromo-1,chloro-2,2,difluoro-ethylene (62) and sevoflurane by forming compound A  = fluoromethyl-2,2,difluoro-1,trifluoromethyl-vinylether. Compound A concentration was found to increase with the extend of flow reduction, with the absorbent´s temperature and the agent´s concentration (63,64). Some authors regard a compound A load of 150 to 240 ppmh as potentially nephrotoxic in humans (65-67) and emphasize not to use this anaesthetic with flows lower than 2.0 l/min. Contrarily, some authors estimate Low Flow Anaesthesia with sevoflurane to be safe, arguing that mean peak concentrations in different studies did not exceed 25 ppm and no signs of renal impairment were observed in any patient (49, 68,69). Mazze recently published the results of an investigation on nephrotoxicity of compound A in primates demonstrating that only at a load of at least 800 ppmh nephrotoxic effects occured (70). Accepting this threshold for nephrotoxic load with compound A  absolutely no flow restriction would be justified. Even long lasting Minimal Flow Anaesthesia with sevoflurane could be performed safely, although compound A peak concentrations were found to reach 50 to 60 ppm with this technique (71). Unlike in the United States, sevoflurane was approved for clinical use without any fresh gas flow restriction in all countries of the European Common Market. Nevertheless, whenever in clinical practice there might be assumed the possibility of accumulation of potentially harmful trace gases, for safety reasons, a low flow technique using a flow of at least 1 l/min should be performed, guaranteeing a sufficient continuous wash out effect (7).
 

7.   Literature
 

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