Sevoflurane in low-flow anesthesia using "equilibration point".

CONTEXT: While giving low-flow anesthesia, it is a routine practice to give fixed duration of initial high-flow. This study was conducted to show the use of equilibration point as changeover point from initial high-flow to low-flow. AIMS: It was to compare the use of equilibration point, hemodynamics, end-tidal agent concentration, recovery time, and recovery score between isoflurane and sevoflurane. SETTINGS AND
DESIGN: It was a prospective randomized study conducted on 100 patients who were admitted for elective surgery expected to be < 2 h duration.
MATERIALS AND METHODS: Patients were randomly assigned to one of the two groups of 50 each. Group I received isoflurane and Group S sevoflurane as an inhalational agent. STATISTICAL ANALYSIS: The observations obtained in both the groups were recorded and compared. Analysis was done using unpaired t-test and Chi-square test.
RESULTS: Hemodynamic parameters were comparable in both the groups. The mean equilibration times obtained for sevoflurane and isoflurane were 8.22 ± 1.060 min and 17.24 ± 10.2 min, respectively. The drift in end-tidal agent concentration over time was less in sevoflurane group. Mean recovery time was 7.92 ± 1.56 min in the sevoflurane group and 12.89 ± 3.45 min in the isoflurane group (P = 0.001). There was no significant difference between intraoperative and postoperative complications.
CONCLUSION: Use of equilibration time of the volatile anesthetic agent as a changeover point, from high-flow to low-flow, can help us to use circle system with low-flow anesthesia in a more efficient way, especially with newer anesthetics such as sevoflurane.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

In spite of modernization in anesthesia and its techniques, developing countries are still using conventional anesthesia techniques with older anesthetic agents such as halothane or isoflurane. They are not frequently able to use newer anesthetics such as sevoflurane and desflurane inspire of their better properties because of financial constraints and lack of infrastructure. Low-flow anesthesia technique with newer anesthetic agents offers a means of reducing expenditure with advantages of better pulmonary dynamics and lesser environment pollution.[1] This technique was introduced by Foldes et al.[2] with a fresh gas flow (FGF) of 1.0 L/min.

In routine practice, low-flow anesthesia cannot be continuously employed for the whole duration of anesthesia and an unspecified period of high-FGF is necessary in the beginning of anesthesia. This defeats the purpose of savings in economy by low-flow anesthesia technique but limiting the duration of high-FGF will increase the efficiency of circle system. This study was taken up with the aim of limiting the initial high-FGF using equilibration point since very few studies have been done using this point as a reference point for switching over to low-FGF. It is a point when ratio of expired (Fe) to inspired (Fi) concentration of inhalational anesthetic agent (Fe/Fi) reaches 0.8.[3] Newer agents such as sevoflurane and desflurane are gaining popularity, these days because of early achievement of equilibration point due to their low-blood gas solubility. They are best suited for low-flow anesthesia because of the shorter time constant. To emphasize the advantage of sevoflurane, we compared it with isoflurane so that developing countries attempt to include sevoflurane in their curriculum, keeping in mind that sevoflurane ultimately turns out to be more economical than isoflurane. Furthermore, modern integrated anesthesia workstations are designed to give complete anesthesia with respiratory gas delivery and monitoring system which helps us to use low-flow anesthesia safely.[456]

MATERIALS AND METHODS

After approval from the Institutional Ethics Committee and written informed consent of parents/guardians of the patients, we conducted this prospective randomized study on 100 patients of the American Society of Anesthesiologist Grade I or II in the age group of 20–60 years. These patients were randomly allocated in two groups of 50 each. Effective sample size was calculated to get the power of study above 90%. Pregnant, morbidly obese, and patients requiring emergency surgery were excluded from the study.

These patients were randomly allocated in two groups of 50 each depending upon volatile anesthetic agent used. Group I received isoflurane and Group S patients received sevoflurane with low-flow anesthesia. The routine preanesthetic checkup was done 1 day before surgery. Airway assessment was done. Routine relevant investigations were done. Patients were given tablet alprazolam 0.25 mg and tablet pantoprazole 40 mg one night before surgery with a sip of water and were kept nil per orally 8 h before surgery.

On the day of surgery, patients were reassessed preoperatively. Multipara monitor was attached to monitor heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, arterial saturation (SpO2), and electrocardiograph. Bispectral index (BIS) was also attached to monitor level of consciousness.

Patients were given intravenous (IV) butorphanol (1 mg), IV midazolam (1 mg), and IV glycopyrrolate (0.2 mg) 5 min before induction. Patients were preoxygenated with 100% oxygen with oxygen flow of 7.5 L/min. When peripheral saturation reached 100%, the induction of general anesthesia was started. Anesthesia was induced by IV propofol 2 mg/kg and IV vecuronium 0.1 mg/kg. Lungs were manually ventilated with the help of a facemask using FGF of oxygen 6 L/min. Intermittent boluses of propofol 20 mg IV each were given at 1 min intervals (without nitrous oxide and inhalational agent) after induction of anesthesia. Trachea was intubated 3 min after administration of vecuronium. The patient was connected to the anesthesia machine with a y-piece connector of breathing circuit. A high-FGF mixture of 6 L/min (oxygen 2 L/min and nitrous oxide 4 L/min) was delivered initially with a volatile inhalational anesthetic agent after tracheal intubation. The volatile inhalational anesthetic agent was set at 1.3 times the agent minimum alveolar concentration (MAC), i.e. 1.5% for isoflurane and 2.6% for sevoflurane. Once the ratio of expired (Fe) to inspired (Fi) volatile inhalational agent concentration became 0.8, that is, “equilibration point” was achieved, high-FGF was reduced to the low-FGF, i.e., 600 mL/min of oxygen and 400 mL/min of nitrous oxide.

During maintenance phase of anesthesia, a minimum inspired oxygen concentration (FiO2) of 0.5 was maintained in the low-FGF mixture. The vaporizer dial setting was changed, if needed, after flow reduction to maintain MAC of 1 or more to maintain adequate anesthesia as required depending on the type of surgery but keeping the FGF constant. Signs that indicated the depth of anesthesia were arterial blood pressure (systolic, diastolic, and mean), heart rate, and BIS. Measuring points were at every 5 min during surgery. The goal was to provide the values of these vital signs within normal physiological ranges. Mean end-tidal volatile inhalational anesthetic agent concentration (MFe) was measured at 5, 10, 15, 60, and 75 min intervals, i.e., in wash in the period (5, 10, and 15 min) and steady state (60, 75 min). Wash in of inhaled anesthetic agent may be defined as the increase in the ratio of inhaled anesthetic fraction or partial pressure in the alveoli (FA) to that in inspired fresh gas (FI), and the steady state is when the uptake of anesthetic agent is minimal other parameters that were also measured (every 5 min) were: Saturation of blood with oxygen, end-tidal carbon dioxide, end-tidal nitrous oxide, and inspired oxygen concentration over time. Diclofenac 1 mg/kg IV in 100 mL normal saline was given to all patients as a part of the multimodal approach to analgesia.

The inhalational anesthetic vaporizer was switched off at the end of surgery. The neuromuscular block was reversed with IV neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg IV was administered after 20 min of the last dose of relaxant or if the patient started spontaneously breathing. Thereafter, nitrous oxide was stopped and only oxygen 6 L/min was given. The trachea was extubated once extubation criteria, namely, resumption of regular respiratory pattern, adequate minute ventilation, oxygen saturation > 95%, and resumption of airway reflexes were met, and the patient was transferred to the postoperative recovery room. During surgery, each patient was given IV infusion of ringer lactate. Before discharging the patient from the recovery room, the patient was interviewed for intraoperative awareness.

“Recovery time” was defined from the time of discontinuation of the inhalational anesthetic agent (vaporizer switched off) to the time the patient opened his/her eyes on verbal command while recovering from anesthesia. During recovery, patient recovery characteristics were defined by a recovery score (1 = no response to painful stimuli; 2 = drowsy but arousal by verbal command; and 3 = awake and responding to command at extubation).

The following parameters were recorded: Hemodynamic characteristics (mean change in the heart rate, mean arterial blood pressure, and oxygen saturation); mean equilibration time of the volatile inhalational agent; mean end-tidal volatile anesthetic partial pressure; end-tidal carbon dioxide and nitrous oxide concentration; inspired oxygen concentration, recovery time, and score; and any critical event if occurred were noted.

The data from this study was systematically collected, compiled, and statistically analyzed to draw relevant conclusions. Data were analyzed using Chi-square test and unpaired t-test. The P value was determined finally to evaluate the levels of significance. The value P > 0.05 was considered nonsignificant, P = 0.01–0.05 was considered significant, and P < 0.01 was considered highly significant. The results were then analyzed and compared with previous studies.

RESULTS

Patients in both the groups were comparable with respect to the demographic parameters were taken [Table 1]. The mean duration of surgery in Group I was 75.86 ± 7.35 min and in Group S was 76.26 ± 7.30 min, and the difference was statistically not significant (P > 0.05). Hemodynamic parameters were also not significant statistically as well as clinically (P > 0.05).

Table 1

Demographic characteristics of patients who received low-flow anesthesia with sevoflurane or isoflurane as inhalational anesthetic agent

Mean equilibration time in Group I was obtained in 17.24 ± 10.2 min and in Group S in 8.22 ± 1.060 min, and the difference was statistically highly significant (P < 0.001) [Table 2].

Table 2

Mean of “equilibration time” of volatile anesthetic agent

Mean end-tidal volatile anesthetic concentrations (MFe) at 5, 10, 15, 60, and 75 min intervals, i.e., in wash in period (readings taken at 5, 10, and 15 min), and steady state (readings taken at 60, 75 min) of sevoflurane were not changed much and were 0.82 ± 0.013, 0.89 ± 0.015, 0.89 ± 0.016, 0.80 ± 0.020, and 0.82 ± 0.014, respectively (P < 0.06). In the isoflurane group, variations were significant over time and values were 0.64 ± 0.011, 0.76 ± 0.018, 0.82 ± 0.013, 0.58 ± 0.018, and 0.56 ± 0.020 at 5, 10, 15, 60, and 75 min intervals, respectively. Changes in measured values were statistically significant between the two groups and within the isoflurane group (P < 0.001), and there was less drift in mean end-tidal concentration in sevoflurane group [Table 3 and Figure 1].

Table 3

Mean end-tidal volatile anesthetic concentration (MFe)

Figure 1

Mean end-tidal concentration of volatile anesthetic agent at different time intervals in Group I and Group S

During whole surgery, BIS was lower in Group S as compared to Group I, showing that patients in Group S were more deeply anesthetized as compared to Group I, and the difference between them was statistically highly significant (P = 0.001) [Table 4 and Figure 2].

Table 4

Bispectral index during surgery

Figure 2

Mean bispectral index at different time intervals in Group I and Group S

In both the groups, end-tidal nitrous oxide concentration fell over time. In Group I, mean end-tidal nitrous oxide concentration was measured from 5 to 75 min duration, it ranged from a minimum of 42.02 ± 1.491 to maximum 60.00 ± 1.539 and in Group S it ranged from a minimum of 41.59 ± 1.456 to maximum 60.04 ± 1.511. In both the groups, mean inspired concentration of oxygen was measured during the whole of the surgery. The oxygen level in Group I varied between a minimum of 35.00 ± 0.90% and a maximum of 44.00% ±2.30% and in Group S varied between 41.96 ± 1.46% and 47.78 ± 1.23%. At no point of time, the concentration fell below 30%. There was an initial rise in the oxygen level but drifted down later. In both the groups, end-tidal Carbon dioxide concentration was maintained between 35 and 45mm Hg [Figures 3 and 4].

Figure 3

Mean end-tidal concentration of N2 O at different time intervals in Group I and Group S

Figure 4

Mean inspired O2 concentration at different time intervals in Group I and Group S

Recovery time in Group I was found to be 12.89 ± 3.45 min and in Group S was 7.92 ± 1.56 min. The difference between the two groups was found to be statistically highly significant (P < 0.01). Patients had a clear-headed recovery in the sevoflurane group: 40 patients out of 50 were alert and awake, and 10 were drowsy but arousable while in isoflurane group 33 patients out of 50 were drowsy but arousable, and 17 patients were alert and awake the difference between the two groups was statistically and clinically highly significant (P < 0.001) [Tables 5 and 6].

Table 5

Comparison of recovery time (in min) between Group I and Group S

Table 6

Comparison of recovery score between Group I and Group S

Intraoperative complications (hypotension and dysrhythmias) and postoperative complications (nausea and vomiting) were compared in both the groups. The difference between both the groups was found to be statistically nonsignificant (P > 0.05).

DISCUSSION

Rising costs and environmental pollution caused by high-FGF with inhalational anesthetic agents have forced many anesthesiologists to use low-FGF in breathing system. Modern inhalational anesthetic agents are metabolized to a small extent only and are largely exhaled unchanged. The use of breathing systems fitted with carbon dioxide absorption units and comprehensive gas monitoring permits the exploitation of this to perform economical and safe “low-flow anesthesia.”[7]

The aim of our study was to compare isoflurane and sevoflurane and choosing a better agent to make best and efficient use of circle system in low-flow anesthesia. Use of mask ventilation with high-FGF can lead to the loss of inhalational agent, defeating the purpose of low-flow anesthesia, and also making it difficult to monitor the level of inhalational agent used during this period. To prevent this, boluses of propofol were used at 1 min intervals after the initial induction as recommended. This method is an effective alternative to the use of inhalational agent at this period of time.[3]

Time of equilibration between Fi and Fe agent concentrations is defined as the time to reach a Fe/Fi ratio of 0.8 or may be said that when uptake of volatile agent reaches 80%. It a changeover point from high-flow to low-flow. After achievement of this point, there are fewer chances of gas volume deficiency when circuit system changed to low-flow, and also sufficient denitrogenation occurs at this point. This point was achieved earlier with sevoflurane decreasing the duration of high-flow thus increasing the efficiency of circle system with low-flow anesthesia. A study was conducted in 1997 by Nel et al. for the use of new agents in the circle system. Using initial high-flows, the time intervals to equilibration between inspired and end-expired agent concentrations were measured; equilibration was defined as FE/FI = 0.8. The mean (standard deviation) times obtained for sevoflurane, desflurane, and isoflurane were 8.2 ± 2.1 min, 3.8 ± 0.7 min, and 19.7 ± 6.5 min, respectively.[8] These times were statistically significantly different from each other.[5] In 1991, Yasuda et al. compared the kinetics of sevoflurane and isoflurane in humans. In this study, pharmacokinetic of sevoflurane and isoflurane during their administration were defined as the ratio of end-tidal anesthetic concentration (Fa) to inspired anesthetic concentration Fi (i.e., Fa/Fi). Consistent with its relative blood/gas partition coefficient, the Fa/Fi of sevoflurane increases more rapidly than that of isoflurane or halothane but slower than that of N2O or desflurane.[9] In 1996, Lee et al. compared isoflurane and desflurane for the efficiency of a circle system for short surgical cases. The inspired and expired concentrations of the volatile agents were measured, and the FGFs reduced to low-flow at the point where the expired concentration was 80%, or greater, of the set inspired concentration. This median time at which flows were reduced was 5 min for desflurane and 19 min for isoflurane, and this difference was statistically significant.[10] Similar study conducted by Mallik et al. comparing desflurane and isoflurane in minimal flow anesthesia using “equilibration time” as changeover point to minimal flow. Mean equilibration time obtained for desflurane and isoflurane were 4.96 ± 1.60 min and 16.96 ± 9.64 min and was statistically significant (P < 0.001).[3] Although in these studies, sevoflurane was not studied, isoflurane and desflurane were compared and time taken to achieve equilibration time in these studies was more with isoflurane.

Mean end-tidal concentrations of inhalational anesthetic agents of both the groups were compared during whole of surgery and was found that end-tidal concentration of sevoflurane was not changed during maintenance phase while in the isoflurane group, variation was significant over time. The persistent reduction in expired values with isoflurane suggests that isoflurane uptake continued to be greater than that delivered by the low-flow rates. It is because of higher blood solubility of isoflurane as compared to sevoflurane. Similar results were obtained with studies conducted by Nel et al. and Mallik et al. Nel et al. found that after flow reduction to 500 mL/min, the initial decline in end-expired agent concentration was minimal with desflurane, intermediate with sevoflurane, and greatest with isoflurane. Both desflurane and sevoflurane are appropriate for efficient use of the circle system during short anesthetics.[8]

In both the groups of our study, end-tidal nitrous oxide concentration fell over time. There was initial rise in oxygen concentration which drifted down later on. This trend is not in agreement with the studies conducted in the past. Usually, in low-flow anesthesia nitrous oxide shows increasing trend because it neither used nor metabolized and oxygen shows decreasing trend because it gets continually used by the body. Reason for decreasing trend of nitrous in our study, first was the less duration of surgery (<2 h), second is well maintenance of FGF with oxygen level higher than nitrous oxide. At any point if oxygen fell below 50% of inspired concentration, inspired oxygen flow was increased by 10% (i.e., 100 mL/min) of total flow, and nitrous oxide decreased by same thus minimizing chances of hypoxia. Similar trend was found in a study conducted by Mallik et al.[3]

During the whole surgery, BIS was kept between 40 and 60. No patient had any history of intraoperative awareness before getting discharged from the recovery room. Hemodynamic response to surgical stimulus was maintained by regulating the depth of anesthesia (BIS monitoring) or using rescue medications such as propofol and esmolol. The dial setting of vaporizer was changed only to maintain BIS. At both the low- and high-FGF rates, the acute hemodynamic response to surgical stimulus was more efficiently treated by increasing or decreasing end-tidal concentration of sevoflurane concentration. It is because of short time constant of sevoflurane. The time constant is a measure for the time required for changes in the composition of the fresh gas to lead to corresponding changes in the composition of the gas in the anesthetic system. Similar results were found in a study conducted by Gupta et al. in 2013 in which comparison of equi-MAC of sevoflurane and isoflurane on BIS values during both wash in and wash out phases was done. At equi-MAC sevoflurane produces lower BIS values during wash in as well as wash out phase as compared to isoflurane, reflecting probably an agent-specific effect, and a deficiency in BIS algorithm for certain agents and their interplay.[11]

Recovery time was less, and recovery characteristics were better with sevoflurane proving it to be having better kinetics than isoflurane. Studies in literature showed similar results. Study of Campbell et al. in 1996 showed smoother clinical course and rapid recovery in sevoflurane group as compared to isoflurane.[12] Chen et al. conducted a study on Chinese adult patients in 1998 and showed rapid recovery in sevoflurane group as compared to isoflurane.[13] Singh et al. in 2009 compared isoflurane and sevoflurane in children undergoing spinal surgery showed earlier recovery and less time to achieve full Aldrete score in sevoflurane group.[14]

Intraoperative complications (hypotension and dysrhythmias) and postoperative complications (nausea and vomiting) were comparable in both the groups. Frink et al. in 1992 compared sevoflurane and isoflurane in healthy patients and the results were comparable with respect to nausea and vomiting in both the groups.[15]

In 2015, a study conducted by Tripathi et al. compared intraoperative awareness, using BIS, between isoflurane and sevoflurane during general anesthesia and found no significant differences in intraoperative and postoperative complication in both the groups.[16] Our study is in accordance with these studies showing no intraoperative and postoperative complications.

Limitations

Low-flow anesthesia is best achieved with desflurane where equilibration point is achieved much earlier. However, desflurane was not available in our setup in a developing country such as ours (India), so we had to compare sevoflurane with isoflurane.

CONCLUSION

It was concluded from the study that newer inhalational anesthetic agents such as sevoflurane have an added advantage of rapid achievement of equilibration point thus decreasing the duration of initial high-flow, less drift in end-tidal anesthetic agent concentration, clear-headed recovery, and minimal intraoperative and postoperative complications.

Low-flow anesthesia technique itself has advantage of savings in economy, environment-friendly, and well maintenance of patient's pulmonary mechanics. Thus, sevoflurane as an anesthetic agent can make us use circle system in a more efficient way with the technique of low-anesthesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest