Target-Controlled Inhalational Anesthesia-Isoflurane Consumption with Adequacy of Anesthesia Monitoring in Conventional and Multimodal Analgesia - A Comparative Study.

Background: In a time of increased concern over the environmental impact of chlorofluorocarbons, there is an impetus to minimize inhalational anesthetic consumption. It is possible with multimodal analgesia (MMA) and the use of end-tidal controlled anesthesia (EtCA) which is a low-flow anesthesia technique with adequacy of anesthesia (AoA) monitoring. In MMA, all four elements of pain processing namely transduction, transmission, modulation, and perception are targeted with drugs having a different mechanism of action. In EtCA, anesthetic gases are automatically adjusted for the set minimal alveolar concentration by newer anesthesia work station (GE Healthcare Aisys CS2). AoA is a derived parameter of entropy and surgical pleth index which measures the depth of anesthesia and analgesia, respectively. Aim: The aim is to assess the difference in isoflurane consumption between MMA and conventional groups for a given period of time with EtCA and AoA monitoring. Setting and Design: This was a prospective randomized controlled trial involving 60 patients undergoing laparoscopic cholecystectomy. They were divided into MMA group and conventional group. Materials and
Methods: Both the groups received preemptive intravenous diclofenac sodium 75 g and 2% xyloadrenaline infiltration at entry ports. MMA group in addition received paracetamol 1 g and clonidine 0.75 μg.kg- 1. Intraoperatively, patients were on EtCA with AoA monitoring. Statistical Analysis: Mean differences in isoflurane consumption between the two groups were compared using an independent t-test. Postextubation adverse effects of analgesic drugs and awareness under general anesthesia were compared using the Chi-square test and presented as numbers and percentages. P < 0.05 was considered a statistically significant.
Results: Mean isoflurane consumption in the conventional group was 12.7 ± 5.3 mL which was significantly higher than the MMA group which was 8.9 ± 4.1 mL (P = 0.002). The duration of anesthesia between the groups was not significant clinically (P = 0.931).
Conclusion: EtCA with MMA significantly reduces isoflurane consumption compared to the conventional group of anesthesia. Copyright:

INTRODUCTION

In a time of increased concern over the environmental impact of chlorofluorocarbons and spiraling costs in anesthesia practice, there is an impetus to minimize inhalational anesthetic consumption. It is possible with low-flow anesthesia (LFA), the effective and safe advanced technology with the latest work stations. It is defined as a technique wherein at least 50% of the expired gases can be returned to the lungs after carbon dioxide (CO2) absorption. It is a closed system in which the fresh gas flow (FGF) is 500–1000 mL.min−1. The inhalational anesthetic agents currently available are metabolized only to a small extent and are largely exhaled unchanged. The inhalational anesthetic agents are metabolized only to a small extent and are largely exhaled unchanged. Hence LFA can be used to administer safe and economic anesthesia.[123]

It can be achieved by manually controlled anesthesia (MCA) or target-controlled (TC) anesthesia. TC anesthesia drug delivery system is also known as end-tidal controlled anesthesia (EtCA). In MCA, the set target of end-tidal (Et) oxygen and anesthetic gases is titrated by anesthesiologists, whereas in EtCA, it is automatically adjusted by newer anesthesia work station (GE Healthcare Aisys CS2).[45]

EtCA with adequacy of anesthesia (AoA) monitoring helps clinicians to deliver tailor-made anesthesia to the patients. AoA is an advanced monitoring technology in anesthesia. It is a derived parameter in which the depth of anesthesia and analgesia is monitored by the entropy and surgical pleth index (SPI).[67]

Operation theater (OT) pollution is reduced with LFA, whereas the excess anesthetic gases vented to the atmosphere through scavenging system have an impact on greenhouse gas emission. To decrease the total consumption of inhalational agents and to minimize atmospheric pollution, multimodal analgesia (MMA) can be practiced.[8] In MMA, all four elements of the pain processing, namely transduction, transmission, modulation, and perception, are targeted with drugs having different mechanisms of action, whereas in conventional analgesic regimen, one or two elements are targeted.[9]

The hypothesis of our study was that the preemptive MMA with EtCA will significantly reduce intraoperative isoflurane consumption in patients undergoing laparoscopic cholecystectomy with AoA monitoring. The aim of the study was to estimate isoflurane consumption in MMA group and conventional group with AoA monitoring.

Ethics

A randomized prospective double-blind study was conducted in a tertiary center after obtaining approval from the institutional ethics committee (IEC Study Ref No. 184/2017). Written informed consent was obtained for participation in the study and the use of the patient data for research and educational purposes. The study was registered in the clinical trial registry with clinical trial registry number REF/2017/12/016517. The procedures follow the guidelines laid down in the Declaration of Helsinki (1964).

MATERIALS AND METHODS

The study was conducted prospectively over a period of 3 years from May 2014 to May 2017. Sixty patients under ASA Physical Status (PS) Classes I and II, undergoing laparoscopic cholecystectomy, aged between 18 and 60 years, with body mass index of 25–30 kg.m−2 were included in the study. Patients who refused, patients with Mallampati grade III and IV, patients on a pacemaker, patients with a history of drug allergy, and patients with a history of gastritis were excluded from the study. Written informed consent was taken from the patients. The sample size was determined following a pilot study. Patients were randomly allocated into two groups (n = 30 patients eacb), study group (MMA group) and conventional regime group by allocation sequence generated by computer generated random number table. The sample size was determined following a pilot study. All patients were monitored with entropy leads. Consort map is shown in Figure 1.

Figure 1

Consort statement of patients included in the study

Anesthesia was administered with GE Healthcare Aisys CS2 anesthesia machine (GE Healthcare, Madison, WI, USA). After confirming the preanesthetic evaluation and consent, in the induction room, electrocardiogram, noninvasive blood pressure, pulse oximeter, entropy leads, Et CO2, and train-of-four (TOF: neuromuscular monitor) were connected for monitoring throughout the surgery. Baseline AoA, SPI, and entropy were documented for statistical analysis.

Securing intravenous (i.v.) line, midazolam 0.03 mg.kg−1, ondansetron 4 mg, and glycopyrrolate 0.2 mg were administered to all the patients included in the study. Patients were preoxygenated with 100% O2 for 3 min before induction. Study drugs were administrated preemptively to all patients as per randomization. Study drugs were prepared by assigned postgraduate students who were not part of the study design. Patients were induced with propofol to achieve entropy of 35–45. Endotracheal intubation was facilitated with an injection of atracurium 0.5 mg.kg−1 when TOF was zero. Both groups received 2% xyloadrenaline infiltration at entry ports and diclofenac sodium 75 g intravenously and fentanyl 3 μg. In addition, the MMA (study) group received i.v. acetaminophen 1 g and clonidine 0.75 μg.kg−1. The conventional group (control) did not receive the above-mentioned acetaminophen and clonidine.

Anesthesia was maintained with isoflurane in air and 40% oxygen with top-up doses of atracurium. Patients were switched over EtCA when inspired and expired minimal alveolar concentration (MAC) of isoflurane was equilibrated. At any given point of time, FiO2 was 0.4 and EtCO2 was between 35 and 45. Depth of balanced anesthesia and analgesia was maintained with AoA monitoring. At the conclusion of surgery, all patients were allowed to recover spontaneously to TOF of T2, and residual neuromuscular blockade was reversed with injection glycopyrrolate 10 μg.kg−1 and injection neostigmine 50 μg.kg−1. Tracheal extubation was done when the following criteria were met: TOF T4/T1 ratio ≥0.9 and AoA split screen dot in court 4 or 1 [Figure 2].

Figure 2

Adequacy of anesthesia split screen view indicates depth of analgesia and amnesia. SE: State entropy, Normal range: 40–60, Deep anesthesia: <40, Lighter planes of anesthesia: >60. SPI: Surgical pleth index, Normal range: 25–50, Intense analgesia: <25, Inadequate analgesia: >50. Dot in court 1 indicates patient is awake. Dot in court 2 indicates patient is adequately sedated but analgesia is inadequate. Dot in court 3 indicates surgical plane when ball is more toward center, more toward zero patients are very deep. Dot in court 4 indicates analgesia is adequate but patient is in light plane of anesthesia

For statistical analysis, the entropy and SPI just before the action point (intubation, skin incision, extubation) and 2 min following the action point were noted down. The total isoflurane consumption and duration of anesthesia for each case were documented. Adverse effects of analgesic drugs were noted. Postoperatively, ward patients were accessed for awareness under general anesthesia using the Brice questionnaire.[10]

Statistical analysis

The sample size was estimated by using the mean isoflurane usage between control and multimodal groups from the pilot study. The mean values obtained from the pilot study were 12.6 ± 6.34 in the control group and 9 ± 3.08 in the multimodal group. Using these values at 95% confidence limit and 80% power, a sample size of 30 was obtained in each group. Hence, a total of 60 subjects were included in the study. Sample size was estimated by using difference in means between two groups. Continuous data were represented as mean and standard deviation. An independent t-test was used as a test of significance to identify the mean difference between the two groups. Mean differences in isoflurane consumption between the two groups were compared using an independent t-test. Postextubation adverse effects of analgesic drugs and awareness under general anesthesia were compared using the Chi-square test and presented as numbers and percentages. P < 0.05 was considered statistically significant. Data entered in Microsoft Excel sheet was analysed by SPSS software. (SPSS Inc., Release 2009. PASW Statistics for Windows, Version 22.0. Chicago, USA: SPSS Inc.).

RESULTS

The mean age of the subjects in the control group was 43.7 ± 13.2 years and in the multimodal group was 40.6 ± 12.3 years. There was no significant difference in age distribution between two groups. There is no significant difference in age distribution between two groups [Table 1]. Among controls, 83.3% had ASA PS Class I and 20% had ASA PS Class II. In the multimodal group, 56.6% were in ASA PS Class I, and 46.6% were in ASA PS Class II. There was no significant association between the two groups with respect to ASA PS Class [Table 2]. There was no significant difference in the duration of anesthesia between both groups [Table 3]. Isoflurane consumption between the two groups was statistically significant. There was lower isoflurane consumption with a multimodal group (8.9 mL) than with the conventional group (12.7 mL), P = 0.002 [Table 4]. The interquartile range of isoflurane consumption in the MMA group was 5 mL and in the control group was 6 mL. No adverse effects were noted in the multimodal group whereas nine people in the control group developed nausea and two developed vomiting [Table 5]. There was no awareness in either of the groups [Table 6].

Table 1

Age distribution ofsubjects in both groups

	Group				P value
	Control (n-30)		Multimodal (n-30)
	Mean	SD	Mean	SD
Age	43.7	13.2	40.6	12.3	0.348

There is no significant age difference between the two groups. SD=Standard deviation

Table 2

American Society of Anesthesia comparison between two groups

	Group
	Control (n-30)		Multimodal (n-30)
	Count	%	Count	%
ASA
1	25	833%	17	56.6%
2	6	20%	14	46.6%

P = 0.079, among controls, 83.3% had ASA of 1, 20% had ASA of 2. In multimodal group, 56.6% were in ASA 1, 46.6% were in ASA 2. There was no significant association between two groups with respect to ASA. ASA=American Society of Anesthesiologists

Table 3

Duration of anesthesia between two groups

	Group				P value
	Control (n-30)		Multimodal (n-30)
	Mean	SD	Mean	SD
Duration (min)	120.3	53.5	121.5	48.0	0.931

There was no significant difference in duration of anesthesia between two groups. SD=Standard deviation

Table 4

Isoflurane between two groups

	Group				P value
	Control (n-30)		Multimodal (n-30)
	Mean	SD	Mean	SD
Isoflurane	12.7	5.3	8.9	4.1	0.002*

*Isoflurane consumption between the two groups was statistically significant. SD=Standarddeviation

Table 5

Comparison of adverse effects of two groups

Adverse effect	Control group(%)	Multimodal group(%)
Nausea	9 (30%)	0
Vomiting	2 (6)	0
Bradycardia	0	0
Bronchospasm	0	0
Respiratory depression	0	0
Gastritis	0	0

Table 6

Awarness between two groups

	Group
	Control (n-30)		Multimodal (n-30)
	Count	%	Count	%
Awarness	30	100.0%	30	100.0%

¦There was no awareness in either of the groups

DISCUSSION

The study hypothesis was that the preemptive MMA with EtCA will significantly reduce intraoperative isoflurane consumption in patients.

It is a well-known fact that inhaled anesthetic carries risk for OT personnel and also has an impact on greenhouse gas emissions. Although scavenging systems have minimized OT pollution, excess gases vented to the atmosphere will still contribute to environmental hazards. In clinical practice to reduce the inhalational anesthetic pollution, LFA was introduced. LFA utilizes a FGF less than the alveolar ventilation. Baker categorized the type of anesthesia based on FGF as: metabolic flow about 250 mL.min−1, minimal flow 250–500 mL.min−1, low flow 500–1000 mL.min−1, medium flow 1–2 L.min−1.[11] For practical purposes, FGF less than 2 L.min−1 may be considered as LFA.

Cotter et al. did a study to assess the consumption of volatile anesthetics between LFA and high-flow anesthesia. They found 54.7% reduction in isoflurane consumption with LFA which was 38.6 mL.h− 1 compared with high-flow anesthesia which was 44.2 mL.h− 1.[12]

Thus, LFA is synonymous with reduced economic and environmental benefits. To further reduce the impact of inhalational hazards by volatile agents, the present workstation is devised with a new anesthesia delivery system: EtCA. It is one of the modalities of anesthesia gas delivery system, wherein anesthesia machines calculate the gas mixture and FGF to deliver targeted Et concentrations. EtCA further reduces isoflurane consumption compared to MCA. It is an advance in anesthesia practice to replace MCA. In MCA, the inhaled anesthetics are manually titrated to achieve the desired Et concentration of the inhaled anesthetic.

Guiliani et al. conducted a study comparing EtCA and MCA. In MCA, the vapouriser dial adjustments were 107 times, whereas in EtCA, once after vapouriser dial setting for the required MAC was adjusted, there was no need for further readjustments. They concluded that EtCA is anesthetically as good and could provide easier and safer management of LFA avoiding the risk of a hypoxic gas mixture.[13]

Tay et al. in their study have demonstrated reduced consumption of inhaled anesthetics with EtCA. It has reduced the cost by 27% and in turn greenhouse gas emissions by 44% and thus contributes to economic and environmental benefits. The volatile anesthetic cost was $18.87 per hour with MCA and was $1.82 per hour with EtCA. They have also stated that hundred years' global warming potential will decrease from 23.2 kg.h−1 of CO2 equivalents to 13 kg.h−1 CO2 equivalents.[14]

Arora et al. did a study with EtCA and MCA and they found that the median desflurane consumption was 15.71 mL and 16.71 mL in thEtCA and MCA, respectively (P = 0.002), after 1 h and 28.71 mL and 32.98 mL in EtCA and MCA, respectively (P < 0.001), after 2 h. In ETCA group, the median number of adjustments was 3.83 times after 1 h and 7 times after 2 h (P < 0.001). In the MCA group, the median number of adjustments was 13.93 times after 1 h and 25.24 times after 2 h (P < 0.001). The cost of anesthetic agent consumed after 1 h in ETCA group was Rs. 562.57 and in the MCA group was Rs. 598.37 (P < 0.002). After 2 h, the cost of anesthetic agent consumed in the ETCA group was Rs. 1008.367 and in the MCA group was Rs. 1173.729 (P < 0.001). They concluded that EtCA reduced inhalational agent consumption and also the number of adjustments required to maintain the depth of anesthesia.[15]

In Meenoti et al.'s study with EtCA, they found that the sevoflurane consumption was 0.17 mL.min−1 and with MCA it was 0.20 ml.min−1. They concluded that with EtCA, the sevoflurane consumption was significantly low compared to MCA.[16]

Singaravelu and Barclay found that the mean sevoflurane usage was 14 mL.h−1 with EtCA and, 45 mL.h−1 with MCA. They concluded that automatic implementation of LFA using Et conventional allows the user to set and maintain a desired Et volatile concentration while using less volatile agents.[4] Studies with EtCA have demonstrated that it is esthetically better than MCA.

To further reduce inhalational agent consumption and green gas, MMA is gaining importance with the rising number of fast-track surgeries and its efficiency in postoperative pain relief.[1718]

Gutierrez-Blanco et al. titrated MAC requirement of isoflurane at the beginning of skin incision based on clinical signs and autonomic response to surgical stimuli with various analgesics. MAC in the conventional group was observed to be 1.74, whereas with fentanyl it was 1.1, lignocaine 1.35, dexmedetomidine 1.16, and with combination of lignocaine, ketamine and dexmedetomidine it was 1.01, in dogs. They also found significant difference in MAC values within the same group after the administration of analgesics compared with the baseline values. There was significant difference when each group was compared to the conventional group.[19] This shows that MMA has a significant role in reducing the requirement of inhaled anesthetics.

Savitha et al. in their study on efficiency of MMA in patients undergoing lumbar spine surgery has found the intra operative morphine consumption was significantly low in the study group (P < 0.001) who had received diclofenac sodium, paracetamol, clonidine, fentanyl and bupivacaine with adrenaline infiltration, compared to conventional group who received all above except diclofenac sodium & bupivacaine skin infiltration.[20]

Chakole et al. found mean MAC (%) of sevoflurane consumption was less in clonidine group (1.25 ± 0.25) in comparison to multivitamin group (1.30 ± 0.20) in patients undergoing FESS surgery.[21]

Shivinder et al did a study to analyze clinical efficiency of oral clonidine premedication and found that clonidine maintained stable haemodynamics and had an isoflurane sparing effect. Where as in placebo group Isoflurane requirement was higher at 1minute and 5 minute post-intubation.[22]

Abhishek et al studied the effect of oral clonidine in attenuating hemodynamic responses and consumption of isoflurane. They found, patients in clonidine group were hemodynamically more stable with isoflurane sparing effect compared to placebo group.[23]

Inomata et al. studied the effect of oral clonidine on MAC requirements of sevoflurane during skin incision and tracheal intubation. They compared MAC requirements among children receiving clonidine 2 or 4 μg.kg-1 with placebo. With clonidine 4 μg.kg-1 MAC was reduced by 43% during skin incision and 35% during endotracheal intubation.[24] All the above mentioned studies with clonidine, clearly demonstrate inhaled anesthetic sparing effect.

In a study by Christiana et al., MMA was found to be highly effective in pain management. Pre operative treatment group who received meperidine, ketorolac and local anesthetic infiltration had lesser intensity of pain. In treatment group 57% of the patients had absence of pain with visual analogue scale (VAS) score of 0-1 which was found to be 4.2% in conventionalgroup. They concluded that combination of local anesthetics, opiod and anti inflammatory drugs were highly effective in pain management.[17]

To summarize, from the literature review, with medium flow anesthesia, the consumption of isoflurane was 44.2 mL.h−1 which was 38.4 mL.h−1 with LFA as per Cotter et al. study in 1991,[12] whereas Pramod et al. in their study have demonstrated a further reduction in isoflurane consumption with EtCA (10.2 mL.h−1) in comparison to MCA (12 mL.h−1).[16] In the present study, isoflurane consumption has further reduced with EtCA and MMA (8.9 mL.h−1) compared with EtCA and conventional analgesic regimen (12.7 mL.h−1). This demonstrates that MMA with EtCA has least inhalational anesthetic consumption.

The present study was targeted to assess the isoflurane consumption with AoA monitoring. None of the patients included in the study had awareness under anesthesia, as AoA is a derived parameter from SPI and entropy to assess the depth of anesthesia and analgesia.

The limitation of the study was that the serum levels of drugs were not looked into and only minimally invasive surgeries such as laparoscopic cholecystectomy were included in the study.

CONCLUSION

In the present study, MMA isoflurane consumption was significantly reduced compared to conventional analgesic regimen. Titrating the depth of balanced anesthesia with AoA monitoring, none of the patients, in either group, included in the study had awareness under anesthesia. Further studies are required with MMA and EtCA along with AoA to support the present study findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.