A comparison of sevoflurane-fentanyl and neuroleptic anaesthesia for laparoscopic cholecystectomy of mildly obese patients

Introduction
The term obesity, derived from the Latin word obesus (fattened by eating), is a condition characterised by excessive accumulation of body fat (1). In clinical practice the body mass index is habitually used to classify patient weight particularly when a state of obesity is suspected. It is calculated by dividing the subject's body weight (in kg) by the square of its height (in m). A body mass index of up to 25 is considered normal, a body mass index ranging from 25 to 30 reflects overweight, whereas a body mass index of greater than 30 is a strong indication of obesity (further classified into obesity class I, II and III, the latter being the most severe) (2). The primary consequence of obesity is a reduction in life expectancy caused by co-morbidities that include insulin resistance/hyperinsulinemia, type II diabetes, hypertension, dyslipidemia, coronary heart disease and some forms of cancer mainly due to significant changes in the endocrine sphere (3, 4).
The current view is that modern anaesthesia and surgical techniques together with the right choice of anaesthetic enable the possibility of safe laparoscopic surgery and recovery of obese patients. The right choice of anaesthetic is very important for obese patients because the physiological changes associated with obesity lead to alterations in the distribution, binding and elimination of many drugs (5, 6). Sevoflurane is an inhalation anaesthetic agent (a methyl-isopropyl ether) for use in induction and maintainance of general anaesthesia. Its administration has been associated with a smooth, rapid loss of consciousness during inhalation induction and a rapid recovery following discontinuation of anaesthesia (7, 8). Intravenous neuroleptic anaesthesia is a state of neuroleptic analgesia evoked by the combination of a neuroleptic tranquiliser (most notably dehydrobenzperidol) and a potent narcotic drug (fentanyl). The former is a potent D2-receptor antagonist with alpha-blocking activity which causes decreased peripheral resistance and reduced filling pressures. The latter (fentanyl) produces analgesia, bradycardia and bradypnea. One of the many positive charateristics of neuroleptic anaesthesia is (like Sevoflurane) the prompt awakening of patients following its removal (9).
The aim of this current work was to compare and contrast the influence of two types of anaesthesia, balanced inhalatory (sevoflurane) and intravenous (neuroleptic), administered to mildly obese patients during laparoscopic cholecystectomy. Peri-operative haemodynamic and respiratory stability, the speed of arousal from anaesthesia, the severity of post-operative pain, the need for additional post-operative analgesia and the hormonal response to both anaesthetic and surgical stress were examined.

Materials and Methods
Patients and clinical methods
A purely academic six-week long blind prospective randomised study took place in summer 2006. Two patient study groups were established according to the type of anaesthesia used. Mildly obese (obesity class I) patients were randomised to receive either sevoflurane-fentanyl or neuro-leptic anaesthesia. Two state-registered anaesthesiologists (V. M. and M. Ð.) were present during all procedures included in the present study. This allowed for procedure uniformity and unprejudiced drug administration. No patients with hormonal disorders, severe cardiovascular and respiratory disorders, metabolic dysfunctions or those on prolonged drug therapy were included in this study. Immediately prior to laparoscopic cholecystectomy patients were graded as ASA I or ASA II risk. The general characteristics of both study groups are described in Table 1. Details of the administration of peri-operative medication and anaesthesia are also described in Table 1.
Routine peri-operative monitoring and estimation of depth of anaesthesia involved continuous electrocardiography, pulse oxymetry, capnography and non-invasive blood pressure measurements, heart rate, urinary output, skin colour, surface temperature and humidity, pupil reflexes, appearance of tears, degree of muscle relaxation, core body temperature and intrapulmonal pressure during mechanical ventilation with intermittent positive pressure of ventilation. Ventilation was maintained by a high breathing volume of 8 - 10 ml/kg (a recommendation from the Association of Laparascopic Surgeons) using a Fabius anaesthesia workstation connected to a gas management system (Drager-Medical). Both groups of patients were woken from anaesthesia after reversion of the neuromuscular block. The speed of arousal from anaesthesia was determined by scoring the beginning of spontaneous breathing, time of extubation, establishment of verbal communication, lifting up head and ability to respond to verbal commands. Intermittent respiratory monitoring (pulse oxymetry and capnography) was performed for 24 hours after the completion of laparoscopic cholecystectomy.
Prior to surgery all patients were interviewed during which time full consent to take part in the study was obtained. None of the patients raised concerns regarding which of the two types of anaesthesia they were going to receive. All patients agreed that their sera and urine could be freely used for research according to internationally accepted ethical standards (The Helsinki Declaration of 1964, as revised in 1975, 1983 and 1989). Venous blood samples were drawn and centrifuged at 1500 x g for 10 minutes at 4°C. Sera were aliquoted for freezing at -20°C to prevent repeated freeze-thawing. All biochemical analyses were performed within 48 hours of surgery.
Biochemistry and statistical analyses
The serum concentrations of cortisol, insulin-like growth factor I (IGF-I), insulin and glucose were measured pre-operatively (early in the morning on the day of surgery before any medication, T1s) and post-operatively (24 hours after completion of surgery, T2s). Urinary cortisol was determined over a 24-hour period before surgery (T1u) and from 24 to 48 hours after surgery (T2u). The concentration of cortisol in serum and urine was determined by radioimmunoassay (RIA-CT-Cortisol, INEP, Belgrade, Serbia) (10). Serum concentration of IGF-I was measured by radioimmunoassay (RIA-IGF-I, INEP, Belgrade, Serbia) (10). Serum insulin was measured by radioimmunoassay (RIA-Insulin, INEP, Belgrade, Serbia) 10. Serum glucose was determined using an automated glucose oxidase/peroxidase/phenol/4-amino-antipyrine method in the clinical chemistry laboratory of "Bežanijska Kosa" Clinical-Medical Centre.
All statistical comparisons were performed using Primer of Biostatistics (version 5), Statgraphic Plus (version 4.2) and CBstat (version 4.3.2) software. Datasets for each measured biochemical parameter within both study groups were subjected to the Kolmogorov-Smirnov test to determine their distribution. As only normal distributions were found, the results were expressed as the mean value and the standard deviation. To evaluate differences between the two study groups (at single specific time points) the Student's t-test was performed. The minimal statistical significance was set at p<0.05.

Results
Our present study included thirty patients divided into two equally sized groups sone receiving sevoflurane-fentanyl (n=15) and the other neuroleptic anaesthesia (n=15)t of which the majority in each group was female (Table 1). There were no differences between the patient groups with respect to age, weight, height and body mass index. The mean body mass index for both patient groups was >30. A few patients in both groups had a body mass index >35 (Table 1). The duration of surgery was similar in both groups (Table 2).
Intra-operative haemodynamic stability, estimated from mean heart rate values and mean arterial pressure, was attained in both groups (Fig. 1, panel A). None of the patients in both groups reported any awareness experiences (assessed by post-operative recall of intra-operative events). The speed of arousal from anaesthesia was significantly shorter in patients that received sevoflurane-fentanyl compared to neuroleptic anaesthesia (p<0.005) (Table 2). No difference in the length of hospitalisation was found between the two study groups (Table 2).
Early post-operative complications after laparoscopic cholecystectomy in both groups showed noteworthy variation (Table 2). A higher frequency of post-operative nausea and vomiting (PONV), urine retention and respiratory insufficiency (diagnosed on the basis of shallow breathing, <90% SaO2, increased CO2 retention, increased arterial pCO2 and decreased arterial pO2) was found in patients that received neuroleptic anaesthesia. Repeated endotracheal intubation was not necessary for any patient. A greater incidence of abdominal pain was reported in patients that received sevoflurane-fentanyl. The severity of post-operative pain was determined using a visual analogue scale ranging from 0-10. Patients that received sevoflurane-fentanyl stated that they endured considerably greater pain (during rest, movement, coughing and walking) compared with those that received neuroleptic anaesthesia at 1, 6 and 12 hours post-surgery (Table 3).
At 24 and 36 hours after surgery the level of pain in both patient groups was practically the same. To minimise post-operative pain ketorolac was administered as a bolus dose of 40 mg immediately after extubation to patients that received sevoflurane-fentanyl and two hours after awakening to patients that received neuroleptic anaesthesia. The number of patients that requested additional ketorolac (limited to a maximum of 90 mg over a 24 hour period) for acute pain suppression (Table 3) directly correlated with the severity of post-operative pain (expressed in visual analogue scale) noted above. At later times (24 and 36 hours) no obvious difference in the proportion of patients requesting ketorolac was apparent. No opioid analgesia was administered to any of the patients during the post-operative period.
In order to investigate if, and to what extent, the two types of anaesthesia induced alterations in certain endocrine parameters both serum and urinary cortisol, serum IGF-I and serum insulin concentrations were measured. In patients that received sevoflurane-fentanyl there was no statistically significant difference in the serum cortisol concentration between T1s and T2s (p>0.05) (Figure 1, panel B).
However, a significant difference in the serum cortisol concentrations between T1s and T2s (p<0.001) was apparent in patients that received neuroleptic anaesthesia. A significantly higher serum cortisol concentration at T2s was found in patients that received neuroleptic anaesthesia compared to that found in patients that received sevoflurane-fentanyl (p<0.001). The urinary cortisol concentration was significantly increased at T2u compared to T1u in both groups of patients (p<0.0001) (Figure 1, panel C). Furthermore at T2u, patients that received Neuroleptic anaesthesia had a higher concentration of urinary cortisol compared to sevoflurane-fentanyl (p<0.0001). Administration of both types of anaesthesia led to a decrease in the concentration of serum IGF-I at T2s when compared to T1s (p<0.0001) (Figure 1, panel D). However, no significant differences between the two patient groups were found at both T1s and T2s. The serum insulin and glucose concentrations showed no significant variations between the two patient groups at T1s and T2s (data not shown).

Discussion
Laparoscopic cholecystectomy is the most common form of operation performed laparoscopically worldwide (11, 12). When compared to traditional open surgery, laparoscopic cholecystectomy offers a significant number of positive attributes. These include reduced abdominal wall trauma, decreased risk of thrombo-embolic complications, less post-operative pain, a reduction in post-operative ileus and rapid patient mobilisation while at the same time providing better cosmetic results (13-16). However, peri-operative complications are possible especially in obese patients, therefore obesity is a relative risk factor for laparoscopic surgery (17, 18). Significant anatomical changes in obese patients (particularly the increase in the mass of fat per kilogramme of total body weight) present difficulties for both surgeons and anaesthesio-logists. Of particular concern for anaesthesiologists are the altered pharmacokinetic and pharmacodynamic profiles of anaesthetic drugs in obese patients (19). Therefore, a careful choice of anaesthetic drug administration to obese patients is critical to ensure safe completion of surgical intervention and less traumatic post-operative recovery (5). For morbidly obese patients both emergence from and post-operative recovery after volatile anaesthetics, particularly desflurane, have made their use increasingly common (20, 21).
The results from our study clearly demonstrated that during laparoscopic cholecystectomy the patients' haemo-dynamic parameters were very similar and within the accepted range regardless of whether sevoflurane-fentanyl or neuroleptic anaesthesia was used. Despite similar surgical duration it was noted that neuroleptic anaesthesia resulted in a considerably longer awakening time and was accompanied by a higher frequency of post-operative complications. In contrast, only post-operative abdominal pain was reported in a higher frequency of patients that received sevoflurane-fentanyl. This was most likely the explanation why patients that received sevoflurane-fentanyl also experienced post-operative pain during rest and activity (moving, coughing and walking) and a higher frequency of them required keterolac. At 36 hours post-surgery the severity of post-operative pain and request for extra analgesia was diminuished in the majority of patients that received sevoflurane-fentanyl.
Obesity is accompanied by changes in the functional activity of the hypothalamo-pituitary-adrenal (HPA) axis with increased sensitivity to stimulation and reduced sensitivity to inhibition (22, 23). Pre-operative analysis of our patients indicated values of serum and urinary cortisol within the physiologically accepted range with a preserved diurnal secretion rhythm. However, the HPA axis is a dynamic system that shows changes in response to stress, illness or pathological states (24). Our investigation showed a significant stress response in patients that received neuroleptic anaesthesia during the 24-hour peri-operative period as an increase in both serum and urinary cortisol was apparent. In patients that received sevoflurane-fentanyl only an increase in urinary cortisol was observed. As the peri-operative glucose and insulin concentrations showed minimal fluctuation we could assume that the patients' regulatory mechanisms were maintained during the peri-operative period. The serum concentration of IGF-I, a possible regulator of serum glucose, was significantly reduced by approximately three-fold after laparoscopy. The synthesis of IGF-I in the liver is under the primary control of growth hormone (GH). One of the consequences of stress conditions is acquired peripheral resistance to GH (25). Reduced GH activity is characterised by a decreased concentration of circulating IGF-I. Another reason for the reduction in serum IGF-I could be due to toxic effects of anaesthesia on protein synthesis in the liver. Thus, despite the fact that laparoscopic cholecystectomy is a minimally invasive procedure, it is still accompanied by a significant hormone response to stress (10, 26). Compared to open cholecystectomy, however, it is significantly less stressful (10, 13, 14, 16, 26).
In summary, balanced inhalatory anaesthesia with sevo-flurane in combination with fentanyl provided satisfactory peri-operative haemodynamic stability in mildly obese patients during laparoscopic cholecystectomy, reduced the consumption of muscle relaxants, enabled faster establishment of respiratory functions and awareness with a significantly higher degree of motor activity. Despite a lesser degree of post-operative stress and a lower frequency of PONV, the need for complimentary analgesia was increased. Laparoscopic cholecystectomy of mildly obese patients employing neuroleptic anaesthesia resulted in good peri-operative haemodynamic stability. However, the arousal from anaesthesia was longer and the degree of peri-operative stress (determined by changes in the concentration of cortisol and IGF-I) was greater. The need for complementary analgesia and complications in the form of PONV were both decreased. As a combination of sevoflurane and a low dose of fentanyl resulted in faster recovery from anaesthesia and less hormonal and metabolic stress, factors positively associated with post-operative complications and frequency of morbidity (27, 28), such a choice of anesthesia followed by post-operative analgesia is suggested for laparoscopic cholecystectomy of mildly obese patients.

Acknowledgements
This work was supported by the Ministry of Science and Environmental Protection of Serbia (project grant number 143019).

References
1. World Health Organisation (WHO). Obesity: Preventing and managing the global epidemic: report of a WHO Consultation on Obesity, Geneva. WHO. 1997.
2. National Institutes of Health. Clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults: The Evidence Report. Washington, DC. Government Printing Office 1998.
3. Sunyer-Pi, X.F. - The obesity epidemic: Pathophysiology and consequences of obesity. Obesity Res., 2002, 10:97S.
4. Lawrence, V.J., Kopelman, P.G. - Medical consequences of obesity. Clin. Dermatol., 2004, 22:296.
5. Adams, J.P., Murphy, P.G. - Obesity in anaesthesia and intensive care. Br. J. Anaesthesiol., 2000, 85:91.
6. Cheymol, G. - Effects of obesity on pharmacokinetics implications for drug therapy. Clin. Pharmacokinet., 2000, 39:215.
7. Young, C.J., Apfelbaum, J.L. - Inhalational anesthetics: desflurane and sevoflurane. J. Clin. Anesth., 1995, 7:564.
8. Grounds, R.M., Newman, P.J. - Sevoflurane. Br. J. Hosp. Med., 1997, 57:43.
9. Yang, H., Choi, PT-L., McChesney, J., Buckley, N. - Induction with sevoflurane-remifentanil is comparable to propofol-fentanyl-rocuronium in PONV after laparoscopic surgery. Can. J. Anaesth., 2004, 51:660.
10. Baricevic, I., Jones, D.R., Malenkovic, V., Nedic, O. - The effect of laparoscopy on the IGF system in patients diagnosed with acute cholecystitis. Clin. Endocrinol., 2006, 65:373.
11. Legorreta, A.P., Silber, J.H., Costantino, G.N., Kobylinski, R.W., Zatz, S.L. - Increased cholecystectomy rate after the introduction of laparoscopic cholecystectomy. JAMA, 1993, 270:1429.
12 Osborne, D.A., Alexander, G., Boe, B., Zervos, E.E. - Laparoscopic cholecystectomy: Past, Present, and Future. Surg. Technol. Int., 2006, 15:81.
13. Dionigi, R., Dominioni, L., Benevento, A., Giudice, G., Cuffari, S., Bordone, N., Caravati, F., Carcano, G., Gennari, R. - Effects of surgical trauma of laparoscopic vs. open cholecystectomy. Hepatogastroenterology, 1994, 41:471.
14. Jakeways, M.S., Mitchell, V., Hashim, I.A., Chadwick, S.J., Shenkin, A., Green, C.J., Carli, F. - Metabolic and inflammatory responses after open or laparoscopic cholecystectomy. Br. J. Surg., 1994, 81:127.
15. Karayiannakis, A.J., Makri, G.G., Mantzioka, A., Karousos, D., Karatzas, G. - Systemic stress response after laparoscopic or open cholecystectomy: a randomized trial. Br. J. Surg., 1997, 84:467.
16. Mrkšic, M., Cabafi, Z., Feher, I., Mirkovic, M. - Surgical trauma in laparoscopic and classical cholecystectomy. Med. Pregl., 2001, 54:327.
17. Pasulka, P.S., Bistrian, B.R., Benotti, P.N., Blackburn, G.L. - The risks of surgery in obese patients. Ann. Intern. Med., 1986, 104:540.
18. Shenkman, Z., Shir, Y., Brodsky, J.B. - Perioperative management of the obese patient. Br. J. Anaesth., 1993, 70:349.
19. Casati, A., Putzu, M. - Anesthesia in the obese patient: Pharmacokinetic considerations. J. Clin. Anesth., 2005, 17:134.
20. Juvin, P., Vadam, C., Malek, L., Dupont, H., Marmuse, J-P and Desmonts, J-M. - Postoperative recovery after desflurane, propofol, or isoflurane anesthesia among morbidly obese patients: A prospective, randomized study. Anesth. Analg., 2000, 91:714.
21. Strum, E.M., Szenohradszki, J., Kaufman, W.A., Anthone, G.J., Manz, I.L. and Lumb, P.D. - Emergence and recovery characteristics of desflurane versus sevoflurane in morbidly obese adult surgical patients: A prospective, randomized study. Anesth. Analg., 2004, 99:1848.
22. Chalew, S., Nagel, H., Shore, S. - The hypothalamic-pituitary-adrenal axis in obesity. Obesity Res., 1995, 3:371.
23. Peeke, P.M., Chrousos, G.P. - Hypercortisolism and obesity. Ann. NY Acad. Sci., 1995, 771:665.
24. Vermes, I., Beishuizen, A. - The hypothalamic-pituitary-adrenal response to critical illness. Best Pract. Res. Clin. Endocrinol. Metab., 2001, 15:495.
25. Jenkins, R.C., Ross, R.J.M. - Acquired growth hormone resistance in adults. Bailliere's Clin. Endocrinol. Metab., 1998, 12:315.
26. Baricevic, I., Malenkovic, V., Jones, D.R., Nedic, O. - The influence of laparoscopic and open surgery on the concentration and structural modifications of insulin-like growth factor binding protein 3 in the human circulation. Acta Physiol. Hung., 2006, 93:361.
27. Kehlet, H. - Manipulation of the metabolic response in clinical practice. World J. Surg., 2000, 24:690.
28. Carli, F. - Postoperative metabolic stress: interventional strategies. Minerva Anesthesiol., 2006, 72:413.

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