Paolo Grossi, Marco Pavesi, Marco Dei Poli, Lucia Capellaro, Andrea Cucchi, Danilo Celleno*
Servizio di Anestesia Polispecialistica e Terapia del Dolore. Istituto Policlinico San Donato
* Department of Anaesthesiology, Intensive Care and Pain Clinic. San Giovanni Calibita - F.B.F. General Hospital, Roma

Influence on metabolic changes
During major procedures although neural stimulus represents a major mechanism for the surgical stress response, it is also activated by various trauma induced endocrine metabolic changes (such as increasing production of ACTH, GH, ADH, PRL, catecholamines, and adrenal hormones) with subsequent increased demands on organ functions; several biological cascade systems (cytokines, complement, arachidonic acid metabolites, nitric oxide, free oxygen radicals etc.) are also activated, leading to pain and clinically significant alterations of pulmonary function, gastro enteric activity and coagulation factors potentially associated to cardiopulmonary, infective, thromboembolic and gastrointestinal complications with consequent prolongation of mean length of hospital stay (Kehlet 1997, Norman et al 1997, Mangano et al 1996).
Epidural anesthetic technique combined with general anesthesia offer several advantages in the postoperative period if compared with general anesthesia alone (Murayi et al 1999). The incidence of postoperative respiratory and cardiovascular complications is decreased. The physiologic stress reaction, which is associated to an hypercoagulable state and immune depression, is attenuated.
The use of local anaesthetics, opioids and alpha2 agonists in combination with systemic NSAID administered in the epidural space leads to protection from surgical stress, satisfactory analgesia and therefore to a rapid mobilisation in the postoperative period (Kehlet 1993, Kehlet 1993, Murayi et al 1999). Local anesthetic agents inhibit nociceptive impulses blunting somatic responses to pain.

Choice of drugs
Bupivacaine is at present the most employed agent for epidural analgesia but there are several advantages in the use the longer acting ropivacaine: lower liposolubility in comparison with bupivacaine, corresponding to a better sensitive/motor block ratio (Zaric et al 1996, Muldoon et al 1998); reduced cardiotoxicity (Reiz et al 1989); known pharmacokinetic for long term (till 72 hours) infusion, with no accumulation of toxic metabolites (Scott et al 1997). In sheep CD50 (dose required to produce convulsion in 50%) of bupivacaine is approximately half that of ropivacaine (De Jong 1994) and in rabbits CD50 of racemic bupivacaine is two thirds that of levobupivacaine (Aberg 1972).
Levobupivacaine consistently produces less central nervous and cardiac effects with quicker recovery than racemic bupivacaine (Harding et al 1998). Bupivacaine and Ropivacaine both share a pKa of 8.1 The addition of 1 mEq of bicarbonate to 10 mEq of local anaesthetic before epidural injection discourages ionisation, allowing uncharged base to penetrate the sheath producing a regional blockade 2 to 3 minutes quicker and raising one dermatome higher than untreated local anaesthetic (bupivacaine in the mentioned study) (Capogna et al 1995). Bupivacaine is shorter acting than ropivacaine and duration of action for both is extended by the addiction of epinephrine (Cederholm et al 1994).

Opioids
The employ of opioids in the epidural blocks offers several advantages: an extension of anaesthetic effect with consequent secondary improving of postoperative respiratory function (Scott et al 1996); an earlier mobilization, with a reduction of the incidence of orthostatic hypotension, attributable to the use of local anaesthetics alone (Bromage 1997, Kehlet et al 1999)
Clinical action of epidural opioids is depending on their ability to reach their specific receptors once penetrated the dorsal horn laminae, on administered dose and route (Furst 1999, Yaksh et al 1981). Others characteristics affecting opioid pharmacodynamic and pharmacokinetics are their physicochemical features (pKa, liposolubility, M.W., pH). On the bases of these features, once in contact with the CSF, each opioid has a different spread with consequent proper distribution and absorption. The ascending movement of CSF leads the drug to the tegmen ventriculi quarti, determining at this level the happening and the duration of opioid side effects (Capogna et al 1995). Onset and power of spinal opioids, if correlated in equianalgesic doses, are directly proportional to their liposolubility while the duration of analgesia is inversely proportional to their liposolubility. Time employed for rostral migration is 4-6 hours for morphine, 2 hours for alfentanil, 2-4 hours for fentanyl and sufentanil. The latter one has a rapid diffusion between meninges after epidural administration and the peak of liquoral concentration is obtained in a few minutes.
Liposoluble opioids (fentanyl, sufentanil) have a faster onset and duration of action, they are therefore more indicated for continuous epidural analgesia or patient controlled epidural analgesia, in combination with local anaesthetics (De Leon-Casasola et al 1996).

Influence of the sympathetic system
The role of inhibition of the sympathetic nervous system in the advantages of perimedullary techniques is probably important. It is important to note that this inhibition can be associated with undesirable consequences in certain patients. These techniques must therefore be used cautiously, and patients who benefit from them must receive careful surveillance (Litz et al 1999).

Cardiovascular system and coagulation
Several others intra and post operative advantages are offered by combined anaesthesia in major surgery: regarding the effects of combined anaesthesia on cardiovascular system the block of sympathetic activity leads to a reduction of preload and afterload whereas the prevalence of vagal tone reduces the hearth rate and level of plasma chatecolamines; this has been shown to lead to an haemodynamic stability (Celle no et al 1999): the incidence of cardiovascular complications has been observed to be reduced (Muray et al 1999); on cardiac outcome this technique act as a main protector against post operative myocardial infarction; thoracic epidural anaesthesia leads to a reduction in myocardial blood flow compensated by reduced O2 demand and reduced work (Saada et al 1992, Mergner et al 1994). To enhance its beneficial effects, analgesia should 72 hours and low doses of local anaesthetics and opioids should be employed.
Effect on rates of myocardial ischemia: the use of thoracic epidural analgesia with bupivacaine + sufentanil did not result in a higher incidence of myocardial ischemia compared with PCA with morphine (Bois et al 1997). A reduced postsurgical hypercoagulablity has been underlined: post surgical hypercoagulable state is a result of surgical stress, sympathetic activity, and atherosclerotic disease. The local anaesthetic bupivacaine inhibits thromboxane A2 leading to a lower rate of platelet aggregation (Brodner et al 1998); best reduction in hypercoagulability state occurs when epidural anaesthesia/analgesia is a part of intra-operative management (Liu et al 1995).
The hypotensive effect due to the sympathetic system and spinal reflex axes block is responding for a reduced intraoperative blood loss with consequent lower transfusion rate (Kida et al 1999, Dauphin et al 1997, Frank et al 1998). The same effect is probably responsible for the improved survival of vessel graft (Brodner et al 1998, Sharrock et al 1993).

Integrated and closed loop Anesthesia
The ‘integrated’ technique allows the maintenance of an adequate depth of anaesthesia with the reduction in MAC of inhalant agent and in opioid requirements. This should be extended to the possibility of maintaining the combined anaesthesia with the only support of O2 + propofol + air (TIVA), avoiding the use of N2O, disadvantageous in several situations (Celleno et al 1999). (see tables 1,2).This may be conducted through the use of OTCI pumps, that design an ideal profile of drug distribution, at the CNS site, at plasma.
This leads to a precise concept of pharmacological awakening. This model is applying to most patients, helping a correct conduction of tiva.
In the future this will be applyable to the most effective method to evaluate the depth of anaesthesia : the Bispectral Index (BIS. The index is a resulting of analysis and elaboration of several patient’s EEG features, comparison with more than 5.000 memorised EEG of previously anaesthetised patients with a final multivariate statistic synthesis. The index (ranging from 0, isoelectric EEG, to 100, awareness) well correlates with increasing sedation and loss of consciousness, exhibiting a linear relationship between depth of anaesthesia and amount of administered hypnotics (Katoh et al 1998, Sennolz et al 2000).

Level of splancnic block
Lumbar epidural approach (LEA) leads to a complete sympathetic activity block in skin and muscles in the lower body, increased sympathetic activity in splancnic nerves due to baroceptor drive. A lumbar approach extended to thoracic level can induce a severe reduction in myocardial blood flow distal to an eventual coronary artery stenosis; moreover a lumbar approach leads to a reduced O2 supply without reduced O2 demand, for the increase of sympathetic tone in intact areas. TEA has therefore a more favourable effects in patients with coronary artery diseases: MBF is compensated by less O2 demand and work (Saada et al 1992, Mergner et al 1994); LEA may induce detrimental effects on cardiac function if it is used without preemptive treatment of cardiac load changes and tachycardia.
A recent study based on echocardiographic evaluation of global left ventricular function during high thoracic epidural anaesthesia underlined how the latter one causes a decrease in CO without changing in LV ejection and diastolic filling performance in healthy subjects.
Left ventricular diastolic filling was noninvasively determined by precordial echocardiography using a pulsed Doppler technique and with a newly developed acoustic quantification (AQ) method that automatically detects endocardial borders and measures cavity area. All measurements were first performed in awake premedicated patients(Niimi et al 1997). In conclusion TEA is better than LEA in patients with compromised cardiac function (Van Aken et al 2000).

Loss of temperature
Heat loss is important to know and to prevent when a central block is combined with general anaesthesia; hypothermia is in fact greater than with general anaesthesia alone because the effects of combined anaesthesia on heat loss are additive, more rapid and longer. Beyond the drop of heat production during general anaesthesia, epidural anaesthesia itself cause vasodilatation in the area affected by sympathetic block, and contributes to the vasoconstriction threshold drop to 3–3.5 °C (Frank et al 1995).

Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand 41(9):1095-1103, 1997

Bois S, Couture P, Boudreault D et al. Epidural analgesia and intravenous patient-controlled analgesia result in similar rates of postoperative myocardial ischemia after aortic surgery. Anesth Analg 85(6):1233-9, 1997

Brodner G, Pogatzki E, Van Aken H. A modern concept of postoperative pain therapy. Anaesthesist 46 Suppl 2:S124-31, 1997

Bromage PR. Combined epidural/general anaesthesia and postoperative outcome. Can J Anaesth 44(12):1319-20, 1997

Capogna G, Celleno D, Laudano D et al. Alkalinisation of local anesthetics: which block, which local anesthetic? Reg Anaesth 20: 369-77, 1995

Cederholm I, Akerman B, Evers H. Local analgesic and vascular effects of intradermal Ropivacaine and Bupivacaine in various concentrations with and without adrenaline in man. Acta Anesthesiol Scand 38: 322-27, 1994

Dauphin A, Raymer KE, Stanton EB, Fuller HD. Comparison of general anesthesia with and without lumbar epidural for total hip arthroplasty: effects of epidural block on hip arthroplasty. J Clin Anesth9(3):200-3, 1997

De Leon-Casasola OA, Lema MJ. Postoperative epidural opioid analgesia: what are the choices? Anesth Analg 83(4):867-75, 1996

De Leon-Casasola OA, Lema MJ, Karabella D, Harrison P. Postoperative myocardial ischemia: epidural versus intravenous patient-controlled analgesia. A pilot project. Reg Anesth 20(2):105-12, 1995

De Leon-Casasola OA, Parker B, Lema MJ, et al. Postoperative epidural bupivacaine-morphine therapy. Experience with 4.227 surgical cancer patients. Anesthesiology 81(2):368-75, 1994

Frank SM, Higgins MS, Breslow MJ, et al. The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia. A randomized clinical trial. Anesthesiology 82(1):83-93, 1995

Hering R, Schumacher T, Muller H. Continuous intra- and postoperative peridural analgesia with combined low dose sufentanil, clonidine and bupivacaine. Anasthesiol Intensivmed Notfallmed Schmerzther 31(9):550-5, 1996

Hogan QH, Stekiel TA, Stadnicka A, Bosnjak ZJ, Kampine JP. Region of epidural blockade determines sympathetic and mesenteric capacitance effects in rabbits. Anesthesiology 83(3):604-10, 1995

Ionescu TI, Taverne RH, Houweling PL, et al. Pharmacokinetic study of extradural and intrathecal sufentanil anaesthesia for major surgery. Br J Anaesth 66(4):458-64, 1991

Katoh T, Suzuki A, Ikeda K. Electroencephalographic derivatives as a tool for predicting the depth of sedation and anesthesia induced by sevoflurane. Anesthesiology 88(3):642-50, 1998

Kehlet H., Mogensen T. Hospital stays of 2 days after sigmoidectomy with a multimodal rehabilitation programme. British Joutnal of Surgery 86(2): 227-230, 1999

Kehlet H. Balanced analgesia: a prerequisite for optimal recovery. British Journal of Surgery 85(1): 3-4, 1998

Kehlet H. The value of multimodal or balanced analgesia in postoperative pain treatment. Anesthesia Analgesia, 77:1048-1056,1993

Mergner GW, Stolte AL, Frame WB, Lim HJ. Combined epidural analgesia and general anesthesia induce ischemia distal to a severe coronary artery stenosis in swine. Anesth Analg 78(1):37-45, 1994

Muldoon T, Milligan K, Quinn P et al. Comparison between extradural infusion of ropivacaine or bupivacaine for the prevention of postoperative pain after total knee arthroplasty. Br J Anaesth. 80(5):680-1, 1995

Norman JG, Fink GW. The effects of epidural anesthesia on the neuroendocrine response to major surgical stress: a randomized prospective trial. Am Surg 63(1):75-80, 1997

Reiz S, Haggmark S, Johansson G, Nath S. Cardiotoxicity of ropivacaine--a new amide local anaesthetic agent. Acta Anaesthesiol Scand 33(2):93-8, 1989

Scott DA, Emanuelsson BM, Mooney PH, Cook RJ, Junestrand C. Pharmacokinetics and efficacy of long-term epidural ropivacaine infusion for postoperative analgesia. Anesth Analg 85(6):1322-30, 1997

Sharrock NE, Mineo R, Urquhart B. The effect of two levels of hypotension on intraoperative blood loss during total hip arthroplasty performed under lumbar epidural anesthesia. Anesth Analg 76(3):580-4, 1993

Zaric D, Hallgren S, Leissner L, et al. Evaluation of epidural sensory block by thermal stimulation, laser stimulation, and recording of somatosensory evoked potentials. Reg Anesth 21(2): 124-38, 1996