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Enhanced suppression of hormonal and metabolic responses to stress by application of combined spinal-epidural and general anaesthesia compared with combined spinal general anaesthesia during colorecta
Vesna Malenkovici, Ivona Baricevici, D.R. Jones, Olgica Nedici, D. Bilanovici (Chirurgia, 103 (2): 205-210)

Introduction
The systemic response to surgical trauma involves sympathetic nervous system activation, an endocrine "stress-response" (hormone secretion and insulin resistance) and immunological /haematological changes (cytokine production, acute phase reaction, neutrophil leucocytosis and lymphocyte proliferation). The release of numerous pituitary-regulated hormones including adrenocorticotropin, cortisol, renin-angiotensin-aldosterone, catecholamines and vasopressin and various cytokines cause major metabolic changes resulting in increased catabolism allowing mobilisation of substrates thereby providing energy sources and mechanisms to preserve salt and water and maintain fluid volume and correct cardiovascular homeostasis (1, 2). Clinical consequences of the stress response include hypertension, tachycardia, arrhythmia, myocardic ischemia, protein catabolism, supression of the immune response and loss of renal excretory function with water and salt retention. The greatest increase of the stress response in the post-operative period correlates with frequent episodes of post-operative complications. The stress response is a significant marker for an increased risk of unsatisfactory outcomes including cardiovascular morbidity, immunosuppression and infection, increased coagulability, inhibition of fibrinolytic activity and thrombosis formation. Thus, reduction and modulation of the stress response during surgery can significantly reduce post-operative complications and frequency of morbidity (3, 4).
Spinal anesthesia is commonly used for relatively short surgical procedures below the line of the umbilicus and is accomplished by injecting local anesthetic into the cerebrospinal fluid (CSF) in the lumbar spine (below L1). The result is rapid onset anaesthesia with a high degree of muscle relaxation (5). This type of regional anesthesia has a distinct advantage in that it can be readily combined with epidural anesthesia via the use of an epidural catheter (EDC). The versatility of the latter allows it to be an anaesthetic in its own right, an analgesic component of general anesthesia or an analgesic during post-operative patient recovery. Combined spinal-epidural (CSE) anaesthesia has a number of benefits and is the anaesthesia of choice particularly in obstetrical, abdominal and lower limb surgery (6, 7). One potential drawback of regional anaesthesia, combined or otherwise, is its time limitation often governed by surgical requirements. Either an increased amount of local anesthetic is applied (in the absence or presence of additional opioids) via the EDC or light (inhalation or intravenous) general anesthetic (GA) is administered resulting in total spinal anesthesia (CSEGA) (8). By limiting stimulation of both the peripheral and central nervous system using components of regional and/or general anaesthesia, a reduction in the magnitude of a number of endocrine (stress response) parameters is achievable and is the goal of surgeons and anaesthesiologists alike. We chose to study the suppression of the hormonal and metabolic response to surgical stress during colorectal surgery in patients administered with CSEGA and to compare it with patients that received combined spinal and general anesthesia (CSGA).

Materials and Methods
Patients
Sixteen patients undergoing elective colorectal surgery due to confirmed non-metastatic cancer at the "Bežanijska Kosa" Clinical-Medical Centre, Belgrade were included in the present study. Patients with hypo-albuminemia (<35 g/L), anaemia (Hb < 10 g/dL), a history of cardiovascular disorders, those receiving hormonal or cytostatic therapy and those with endocrine, hepatic and renal disorders were excluded. Furthermore, any subjects on medication that influenced their metabolism and those where the application of central blocks was contraindicated were also barred. Patient characteristics are summarised in table 1. All the patients consented to take part in the study and agreed that their sera and urine could be used for research according to internationally recognised ethical standards (The Helsinki Declaration of 1964, as revised in 1975, 1983 and 1989). Approval for the study was granted by local ethical committees based in Belgrade.
Clinical
A purely academic six-week long blind prospective rando-mised study took place in summer 2006. Two study groups of patients were established according to the type of anesthesia used (either CSGA or CSEGA). Two state-registered anaesthesiologists (V. M. and D. B.) were present during all procedures included in the present study. This allowed for procedure uniformity and unprejudiced drug administration.
All patients were placed in the lateral decubitus position. The L3-L4 intervertebral space was located via standard anatomical navigation. Using the "loss of resistance method" a 16 gauge epidural (Touhy) needle was inserted into the epidural space. Through the epidural needle, a "pencil point" 27 gauge spinal needle was inserted into the sub-arachnoid space until free flow of cerebral spinal fluid (CSF) was observed. Via the spinal needle 0.2 mg morphine mixed with 1.8 ml of 0.25% mildly hypobaric bupivacaine (4.5 mg) was injected into the sub-arachnoid space (spinal anesthesia) ("needle-through-needle" technique). The spinal needle was removed and an epidural catheter (EDC) was threaded into the epidural space.. Once the catheter was inserted the epidural needle was removed. Via the EDC fractional application of 0.2% mildly hypobaric buipivacaine (32.5-70.5 mg) was administered according to patient weight, the phase of surgery and haemodynamic responses of the patient (epidural anaesthesia). General anesthesia (following standard procedures that involved endotracheal intubation and mechanical ventilation and relaxation) was administered using a combination of systemic propofol (CSGA: 2-5 mg/kg; CSEGA: 1-2 mg/kg) and fentanyl (CSGA: 1.0-1.2 mg; CSEGA: 0.1-0.5 mg). Details of pre-operative medication, anaesthesia and post-operative analgesia are indicated in Table 1. The haemodynamic stability of the patients in the peri-operative period was estimated on the basis of blood pressure, pulse frequency, continual electrocardiography and hourly diuresis observations. Monitoring the patients' respiratory functions involved recording breathing frequency and amplitude, pulse oximetry and arterial blood gas analyses. Estimation of the depth of anaesthesia involved continuous electrocardiography, pulse oximetry, 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 and core body temperature.
Venous blood was drawn from the patients at four different time points: At 8 am in the morning (30 minutes after administration of pre-medication) (Time I, pre-operative sample), 60 minutes after incision (Time II), 3 hours after the operation and extubation (Time III) and 24 hours after completion of surgery (Time IV). Two urine samples were collected: The first during a 24 hour period leading up to surgery (pre-operative sample) and the second (surgical sample) during a 24 hour period from the moment when surgery commenced. All surgical procedures started at 8 am.
Biochemistry
The concentrations of cortisol, insulin-like growth factor (IGF)-I and IGF-II in serum were determined using radio-immunoassays (9). Serum glucose and urinary catecholamines were quantified using standard procedures within the clinical chemistry laboratory at the Clinical-Medical Centre "Bežanijska kosa".

Data analysis
All statistical comparisons were performed using Primer of Biostatistics (version 5), STATGRAPHIC Plus (version 4.2) and CBstat (version 4.3.2) software. Data for each measured biochemical parameter within all the examined study groups were subjected to the Kolmogorov-Smirnov test. As only normal distributions were found for each measured parameter, the results were expressed as the mean value and the standard deviation. To evaluate differences between all study groups a repeated measurement ANOVA test was performed. In order to determine differences between specific groups the Tukey HSD post hoc test was employed. The minimal statistical significance was set at p < 0.05.

Results
Our current study included 18 patients randomly divided into two groups that differed according to the type of anaesthesia (CSEGA and CSGA). The majority of patients in each group were male (Table 1). No differences between the patient groups with respect to age, weight or surgical duration were apparent (Table 1). The mean volume of lactated Ringer's solution required during surgical interventions within the CSEGA group was approximately 50% greater than that required for the CSGA group (Table 1). A greater amount of local anesthestic administered to the CSEGA patient group caused a decrease in blood pressure (via the local anaesthestic's vasomotor effects resulting in vasodilation) which required intravenous compensation (greater compared to that in the CSGA patient group). No post-operative complications (including post-dural puncture headaches) were recorded and no patients died as a result of the elective surgery. Both groups of patients had satisfactory haemodynamic stability during surgery. Both the mean arterial pressure (MAP) and heart rate (HR) were significantly reduced (at time points II, III and IV) in the patients given CSGA compared to the patients that received CSEGA (Fig. 1, panels A and B). Despite the notable bradycardia and hypotension ephedrine was not administered to any patient during the peri-operative period. Haemoglobin oxygen saturation (SaO2) was slightly higher during surgery in patients given CSGA (fig. 1, panel C). Post-operative respiratory and circulatory functions were more favourable in the group of patients given CSEGA, reflected by a higher SaO2 value (fig. 1, panel C).
To determine the effect of colorectal sugery (under either CSEGA or CSGA) on endocrine stress parameters, we measured the concentration of both serum glucose and cortisol and urinary catecholamines (adrenaline, noradrenaline and dopamine). The concentration of glucose in patients that received CSGA increased sharply and remained high 24 hours after surgery (fig. 2, panel A). In patients that received CSEGA the increase in serum glucose was less dramatic and showed a tendency to decrease at 24 hours (fig. 2, panel A). Statistically significant differences in the serum glucose concentration between the two study groups were found at time points II and IV. Serum cortisol progresively increased in patients that received CSGA. At timepoint IV the concentration was over 3-fold compared with that at timepoint I (fig. 2, panel B). In contrast, a modest increase in the serum cortisol concentration was recorded in patients that received CSEGA. At timepoint IV the serum cortisol concentration was barely elevated above that at timepoint I (fig. 2, panel B). Statistically significant differences in the serum cortisol concentration between the two study groups were found at time points II, III and IV.
Urinary catecholamine excretion was greater after commencement of surgery in both CSEGA and CSGA groups when compared to basal pre-operative values (fig. 2, panel C). Both adrenaline and noradrenaline excretion were greater (and statistically significant) in patients that received CSGA compared to patients that received CSEGA (fig. 2, panel C). In the urine from patients that received CSGA the mean concentration dopamine was greater than that in the urine from patients that received CSEGA (fig. 2, panel C), but just fell short of the cut-off point for statisical significance.
Due to the higher concentration of serum glucose and cortisol and urinary adrenaline and noradrenaline in patients that received CSGA, we decided to further explore the changed metabolic situation in these patients by measuring the concentration of serum IGF-I and IGF-II. The concentration of IGF-II in all patients at all time points was within the reference range. However, the concentration of IGF-I exhibited considerable variation. Both normal concentrations (within the reference range) and low concentrations were detected in patients. We could not establish any regularity when we attempted to correlate IGF-I with cortisol. There were patients with extremely high cortisol in combination with normal IGF-I, moderately elevated cortisol in combination with normal IGF-I and low IGF-I in combination with extremely high cortisol or moderately elevated cortisol (data not shown). Clearly, the changes in the concentration of IGF-I in CSGA patients were not directly correlated with those of cortisol, thereby implicating other regulatory factors (including cytokines, other hormones and acute phase reactants).

Figure 1
Figure 2

Discussion
Colorectal surgery is accompanied with high levels of surgical trauma, nociceptive afferent nerve stimulation and a hormonal and metabolic response to stress that correlates with the trauma level but can be modified by applying different anaesthetic and analgetic agents (10). Furthermore, patient recovery after abdominal surgery is also dependent on anaesthetic and analgetic regimes (11-14). It has been known for some time that when applied separately neither sub-arachnoid nor epidural blockade completely abolishes neural transmission in 'blocked' regions. However, CSE can produce a physiologically denser block than either technique alone (15). Our results clearly demonstrated the effectiveness of CSE within a CSEGA regimen to provide greater post-operative haemodynamic and respiratory stability in parallel with a markedly blunted post-operative endocrine stress response (serum glucose and cortisol and urinary catechola-mines) when compared to CSGA. Therefore the epidural component within CSEGA was a positive attribute. Spinal administration of morphine reduces the hormonal response to stress by blocking parasympathetic nociceptive stimulation carried by the dorsal nuclei of the vagal nerve. The action of morphine on dorsal nuclei is attained by its cephalic migration under epidural pressure (16). This in combination with epidural administration of a local anesthetic, immediately after the application of sub-arachnoidal morphine, allowed for a more favourable distribution of opioids and a higher degree of neuroaxial blockade in the patients that received CSEGA. Furthermore, the inclusion of epidural administration of bupivacaine resulted in a decreased quantity of applied systemic propofol and fentanyl required for GA. This result is consistent with others previously published (17-19). However, despite the advantages of CSEGA complete suppression of the hormonal response was not attained (as indicated by elevated serum glucose and urinary catecholamine measurements). This may have been due to insufficient cephalic migration of morphine and/or epidural spread of bupivacaine, as a high thoracic block (up to T4) is required to significantly attenuate surgery-induced hormonal responses (20).
Despite the fact that full blockade of the hormonal stress response was not achieved, we conclude that CSEGA is advantageous as it may (i) reduce cardiovascular, pulmonal and haematological morbidity due to decreased doses of individual anaesthetics, (ii) allow enhanced intrathecal distribution of components of anaesthesia and (iii), perhaps most importantly, allow the summation of the positive effects of low-dose local and general anesthesia.

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

References
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