Pain involves a series of neurochemical events, collectively known as nociception, consisting of four physiologic processes: transduction, transmission, modulation and perception .
During the last decades, a vast amount of knowledge has accumulated on the neural, endocrine, metabolic and immunological aspects of the stress response. Surgical trauma produces a stress response by which the central and peripheral nervous system elicit the release of corticotropin, cortisol, renin, angiotensin, aldosterone and catecholamines. This neuroendocrine response begins at the onset of surgery and continues several days postoperatively . The autonomic nervous system response of increased sympathetic activity begins at the time of surgery and high plasma catecholamine levels are maintained for about a week . The more protracted and extensive the surgical trauma, the stronger and long lasting is the catecholamine release [4,5]. It has been demonstrated that inhalational general anaesthesia alone cannot reduce the surgical stress response as opposed to epidural anaesthesia, which is considered the best stress response-reducing method in the adult population .
Caudal epidural block is widely used in paediatric surgical patients because of its high efficacy, ease of placement and safety. Caudal anaesthesia/analgesia facilitates the use of lower doses of intravenous (i.v.) opioids with less side-effects, decreases the necessity for postoperative opioids requirement and enables a more rapid awakening . Caudal epidural block has been demonstrated to modulate the surgical stress response in the paediatric population [8,9].
Fentanyl, a synthetic opiate, is an agonist to the Mu receptor at supraspinal and spinal levels. It is widely used in ambulatory minor procedures in a dose of 1–3 μg kg−1 . Taylor and colleagues  demonstrated that adding i.v. fentanyl in doses of 3 and 15 μg kg−1 to inhalational anaesthesia did not modify the stress response as reflected by interleukin-6 levels. On the other hand, studies of high doses of fentanyl (75 μg kg−1) have shown a significant suppression of the stress response to surgery , but such high doses are not practical in short ambulatory surgical procedures. Our previous study showed that adding fentanyl 1 μg kg−1 to bupivacaine in a caudal block had no additional benefit in reducing the stress response in a similar paediatric population that underwent the same surgical procedure as the one selected for the present study .
The purpose of this study was to assess whether multimodal analgesia, specifically the addition of i.v. low-dose fentanyl to a caudal block and general anaesthesia decreases the stress response in children undergoing elective unilateral herniorrhaphy compared with caudal block and general anaesthesia alone. Stress response was quantified by measuring plasma catecholamine (epinephrine and norepinephrine) levels.
Materials and methods
After receiving approval from the hospital Ethics Committee and obtaining written parental consent in all cases, 50 children, between 1 and 8 yr of age (ASA Grade I or II), scheduled for unilateral ilioinguinal herniorrhaphy, were included in this study. The following non-inclusion criteria were applied: haemoglobin concentration below 11 g dL−1, asthmatic patients, allergy to anaesthetic agents, episodes of intraoperative hypothermia (<36°C), events of hypoxia (SaO2 < 95%) or hypercapnia (CO2 > 55 mmHg) for 1 min or more, failed caudal epidural block, episodes of hypoxia or hypothermia (<36°C) with or without chills in the recovery room and bleeding diatheses. Failed block was defined in cases when the necessity arose to add i.v. fentanyl or increase the concentration of inhaled anaesthetics in response to a 20% increase from baseline of the systolic blood pressure (BP) and/or heart rate (HR) for more than 3 min.
The study participants were randomly assigned to two groups using a computer-based random number generator: Group A, general inhalational anaesthesia + caudal anaesthesia alone and Group B, general inhalational anaesthesia + caudal anaesthesia (identical to that given in Group A) + i.v. fentanyl.
No patient was premedicated, and all children were anaesthetized in the presence of their parents in a special induction room. Anaesthesia induction and caudal block were performed by the same specialist paediatric anaesthesiologist (MS) who also collected blood for catecholamine plasma levels, but did not participate in the perioperative data collecting process.
Patients of both groups had the same inhaled anaesthesia combined with a caudal block. Anaesthesia was induced with N2O/O2 (50 : 50) and sevoflurane up to 6% (through a Bain circuit). A laryngeal mask airway was inserted after eyelash reflex disappearance. End-tidal isoflurane was maintained between 1–1.5 minimal alveolar anaesthetic concentrations. Manual-assisted ventilation was performed to keep end-tidal CO2 (ETCO2) between 30–48 mmHg. An i.v. catheter was inserted after the patient was asleep. After anaesthesia induction, the patient was placed in the lateral position and a 23- or 21-G needle was inserted into the caudal space through the sacrococcygeal membrane using an aseptic and no-touch technique. When the aspiration test was negative, a test dose of lidocaine 1% 0.1 mL kg−1 with epinephrine 1 : 200 000 was injected. If this test was negative (i.e. no increase in HR of more than 15 beats min−1 or ST segment amplitude changes on electrocardiogram), bupivacaine 0.25% 1 mL kg−1 was injected (maximum dose 25 mL). The block was considered successful if the operation was performed without the need to increase the concentration of the inhalational agent or to add more fentanyl as determined by an increase in HR and BP of more than 20% from baseline values.
In addition to the above-described combined general and caudal anaesthesia, Group A patients were infused with 100 mL of normal saline solution alone over 15–20 min. Group B patients received 100 mL of normal saline solution with 2 μg kg−1 fentanyl over the same time interval with the intent to create identical conditions in the two groups. Surgery was begun approximately 20 min after the onset of anaesthesia induction. All patients received 0.01 mg kg−1 atropine i.v. and rectal paracetamol in a dose of 25 mg kg−1 up to a maximum dose of 1 g.
All children were adequately hydrated with lactate Ringer's solution at a rate of 4–6 mL kg−1 h−1 by means of an infusion pump. HR, non-invasive systolic and diastolic BP, pulse oximetry, ETCO2 and temperature were monitored in all patients by means of a AS/3 monitorTM (Datex-Engstrom, Helsinki, Finland). Values of these parameters were recorded every 5 min during surgery.
Blood samples of 3 mL for catecholamine plasma levels were drawn through the venous catheter three times: at the induction time (T0), at the end of surgery (T1) and when a modified Aldrete recovery score of 10 points was obtained in the postanaesthesia care unit (PACU) (T2) . The samples were centrifuged, frozen and sent for assay by reversed-phase high-performance liquid chromatography and electrochemical detection after prior extraction with aluminia . Coefficients of variation for the epinephrine and norepinephrine assay were 6–11% at 0.5 ng mL−1 and 3–5% at 1 ηg mL−1, respectively. The limit of accurate detection was 45 pg mL−1 for epinephrine and 30 pg mL−1 for norepinephrine. The normal range for children up to 15 yr old is 20–500 pg mL−1 for epinephrine and 70–1500 pg mL−1 for norepinephrine . The anaesthesiologist and the nurses who collected the data during surgery as well as in PACU and the surgical ambulatory setting were blinded to study group assignments.
Postoperative pain was assessed at 20, 40 and 60 min in the PACU using a modified Children's Hospital of Eastern Ontario Pain Score (mCHEOPS) . Patients with a pain score of 4 or greater were given 1 μg kg−1 i.v. fentanyl in incremental doses in the PACU or 15 mg kg−1 of paracetamol in the surgical ward. The time to first i.v. fentanyl in PACU and paracetamol in the surgical ward was also recorded.
Complications such as pruritus and emesis were recorded. An episode of vomiting was defined as expulsion of any stomach contents through the mouth, and an episode of retching was defined as an attempt to vomit. An emetic episode was defined as a single vomit or retch or a number of continual vomits and/or retches. Nausea, a subjective feeling of the urge to vomit, is difficult to quantify in children; therefore, it was not assessed. Respiratory depression (respiratory rate <12/min−1) was also recorded every 15 min.
Patients were observed in the PACU for 1−1½, followed by 10 h of surveillance in the surgical ward. Patients were discharged from the hospital when a modified postanaesthesia discharge score of ≥9 was achieved .
Comparison between the three periods (induction time – T0, end of surgery – T1, PACU – T2) of the study within each group was performed using an analysis of variance for repeated measurements, followed by the Bonferroni's test. The unpaired t-test was used when each period was compared between the two groups. A power calculation was not performed; however, in two studies that we carried out previously with cohorts of 40 and 50 patients, respectively [8,9], a value greater than 80% was computed based on the significant differences yielded by the comparisons of epinephrine and norepinephrine plasma levels in two groups at all study times (T0, T1 and T2).
Twenty-five children undergoing elective unilateral herniorrhaphy were included in each group. Two patients from the control group were excluded from the study due to failed caudal blocks, whereas one patient from the fentanyl group was excluded because of a drop in the oxygen saturation to 90% for 2 min. Further, three more children were included in order to re-establish the total number of study participants.
In both groups, there was a significant decrease in the mean values of the plasma epinephrine (Fig. 1) and norepinephrine levels (Fig. 2) when comparing T0 (induction time) with T1 (end of surgery) and T2 (in PACU) (P < 0.0001). Catecholamine levels were well within the normal ranges at induction time.
There were no statistically significant differences between the two groups in the epinephrine plasma levels at either T0 (induction time) (mean difference 9.5 pg mL−1, 95% CI: −111 to 30, P = 0.87) or T1 (end of surgery) (mean difference 27 pg mL−1, 95% CI: −11 to 98, P = 0.11) (Fig. 1). In contrast, the epinephrine plasma levels at T2 (in PACU) were significantly lower in the fentanyl group when compared with the control group (mean difference 55.6 pg mL−1, 95% CI: 4 to 107, P < 0.034) (Fig. 1). Also, there were no significant differences in the norepinephrine plasma levels between the two groups at all three study times (95% CI: −231 to 98, −79 to 60 and −58 to 70, respectively, and P = 0.41, 0.78 and 0.84, respectively) (Fig. 2).
There were no differences in patient characteristics data. No statistically significant differences were found in BP and HR between the two groups at all three study times (T0, T1 and T2) or between these times within each group. Similarly, ETCO2 values were not statistically different between the two groups, and these levels did not increase significantly over the time of surgery within the groups (Table 1).
Pain scores according to mCHEOPS were similar in both groups. No statistically significant differences between the two groups were found with regard to either the time of the first i.v. fentanyl administration or the number of patients who required fentanyl. There were also no significant differences between the two groups with respect to the time of the first dose, and the number of patients who received paracetamol in the surgical ward (Table 2).
No episode of respiratory depression was recorded in either group. Three control group patients and five fentanyl group patients experienced emetic episodes. Two patients from the control group and six from the fentanyl group had nasal pruritus in the PACU and in the ward. There was no statistically significant difference between the two groups with respect to vomiting or pruritus (P = 0.72 and 0.247, respectively, by Fisher's exact test). All adverse effects were treated appropriately, with either ondansetron or naloxone and the children were discharged without delay. All study participants reached 10 points on the modified Aldrete recovery score within an hour in the PACU, without any relative delay in the fentanyl group compared with the control group.
For reduction of the stress response, as measured by plasma catecholamine levels, we found that the multimodal analgesic technique using inhalational sevoflurane, a low dose of i.v. fentanyl, and a caudal epidural block, has an advantage compared with the control group in which caudal block was given with the inhalational agent alone but without fentanyl.
Many studies have investigated the application of unimodal analgesic approach and its effect on the surgical stress response in the paediatric population, whereas the investigation of the influence of multimodal analgesic techniques on the surgical stress hormones in children undergoing infraumbilical surgery has been less often reported .
The rationale for the multimodal analgesia approach is that it enables the suppression of nociception at several levels (i.e. transduction, transmission, modulation and perception). This analgesic technique enables a reduction in the doses of general and local anaesthetic agents, with less adverse effects, reduced morbidity and shorter hospitalization in high-risk patients [20,21].
Gaitini and colleagues demonstrated that the addition of a caudal block to a general anaesthetic significantly reduced the neurohormonal response in children undergoing ilioinguinal herniorrhaphy as opposed to those undergoing general anaesthesia combined with i.v. fentanyl 2 μg kg−1 . Wolf and colleagues found that i.v. fentanyl 1 μg kg−1 at induction followed by 0.1 mg kg−1 of morphine did not cause a reduction in either the neurohormonal response or pain scores during and after surgery compared with spinal and epidural anaesthesia . On the other hand, Walsh and colleagues  found that high-dose opioids given to children in cardiac surgery entailed a significant reduction in the stress response of major surgical trauma. High-dose opioids would necessitate postoperative controlled ventilation, thereby requiring longer postoperative recovery times, which may be impractical in an outpatient surgery setting for hernia repair. In summary, a dose of i.v. fentanyl 2 μg kg−1 alone has no additional stress response-modulating effect, whereas stress response-reducing high doses of fentanyl are not feasible in short outpatient procedures. This deadlock laid the grounds for using the multimodal analgesic strategy in the present study where i.v. fentanyl was used in a dose of 2 μg kg−1 with the purpose to impinge on the perception and modulation phases of nociception while still keeping the opioid adverse effects at a minimum, whereas the addition of a caudal block using a local anaesthetic inhibited the transmission of the nociceptive impulses.
Norepinephrine binds to alpha1 and alpha2 adrenergic receptors. The alpha1 receptors are found in smooth muscle where their stimulation generates contraction. A high concentration of alpha2 adrenergic receptors is found in the descending spinal tracts, including the descending antinociceptive pathways where biogenic amines (serotonin and norepinephrine) as well as endogenous opioids are implicated as neurotransmitters. These pathways can be activated by electric stimulation, systemic or neuraxial injection of opioids and neuraxial injection of alpha2 agonists, as well as by stress, suggestion and pain. Thus, norepinephrine can depress nociception similar to the endogenous opioid-mediated analgesia by means of its effect on postsynaptic alpha2 receptors. On the other hand, norepinephrine that is present in the synaptic cleft, causes a feedback inhibition of its own secretion by binding to presynaptic alpha2 receptors. The latter process is independent of the kind of anaesthesia/analgesia or the administration of opioids; therefore, norepinephrine was expected to be similarly reduced in the two study groups at the end of surgery. The main source of peripheral catecholamine is its secretion from the adrenal medulla, with a distribution of 1 : 4 between norepinephrine and epinephrine . In this study, we found that the level of plasma norepinephrine in the patients who received i.v. fentanyl was not statistically different from that measured in controls. In contrast, significantly lower epinephrine plasma levels were noted postoperatively in the group with the systemic opioid. On the basis of the fact that norepinephrine's feedback autoregulation is not affected by opioids, it is hypothesized that the peripheral effect of opioids is significant with reference to the reduction of epinephrine, and not that of norepinephrine, via blocking the secretor activity of the adrenal medulla, thus explaining our results.
Every pain-rating method has limitations, particularly in children unable to verbalize. Stress response hormone levels can therefore serve as an objective method to assess the analgesic efficacy of various regional analgesic/anaesthetic techniques before infraumbilical or lower extremity surgery in children. Pain relief is not sufficient to influence postoperative morbidity unless the technique concomitantly reduces the surgical stress response, particularly in the high-risk patient. Sympathetic nervous system activation can have detrimental effects on the cardiovascular system, protein metabolism and metabolic rates [23,24]. These responses could seriously affect high-risk children with cardiac diseases and those with poor nutritional status.
The combined i.v. fentanyl and caudal block is not without complications. Intravenous fentanyl at a dose of 1 μg kg−1 added to caudal anaesthesia was not found to show any advantage in analgesic efficacy over a control group given only caudal block and, moreover, this dose only caused more postoperative vomiting and nausea episodes . Similarly, in our study, there were more patients in the fentanyl group who experienced emetic episodes and nasal pruritus, albeit not to a degree of statistical significance. Nonetheless, all these patients were treated appropriately, with a good response, and were discharged from the outpatient surgery unit within 10 h.
The present study determined the effect of a balanced multimodal analgesia regimen in diminishing the response of the sympathetic nervous system. For more reduction of the stress response, as measured by the plasma catecholamine levels, the combination of multiple analgesic techniques using low-dose i.v. fentanyl with caudal epidural block added to general inhalational anaesthesia provided a partially advantageous effect over the caudal block with inhalational agent alone. The relative benefit of the multimodal approach on the epinephrine blood level may promote further similar studies on the use of non-opioid systemic analgesics and lower concentrations of local anaesthetics and their effect on the stress response hormones.
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