Surgery induces a combination of endocrine, metabolic, and immunologic responses of varying clinical significance. The intensity of these surgical stress responses depends on the severity and duration of tissue injury.1,2 A stress response is a significant risk factor for an unsatisfactory outcome, especially in patients with cardiovascular disease, endocrine, metabolic, and immune disorders, as well as in patients with infections and immunosuppression.3 Thus, intraoperative modulation of the stress response may potentially reduce the incidence of postoperative complications and morbidity.4,5
Clinically, combining epidural with general anesthesia may be advantageous to patients undergoing major thoracic, abdominal, or orthopedic surgery. Epidural anesthesia can attenuate sympathetic hyperactivity and blunt the surgical stress response, spare the use of opioids, and facilitate the postoperative feeding and physiotherapy.6–9 However, placing an epidural catheter is not without risks and contraindications, including technical failure, unintentional dural puncture, back pain, and local anesthetic toxicity.10–12 When neurologic complications occur, the resulting morbidity and mortality can be catastrophic.
Dexmedetomidine is a potent α2-adrenoceptor agonist with an 8 times greater affinity to α2-adrenoceptors than to clonidine. This class of agents is known to have sedative-, anxiolytic-, antishivering-, analgesic-, and anesthetic-sparing effects.13–17 In addition, α2-adrenoceptor agonists reduce central sympathetic outflow and attenuate the stress response associated with surgery18 and are easier to administer when compared with epidural analgesia. However, the degree to which these 2 modalities reduce the stress response has not been directly compared.
We hypothesized that when used in conjunction with total IV anesthesia (TIVA) for abdominal surgery, dexmedetomidine reduces the surgical stress responses to an extent comparable to epidural anesthesia.
The study protocol was approved by the ethics committee of The Second Affiliated Hospital of Anhui Medical University and registered at http://www.clinicaltrials.gov (NCT01657812), and written informed consent was obtained from each patient. Inclusion criteria included all patients aged 18 to 65 years scheduled for open gastrectomy, with no contraindication to epidural or dexmedetomidine; ASA physical status I and II; and body mass index <30 kg/m2. Obese patients as well as patients with pulmonary, cardiac, renal, hepatic, cerebrovascular, or psychiatric diseases were excluded from the study. Patients were randomized into 3 groups by a computerized random-number generator: a control group receiving TIVA only (group C); an epidural group (group E) receiving epidural anesthesia and TIVA; and a dexmedetomidine group (group D) receiving IV dexmedetomidine and TIVA. All patients had their surgery performed by the same operative team.
No preoperative sedatives or analgesics were administered before arrival to the operating room. All patients received a standard IV infusion of 10 mL/kg lactated Ringer’s solution. Before induction of anesthesia, routine monitoring was established, including pulse oximetry, electrocardiogram, invasive arterial blood pressure, and end-tidal carbon dioxide. In group E, an epidural catheter was placed at the T8-T9 interspace with the use of the paramedian approach and loss-of-resistance to saline technique. After successful epidural placement and before induction, 4 mL of 1.6% lidocaine was given as a test dose. The block was then established before induction with 5 mL of 0.375% ropivacaine followed by a continuous epidural infusion of the same concentration of solution at 5 mL/h during surgery. The level of anesthesia was determined by loss of pinprick sensation, with the aim being a segmental blockade of levels T4–T11. Patients were excluded from the study if epidural anesthesia could not be successfully established. Group D received an initial loading of dexmedetomidine at 0.6 μg/kg administered IV over 15 minutes before induction, followed by an infusion rate of 0.4 μg/kg/h until peritoneal closure. Groups C and group E received an IV infusion of 0.9% saline over 15 minutes, followed by continuous infusion until peritoneal closure.
General anesthesia was induced in all 3 groups with target-controlled infusion of propofol (AstraZeneca S.P.A., Macclesfield, UK) aiming at a plasma concentration of between 3.0 and 3.5 μg/mL, bolus remifentanil 1.5 μg/kg (Yichang Humanwell Pharmaceutical Co., Ltd., Yichang, China), and rocuronium 0.6 mg/kg (N.V.Organon, Oss, The Netherlands). After tracheal intubation, ventilation was established with variables adjusted to target an end-tidal carbon dioxide between 35 and 45 mm Hg. Anesthesia was maintained with IV remifentanil (0.2–0.3 μg/kg/min), target-controlled infusion propofol, and cisatracurium besylate (0.1 mg/kg/min). During the operation, bispectral index (BIS) values were maintained within 45 ± 5 by regulating the infusion rate of propofol in all groups. After the peritoneum was closed, cisatracurium besylate infusion was stopped. Propofol and remifentanil were turned off in all 3 groups after wound closure.
Intravascular volume treatment was controlled in all 3 groups with crystalloids and colloids to keep the patient in stable fluid balance. Bradycardia (heart rate [HR] <40 beats/min) was treated with IV atropine 0.5 mg. Hypotension, defined as mean arterial blood pressure (MAP) <60 mm Hg, was treated with IV phenylephrine 0.1 mg. All patients in group D and group C received a bolus of morphine (0.05 mg/kg) at incision and peritoneal closure. Body temperature was maintained between 36°C and 37°C with a forced air-warming blanket (WarmTouch, Nellcor; Tyco Healthcare, Pleasanton, CA) during the whole procedure.
Oral suction was performed when the surgery was completed, and reversal agents (atropine 0.02 mg/kg and neostigmine 0.04 mg/kg) were given after adequate recovery of neuromuscular blockade. The endotracheal tube was removed when patients were able to follow verbal commands to open their eyes and the T4/T1 ratio was 90%. Patients were kept in the postanesthesia care unit (PACU) for 2 hours.
The MAP and HR were continuously measured and recorded before administration of dexmedetomidine or epidural anesthesia (baseline), before induction, before tracheal intubation, after tracheal intubation, incision, at the time of celiac exploration, and immediately after tracheal extubation. The number of patients requiring treatment with atropine or phenylephrine was noted. Duration of anesthesia, surgical duration, anesthetic consumption, and recovery profiles (the time periods between cessation of propofol and eye opening, and cessation of propofol and tracheal extubation, side effects such as nausea, vomiting, and shivering in the PACU) were recorded.
Emergence was defined as the time interval from end of surgery to 2 minutes after extubation. During emergence, the level of agitation was evaluated with the Ricker sedation-agitation scale19: 1 = minimal or no response to noxious stimuli; 2 = arouse to physical stimuli but does not communicate; 3 = difficult to arouse but awakens to verbal stimuli or gentle shaking; 4 = calm and follows commands; 5 = anxious or physically agitated and calms to verbal instructions; 6 = requiring restraint and frequent verbal reminding of limits; and 7 = pulling at tracheal tube, tries to remove catheters, or strikes at staff. Emergence agitation was defined as any score on the sedation-agitation scale ≥5. The highest score for any individual patient during emergence was recorded for comparison.
Plasma levels of norepinephrine (NE), epinephrine (E), and cortisol (Cor) were measured at baseline, immediately after tracheal intubation and extubation, incision, and celiac exploration as were plasma levels of the cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10. All samples were placed in prechilled tubes in ice and centrifuged within 60 minutes, and the plasma was separated and stored at −70°C until analysis. The 3 stress hormones and cytokines were measured with enzyme-linked immunosorbent assay kits (CUSABIO BIOTECH CO., Ltd., Wuhan, China).
This study was powered to detect a difference in the plasma level of E at the time of celiac exploration among the 3 groups with a β value set at 0.1 and α value set at 0.05. We estimated the sample size using the formula
, where ψα,β,k − 1,
and Si, respectively, represent the estimate value of the mean and SD of the i sample,
. The mean and SD values of plasma E among groups from our pilot data were as follows:
, S1 = 10.3 pg/mL, S2 = 13.3 pg/mL, S3 = 16.4 pg/mL, ψ = 2.52, k = 3, and considering a possible 20% dropout rate, a sample with a minimum of 25 patients per group was calculated.
Parametric values were expressed as mean (SD), median (range), or percentages of the total number of patients (%). Thereafter, a 1-way ANOVA (Analysis of Variance) was performed, and post hoc comparisons with the control group were performed by using a 2-tailed Dunnett test for NE, E, Cor, cytokines, and hemodynamic data. Categorical data were analyzed by using χ2 or Fisher exact test as appropriate. A linear mixed-effects model (unstructured) with subject-specific random effect, treatment groups, and time points as fixed effect using the restricted maximal likelihood method was conducted on the NE, E, Cor, cytokines, and hemodynamic data to test for the difference among groups with repeated measurements over time and to assess the interaction among groups and times. The −2 restricted log likelihood was used to assess the statistical model and Akaike information criterion to verify the best correlation structure. The Kolmogorov-Smirnov with Lilliefor correction test was performed for normality of the residuals of each model, and Levene test was used for homogeneity of variances. P value <0.05 was considered statistically significant. All statistical analyses were performed with SPSS 16.0 (SPSS, Chicago, IL).
Ninety patients were assessed for the study, but 2 were excluded based on the exclusion criteria (Fig. 1). There were no baseline differences among groups with respect to age, sex, weight, length of surgery, and anesthesia (Table 1).
There were no statistically significant difference within the groups regarding the basal level of NE, E, and Cor. Compared with group E, there were no differences in group D for all time points regarding the level of NE, E, and Cor (Fig. 2 and Table 2). The values of NE and E were significantly lower in groups D and E compared with group C immediately after tracheal intubation (all P < 0.0001), incision (P = 0.001, P = 0.004; P < 0.0001), celiac exploration (all P < 0.0001), and immediately after tracheal extubation (all P < 0.0001) (Fig. 2 and Table 2). The level of Cor was significantly increased in group C at celiac exploration (P = 0.017, P = 0.019) and immediately after tracheal extubation (all P < 0.0001) compared with groups D and E (Fig. 2 and Table 2).
There was no obvious difference in plasma TNF-α, IL-6, and IL-10 among the 3 groups at baseline. All these levels increased after celiac exploration in all groups (all P < 0.0001 except at celiac exploration in groups D and E, which were 0.015 and 0.003 for TNF-α) (Fig. 3 and Table 3). The IL-6/IL-10 ratio was significantly increased immediately after tracheal extubation in group E (P = 0.011) and after the celiac exploration in group C (P = 0.0002, P < 0.0001) compared with baseline. The levels of plasma TNF-α, IL-6, and IL-6/IL-10 ratio were greater in group C than in groups D and E at celiac exploration (P = 0.005, P = 0.038; P < 0.0001; P = 0.049, P = 0.038) and tracheal extubation (P < 0.0001; P < 0.0001; P < 0.0001, P = 0.002) (Fig. 3 and Table 3). Compared with group E, there were no differences regarding the level of TNF-α, IL-6, and IL-10 in group D for all time points.
Hemodynamic data are presented in Figure 4. HR was significantly slower in group D after IV infusion of dexmedetomidine (all P < 0.0001 except at tracheal extubation which was 0.032) when compared with baseline and group C. In group E, HR was significantly slower at incision and at celiac exploration (P = 0.003, P = 0.006) relative to baseline. MAP in group D was significantly lower before induction than at baseline. In group E, MAP was significantly lower at incision and celiac exploration, relative to baseline (P = 0.006, P = 0.015). The number of patients who required pharmacologic intervention because of intraoperative hypotension was greater in group E (36.7%) than in groups D and C (13.3% and 10.0%) (P = 0.037, P = 0.015).
There were no differences in consumption of propofol and remifentanil between group D and group E but both consumed significantly less compared with group C (P = 0.002, P = 0.018; P = 0.001, P < 0.0001) (Table 4).
The recovery profile was assessed by the time taken from cessation of propofol to eye opening and tracheal extubation. There was no statistically significant difference among groups (Table 4). The incidence of agitation was less in group D (6.7 %) than in group C (26.7%) (P = 0.038) (Table 4). No patients experienced nausea, vomiting, or shivering in the PACU. No other severe adverse effects were observed in any group.
The results of the present study indicate that dexmedetomidine can be used as an adjunct to general anesthesia to suppress stress responses in open gastrectomy surgery. The effects of a combined a dexmedetomidine/TIVA technique on the surgical stress response were comparable to that of a combined epidural/TIVA technique.
The stress response to surgery initiates a predictable cascade of physiologic and metabolic events through direct activation of the sympathetic and somatic nervous systems.20 The effects of combined epidural/general anesthesia on the plasma concentrations of catecholamines and Cor have been investigated in several studies. Some studies have demonstrated that the levels of catecholamines do not increase significantly among patients receiving general anesthesia combined with epidural anesthesia.21,22 Li et al.22 reported that intraoperative epidural analgesia attenuated the plasma concentration of Cor during nephrectomy. The authors hypothesized that epidural blockade attenuates or inhibits surgical stress by preventing afferent neural stimuli from reaching the central nervous system and efferent activation of the sympathetic nervous system.
Dexmedetomidine is a highly specific, potent, and selective α2-adrenoceptor agonist that decreases plasma catecholamine levels by suppressing their release into the plasma. Aho et al.18 found that patients receiving dexmedetomidine before surgery had significantly lower intraoperative catecholamines and Cor levels compared with those who did not receive the drug before surgery. In our study, epidural analgesia and dexmedetomidine significantly reduced the levels of NE, E, and Cor intraoperatively compared with the levels in the control group.
Over the past few years, cytokines and the more accepted stress hormones such as Cor and catecholamines have received attention as mediators of perioperative responses to surgery.1,23 Many clinical studies have shown that proinflammatory and antiinflammatory cytokines are pivotal for the acute-phase inflammatory and immunologic response after surgical trauma, and the most important cytokines in this regard are TNF-α, IL-6, and IL-10.24–26 The release of TNF-α is 1 of the main cytokines that mediate the early response to tissue injury. IL-6 is the primary stimulus for acute responses, and plasma levels of IL-6 are reportedly related to the severity of surgical trauma.27 IL-10 is involved in immunomodulation and has an inhibitory action. IL-10 also has been shown to inhibit the synthesis of IL-6 by monocytes and act as a natural antagonist to inflammatory cytokines in a host-protective manner.28 Moselli et al.29 reported that intraoperative epidural analgesia attenuated the surgery-induced proinflammatory response (TNF-α and IL-6) and increased anti-inflammatory IL-10. In recent years, the antiinflammatory effects of dexmedetomidine have also been evaluated. Studies in animals and in intensive care patients have shown that dexmedetomidine can reduce cytokine secretion, which subsequently alleviates inflammation and reduces mortality.30,31 Plasma TNF-α and IL-6 in our groups had a significantly rapidly increased and circulating IL-10 concentrations also increased during and after surgery, and the level of TNF-α, IL-6, and IL-6/IL-10 ratio was significantly different among groups. Epidural anesthesia and dexmedetomidine seemed to have a significant effect on TNF-α and IL-6 release. The IL-6/IL-10 ratio was related to the prognosis of patients with the systemic inflammatory reaction syndrome with a high ratio indicating poor prognosis.32 Our study certainly suggests that the IL-6/IL-10 ratio was greater in group C than in groups D and E at celiac exploration and tracheal extubation. Thus, with respect to the limitation of surgery-associated stress, epidural anesthesia and dexmedetomidine partially attenuated surgical stress responses among patients undergoing elective open gastrectomy.
The use of α2 agonists in the perioperative period has been associated with attenuated HR and MAP responses to surgical insult. In the present study, hemodynamic variables during the surgical procedures were blunted in groups D and E. HRs were significantly slower in group D relative to group C during most of the intraoperative periods.
Menda et al.33 showed that dexmedetomidine attenuated the increase in HR and MAP during intubation. Several studies have shown that HR decreases after dexmedetomidine injection, which may or may not be associated with a transitory increase in MAP.34–36 A moderate dose of dexmedetomidine was used in this study so as to avoid the side effects usually associated with higher infusion rates, including bradycardia, hypotension, and/or hypertension. Study patients anesthetized with dexmedetomidine did not experience any episodes of bradycardia during surgery.
The effects of α2 agonists on the cardiovascular system may be beneficial in high-risk patients.37 There is a concern that hypotension from epidural blockade may accentuate the cardiovascular depression induced by general anesthesia. Borghi et al.38 reported the induction of general anesthesia in patients with an epidural block increased the odds of clinically relevant hypotension nearly 4 times compared with patients without an epidural block. Our results showed that the incidence of hypotension was higher in group E than in groups D and C.
The anesthetic- and analgesic-sparing effects of dexmedetomidine have been well documented in animal and human studies.39,40 Dutta et al.41 reported that a dexmedetomidine plasma concentration of 0.66 ng/mL reduced the propofol dose required for sedation and induction of anesthesia by 40% to 70%. Previous studies42–44 have shown that epidural anesthesia may reduce anesthetic requirements. In the present study, anesthetic doses required to maintain the same BIS values were significantly reduced by dexmedetomidine and combined epidural/general anesthesia.
Rapid emergence from anesthesia and postoperative recovery are important demands on modern anesthetics. In general, both propofol and remifentanil meet these criteria.45 Some studies suggest that the sedative property of dexmedetomidine delays postoperative recovery and prolongs discharge time.46,47 In our study, the depth of anesthesia was maintained by the same BIS value, and dexmedetomidine was discontinued at peritoneal closure. There was no difference in the groups regarding the time of eye opening and tracheal extubation.
Emergence agitation has been reported in up to 20% of adult patients after general anesthesia.48,49 In several studies, intraoperative administration of dexmedetomidine reduced emergence agitation in children by 57% to 70% compared with control groups.50,51 Kim et al.52 reported that intraoperative dexmedetomidine infusion significantly reduced emergence agitation after nasal surgery in adult patients. Consistent with previous results,52 dexmedetomidine was also effective in reducing emergence agitation in our study.
There are several limitations to this study. First, we used single blinding because the patients in the epidural group had an obvious epidural infusion pump attached to them. The lack of blinding, however, should not have affected the primary outcome of the stress response but may have possibly influenced clinical assessment in the PACU. Second, we only enrolled patients undergoing elective open gastrectomy and excluded patients with ASA physical status ≥III and body mass index ≥30 kg/m2, which limited the external generalizability of our results. Third, it was necessary to give morphine to the dexmedetomidine and control groups for pain relief, and this may potentially have confounded the results. Most significantly, our study focused only on the intraoperative effects of dexmedetomidine or epidural combined with TIVA. This was a short study and it did not assess for functional outcomes such as recovery of bowel function because this may have required a larger study population and a longer study period. Given that the degree of stress response throughout the perioperative period may have affected different outcomes, the results from this study would justify the conduct of a more comprehensive trial involving sicker patients, a longer period of dexmedetomidine administration, the assessment of various functional outcomes, and the measurement of more specific markers such as various ILs and TNF.
In summary, intraoperative infusion of dexmedetomidine reduces surgical stress responses to an extent comparable to epidural anesthesia when combined with TIVA for abdominal surgery, without compromising hemodynamic stability. Further studies are required to see whether the reduction in stress response translates to improved clinical outcomes.
Name: Yun Li, MD.
Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and write the manuscript.
Attestation: Yun Li has approved the final manuscript, attested to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.
Name: Bin Wang, MD.
Contribution: This author helped conduct the study, collect the data, and analyze the data.
Attestation: Bin Wang has approved the final manuscript.
Name: Li-li Zhang, MD.
Contribution: This author helped collect the data.
Attestation: Li-li Zhang has approved the final manuscript.
Name: Shu-fang He, PhD.
Contribution: This author helped prepare and revise the manuscript.
Attestation: Shu-fang He has approved the final manuscript.
Name: Xian-wen Hu, MD.
Contribution: This author helped design the study and supervise the study.
Attestation: Xian-wen Hu has approved the final manuscript.
Name: Gordon T. C. Wong, MD.
Contribution: This author helped design the study and revise the manuscript.
Attestation: Gordon T. C. Wong has approved the final manuscript.
Name: Ye Zhang, PhD.
Contribution: This author helped design the study, supervise the study, sponsor the study, and analyze the data.
Attestation: Ye Zhang has approved the final manuscript and attested to the integrity of the original data and the analysis reported in this manuscript.
This manuscript was handled by: Terese T. Horlocker, MD.
The authors thank Dr. Jun Li from the Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University for revised the manuscript.
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