|Year : 2019 | Volume
| Issue : 3 | Page : 423-429
Esmolol infusion reduces blood loss and opiate consumption during fertility preserving myomectomy
Jehan Mohammad Ezzat Hamed1, Walid Mamdouh Ataalla2
1 Department of Anesthesia and ICU, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Obstetrics and Gynecology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Web Publication||20-Sep-2019|
Jehan Mohammad Ezzat Hamed
Department of Anesthesia and ICU, Faculty of Medicine, Tanta University, El-Geish Street, Tanta 31527
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objectives: The objective of this study is to evaluate the effect of esmolol-induced hypotensive anesthesia (EIHA) on intra-operative (IO) bleeding during open myomectomy. Patients and Methods: Eighty-eight women were randomly divided into the study group received EIHA without uterine tourniquet and control group who received normotensive anesthesia with uterine tourniquet. EIHA was provided as priming dose of esmolol (0.5 mg.kg-1) before the induction of anesthesia and esmolol infusion (0.05-0.3 mg.kg-1.min-1) to maintain mean arterial pressure at 60–70 mmHg that was stopped on completion of myomectomy. Fentanyl was used as IO analgesia (loading dose: 1.0 μg.kg-1 then infusion of 0.2-0.4 μg.kg-1.h-1). All patients received 6% hydroxyethyl starch (HES; initially, 3 mL.kg-1 over 5-10 minutes and supplemental doses according to requirements) and Lactated Ringer's solution (LR; 5 mL.kg-1.h-1). Trigger for blood transfusion was hemoglobin concentration (HBC) <7 g.dL-1. Study outcomes included the extent of postoperative (PO) HBC deficit in relation to preoperative HBC, frequency of tourniquet application for the study patients, and total fentanyl consumption. Results: EIHA significantly reduced blood pressure measures since laryngoscopy and tracheal intubation till the end of surgery in the study group compared to control group. Eight study patients (18.9%) required tourniquet application for control of bleeding; however, amount of IO blood loss; total field visibility score and PO HBC deficit were non significantly lower in the study group. EIHA allowed significant reduction of the IO amount of LR and additional amounts of HES infusions. Study patients group consumed significantly lower IO fentanyl doses with significantly longer duration till the 1st PO request and the number of additional fentanyl, and lower numeric rating scale scores in study group compared to controls. Conclusion: Open myomectomy under EIHA is feasible and safe and allows fertility-sparing with minimal risk of blood transfusion. The applied procedure of EIHA allowed blunting of pressor reflexes secondary to LIT, surgical stresses and extubation, and allowed reduction of IO and PO opioid doses.
Keywords: Bleeding, esmolol, fentanyl, hemoglobin deficit, hypotensive anesthesia, myomectomy
|How to cite this article:|
Hamed JM, Ataalla WM. Esmolol infusion reduces blood loss and opiate consumption during fertility preserving myomectomy. Anesth Essays Res 2019;13:423-9
|How to cite this URL:|
Hamed JM, Ataalla WM. Esmolol infusion reduces blood loss and opiate consumption during fertility preserving myomectomy. Anesth Essays Res [serial online] 2019 [cited 2020 Jan 19];13:423-9. Available from: http://www.aeronline.org/text.asp?2019/13/3/423/266749
| Introduction|| |
Esmolol is a unique cardioselective β1-adrenergic receptor antagonist with strongly β1 selective activity at usual clinical doses. Esmolol is highly effective in the prevention and treatment of tachycardia secondary to sympathoadrenal system activation during anesthesia induction and intra-operative (IO) period.
Esmolol may be administered by intermittent, intravenous bolus doses, or by continuous infusion, but infusions should be preceded by loading doses. Low dose of esmolol might induce vasodilator effect, resulting in changes in the resistance of vessels and thus provides perioperative cardiac safety, stable IO hemodynamics, and protection against surgical stress response.
Esmolol is ultrashort acting drug for being metabolized by red blood cell esterases, resulting in a 9-min half-life, and at 15-min after a bolus dose, esmolol is difficult to detect in the plasma, hence, esmolol dosing regimen must vary with the patient's status, clinical situation, concomitant medications, and desired result and duration of surgery. Esmolol administration may be associated with increased risk of hypotension, and hence, continuous monitoring of patients receiving esmolol is mandatory.
Uterine myomas are the most common benign tumors in women of reproductive age  with an estimated prevalence of up to 15%–50% after the age of 35 years. Uterine fibroids can significantly impact woman's health, fertility, and quality of life  through induction of recurrent attacks of abnormal uterine bleeding, pelvic pressure manifestations, and low back pain. However, uterine myomas may be discovered incidentally during routine gynecological evaluation.
Uterine fibroids are manageable by surgical or pharmacological approaches, but myomectomy is the standard surgical treatment when fertility-sparing is claimed. However, IO bleeding during myomectomy is still a challenge as it can necessitate emergency blood transfusion if excessive or was life-threatening.
Numerous medical and surgical techniques were tried to minimize potentially significant blood loss during myomectomies. Preparation using gonadotropin-releasing hormone analogs for 3-month treatment before myomectomy  or prophylactic tranexamic acid treatment were tried to reduce operative bleeding during abdominal myomectomy. Hypotensive anesthesia allowed significant decrease of blood loss without compromising vital organ perfusion  and subsequently reduces transfusion requirements and minimizes allogenic transfusions risks.
This study hypothesized that esmolol-induced hypotensive anesthesia (EIHA) can reduce IO bleeding down to a level that can allow sparing tourniquet use.
The study design involves prospective comparative clinical trial.
The study was conducted at tertiary referral hospital, KSA.
| Patients and Methods|| |
This prospective study was conducted in the Departments of Gynecology and Anesthesia from January 2016 to March 2019. The study protocol was approved by the Local Ethical Committee. All enrolled women and/or their husbands signed a fully informed written consent for the study participation and receiving the assigned lines of anesthetic and surgical management. Inclusion criteria included women in the childbearing period, had large or multiple myomas, presenting by infertility or dysfunctional uterine bleeding and assigned for fertility-preserving myomectomy.
Patients with gynecological malignancy, acute uterine bleeding, American Society of Anesthesiologists physical status Classes III or IV, cardiovascular disease, hypertension, bleeding diathesis, and maintained on aspirin or other medications affecting coagulation system and patients with kidney or liver dysfunctions were excluded from the study. Clinical evaluations entail the collection of demographic data including age and body mass index data. All patients underwent complete gynecological examination, transvaginal ultrasonography and underwent routine laboratory investigations including complete blood count. Women with hemoglobin concentration (HBC) of <7 g.dL -1 received preoperative blood transfusion to adjust HBC at ≥8 g.dL -1.
Randomization and grouping
Randomization was conducted using sealed envelopes-containing cards carrying the group label and prepared by an assistant who was blinded about target for each group and envelopes were chosen by patient herself. Patients fulfilling the inclusion criteria were randomly allocated into two equal groups according to the applied anesthetic procedure and use of IO tourniquet as Control group which included patients who will receive normotensive anesthesia and uterine tourniquet for control of bleeding and study group which included patients who will receive EIHA and no uterine tourniquet.
Heart rate (HR), systolic blood pressure (BP), diastolic BP and mean arterial pressure (MAP) were noninvasively determined in patients of the study group with the patient in the supine position. Esmolol was given as an intravenous bolus dose of 0.5 mg.kg -1 diluted in 10 mL of 0.9% normal saline as priming dose before the induction of anesthesia. Then, esmolol infusion was started at rate of 0.05-0.3 mg.kg -1.min -1 to maintain MAP of 60-70 mmHg until the completion of myomectomy; then, esmolol infusion was stopped to allow restoration of BP before end of surgery to allow perfect hemostasis.
All patients were premedicated with midazolam (0.05 mg.kg -1), 2 min before induction of anesthesia. For patients of both groups, anesthesia was induced using propofol 2 mg.kg -1, fentanyl 1-2 μg.kg -1, and rocuronium 0.6 mg.kg -1. Balanced anesthesia was continued with sevoflurane, fentanyl, and rocuronium according to patient's physiological reaction to surgical stimuli and after tracheal intubation, the lungs were ventilated with 100% O2 in the air using a semi-closed circle system for a tidal volume of 6-8 mL.kg -1, and the ventilatory rate was adjusted to maintain an end-tidal carbon dioxide (paCO2) of 32-35 mmHg. Patients were continuously noninvasively monitored for MAP and HR. IO analgesia for patients of both groups was provided as a loading dose of fentanyl (1.0 μg.kg -1) over 1 min followed by a continuous infusion of 0.2-0.4 μg.kg-1.h -1 according to need to reduce surgical stress effect on BP measures to maintain the target pressure. At end of surgery, residual neuromuscular blockade was reversed with intravenous injection of neostigmine 0.05 mg.kg -1 with atropine 0.02 mg.kg -1 i.v., patients were extubated and transferred to the postanesthetic care unit (PACU).
Fluid therapy targets and policies
Both groups received an initial bolus of 6% hydroxyethyl starch in saline (6% HES 130/0.4; Voluven) in a dose of 3 mL.kg -1 over 5–10 min and lactated Ringer's (LR) solution in a dose of 5 mL.kg -1.h -1 throughout operative time. IO supplemental fluid therapy consisted of additional blouses of HES according to the targeted BP of each study group. The target for the study group was to maintain MAP in the range of 60-70 mmHg and ≥75 mmHg in the control group with urine output (UOP) >0.5 mL.kg -1.h -1 for both groups.
Intraoperative collected data
- Hemodynamic response to stress during intubation
- Total dose of fentanyl required to control intubation and surgical stress response
- The frequency of the need for tourniquet and/or vascular clamps application for patients of the study group to control bleeding and allow field visibility
- Surgical field bleeding and filed visibility was graded using 6-point scale: (0) no bleeding, (1) slight bleeding not necessitating evacuation, (2) slight bleeding that sometimes needed to be evacuated, (3) low bleeding, blood has to be often evacuated and operative field is visible after evacuation, (4) average bleeding, blood has to be often evacuated and operative field is visible only right after evacuation and (5) high bleeding and constant blood evacuation is needed, but sometimes bleeding exceeds evacuation and surgery is hardly possible or impossible at all 
- Amount of IO blood loss calculated as the sum of the amount of blood collected in the empty suction canister and the calculated net weight of gauze swabs (wet-dry weight) and supposing the density of blood equals the unit, so volume equals the weight
- Calculated amount of UOP.
- Postoperative (PO) HBC was estimated, and the trigger for blood transfusion was a concentration <7 g.dL -1. The percentage of decrease of HBC was calculated as preoperative minus immediate PO concentration divided by the preoperative HBC and multiplied by 100
- PO pain scoring and management plain: At PACU, patients were monitored for pain sensation, for 24-h PO, using 11-point numeric rating scale (NRS) with numbers from 0 to 10 where 0 indicates no pain and 10 indicates worst pain imaginable. NRS was chosen for being more practical than the graphic visual analog scale, easier to understand for most people, and does not need a clear vision, paper, and pen. Rescue analgesia was provided as continuous fentanyl infusion of 0.2 μg.kg -1.h -1 to maintain NARS of <4 and a fentanyl shot-dose of 0.2 μg.kg -1 was given on NARS of 4 and patients' request
- Noninvasive monitoring of HR and MAP.
- Primary outcome was the extent of PO HBC deficit in relation to preoperative HBC
- Secondary outcome:
- Success rate of EIHA to control IO bleeding that was evaluated as the frequency of the need for tourniquet application to control IO blood loss to improve field visibility
- Total IO and PO fentanyl consumption.
Sample size calculation
Previously, Alobaid et al. reported a drop in HBC after myomectomy with the uterine vascular cut-off technique of 1.23 g.dL -1 Considering the primary outcome measure was the extent of PO HBC deficit in relation to preoperative HBC; the current study supposed to achieve an HBC deficit similar to that previously reported by Alobaid et al. and to detect nonsignificant difference between both groups with effect size (ρ) of 0.26, an α value of 0.06, and β value of 0.2, the calculated total sample size was 83 patients.
Obtained data were presented as a mean ± standard deviation, median, numbers and percentages. Results were analyzed using one-way ANOVA test, Mann–Whitney test for median value, and Chi-square test for nonnumerical data. Statistical analysis was conducted using the IBM SPSS (Version 23, 2015; IBM, South Wacker Drive, Chicago, USA) for Windows statistical package. P value <0.05 was considered statistically significant. Value of P < 0.05 was considered statistically significant.
| Results|| |
One-hundred and thirteen patients presented with manifestations of myoma disease were assessed for enrolment; 25 patients were excluded for not fulfilling inclusion criteria and 88 patients were eligible for randomization [Figure 1]. Enrollment data of patients of both groups showed nonsignificant (P > 0.05) differences, as shown in [Table 1].
Esmolol infusion allowed perfect control on surgical stress responses as manifested by the proper control on IO measures of HR and BP that were significantly lower than that reported in patients of the control group. Moreover, the adjusted rate of esmolol infusion allowed MAP to be maintained at the targeted level until the completion of myomectomy. Interestingly, esmolol bolus given before the induction of anesthesia allowed control on tracheal intubation-induced vasopressor reflex as manifested by the significantly lower HR and BP measures reported during laryngoscopy and tracheal intubation (LTI) in the study compared to control group. Furthermore, the hemodynamic control of esmolol do not fade away rapidly on discontinuation of infusion as manifested by the reported significantly lower MAP at 10-min (P = 0.00011) and 20-min (P = 0.037) after infusion stoppage on completion of myomectomy in comparison to patients who did not receive esmolol infusion [Table 2] and [Figure 2].
|Figure 2: Mean arterial pressure measures reported in patients of both group till 20-min after completion of myomectomy|
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Operative time showed nonsignificant difference between both groups. Eight of the study patients (18.9%) required tourniquet application for control of bleeding and improving field visibility. However, the amount of IO blood loss was nonsignificantly lower with nonsignificantly lower total field visibility score in patients of the study group. Twenty-five patients (28.4%) required preoperative transfusion and 19 patients (21.6%) required IO or PO transfusion with nonsignificant differences between patients of both groups. Mean HBC deficit showed nonsignificant difference between patients of both groups; however, in comparison to preoperative HBC, the percentage of HBC deficit was significantly lower with EIHA than with tourniquet. The median number of transfused blood units was 2 (IQR: 1–2) with nonsignificant difference between both groups. Moreover, esmolol hypotensive anesthesia allowed significant reduction of the additional amount of HES (P = 0.011) and amount of LR (P = 0.026) infusions used during surgery to maintain BP measures [Table 3].
Another interesting finding for esmolol infusion was the significantly reduced use of IO fentanyl both as a loading dose and total amount used as IO infusion and as total IO consumption. Concerning PO data, duration till the first request of additional fentanyl was significantly longer in patients of the study group with significantly lower NRS scores and significant reduction of number of requests of additional fentanyl doses than in patients of control group. Moreover, total IO and PO consumption of fentanyl was significantly lower in patients received esmolol infusion than in patients who did not receive esmolol infusion [Table 4].
|Table 4: Postoperative pain and analgesic data of patients of both groups|
Click here to view
| Discussion|| |
Priming of patients of study group using a bolus of esmolol before induction of anesthesia allowed control of patients' pressor reflexes to LTI, as manifested by the significantly lower HR and BP measures in patients of study compared to control group. These findings go in hand with previous studies that reported significant blunting of pressor reflexes to LTI with esmolol injection compared to placebo, diltiazem  and lidocaine., In support of the efficiency of the priming dose of esmolol, Thiruvenkatarajan et al. screened the published databases for randomized controlled trials comparing the effect of esmolol and placebo on the corrected QT (QTc) interval prolongation associated with LTI in patients undergoing cardiac and noncardiac surgeries and found esmolol significantly reduced the QTc and protected the heart against intubation-induced arrhythmias.
Furthermore, esmolol infusion perfectly controlled surgical stress-induced pressor reflexes and could maintain MAP within the targeted range during myomectomy. Similarly, Zhang et al. found IO esmolol can effectively reduce the cardiovascular responses in operation, sustain hemodynamic stable, reduce myocardial oxygen consumption, and prevent perioperative adverse cardiovascular events during laparoscopic surgery for gastrointestinal cancer. Also, Verma et al. and Bhattacharjee et al. in placebo-controlled study, found both esmolol and diltiazem  and dexmedetomidine  infusions, provided stable IO hemodynamics and protected against stress response triggered by pneumoperitoneum during laparoscopic surgery, but esmolol significantly lowered HR and BP than in diltiazem at the creation of pneumoperitoneum.
Esmolol infusion was found to be still effective for BP control till 20-min after infusion stoppage, this allowed the gradual resumption of BP giving chance for proper hemostasis and allowed safe extubation. These findings go in hand with previous studies reported higher efficacy for esmolol infusion for control of pressor reflexes during and after extubation.,
Eight of study patients (18.9%) required tourniquet application for control of bleeding and improving field visibility. However, esmolol hypotensive anesthesia allowed nonsignificant reduction of the amount of IO blood loss, number of patients required transfusion and PO HBC deficit, but significantly reduced the additional fluid therapy. These findings go in hand with previous studies used esmolol hypotensive anesthesia during nasal, scoliosis, functional endoscopic sinus, and breast reduction surgeries.
The reported improved field visibility (35 compared to 26 had score 0–1) with EIHA despite of the nonsignificant amount of blood loss between patients of both groups could be attributed to vasoconstriction of the mucous membrane arterioles and precapillary sphincters that resulted from unopposed α-adrenergic effects of endogenous catecholamines and the increased sympathetic tone.
Interestingly, patients received esmolol infusion consumed significantly lower dose of IO and PO fentanyl; a finding suggesting an analgesic effect for esmolol. These findings go in hand with Ono et al. who experimentally, found intrathecal administration of esmolol produced antinociceptive effects of short duration in a rat PO pain model. Clinically, Lee et al. found pretreatment with esmolol or remifentanil equally decreased pain during propofol injection with no significant differences in pain incidence or severity. Thereafter, Vahabi et al. documented that IO esmolol infusion is a valid method to reduce PO pain and provide lesser need to analgesics with hemodynamic stability in the first 3 h of after rhinoplasty surgery. The finding of the current study regarding PO pain scores and requests for additional fentanyl doses was in line with that reported by Vahabi et al. and are in accordance with the findings reported by Gelineau et al. who performed a meta-analysis to determine if IO use of esmolol reduces opioid consumption or pain scores and found it significantly decreased IO opioid consumption in 433 patients from 7 trials, and in 659 patients from 12 trials, IO esmolol significantly decreased PACU opioid consumption, so concluded that IO esmolol use reduces both IO and PO opioid consumption.
On contrary to the results of the current study and that previously reported in the literature, Ander et al. using a group of healthy volunteers reported no direct analgesic effect of esmolol and attributed the PO opioid-sparing effect of esmolol, demonstrated in previous studies, to other factors such as avoidance of opioid-induced hyperalgesia, synergy with co-administered opioids, or altered pharmacokinetics of those drugs. However, the findings provided by Ander et al. could be criticized for the evaluation of esmolol in healthy persons with competent body systems and were free of preadministration stresses and surgical pain surely overweighs that secondary to cold pressor test. In support of these criticisms, Kim et al. suggested that esmolol played an immunomodulatory role and mitigated PO inflammatory response in patients under surgical and anesthetic stress. Thereafter, in placebo-controlled study, Kim et al. reported significantly reduced serum levels of nociceptive inflammatory cytokines; interleukin-6 (IL-6), IL-4, and IL-10 in IO and PO serum samples with significantly lower CRP levels on day-1 PO in esmolol-treated groups, in a dose-dependent manner. Furthermore, Dhir et al. found intravenous esmolol influences the IO and PO analgesic requirements by modulation of the sympathetic component of the pain.
| Conclusion|| |
Open myomectomy for large and/or multiple under esmolol-induced hypotensive anesthesia is feasible and safe and allows fertility-sparing with minimal risk of blood transfusion. The applied procedure of esmolol use allowed blunting of pressor reflexes secondary to LIT, surgical stresses and extubation. IO Esmolol infusion allowed reduction of IO and PO opioid doses. However, wider scale comparative studies are mandatory to establish the antinociceptive effect of esmolol and its probable mechanisms.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]