A Comparative Study of Intrathecal Injection of Bupivacaine Alone or with Fentanyl, Clonidine, and Neostigmine in Lower Abdominal Surgeries

Background: Anesthesiologists are responsible for the development of pain services in the current era. Hence ideal adjuvants that can be used with bupivacaine for stable intraoperative conditions and prolonging the postoperative analgesia with fewer side effects are being investigated. Opioids, despite useful as adjuvants, are associated with undesirable side effects. Aim of the work: The study was done to compare analgesic efficacy and hemodynamic of intrathecal injection of bupivacaine alone or with fentanyl, clonidine, and neostigmine in lower abdominal surgeries, over the first 24 postoperative hours, in a randomized, double-blind, and clinical trial. Methods: 100 Patients were randomized into four equal groups, 25 patients in each group; Group B patients received 2.5 ml of 0.5% hyperbaric bupivacaine and 0.5 ml of normal saline. Group BF patients received 2.5 ml of 0.5% hyperbaric bupivacaine with (25 mics) of fentanyl. Group BC patients received 2.5 ml of 0.5% hyperbaric bupivacaine with 0.5 ml (75 mics) of clonidine. Group BN patients received 2.5 ml of 0.5% hyperbaric bupivacaine with 0.1 ml of neostigmine (50 mics) and 0.4 ml of normal saline. Intrathecal anesthesia was done with a recording of parameters intraoperative and the post-operative period. Each patient was assessed for hemodynamic parameters and effective analgesia in operation, and presence of complications (nausea, vomiting, sedation and pruritus) visual analogue pain score (VAS) postoperatively by a blinded investigator in the post-anesthesia care unit (PACU) and at 1, 2, 3, 4, 8 12, 18 and 24 h postoperatively. Results: The postoperative analgesia is more effective with group BC (the gold standard) than group B, group BF, and group BN. As regard complications during the study in all groups, complications as nausea, and vomiting were mainly with group BN; hypotension was primarily in group BC. Conclusion: Bupivacaine clonidine, bupivacaine neostigmine, and bupivacaine fentanyl intrathecal anesthesia produced a longer duration How to cite this paper: Abdelzaam, E.M. and Elrahman, A.H.A. (2019) A Comparative Study of Intrathecal Injection of Bupivacaine Alone or with Fentanyl, Clonidine, and Neostigmine in Lower Abdominal Surgeries. Open Journal of Anesthesiology, 9, 83-98. https://doi.org/10.4236/ojanes.2019.94009 Received: March 19, 2019 Accepted: April 27, 2019 Published: April 30, 2019 Copyright © 2019 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/


Introduction
Transmission of pain from peripheral tissues to higher centers in the brain is adjusted in the dorsal horn of the spinal cord. Incoming messages can be increased or decreased by different transmitters derived from either primary afferent A delta and C fibers, interneurons or descending bulbospinal fibers. After noxious stimulation, excitatory neurotransmitters are released from afferent fibers. Compensatory inhibitory neurotransmitters include (norepinephrine and acetylcholine). Therefore, an interplay between excitatory and inhibitory spinal neuronal systems will detect the message conveyed to higher levels of the central nervous system. Increased understanding in spinal processing of pain has to lead to the development of specific drugs that inhibit pain transmission without motor blockade [1].
Intrathecal opioid and local anesthetic combination are popular for analgesia because of rapid, effective pain relief, but the duration of analgesia is limited. This study will be done to detect whether the addition of, fentanyl and neostigmine to intrathecal bupivacaine will increase the length of analgesia without increasing complications for patient [2]. Bupivacaine is the most commonly employed local anesthetic for a subarachnoid block but has a limited duration of action. Perioperative hemodynamic status is also a concern. Opioids, in spite of useful as adjuvants, are associated with undesirable complications. Therefore, ideal adjuvants that can be used with bupivacaine for stable intraoperative conditions and prolonging the postoperative analgesia with fewer complications are being investigated [3].
Intrathecal local anesthetic acts by inhibiting voltage-gated sodium channels in the spinal cord, which interferes with afferent and efferent sensory and motor impulses. The degree of sensory and motor block depends on technique, agent, and dose administered. Opioids act in the intrathecal space by activating opioid receptors in the dorsal gray matter of the spinal cord, which adjusts the function of afferent pain fibers [4].
Clonidine, a selective alpha two agonist agent, routinely used as a premedication for general anesthesia decreases the requirement of analgesics and anesthetic drugs intraoperative. Intrathecal clonidine produces analgesia by indirectly inhibiting the activity of wide dynamic range (WDR) neurons [5]. it releases acetylcholine to provide analgesia. Clonidine also has an intrinsic block of A delta and C-fibers at lamina, utilizing that, generating analgesia [6].
Clonidine has been used by oral, epidural, spinal, perneural and parenteral routes to achieve postoperative analgesia [7].
Neostigmine is an anticholinesterase agent which increases the acetylcholine concentrations at cholinergic synapses. Spinal neostigmine activates descending pain inhibitory systems that rely on a spinal cholinergic interneuron, probably exacerbating cholinergic tonus that is already activated during the postoperative period, and seems to be extremely efficient for soothing somatic pain [8].
But intrathecal administration of neostigmine causes well-known complications of nausea and vomiting postoperatively due to a rostral spread of neostigmine to brainstem site [9].

Ethics Committee
After achieving approval by the Benha University Hospital Ethics Committee, and written informed consent from the patient, this study was conducted on 100 patients their ages ranged between 18 and 65 years old, ASA grade I and ІІ of both sexes, from February 2018 to February 2019, randomization was done into four equal groups by lottery method. These patients were scheduled for elective lower abdominal surgeries. All cases were done in Benha University Hospitals after agreed consent of the patients.

Type of Study
A prospective, comparative, double-blind, randomized clinical study.

Inclusion Criteria
1) ASA physical status classes I, II.
3) Type of operation lower abdominal surgeries. 4) Patients were giving valid informed consent.

Exclusion Criteria
Patient refusal: 1) Age < 18 or >65 years; 2) Infection at the site of the injection; 3) Any preexisting neurological disease; 4) The patients with a known history of allergy to local anesthetics drugs;

Group Allocation
Patients were randomly divided into four-study groups of 25 patients each as per computer-generated random number list. The name of the drug to be given was sealed in envelopes numbered 1 -100, which was opened by an anesthesiologist not included in the intraoperative and postoperative care of the patient and prepared in an unlabeled 3 ml syringe. This was then handed over to the attending anesthesiologist in a coded form who was blind to the nature of drug given. 100 patients will be randomly divided into four equal groups: Group I: intrathecal bupivacaine (control group) (B), Group B (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine with 0.5 ml of normal saline.
Group BN (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine along with 0.1 ml of neostigmine (50 mics) and 0.4 ml of normal saline.
They will be compared with regards to sensory characteristics, motor characteristics, hemodynamic stability, and any complications.

Methodology
Anesthetic management: All patients were evaluated one day before surgery initially by medical history

Results
In the current study; One hundred patients were randomly divided into four equal groups each group were 25 patients There were no significant differences between the four groups regard to age, height, and body mass index, sex (male or female) and ASA grade (I or II) ( On comparing the four studied groups as regards the duration of analgesia, There was a highly significant difference between four groups sees to duration of analgesia being the bupivacaine clonidine the longest duration 0f analgesia as   Figure 1. Comparison between the studied groups regarding a sensory level. mean and stander deviation 238.00 ± 125.79 (Table 3).
On comparing the four studied groups as regards the conscious level at 5, 10, and 15 minutes after block there was no significant difference among the four groups, as P value > 0.05 ( Figure 2). Open Journal of Anesthesiology  There was a highly significant difference between four groups regards to requirements of analgesia, being the bupivacaine clonidine the lowest elements of analgesia as mean and stander deviation 74.0 ± 34.4, and the most requirements of analgesia as in group B 191.6 ± 51.3 ( Figure 3).
On comparing the four studied groups as regards the visual analogue scale ( Figure 4)  On comparing the four studied groups as regards the mean arterial pressure    On comparing the four studied groups as regards the heart rate ( Figure 6):  But it showed a significant difference at: On comparing the four studied groups as regards to hypotension (Figure 7), there was significant difference as P value < 0.05, group B: 4 patients, group BF: 3 patients, group BC: 6 patients, group 18 patients. High incidence occurred with clonidine.
On comparing the four studied groups as regards vomiting (Figure 8), there was a significant difference among the four groups as a P value < 0.05, group B: 1 patient, group BF: 2 patients, group BC: 5 patients, group 12 patients, high incidence occurred with neostigmine.
On comparing the four studied groups as regards nausea (Figure 9), there was a significant difference among the four groups as a P value < 0.05, group B3 patients, group BF: 2 patients, group BC: 6 patients, group 10 patients, high incidence occurred with neostigmine.

Discussion
This study was held in Benha University Hospital; to compare between intrathecal injection of bupivacaine alone or with fentanyl, clonidine, and neostig-    Opioid receptors were detected in the central nervous system in 1971 [12] later, in 1977; these receptors were precisely localized in the posterior horn of the spinal cord [13]. The effectiveness of intrathecal opioids relies on their bioavailability. Penetration into medullary tissue is affected by their molecular weight, a degree of ionization, and lipophilicity. Fentanyl and pethidine are absorbed more rapidly than morphine for these reasons. They bind more firmly to neural tissue. Clearance depends on diffusion along the neuraxis, as well as vascular absorption. The drug reaches the cerebellomedullary cistern via distribution where it is absorbed by the arachnoid granulations. This is especially true in the case of morphine.
The present study was conducted on 100 patients of both sexes 18 to 65 years old, with ASA physical status I or II, who were scheduled for lower abdominal procedures. All patients received intrathecal anesthesia. The patients were fortuitously divided into four groups: Group I: intrathecal bupivacaine (control group) (B), group B (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine with 0.5 ml of normal saline.
Group BN (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine along with 0.1 ml of neostigmine (50 mics) and 0.4 ml of normal saline.
They were being compared with regards to sensory characteristics, motor characteristics, hemodynamic stability, and drawbacks.
The patients and monitoring anesthesiologist were blinded to the study solu- medulla, by means of that, producing a reduction in arterial blood pressure. The severity of the arterial hypotension seems to be related to the level of the injection as well as with the drug dose used. In addition, the activation of the alph2-postsynaptic receptors in the brain stem along with the peripheral alph2-presynaptic receptors contributes towards an even greater decrease in arterial blood pressure by reducing sympathetic activity [14].
As regards the need for ephedrine, there was a statistical difference in the use of ephedrine, among the four groups. The highest number of patients who required small titration (6 -15 mg) of ephedrine was in (bupivacaine-clonidine) group was 22 patients. The lowest number was in (bupivacaine-fentanyl) was three patients As regards the heart rate changes assessment among the studied groups, there was an insignificant statistical decrease at baseline, 5, 10, 60 and 90 minutes after injection. But their significant statistical reduction was noticed at 15, and 20 minutes after injection. There was highly substantial statistical decrease at 30 minutes difference was seen between BN group and the other three groups as the heart rate decrease all over the study in Neostigmine group but, not below 70 beats/minutes and did not require any interference.
In addition, the study of heart rate inside each studied group though out the study showed a significant decrease in the heart rate in relation to the baseline which continued for more than 60 minutes after the block. This has appeared in two groups BC & BN groups.
The occurrence of bradycardia was more in the neostigmine groups though the difference was not statistically significant. All the patients responded to intravenous atropine. Neostigmine 50 ug caused bradycardia at 60 -70 min after administration of spinal anesthesia and bradycardia was successfully treated with atropine.
In view of the time for onset of sensory blockade (sec) and the duration of it (min); in the present study, there was a statistically significant difference among the studied groups. The more rapid onset was noticed in the (bupivacaine-neostigmine). As neostigmine increases action of spinally administered local anesthesia, spinal administration of neostigmine, an acetylcholinesterase inhibitor, inhibits the breakdown of the endogenous neurotransmitter acetylcholine, thereby inducing analgesia, hence it is another alternative nonopioid additive to local anesthetics devoid of opioid-associated side effects. And the longest duration of sensory blockade was noticed in the bupivacaine-clonidine) group which could be explained as clonidine produces local vasoconstriction by acting on vascular smooth muscle (alpha receptors), which decreases absorption of local anesthetics from subarachnoid space thereby prolongation the duration of action.
In view of the sedation scale assessment, it showed statistically insignificant differences among the four groups. Only three patients in fentanyl group and two patients clonidine group reached level 3, and two patients in neostigmine group achieved level 2 sedation, and they were easily aroused. this could be ex-Open Journal of Anesthesiology plained by the variability in length and drug response between the patients.
This was in agreement with the study of who studied the combination of intrathecal bupivacaine with fentanyl in different doses and found that dose of fentanyl in a treatment of 25 ug did not produce significant sedation [15].
As regards the visual analogue score (VAS), There was a statistically significant difference among the four groups. The most powerful analgesic agent is intrathecal clonidine combined with bupivacaine followed by bupivacaine-fentanyl.
There was also the time-related decrease in VAS in relation to the baseline in each studied group (inside each group, in the four groups) started with the onset of action of analgesia and continued throughout the time of the study.
As regards adverse effects hypotension most occurred in a group (bupivacaine-clonidine), nausea and vomiting most happened in a group (bupivacaine-neostigmine). That also is in the study done by [16]. There was significant difference in nausea where group (bupivacaine-neostigmine) BN had the highest incidence (10 patients) and the lowest incidence with (bupivacaine-fentanyl) group (2 patients) the nausea was mild and responding well to the second dose of metoclopramide 10 mg. However, in Gupta S study, hypotension in the group receiving neostigmine 75 ug was more than the other group receiving 50 ug.
Intrathecal neostigmine causes nausea in a dose-dependent manner. This high occurrence of nausea and vomiting could be due to cephalad migration of neostigmine to the brain stem where it produces an accumulation of acetylcholine.
This increased acetylcholine leads to vomiting by stimulating the chemoreceptor trigger zone. The injection of neostigmine in hyperbaric dextrose solution while maintaining the patient in head up position reduces the incidence of vomiting [17].
In another study show that the administration of intrathecal neostigmine 25 ug/kg with bupivacaine leads to increased the duration of sensory, motor block and also time to the first rescue of analgesia compared to the control group after lower limb surgeries [18]. This is a present study in agreement with a study done by Kothari et al., that found 35% to 45% of patients drowsy by addition of 50ug of clonidine to bupivacaine [19].
Also, this study in agreement with another research which studies the effect of intrathecal fentanyl (12 -25 ug) when added to different doses of bupivacaine (3 -5 mg) in postoperative analgesia for knee arthroscopy, that found the addition of fentanyl lead to decrease the failure rate and improve the visual analogue score [20].

Conclusion
Bupivacaine-clonidine mixture had the longest duration of analgesia, but with an increased incidence of hypotension. So bupivacaine-fentanyl mixture with moderate duration of analgesia and fewer complications is the safest for the patients.