|Year : 2018 | Volume
| Issue : 3 | Page : 205-212
Adding dexmedetomidine to bupivacaine–fentanyl mixture in high-risk elderly patients undergoing orthopedic surgery: a randomized, double-blind, controlled study
Sohair A Megalla
Department of Anesthesia and Intensive Care, Minia University, Minya, Egypt
|Date of Submission||14-Mar-2017|
|Date of Acceptance||20-Nov-2017|
|Date of Web Publication||31-Aug-2018|
Sohair A Megalla
Department of Anesthesia and Intensive Care, Minia University, Minya, 61519
Source of Support: None, Conflict of Interest: None
Objectives The increased demand for spinal anesthesia in high risk elderly patients with comorbidity dictates the continual search for drug combinations to improve perioperative analgesia while limiting side effects. This study was designed to compare block characteristics, postoperative analgesia and hemodynamic effects associated with intrathecal dexmedetomidine when added to bupivacaine–fentanyl mixture in high risk elderly patients undergoing orthopedic surgery.
Methods This prospective, double blind, randomized controlled study included fifty patients ≥60 years old, of either sex, ASA III and IV undergoing elective orthopedic hip surgery in one lower limb under unilateral spinal anesthesia. The patients were randomized in two groups to receive; Group F: 12.5 mg of 0.5% hyperbaric bupivacaine + 20 μg fentanyl. Group FD: 12.5 mg of 0.5% hyperbaric bupivacaine + 20 μg of fentanyl + 6 μg dexmedetomidine. Block characteristics, hemodynamic changes, postoperative analgesia and adverse effects were studied.
Results The addition of dexmedetomidine (DEX) had no significant impact on the onset or highest level of sensory or motor blockade. DEX, however, significantly increased the duration of sensory and motor block and postoperative analgesia. Average times to first request for analgesia were longer in FD group (522.79±59.0 min) compared to (207.37±20.19 min) in F group (P=0.000). Blood pressure and heart rate changes were not significantly different among both groups. Pruritis was observed in 12% in F Group, whereas sedation was significantly more frequent in Group FD.
Conclusion Addition of 6 μg dexmedetomidine to 12.5 mg bupivacaine + 20 µg fentanyl intrathecally greatly enhanced the duration of postoperative analgesia and was not associated with hemodynamic instability or other complications in high risk elderly patients undergoing orthopedic surgery under unilateral spinal anesthesia.
Keywords: dexmedetomidine, fentanyl, high risk elderly, orthopedic surgery
|How to cite this article:|
Megalla SA. Adding dexmedetomidine to bupivacaine–fentanyl mixture in high-risk elderly patients undergoing orthopedic surgery: a randomized, double-blind, controlled study. Res Opin Anesth Intensive Care 2018;5:205-12
|How to cite this URL:|
Megalla SA. Adding dexmedetomidine to bupivacaine–fentanyl mixture in high-risk elderly patients undergoing orthopedic surgery: a randomized, double-blind, controlled study. Res Opin Anesth Intensive Care [serial online] 2018 [cited 2019 Apr 24];5:205-12. Available from: http://www.roaic.eg.net/text.asp?2018/5/3/205/240268
| Introduction|| |
Lower limb fractures are very common in the geriatric population, and spinal anesthesia is very often used during their surgical repair. Regional anesthesia is the choice in elderly patients owing to lower incidence of postoperative delirium and confusion than general anesthesia . Postoperative pain control is a problem in these surgeries owing to the relatively short duration of action of available local anesthetics.
Many augmentation strategies for intrathecal analgesia have been proposed. A meta-analysis by Popping et al.  concluded that the concomitant use of an opioid such as fentanyl intrathecally allows the reduction in the dose of local anesthetic, while augmenting its analgesic potency thereby decreasing its adverse effects.
Dexmedetomidine (DEX) is a potent, selective α2 adrenergic agonist and when given intrathecally, it exerts its analgesic effect via stimulating spinal α2 receptors . Wu et al. , in their meta-analysis showed that addition of intrathecal DEX significantly increased the duration of postoperative analgesia and reduced analgesic consumption. The increase in duration of postoperative analgesia is dose dependent but with increase in the incidence of bradycardia .
As the analgesic effect produced by intrathecal α2 adrenergic agonists and intrathecal opioids is through different pathways, their combination would lead to additive effects. Therefore, by using low dose of both DEX and fentanyl the incidence of adverse effects of both drugs could be reduced while greatly prolonging postoperative analgesia. This would be beneficial in high-risk elderly patients as it reduces the need for postoperative opiates or NSAIDs.
After extensive literature review, no trials could be found comparing the addition of both DEX+fentanyl to local anesthetic on characteristics of spinal anesthesia, hemodynamic stability, and postoperative analgesia in high-risk elderly patients undergoing orthopedic surgery.
The primary outcome of the present study was duration of postoperative analgesia (time to first analgesic request). Secondary outcome included sensory and motor block characteristics, hemodynamic variations, and adverse effects.
| Patients and methods|| |
This is a prospective, randomized, double-blind controlled clinical trial. It was conducted on patients older than 60 years with ASA status III and IV, undergoing elective orthopedic hip surgery in one lower limb. The study protocol was approved by the ethics committee of our institution. All patients provided written, informed consent before their inclusion into the study. Patients with known hypersensitivity to bupivacaine, fentanyl, or DEX; a history of neurological or psychiatric conditions; or vertebral column deformities were excluded. Patients were randomized into two groups using computer-generated random numbers. The random assignment slip was placed in serially numbered envelopes which were opened following enrollment of the patient. The study solutions were prepared under strict aseptic conditions by an anesthesiologist blinded to the study procedures and did not participate in patient assessment. The anesthesiologist who administered anesthesia and the patients were blinded to the group allocation. As it has become routine in our institution to add opioid to intrathecal bupivacaine for orthopedic surgery, we designated that as the control group and compared the benefits of adding DEX to the mixture.
Group F received 12.5 mg hyperbaric bupivacaine +20 μg fentanyl (total volume 2.9 ml). Group fentanyl–dexmedetomidine (FD) received 12.5 mg hyperbaric bupivacaine +20 μg fentanyl +6 μg DEX (Precedex 200 μg/2 ml vial; Hospira Inc., Lake Forest, Illinois, USA) (total volume 2.96 ml, making no apparently significant volume difference).
Patients received no premedication before arrival into the operation theater. Standard monitoring included continuous ECG, noninvasive blood pressure, and pulse oximetry. Invasive monitoring such as central venous pressure and arterial blood pressure was done only if a specific indication was present. A urinary catheter was placed to monitor urine output.
Before spinal block, each patient received an infusion of 8 ml/kg of lactated Ringer’s solution. Lumbar puncture was performed in the lateral position, with the operative side down, at the L3–L4 interspace with a 25-G Quincke spinal needle using paramedian approach with the bevel towards the desired side. Injections were administered over 15–20 s. After completion of the injection, the patient remained positioned lateral with the fractured side down for at least 20 min. Then the patient was turned supine and properly positioned for surgery. Oxygen at 4 l/min via nasal cannula was given to all patients throughout the surgical procedure. No additional sedative medications were given during the operation.
Vital parameters such as heart rate (HR) and mean arterial pressure were recorded before spinal anesthesia, just after spinal anesthesia, and then every 5 min till the end of surgery. Oxygen saturation was continuously monitored. Hypotension was defined as a systolic blood pressure of less than 90 mmHg or a decrease of more than 25% from the baseline systolic pressure and was treated with an intravenous bolus of ephedrine 5–10 mg and fluids as necessary (5 ml/kg saline). A HR less than 50 beats/min was considered as bradycardia and treated with intravenous atropine in 0.2 mg increments.
Pinprick testing in the midclavicular line every 2 min was used to establish onset and peak level of sensory blockade in the desired limb and contralateral limb, and then every 20 min till the end of surgery. A sensory block level of T10 or higher was required to begin surgery. After 30 min, if anesthetic level was inadequate, general anesthesia was given as necessary, and the patient was removed from the study.
Motor block of lower limbs was assessed bilaterally using modified Bromage scale  as 0=no paralysis, 1=cannot raise extended leg, 2=cannot flex the knee, and 3=cannot dorsiflex the ankle. Assessment was done every five minutes, for 30 min after spinal anesthesia, and then every 20 min until the end of surgery.
Intraoperative pain was evaluated using a 10-point Visual Analog Score (VAS) (0=no pain, 10=worst imaginable pain). A VAS of at least 4 was treated with intravenous fentanyl 25 μg. Five minutes later, the VAS was assessed, and if necessary, propofol infusion or general anesthesia was given, and the patient was removed from the study.
Sedation was assessed using a four-point scale as per Filos et al. : 1=awake and alert; 2=somnolent, responsive to verbal stimuli; 3=somnolent, arousable to physical stimuli; and 4=unarousable.
Adverse effects such as itching, nausea, vomiting, shivering, and headache were recorded. Duration of analgesia was considered as time to first analgesic request. Patients were given paracetamol 1 g intravenous as rescue analgesia, and if still there is pain, nalbuphine 5–10 mg was given.
Postoperatively, patient satisfaction was evaluated using the following scoring system: 0=not pleased, 1=moderate, 2=good, and 3=very pleased.
Sample size determination
A sample size of 21 patients per group was determined through a power analysis (assuming α=0.05, and a power of 0.90) to detect a mean difference in duration of analgesia of at least 60 min. Adding 10% to compensate for potential dropouts and protocol violations, we enrolled 25 patients per group.
Data were analyzed using SPSS software (version 18.0 for Windows; SPSS Inc., Chicago, Illinois, USA). Demographics, time intervals, and continuous variables were analyzed and compared using the Student t-test. Categorical data (ASA, sex, and highest motor block achieved) were analyzed using the χ2-test. In all cases, P value of less than 0.05 was considered statistically significant.
| Results|| |
Fifty patients completed this study ([Figure 1]). Patients were comparable regarding age, weight, height, sex, ASA status, and duration of surgery ([Table 1]). Associated comorbidities are shown in [Table 2]. In both groups, anesthesia was adequate for the surgical procedure, and no patient in either group complained of intraoperative pain or required supplemental analgesics. None of the patients required conversion to general anesthesia owing to inadequate spinal block.
The characteristics of sensory block in the desired limb for both groups are shown in [Table 3]. The median highest sensory level achieved and the times to reach peak sensory level were comparable among the two groups. Significantly slower two segment regression was observed in the group receiving DEX (212.5±34.54 min) as compared with fentanyl only (106.25±12.09 min) (P=0.000). The characteristics of the motor blockade achieved in the two groups are also listed in [Table 3]. Both groups showed grade 3 Bromage score in the desired limb, and time to reach maximum motor blockade was also comparable (P=0.299). The patients in the F group requested postoperative analgesia earlier than patients in the FD group, as the average times to first request for analgesia were 207.37±20.19 and 522.79±59.0 min, respectively (P=0.000).
None of the patients in both groups showed pure unilateral spinal block but in all patients the blockade spread to the nondependent side. Sensory loss achieved in the operated leg was of much higher level than nonoperated leg (T8 vs. T12) ([Table 4]). Similarly, assessment of motor block showed some degree of motor block in the nonoperated leg, again at a lower degree than the operated side ([Table 4]). Motor blockade appeared later in the contralateral limb.
Hemodynamic stability was shown in both groups. The intraoperative mean blood pressures for the study groups are presented in [Figure 2].
|Figure 2 Perioperative changes in mean blood pressure. Group F: fentanyl group; group FD: fentanyl–dexmedetomidine group. Values are in mean±SD (vertical lines).|
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The complications observed during the study are listed in [Table 5]. Two patients in both groups had hypotension and were treated with 5–10 mg ephedrine. Transient bradycardia, which did not necessitate treatment, was seen in two patients in the group receiving DEX as compared with none in the F group (P=0.155). The intraoperative mean HRs for the study groups are presented in [Figure 3].
|Figure 3 Perioperative changes in mean heart rate. Group F: fentanyl group; group FD: fentanyl–dexmedetomidine group. Values are in mean±SD (vertical lines).|
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Pruritis was observed in three patients in F group as compared with none of the patients in FD group (P=0.076). Sedation was more with the addition of DEX. The highest sedation score was 2. In group FD, 72% of the patients had a sedation score of 2 and 28% had a score of 1, whereas, in group F, only 8% of the patients had a sedation score of 2 and 92% had a score of 1 (P<0.0001). No patient was excessively sedated ([Table 5]).
The level of satisfaction was ‘very good’ in 100% of the patients in the FD group, whereas only 80% of the patients in F group rated the procedure as ‘good’ ([Table 6]).
| Discussion|| |
The results of this study demonstrated that adding intrathecal DEX 6 μg to bupivacaine–fentanyl mixture in high-risk elderly patients receiving unilateral spinal anesthesia for major orthopedic surgery provides significantly longer postoperative analgesia with mean time to first analgesic request in FD group of 522.79±59.0 min compared with 207.37±20.19 min in F group, with P=0.0001. DEX enhanced the onset of sensory and motor blockade, but without statistical significance. Hemodynamic stability was observed in both groups. Pruritis was recorded in fentanyl group (12%) compared with none in FD group. Sedation was more in FD group.
Similar results were seen by Routray et al. , who observed prolonged postoperative analgesia when they compared adding either 5 μg DEX or 25 μg fentanyl to 15 mg bupivacaine. They reported time to first analgesic request of 299±33.92 min with DEX. This was much lower than our results probably owing to the synergistic effect offered by the addition of α2 agonist to opioids. Mahendru et al.  also compared adding 25 μg fentanyl or 5 μg DEX to 12.5 mg bupivacaine for orthopedic surgery. DEX showed prolonged sensory and motor blockade, less postoperative analgesic requirement, and good hemodynamic stability.
In the present study, dose of fentanyl was 20 μg. Reuben et al.  stated that the least dose of intrathecal fentanyl needed to provide satisfactory postoperative analgesia in elderly patients undergoing revascularization procedures was 20 μg. Kim et al.  observed increasing intrathecal fentanyl dose more than 25 µg did not further increase duration of analgesia. Early respiratory depression was reported by Varassi et al.  after administration of 50 µg, but not 25 µg of intrathecal fentanyl. Moreover, itching was more common after doses of at least 25 µg .
We used 12.5 mg of bupivacaine. McNamee et al.  administered 17.5 mg of intrathecal bupivacaine to patients with age 66–76 years undergoing orthopedic surgery and reported sensory block level of T2 (which is quite high) and an increased incidence of hypotension with ephedrine use in 26% of patients. Age-related reduction in the cerebrospinal fluid, degenerations in the central and peripheral nervous systems, and anatomical changes in the dorsal and lumbar spine may contribute to increased sensory and sympathetic block levels in the elderly .
On the contrary, Hoda et al.  studied adding 20 µg fentanyl to low-dose bupivacaine 6 and 8 mg in elderly patients for hip surgery. Although the reduced dose of bupivacaine led to more stable hemodynamics, the duration of spinal anesthesia was only 123 and 136 min, respectively. A study by Ben David et al.  used mini-dose bupivacaine 4 mg plus 20 µg fentanyl and demonstrated effective anesthesia sufficient for hip surgery in elderly patients with mean operative time between 50 and 110 min. Using a small dose of local anesthetic may prevent hypotension but unfortunately it may not provide acceptable anesthesia, as in our study operative times were between 100 and 160 min.
A dose of 6 μg DEX was used in our study. The idea behind adding intrathecal DEX is to produce a high drug concentration in the vicinity of α2 adrenoreceptors present in the spinal cord, thereby blocking the conduction of C and Aδ fibers, hyperpolarization of postsynaptic dorsal horn neurons, and intensifying local anesthetic-induced conduction block . Based on a meta-analysis by Abdallah et al. , there is no single dose recommended for intrathecal DEX, and it may vary between 3 and 15 µg when added to local anesthetic in spinal anesthesia. Wu et al.  in their meta-analysis demonstrated average prolongation of sensory block duration of 43 min for up to 5-μg DEX versus 102 min for more than 5-μg DEX . With increase in dose to 10 and 15 μg, risk of bradycardia is increased .
Both groups in our study showed hemodynamic stability. Alonso et al.  showed that when intrathecal fentanyl is added to hyperbaric bupivacaine in elderly patients undergoing orthopedic surgery, it results in greater hemodynamic stability and allows the use of a lower dose of local anesthetic thereby reducing the need for intravenous ephedrine during surgery. The meta-analysis by Zhang et al.  also showed the addition of low-dose DEX was not associated with increased incidence of hypotension or bradycardia, but this effect is dose dependent. The use of unilateral spinal anesthesia in our study added to this stability.
DEX was associated with a higher incidence of sedation, with P value of less than or equal to 0.0001. Al Mustafa et al.  found maximum sedation score of 2 in their patients when they added 5 or 10 μg of DEX to 12.5 mg of bupivacaine. When administered via an intrathecal or epidural route, α2 agonists show analgesic effect without deep sedation, as supraspinal central nervous system sites are not exposed to high drug concentrations .
Unilateral spinal anesthesia offers more hemodynamic stability when compared with conventional spinal, as hypotension is reduced four-folds . Unfortunately, none of the patients in our study had strictly unilateral spinal block, some sensory and motor blockade was present in the contralateral limb but at a much lower level. Cohan et al.  calculated the dose of hyperbaric intrathecal bupivacaine according to the patients’ height, where those shorter than 155 cm received 1.1 ml, from 155 to 170 cm received 1.5 ml, and taller than 170 cm got 1.8 ml and were kept on the desired side for 10 min. There was still sensory and motor blockade in the opposite limb. Determining the optimal time period for the patient to remain in the lateral position is difficult as the anesthetic drug may still have some spillover effect even if the patient is placed for 30–60 min in the lateral position, especially with hyperbaric bupivacaine doses 12–20 mg . Use of lower doses such as 5–8 mg hyperbaric bupivacaine and maintaining lateral position for 10–15 min may prevent migration of the anesthetic drug to the nonoperated side  but at the expense of the duration.Although FDA has not yet approved intrathecal use of DEX, a plethora of studies have been published and no harmful effects have been reported yet . Incidences of cardiac arrest were reported with intravenous infusion of DEX when used in patients older than 50 years or with concomitant cardiac abnormalities . Animal studies found evidence of neurotoxicity when DEX was given epidurally without local anesthetic in rabbits in a dose of 6.1 μg/kg . Yet other studies proved intrathecal DEX to possess neuroprotective effects by virtue of its presynaptic α2 adrenoreceptor inhibition. By inhibiting catecholamine release, vasospasm is reduced and spinal cord perfusion is enhanced . It showed a neuroprotective profile comparable to methylprednisolone when given intrathecally within 8 h of spinal cord injury in rats .
Limitation of our study includes the need to determine the effect of further lowering the doses of bupivacaine, fentanyl, and DEX to determine an ideal combination with the least adverse effects without compromising the prolonged postoperative analgesia.
| Conclusion|| |
The addition of 6 μg intrathecal DEX to hyperbaric bupivacaine–fentanyl mixture seems to be a better choice for long-duration orthopedic procedures in high-risk elderly patients, as it offers prolonged postoperative analgesia, stable hemodynamics, minimal adverse effects, and better patient satisfaction.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]