Adding Dexmedetomidine to Bupivacaine-Fentanyl mixture in high risk elderly patients undergoing orthopedic surgery. A randomized, double blind, controlled study.
Introduction:
Lower limb fractures are very common in the elderly population and spinal anesthesia is very often used for their surgical repair. Regional anesthesia is well tolerated by geriatric patients as it produces less postoperative confusion and delirium than general anesthesia[1].
Postoperative pain control is also a major problem in these surgeries due to the relatively short duration of action of available local anesthetics, therefore, early analgesic intervention is needed in the postoperative period and as many elderly patients have co morbidities, opioids or NSAIDs analgesics may cause serious side effects. Improved perioperative pain management in elderly patients not only increases comfort but reduces morbidity, enhances early ambulation and improves long term outcome.
Many augmentation strategies for intrathecal analgesia have been proposed. A meta-analysis by Popping et al [2] concluded that the concomitant use of an opioid as Fentanyl intrathecally allows the reduction in the dose of local anesthetic, while augmenting its analgesic potency thereby decreasing its side effects. Fentanyl is a highly lipid soluble, pure μ-agonist opioid with rapid onset and short duration of action.
Dexmedetomidine is a selective, potent α 2 adrenergic agonist with a 1620:1 ratio of α2: α1 receptor selectivity. It mediates its analgesic effect via spinal α2 receptors [3]. Wu et al, in their meta-analysis showed that intrathecal DEX significantly increased the duration of post operative analgesia and greatly reduced post operative analgesic consumption[4]. Concomitant intrathecal dexmedetomidine increases duration of postoperative analgesia in a dose dependant manner, but with increase in incidence of bradycardia [5].
Since intrathecal alpha 2 adrenergic agonists produce analgesia through a different mechanism than intrathecal opioids, the effect of their combination would be additive.
Therefore, by using low dose of both dexmedetomidine and fentanyl the incidence of adverse effects of these 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.
To the best of our knowledge, there are no trials in the available literature comparing the addition of both dexmedetomidine +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 post operative analgesia (time to first analgesic request). Secondary outcome included sensory and motor block characteristics, hemodynamic variations and side effects.
Patients and methods
This prospective, randomized, double-blind controlled clinical trial was conducted on patients ≥ 60 years old, ASA 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 prior to their inclusion into the study. Patients with known hypersensitivity to bupivacaine, fentanyl, or dexmedetomidine, 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 intervention assignment slip was placed in serially numbered and sealed envelopes which were opened following enrollment of the case. 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 dexmedetomidine to the mixture.
Group F received 12.5 mg hyperbaric bupivacaine +20 µg fentanyl (total volume 2.9ml). Group FD received 12.5 mg hyperbaric bupivacaine +20 µg fentanyl+6 µg dexmedetomidine(Precedex 200µg/2ml vial, Hospira) (total volume 2.96ml, making no apparently significant volume difference).
Patients received no premedication before arrival in the operating theater. Standard monitoring included continuous electrocardiogram, noninvasive blood pressure and pulse oximetry. Invasive monitoring such as CVP and arterial blood pressure was done only if a specific indication was present. A urinary catheter was placed to monitor urine output and avoid fluid overloading.
Before spinal block, each patient received an infusion of 8 ml/kg of lactated Ringer’s solution. Lumbar puncture was performed in the sitting position at the L3–L4 interspace with a 25-gauge Quincke spinal needle using paramedian approach with the bevel towards the desired side. Injections were made over 15-20 s. After completion of the injection the patient was immediately 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 4L/min via nasal cannula was given to all patients throughout the surgical procedure. No additional sedative medications were given during the operation.
Vital parameters heart rate (HR) and mean arterial pressure (MAP) were recorded using automated blood pressure (BP) cuff before spinal anesthesia, just after spinal anesthesia, then every 5 min for 30 min, then every 10 min till end of surgery. Oxygen saturation was continuously monitored. Hypotension was defined as a systolic blood pressure of < 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 (5ml/kg saline). A heart rate < 50 beats/min was considered as bradycardia and treated with iv atropine 0.5 mg.
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. A sensory block level of T10 or higher was required to commence surgery. After 30 min, if anesthetic level was inadequate general anesthesia was given as necessary and patient was removed from the study.
Motor block of lower limbs was assessed bilaterally using modified Bromage scale [6] as 0 = no paralysis; 1= cannot raise extended leg; 2= cannot flex the knee; 3= cannot dorsiflex the ankle.Assessment was done every five minutes, for 30 minutes after spinal anesthesia then every 20 minutes 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 ≥4 was treated with IV 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 [7] 1: Awake and alert 2: Somnolent, responsive to verbal stimuli 3: Somnolent, arousable to physical stimuli 4: Unarousable
Side-effects such as itching, nausea, vomiting, shivering, and headache were recorded. Duration of analgesia was taken as time to first analgesic request. Patients were given Paracetamol 1gm iv as rescue analgesia.
Postoperative, patient satisfaction was evaluated using the following scoring system: 0 = not pleased, 1 = moderate, 2 = good, 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.
Statistical Analysis
Data were analyzed using SPSS software (ver. 18.0 for Windows; SPSS Inc., Chicago, IL, USA). Demographics, time intervals, and continuous variables were analyzed and compared using the one-way analysis of variance (ANOVA) test. Categorical data (ASA, sex, highest motor block achieved), number of patients receiving intraoperative rescue fentanyl and patient satisfaction were analyzed using the X2 test. In all cases, P <0.05 was considered statistically significant.
Results
Fifty patients completed this study ( Fig 1). Patients were comparable as regards age, weight, height, gender, ASA status and duration of surgery (Table 1). In both groups, anesthesia was adequate for the surgical procedure and no patient in either group complained of intraoperative pain or required supplemental analgesics intraoperatively. None of the patients required conversion to general anesthesia due to inadequate spinal block.
The characteristics of sensory block in the desired limb for both groups are shown in (Table 2). 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 dexmedetomidine (212.5±34.54min) as compared to fentanyl only (106.25±12.09min) (P=0.000). The characteristics of the motor blockade achieved in the two groups are also listed in Table 2. 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±20.19min and 522.79±59.0min, 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 non-operated leg (T8 vs T12) Table 3.Similarly, assessment of motor block showed some degree of motor block in the non-operated leg again at a lower degree than the operated side (Table 3). Initially both legs had motor blockade but after 5minutes as the drug became fixed to the dependant leg no further increase in degree of motor blockade on the non dependant side occurred.
Hemodynamic stability was shown in both groups. The intraoperative mean blood pressures for the study groups are presented in Figure 2.
The complications observed during the study are listed in Table 4. Two patients in both groups had hypotension that was treated with 5-10mg ephedrine. Transient bradycardia, which did not necessitate treatment, was seen in two patients in the group receiving dexmedetomidine as compared to none in the fentanyl group (P=0.155). The intraoperative mean heart rates for the study groups are presented in Figure 3.
Pruritis was observed in three patients receiving fentanyl only as compared to none of the patients who received fentanyl +dexmedetomidine (P=0.076). Sedation was more with the addition of dexmedetomidine. 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 4
The level of patient satisfaction was “very good” in 100% in fentanyl+dexmedetomidine group, while patients in fentanyl only group 80% rated the procedure as “good” (Table 5).
Discussion
The results of this study demonstrated that adding intrathecal dexmedetomidine 6µg 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 fentanyl-dexmedetomidine (FD) group (522.79±59.0min) compared to (207.37±20.19min) in fentanyl (F) group with P=0.0001. Dexmedetomidine enhanced the onset of sensory and motor block characteristics, but without statistical significance. No hemodynamic instability was observed in either group. Pruritis was recorded in Fentanyl group (12%) compared to none in FD group. Sedation was more in FD group.
Similar results were seen by Routray et al[8], who observed prolonged postoperative analgesia when they compared adding either 5µg dexmedetomidine or 25µg fentanyl to 15mg bupivacaine. They reported time to first analgesic request of 299±33.92min with dexmedetomidine. This was much lower than our results probably due to the synergistic effect offered by the addition of α2 agonist to opioids. Mahendru et al, also compared adding 25µg fentanyl or 5µg DEX to 12.5mg bupivacaine for orthopedic surgery. DEX showed prolonged sensory and motor blockade, less postoperative analgesic requirement and good hemodynamic stability[9].
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[10]. Kim et al, observed increasing intrathecal Fentanyl dose beyond 25μg produced no benefit to duration of analgesia[11]. Early respiratory depression was reported by Varassi et al. after administration of 50μg, but not 25 μg of intrathecal Fentanyl. Also, itching was more common after doses ≥25μg [12].
We used 12.5mg bupivacaine, McNamee et al [13] administered 17.5mg intrathecal bupivacaine to patients with age 66-76yrs, undergoing orthopedic surgery and reported average 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 occurring in the central and peripheral nervous systems and changes taking place in the thoracic and lumbar spine may contribute increased sensory and sympathetic block levels in the elderly[14].
On the other hand, Hoda et al [15] 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 4mg plus 20 μg fentanyl and demonstrated effective anesthesia sufficient for hip surgery in elderly patients with mean operative time between 50-110min [16]. The use of a low-dosage local anesthetic may limit the associated hypotension, unfortunately it may not provide acceptable anesthesia as in our study operative times were between 100-160min.
A dose of 6µg Dexmedetomidine was used in our study. The rationale behind adding intrathecal dexmedetomidine is to achieve 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 conduction block induced by the local anesthetic[3]. Based on a meta-analysis by Abdallah et al [17], there is no specific recommended dose for intrathecal dexmedetomidine, it can vary from 3 to 15 μg as an adjuvant to local anesthetic in spinal anesthesia.
Wu et al in their meta analysis demonstrated average prolongation of sensory block duration of 43min for ≤ 5µg vs. 102 min for ˃ 5µg dexmedetomidine[4 ]. With increase in dose to 10 and 15 µg, risk of bradycardia is increased[5].
Both groups in our study showed hemodynamic stability. Chico et al [18] showed that adding fentanyl to the local anesthetic used for subarachnoid anesthesia in elderly patients is effective for maintaining greater hemodynamic stability, allowing use of a lower dose of hyperbaric bupivacaine and reducing the need for intravenous ephedrine during surgery. The metaanalysis by Zhang et al showed low dose DEX was not associated with increased incidence of hypotension or bradycardia but this effect is dose dependant[5 ].
Dexmedetomidine was associated with a higher incidence of sedation P≤0.0001. Al Mustafa et al found maximum sedation score of 2 in their patients when they added 5 or 10 µg DEX to 12.5mg bupivacaine[19]. Alpha2 agonists administered via an intrathecal or epidural route provides analgesic effect without severe sedation due to sparing of supraspinal CNS sites from excessive drug exposure, resulting in robust analgesia without heavy sedation[20].
None of the patients in our study had strictly unilateral spinal block as pain at the fracture site prevented administration of spinal in the lateral position. The incidence of clinically relevant hypotension is reduced four-folds with unilateral spinal block and provides more stable cardiovascular parameters as compared with conventional spinal[21]. Determining the optimal time period for the patient to remain in the lateral position is difficult as the anesthetic drug may still have some spill-over effect even if the patient is placed for 30-60 min in the lateral position, especially with hyperbaric bupivacaine doses 12-20mg [22]. Use of lower doses as 5-8 mg hyperbaric bupivacaine and maintaining lateral position for 10-15 min may prevent migration of the anesthetic drug to the non-operated side[23].
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[5]. Reported fatal complications of DEX were mainly related to its intravenous use as infusion in the elderly and in patients with cardiac disease[24]..Animal studies found evidence of neurotoxicity when DEX was given epidurally without local anesthetic in rabbits in a dose of 6.1µg/kg [25]. But in human studies, DEX showed protective or growth promoting properties in tissues, including nerve cells from cortex and has a neuroprotective effect similar to methylprednisolone in spinal cord injury when used intrathecally[26].
Limitation of our study includes the need to determine the effect of further lowering the doses of bupivacaine, fentanyl and dexmedetomidine to determine an ideal combination with the least side effects without compromising the prolonged postoperative analgesia.
Conclusion The addition of 6 µg intrathecal dexmedetomidine 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 side effects and better patient satisfaction.
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