Effect of low dose Bupivacaine with Fentanyl on hemodynamic response: A Prospective cohort study


 Background: A conventional dose of local anesthetics is used during spinal anesthesia. However an unwanted hemodynamic effect by administration of adjuvants with low dose of local anesthetics has been observed. The purpose of the study was to compare the effect of low dose Bupivacaine with Fentanyl versus normal dose Bupivacaine alone on hemodynamic response in elderly patients. Methods: A Prospective cohort study was employed on a total of 64 elderly patients undergoing lower extremity orthopedics surgery. An exposed group (group BF) received 10mg of 0.5% isobaric bupivacaine with 25mcg of fentanyl and a non-exposed group (Group B) received 15 mg of 0.5% isobaric bupivacaine alone. Systematic random sampling technique was used to select study participants. Parametric data was analyzed by using independent t-test, nonparametric data by using Mann-Whitney U-test and homogenous categorical data by using chi-square test and fisher exact test. The level of statistical significance for all tests was found to be P < 0.05. Results: The incidence of hypotension was higher in group B than group BF (37.5% vs. 9.4%, respectively) and statistically significant differences was observed (p=0.008). The onset of sensory block and regression of motor block to zero were faster in group BF than in group B (p <0.05). TAR was also prolonged in group BF (P<0.05). Conclusion: Low dose Bupivacaine with Fentanyl has lower incidence of hypotension, fast onset of sensory block and prolonged first analgesia request time than bupivacaine alone Therefore, we recommends the use of low dose bupivacaine with fentanyl to have a better hemodynamic stability than conventional dose of bupivacaine for elderly patients who undergoes lower extremity surgery.


Introduction
Spinal anesthesia (SA) is a type of regional anesthetic technique which is commonly used for surgery in the elderly patients. It is often preferred for its simplicity, e cacy, rapidity, high success rate, minimal effect on mental status, reduction of blood loss, and protection against thromboembolic complications compared with general anesthesia [1,2]. Spinal anesthesia may be indicated as the primary anesthetic used for major or minor surgeries involving the abdomen, perineum, or lower extremities [2].
Advanced diagnostic and therapeutic facilities have enhanced the life expectancy of humans, as a result of which elderly population is expected to rise 25% by 2020; 506 million as of 2008 and by 2040 will increase to 1.3 billion across the world [3]. As humans age increases, there is a general decline in organ function, although there is wide inter individual variability (e.g., some organs might be affected more than others). Most importantly, the cardiovascular and pulmonary systems have reduced function that might impact patients' physiologic responses during surgery and anesthesia [4].
Age and concurrent diseases make these patients at high risk for perioperative complications. Despite regional anesthesia has a better postoperative outcome, hypotension and bradicardia is common and increases the risk of myocardial ischemia. The main effect of spinal anesthesia was the reduction of systemic vascular resistances (SVR) which were reduced by 18% ± 17.2%. The average cardiac index (CI) was initially reduced by 5.2-6.6%, and it was persistently reduced during the surgical period [5,6].
The elderly population is especially challenging when one has to consider all of the pharmacodynamics changes that occur with normal aging. Blood vessel distensibilty is drastically decreased in elderly patients and, combined with increased intimal thickness and endothelial dysfunction, will increase systolic blood pressure, as well as left ventricular workload. Myocardial hypertrophy, along with increased collagen content, creates a stiff left ventricle that depends on adequate preload to maintain cardiac output. This makes elderly patients much more susceptible to uid overload and this is due failure of autonomic re exes responsible for of cardiovascular homeostasis in aged population [7,8].
Orthopedic injuries, especially to the long bones such as the femoral neck, osteoarthritis and rheumatoid arthritis increase with age, were the most common injury which needs surgery in elderly patients [9,10].
Spinal anesthesia in the elderly is associated with exaggerated responses to conventional doses of local anesthetics, thereby increasing the incidence of hemodynamic complications. Some studies suggested that Spinal anesthesia for elderly patients undergoing lower limb surgeries with 2cc bupivacaine 0.5% and 25μg fentanyl is a safer and better option, both in terms of maintaining hemodynamic stability and lower incidence of complications without compromising the surgical conditions [11].
Bupivacaine is an amide-type, long-acting local anesthetic widely used for spinal anesthesia [12].
Hypotension after conventional dose of bupivacaine accounts about 50% [11]. Whereas low dose of bupivacaine with fentanyl caused dramatically less incidence of hypotension during spinal anesthesia in elderly patients which also eliminates the need for vasopressor and intravenous uids [13].
As far as the investigators knowledge, there is no published data found in Ethiopia that shows the effects of low-dose bupivacaine with fentanyl versus conventional dose of bupivacaine on hemodynamic response in elderly patients. Therefore, the aim of this study was to compare hemodynamic response of low dose bupivacaine with fentanyl versus conventional dose of bupivacaine in elderly patients who undergo lower extremity orthopedics surgery under spinal anesthesia at black lion Specialized hospital (BLSH), Addis Ababa, Ethiopia.

Methods And Materials
Institutional based prospective cohort study was used from November, 2018 -April, 2019 at black lion Specialized hospital. Source population were all elderly patients who undergone orthopedics lower extremity surgery under spinal anesthesia during study period. Selected elderly patients who undergone elective orthopedics lower extremity surgery under spinal anesthesia on the study period. Preoperative hyper or hypotensive patients, failed spinal anesthesia, Allergic to medication and emergency procedures were excludedfrom the study.
Hemodynamics response (hypotension) was one of our primary outcome indicators and preliminary data was taken from India showed the incidence of intraoperative hypotension with conventional dose of bupivacaine alone and low dose of bupivacaine with fentanyl group were 40% and 10% respectively [14].
Systematic random sampling technique was used to select study participants. From BLSH Orthopedics operation registration book, we got 88 elective orthopedics lower extremity procedures were performed in elderly patients for four consecutive months before study period. To recruit 64 study participants 1.5 skipping interval was used. Two patients from every 3 patients were recruited from the elective surgical schedule during the study period.
2 BSC anesthetists collected the data and 1 MSc anesthetist supervised by using pretested structured check list. Assessing onset of sensory block and onset and regression of motor block was documented during and after surgery after providing brief explanation for the patients preoperatively, and an informed consent was taken. We named bupivacaine 15mg alone group as Group B and the 10mg bupivacaine with fentanyl regime as Group BF. Hemodynamic response (SBP, DAP, MBP, PR, RR and SpO 2 ) at baseline then after administration of spinal anesthesia at 5 min, 10min, 15 min, 30 min, 60 min, 90 min and 120 min for both the groups were Monitored.
The mean BP, HR, SaO2 and intraoperative patient complaints were recorded. Hypotension was de ned as systolic blood pressure decrease of more than 25% from baseline. PR <60/min was graded as bradycardia. Respiratory rate was monitored and respiratory depression was estimated as a decrease in SaO2 less than 90%. Patients were followed for 24 hours postoperatively to assess postoperative pain.
The onset of sensory block was assessed by using cold sensation every minute following spinal anesthesia administration. Motor blockwas assessed at the same time intervals up to onset of motor block using modi ed Bromage scale and we decide the motor block, at Bromage score of 3. Duration of analgesia was calculated in both groups from the time of spinal block to the time of rst analgesic requirement. Complication of spinal anesthesia such as shivering, pruritus, seizures, nausea and vomiting and severity were graded and recorded intra and postoperatively. Pretesting with 10% of respondents (3 patients in each group) was done at Zewditu memorial referral hospital to assure quality of data. Investigators cross checked data completeness and consistency and accuracy on daily basis. Finally data was sorted, categorized and summarized.

Data Processing and Analysis
Data were checked and cleaned manually for completeness and then coded and entered in to SPSS version 25 computer program for analysis. Descriptive statistics were summarized with tables and gures reported as means ± SD for continuous variables, and numbers or percentages for quantitative variables. Normality of distribution for continuous variable was tested by Shapiro-Wilk test and parametric variables were analyzed by independent t-test and Mann-Whitney for nonparametric test as needed, while chi-square test was used for hypotension. Association was measured by 95% con dence interval and p<0.05 was considered as statistically signi cant.

Operational De nitions
Bromage scale: is a tool used to assess motor block after administration of spinal anesthesia as scored below in this study Activity Score Able to lift legs against gravity 0 Able to ex knee but unable to ex legs 1 Able to move feet but unable to ex knee 2 Unable to move any joints 3 Conventional dose of bupivacaine: is a dose of intrathecal 0.5% of 15mg bupivacaine alone Elderly patients: refers to patients that are 60 years old and above.
Elective surgery: is surgery done before on set (appearance) of any complication that may constitute urgent surgical indication.
Emergency surgery: is surgery done at onset or near appearance of any complication that may constitute urgent indication.
Failed Spinal anesthesia: implies that spinal anesthesia was attempted, but without resulting in a sensory block or a block that resulted is inadequate for that surgery Grading status of shivering: "0" = no shivering, 1 = One or more of: pilioerection, 2 = visible muscular activity con ned to one muscular group, 3 = visible muscular activity more than one muscular group and 4 = gross muscular activity involving the whole body. Ethics approval and consent to participate Ethical clearance letter was taken from Institutional Review Board of Addis Ababa University, department of anesthesia research ethical committee. Additionally, permission was obtained from BLSH administration. Finally, verbal consent was requested from each study participants during data collection process after giving brief explanation about the objectives of the study. Furthermore, con dentiality was maintained through not asking personal identi ers like name and address.

Sociodemographic and Perioperative characteristics
A total of 64 patients were included in the study and 32 in each group. Group B given 15mg of 0.5% bupivacaine alone and group BF took 10mg of 0.5% bupivacaine with 25mcg fentanyl. Age, gender, height, weight was compered in our study and they were comparable (p>0.05). There were also no statistically signi cant difference between the groups in ASA physical status, BMI, duration of surgery preload uid administered and preoperative hemodynamic parameters. Signi cant difference was obtained while comparing mean of total uid intake between the two study groups. Which was statistically signi cant having (p<0.001) ( Table 1).

Change in systolic blood pressure
In group B maximum fall of 11.5% in mean systolic BP was observed at 30 min following spinal block. In Group BF, maximum fall of 6.5% in mean SBP at 30min. But no statistically signi cant difference was observed between groups ( Figure 1).

Incidence of hypotension and Mean arterial pressure
Relatively higher incidences hypotension were observed in group B (12(37.5%) than group BF 3(9.4%) ( Figure 2). In addition, higher normal values of MAP was found in BF group (Figure 3) Change in Heart rate HR was compared between groups; a decreased mean heart rate was noticed in Group B at 15 minutes after spinal block but no statistically signi cant differences were seen between the groups at all study timings ( Table 2). Independent t-test for Mean and standard deviation at 10, 15, 60 and 120minutes, Mann-Whitney Utest for median at 05, 30 and 90minutes.
When we compared SaO 2 between groups: there was no statistically signi cance different at all-time interval but at 30min after spinal anesthesia block lower mean SaO 2 observed in group BF in respect to Group B (Table 3).

Spinal anesthesia block characteristics
The onset of sensory block and regression of motor block to zero was faster in group BF than in group B (p <0.05).. TAR was also prolonged in group BF (P<0.05).The mean level of sensory block at surgery, onset of motor block and motor bromage score at start of surgery were compared and found that values were not signi cant in both the groups (Table 4). According to numeric rating scale (NRS) pain severity score in our study, statistically signi cant difference was observed at 4hrs after spinal block (p = 0.014). Otherwise in all-time interval comparable result was seen (Table 5).

Discussion
This study aimed to compare hemodynamic response of conventional dose of bupivacaine versus low dose bupivacaine with fentanyl elderly patients who undergo lower extremity orthopedics surgery under spinal anesthesia at Black lion specialized hospital, Addis Ababa, Ethiopia,2019. The result of this study showed that, the overall incidence of hypotension was 37.5% in non-exposed (group B), ((0.5% of 15mg isobaric bupivacaine) and 9.4% in study groups (0.5% of 10mg isobaric bupivacaine with 25mcg fentanyl) (group BF). Higher incidence of hypotension was observed in non-exposed than study groups and it is statistically signi cant between groups. This result is incomparable with study done in India [14] and Pakistan [15], which showed higher incidence of hypotension in non-exposed group (73%) than study groups (10%).
On this study, maximum fall in MAP in group B was greater than in group BF after administration of spinal anesthesia. Similarly another comparative study in India [11], showed more decreased in systolic BP in non-exposed group than study group. In contrast to the present study, comparative study conducted in Australia [16], showed there were no differences on incidence and severity of hypotension between the groups.
The result of this study showed statistically insigni cant differences on HR value between the groups after administration of spinal anesthesia and none of the patients were treated for bradycardia. This is in agreement with comparative study conducted in India [11], revealed HR was better maintained in group BF than group B but it was not statistically signi cant.
The onset of sensory block and regression of motor block to zero was faster in group BF (p <0.05).. TAR was also prolonged in BF group (233.41±46.46 min) than in group B (213.19±51.46 min), and it is statistically signi cant (p<0.05).This result is in accordant with prospective comparative study done in India [14], showed earlier onset of sensory analgesia, time to achieve peak sensory level, and recovery from motor blockade in group BF than in group B. This is also in line with another study conducted in Iran [17] [22], showed the mean duration of sensory block was much longer in group BF than in group B but time to achieve maximum level of block and Mean time of two-segment regression was much shorter in group BF than in group B.
When we compare pain severity between groups according to numeric rating scale (NRS) pain severity score in this research, statistically signi cant difference was observed at 4hrs after spinal block (p = 0.014). This result is in line with prospective comparative study done in India [21], revealed that the time of rst analgesia request (FAR) was lower in BF group than in group B, (p <0.01).
Strength of the study: Both the exposed and unexposed groups were selected from the same source population. No lost to follow up of patients which results in missing data.
Limitations of the study: Inaccessibility of invasive arterial blood pressure to measure parturient beat to beat systolic blood pressure. Duration of hypotension couldn't measure with every hypotensive episodes.