Spinal Nerve Block and Recovery after Spinal Anesthesia in Frail Patients - a Prospective Cohort Study

Background: Frailty in surgical patients is associated with signicantly higher incidences of perioperative mortality and complications. Although neuraxial anesthesia is preferable alternative to general anesthesia in frail patients, it remains undetermined whether the pharmacodynamic proles of local anesthetics used in intrathecal spinal nerve blocks are altered in this population. Methods: This prospective observational cohort study recruited 62 patients scheduled for operations that were able to be performed under spinal anesthesia between April 22 to June 30, 2020 in our hospitals. Levels of dermatome blockage after spinal anesthesia and the recovery of spinal nerve sensory and motor function were recorded. Results: The prevalence of frailty in patients receiving spinal anesthesia in this study was 25.8%. Compared with non-frail patients, frail patients were signicantly older, had a higher proportion of females, and tolerated less intense metabolic equivalent activities. The pre-surgical incision sensory blockage levels were not different between frail and non-frail patients following intrathecal administration of similar dose of bupivacaine. Time intervals to pain sensation at surgical sites (sensory recovery) and voluntary knee exion (motor recovery) were also similar between the frail and non-frail groups. But, frail patients were associated with more episodes of hypotension and required more vasopressors during operations. Conclusion: Our study illustrates that bupivacaine sensitivity in spinal nerve blocks is not signicantly affected by frailty. However, special attention should be paid to correct intraoperative hypotension after spinal anesthesia in frail patients.

blockage levels were not different between frail and non-frail patients following intrathecal administration of similar dose of bupivacaine. Time intervals to pain sensation at surgical sites (sensory recovery) and voluntary knee exion (motor recovery) were also similar between the frail and non-frail groups. But, frail patients were associated with more episodes of hypotension and required more vasopressors during operations.
Conclusion: Our study illustrates that bupivacaine sensitivity in spinal nerve blocks is not signi cantly affected by frailty. However, special attention should be paid to correct intraoperative hypotension after spinal anesthesia in frail patients.

Background
Frailty is a multi-dimensional state of decreased physiologic reserve that results in diminished resiliency, loss of adaptive capacity, skeletal muscles weakness and increased vulnerability to stressors [1]. The prevalence of frailty in general surgical patients ranges from 2-13%. Frailty in surgical patients is associated with signi cantly higher incidences of 30-day mortality, surgery-related complications, prolonged hospital stays, cognitive disorders and postoperative pain, particularly after general anesthesia [2,3]. De cits in multiple organ systems seen in frailty can result in alterations to anesthetic pharmacokinetics and pharmacodynamics [4]. Changes in receptor numbers at target sites, signal transduction after receptor binding, and dysregulation of homeostatic processes can all signi cantly affect anesthetic pharmacodynamics in elderly or frail patients, leading to increased or decreased drug sensitivity [5]. Since regional anesthesia reduces the need for perioperative airway manipulation and neuraxial anesthesia has been shown to be associated with improved survival and wound outcomes in frail patients [6], regional and neuraxial anesthesia may be a preferable alternative to general anesthesia for clinical anesthesiologists [4]. However, it remains unclear whether the pharmacodynamic pro les of local anesthetics used in intrathecal spinal nerve blocks are altered in patients with frailty and whether the therapeutic dose of local anesthetics should be adjusted and post-anesthesia care period extended in this population. Therefore, the primary aim of this study was to compare spinal nerve blocking responses following intrathecal administration of bupivacaine in frail and non-frail patients.

Methods
This prospective observational cohort study was conducted in patients who received elective surgery under spinal anesthesia in E-Da Hospital, Taiwan from April 22 to June 30, 2020 in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of E-Da Hospital, Taiwan. This study excluded patients receiving emergency or after-hours operations and patients who were admitted to intensive care units after surgery (Fig. 1). Patient frailty was assessed using Fried's 5-point frailty assessment (frail: 3-5 criteria; pre-fail: 1-2 criteria; non-frail: no positive criteria) before operation [7]. Anesthetic staff responsible for clinical care were blinded to the frailty status

Results
During the study period, a total of 102 patients were scheduled for operations that were able to be performed under spinal anesthesia. 24 patients were excluded due to the operation being an emergency operation or the operation being done under general anesthesia. Therefore, a total of 81 patients were recruited and 19 patients were excluded from the nal analysis due to incomplete clinical data ( Fig. 1). In the remaining 62 patients used in the nal analysis, 16 (25.8%) of them were considered frail (Fried's score ≥3) ( Table 1). Compared with non-frail patients, frail patients were signi cantly older, had a higher proportion of females, tolerated less intense metabolic equivalent (MET) activities, and had lower levels of education (Table 1). The American Society of Anesthesiologists (ASA) physical classi cations were similar between the two groups. Most of the participants undertook orthopedic or urological surgery (Table 1). After propensity matching, a total of 12 patients were selected from the non-frail patients and serve as the matched control group (Table 1). There were no differences in bupivacaine doses administered into the intrathecal space and pre-surgical incision sensory blockage levels were similar between frail and non-frail or matched non-frail patients (Table 2). However, frail patients were associated with more episodes of hypotension and required more vasopressors during operations ( Table 2). Time intervals to pain sensation at surgical sites (sensory recovery) and voluntary knee exion (motor recovery) were similar between the frail and non-frail patients ( Table 2). There were no in-hospital mortality or other major postoperative events in this study.

Discussion
Consistent with other observational studies [2], our cohort found that frailty was more commonly diagnosed in older (mean age of 71.6 years) and female patients, and they had more limitations in their daily physical performance (MET). Since functional frailty status is not a routine consideration used in pre-anesthesia clinics for perioperative outcome predictions [8], this study did not nd differences in the ASA physical classi cations between the frail and non-frail surgical patients.
The prevalence of frailty in patients receiving spinal anesthesia in this study population was 25.8%, which is comparable with the ndings of a previous larger-scale study (21.5%) [6]. The higher prevalence rates of frailty in surgical patients receiving neuraxial anesthesia over general anesthesia could simply be an implication that anesthesiologists generally consider regional blocks a safer option, associated with fewer perioperative complications in sicker and elderly patients [4,9]. In a recent cohort study, the Mayo Clinic study group found that frail patients who had knee arthroplasties done under neuraxial blocks were associated with signi cantly lower mortality (hazard ratio 0.49; 95% CI 0.27-0.89) and wound complication rates (hazard ratio 0.71; 95% CI 0.55-0.90) in comparison to those who received general anesthesia [6]. With neuraxial anesthesia, it is important to take into consideration whether frail patients are more sensitive to local anesthetics during spinal nerve blocks [4], and if so, whether local anesthetic dosages should be reduced for spinal anesthesia.
Our study showed that sensory dermatome blockage levels achieved by similar doses of intrathecal bupivacaine were not different between frail and non-frail patients, as the anesthesiologists were blinded to patients' frailty status. Most importantly, we found that time intervals to pain sensation at the surgical site (sensory recovery) and voluntary movement of lower limbs (motor recovery) also showed no signi cant difference between the frail and non-frail groups, highlighting that bupivacaine sensitivity for spinal nerve blocks was not signi cantly affected by frailty. However, we observed more hypotensive events in frail patients and these patients also required more vasopressor therapy after spinal anesthesia. It is known that autonomic dysregulation is the main cause of developing intraoperative hypotension in the frail [10].
The ndings of this study must be interpreted in light of several limitations. Although this was a prospective study, patients in the frail groups were older and consisted of signi cantly more female, which might have confounded the clinical outcomes observed during spinal anesthesia. After propensity matching, 12 non-frail patients with more identical characteristics (similar in gender, age, educational levels and smokers) were selected from the non-frail patients for matched comparison of the outcome assessments. Our results suggested that the pharmacodynamics of local anesthetics used in spinal nerve blocks are not signi cantly altered in frail patients even when compared with younger, predominantly male non-frail individuals. Furthermore, we do not expect elderly and frail patients to require higher doses of local anesthetics than younger patients to achieve similar levels of spinal anesthesia. Secondly, we used Fried's phenotypic criteria to assess frailty, where the frailty index has been recognized as a more comprehensive tool for multiple-domain assessment of frailty [1]. Clinically, measurements using frailty phenotypes require less geriatric expertise and has a shorter assessment time. Nevertheless, the Fried's criteria employ quantitative evaluation, making it a valid subjective clinical instrument for preoperative assessment of frailty [1,7]. Thirdly, time to pain sensation at the surgical site was used as a surrogate indicator for sensory recovery after spinal anesthesia instead of precise measurement of spinal dermatomes. However, as patients were cared in the PACU and on the wards after surgery, surgical pain may be considered a more subjective than dermatome measurement; as spinal dermatome measurements will be done by different medical staff in the two units, leading to inconsistent interrater reliability among anesthetic, PACU, and ward personnel. Lastly, this study focused on the effects of bupivacaine and may not be generalizable to other local anesthetics.

Conclusion
This study illustrates that bupivacaine sensitivity in spinal nerve blocks is not signi cantly affected by frailty, even when compared with younger, male non-frail patients. However, special attention should be paid to correct intraoperative hypotension after spinal anesthesia in frail patients. Availability of data and material: All data generated during this study are included in this published article as a supplementary le.

Abbreviations
Competing interests: The authors declare that they have no competing interests.
Funding: This study was funded, in part by the Ministry of Science and Technology of Taiwan (grant number MOST 109-2314-B-650-007-MY2 to CFL) and institutional grants from the E-Da Hospital, Taiwan (EDPJ109064 to CFL and EDAHP 108055 to YKS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Authors' contributions: TLL, SCC, YKS and TSC contributed to acquisition and analysis of the data. TLL, SCC, YKS and CFL contributed to the study conception and design and the acquisition, analysis, and interpretation of the data. TLL, SCC, YKS and CFL contributed to drafting of the article. All authors reviewed and approved the nal version of the manuscript.