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Study 1 Overview (Chang et al)
Objective: To assess the incidence of postoperative delirium (POD) following propofol- vs sevoflurane-based anesthesia in geriatric spine surgery patients.
Design: Retrospective, single-blinded observational study of propofol- and sevoflurane-based anesthesia cohorts.
Setting and participants: Patients eligible for this study were aged 65 years or older admitted to the SMG-SNU Boramae Medical Center (Seoul, South Korea). All patients underwent general anesthesia either via intravenous propofol or inhalational sevoflurane for spine surgery between January 2015 and December 2019. Patients were retrospectively identified via electronic medical records. Patient exclusion criteria included preoperative delirium, history of dementia, psychiatric disease, alcoholism, hepatic or renal dysfunction, postoperative mechanical ventilation dependence, other surgery within the recent 6 months, maintenance of intraoperative anesthesia with combined anesthetics, or incomplete medical record.
Main outcome measures: The primary outcome was the incidence of POD after administration of propofol- and sevoflurane-based anesthesia during hospitalization. Patients were screened for POD regularly by attending nurses using the Nursing Delirium Screening Scale (disorientation, inappropriate behavior, inappropriate communication, hallucination, and psychomotor retardation) during the entirety of the patient’s hospital stay; if 1 or more screening criteria were met, a psychiatrist was consulted for the proper diagnosis and management of delirium. A psychiatric diagnosis was required for a case to be counted toward the incidence of POD in this study. Secondary outcomes included postoperative 30-day complications (angina, myocardial infarction, transient ischemic attack/stroke, pneumonia, deep vein thrombosis, pulmonary embolism, acute kidney injury, or infection) and length of postoperative hospital stay.
Main results: POD occurred in 29 patients (10.3%) out of the total cohort of 281. POD was more common in the sevoflurane group than in the propofol group (15.7% vs 5.0%; P = .003). Using multivariable logistic regression, inhalational sevoflurane was associated with an increased risk of POD as compared to propofol-based anesthesia (odds ratio [OR], 4.120; 95% CI, 1.549-10.954; P = .005). There was no association between choice of anesthetic and postoperative 30-day complications or the length of postoperative hospital stay. Both older age (OR, 1.242; 95% CI, 1.130-1.366; P < .001) and higher pain score at postoperative day 1 (OR, 1.338; 95% CI, 1.056-1.696; P = .016) were associated with increased risk of POD.
Conclusion: Propofol-based anesthesia was associated with a lower incidence of and risk for POD than sevoflurane-based anesthesia in older patients undergoing spine surgery.
Study 2 Overview (Mei et al)
Objective: To determine the incidence and duration of POD in older patients after total knee/hip replacement (TKR/THR) under intravenous propofol or inhalational sevoflurane general anesthesia.
Design: Randomized clinical trial of propofol and sevoflurane groups.
Setting and participants: This study was conducted at the Shanghai Tenth People’s Hospital and involved 209 participants enrolled between June 2016 and November 2019. All participants were 60 years of age or older, scheduled for TKR/THR surgery under general anesthesia, American Society of Anesthesiologists (ASA) class I to III, and assessed to be of normal cognitive function preoperatively via a Mini-Mental State Examination. Participant exclusion criteria included preexisting delirium as assessed by the Confusion Assessment Method (CAM), prior diagnosed neurological diseases (eg, Parkinson’s disease), prior diagnosed mental disorders (eg, schizophrenia), or impaired vision or hearing that would influence cognitive assessments. All participants were randomly assigned to either sevoflurane or propofol anesthesia for their surgery via a computer-generated list. Of these, 103 received inhalational sevoflurane and 106 received intravenous propofol. All participants received standardized postoperative care.
Main outcome measures: All participants were interviewed by investigators, who were blinded to the anesthesia regimen, twice daily on postoperative days 1, 2, and 3 using CAM and a CAM-based scoring system (CAM-S) to assess delirium severity. The CAM encapsulated 4 criteria: acute onset and fluctuating course, agitation, disorganized thinking, and altered level of consciousness. To diagnose delirium, both the first and second criteria must be met, in addition to either the third or fourth criterion. The averages of the scores across the 3 postoperative days indicated delirium severity, while the incidence and duration of delirium was assessed by the presence of delirium as determined by CAM on any postoperative day.
Main results: All eligible participants (N = 209; mean [SD] age 71.2 [6.7] years; 29.2% male) were included in the final analysis. The incidence of POD was not statistically different between the propofol and sevoflurane groups (33.0% vs 23.3%; P = .119, Chi-square test). It was estimated that 316 participants in each arm of the study were needed to detect statistical differences. The number of days of POD per person were higher with propofol anesthesia as compared to sevoflurane (0.5 [0.8] vs 0.3 [0.5]; P = .049, Student’s t-test).
Conclusion: This underpowered study showed a 9.7% difference in the incidence of POD between older adults who received propofol (33.0%) and sevoflurane (23.3%) after THR/TKR. Further studies with a larger sample size are needed to compare general anesthetics and their role in POD.
Commentary
Delirium is characterized by an acute state of confusion with fluctuating mental status, inattention, disorganized thinking, and altered level of consciousness. It is often caused by medications and/or their related adverse effects, infections, electrolyte imbalances, and other clinical etiologies. Delirium often manifests in post-surgical settings, disproportionately affecting older patients and leading to increased risk of morbidity, mortality, hospital length of stay, and health care costs.1 Intraoperative risk factors for POD are determined by the degree of operative stress (eg, lower-risk surgeries put the patient at reduced risk for POD as compared to higher-risk surgeries) and are additive to preexisting patient-specific risk factors, such as older age and functional impairment.1 Because operative stress is associated with risk for POD, limiting operative stress in controlled ways, such as through the choice of anesthetic agent administered, may be a pragmatic way to manage operative risks and optimize outcomes, especially when serving a surgically vulnerable population.
In Study 1, Chang et al sought to assess whether 2 commonly utilized general anesthetics, propofol and sevoflurane, in older patients undergoing spine surgery differentially affected the incidence of POD. In this retrospective, single-blinded observational study of 281 geriatric patients, the researchers found that sevoflurane was associated with a higher risk of POD as compared to propofol. However, these anesthetics were not associated with surgical outcomes such as postoperative 30-day complications or the length of postoperative hospital stay. While these findings added new knowledge to this field of research, several limitations should be kept in mind when interpreting this study’s results. For instance, the sample size was relatively small, with all cases selected from a single center utilizing a retrospective analysis. In addition, although a standardized nursing screening tool was used as a method for delirium detection, hypoactive delirium or less symptomatic delirium may have been missed, which in turn would lead to an underestimation of POD incidence. The latter is a common limitation in delirium research.
In Study 2, Mei et al similarly explored the effects of general anesthetics on POD in older surgical patients. Specifically, using a randomized clinical trial design, the investigators compared propofol with sevoflurane in older patients who underwent TKR/THR, and their roles in POD severity and duration. Although the incidence of POD was higher in those who received propofol compared to sevoflurane, this trial was underpowered and the results did not reach statistical significance. In addition, while the duration of POD was slightly longer in the propofol group compared to the sevoflurane group (0.5 vs 0.3 days), it was unclear if this finding was clinically significant. Similar to many research studies in POD, limitations of Study 2 included a small sample size of 209 patients, with all participants enrolled from a single center. On the other hand, this study illustrated the feasibility of a method that allowed reproducible prospective assessment of POD time course using CAM and CAM-S.
Applications for Clinical Practice and System Implementation
The delineation of risk factors that contribute to delirium after surgery in older patients is key to mitigating risks for POD and improving clinical outcomes. An important step towards a better understanding of these modifiable risk factors is to clearly quantify intraoperative risk of POD attributable to specific anesthetics. While preclinical studies have shown differential neurotoxicity effects of propofol and sevoflurane, their impact on clinically important neurologic outcomes such as delirium and cognitive decline remains poorly understood. Although Studies 1 and 2 both provided head-to-head comparisons of propofol and sevoflurane as risk factors for POD in high-operative-stress surgeries in older patients, the results were inconsistent. That being said, this small incremental increase in knowledge was not unexpected in the course of discovery around a clinically complex research question. Importantly, these studies provided evidence regarding the methodological approaches that could be taken to further this line of research.
The mediating factors of the differences on neurologic outcomes between anesthetic agents are likely pharmacological, biological, and methodological. Pharmacologically, the differences between target receptors, such as GABAA (propofol, etomidate) or NMDA (ketamine), could be a defining feature in the difference in incidence of POD. Additionally, secondary actions of anesthetic agents on glycine, nicotinic, and acetylcholine receptors could play a role as well. Biologically, genes such as CYP2E1, CYP2B6, CYP2C9, GSTP1, UGT1A9, SULT1A1, and NQO1 have all been identified as genetic factors in the metabolism of anesthetics, and variations in such genes could result in different responses to anesthetics.2 Methodologically, routes of anesthetic administration (eg, inhalation vs intravenous), preexisting anatomical structures, or confounding medical conditions (eg, lower respiratory volume due to older age) may influence POD incidence, duration, or severity. Moreover, methodological differences between Studies 1 and 2, such as surgeries performed (spinal vs TKR/THR), patient populations (South Korean vs Chinese), and the diagnosis and monitoring of delirium (retrospective screening and diagnosis vs prospective CAM/CAM-S) may impact delirium outcomes. Thus, these factors should be considered in the design of future clinical trials undertaken to investigate the effects of anesthetics on POD.
Given the high prevalence of delirium and its associated adverse outcomes in the immediate postoperative period in older patients, further research is warranted to determine how anesthetics affect POD in order to optimize perioperative care and mitigate risks in this vulnerable population. Moreover, parallel investigations into how anesthetics differentially impact the development of transient or longer-term cognitive impairment after a surgical procedure (ie, postoperative cognitive dysfunction) in older adults are urgently needed in order to improve their cognitive health.
Practice Points
- Intravenous propofol and inhalational sevoflurane may be differentially associated with incidence, duration, and severity of POD in geriatric surgical patients.
- Further larger-scale studies are warranted to clarify the role of anesthetic choice in POD in order to optimize surgical outcomes in older patients.
–Jared Doan, BS, and Fred Ko, MD
Icahn School of Medicine at Mount Sinai
1. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. J Am Geriatr Soc. 2006;54(10):1578-1589. doi:10.1111/j.1532-5415.2006.00893.x
2. Mikstacki A, Skrzypczak-Zielinska M, Tamowicz B, et al. The impact of genetic factors on response to anaesthetics. Adv Med Sci. 2013;58(1):9-14. doi:10.2478/v10039-012-0065-z
Study 1 Overview (Chang et al)
Objective: To assess the incidence of postoperative delirium (POD) following propofol- vs sevoflurane-based anesthesia in geriatric spine surgery patients.
Design: Retrospective, single-blinded observational study of propofol- and sevoflurane-based anesthesia cohorts.
Setting and participants: Patients eligible for this study were aged 65 years or older admitted to the SMG-SNU Boramae Medical Center (Seoul, South Korea). All patients underwent general anesthesia either via intravenous propofol or inhalational sevoflurane for spine surgery between January 2015 and December 2019. Patients were retrospectively identified via electronic medical records. Patient exclusion criteria included preoperative delirium, history of dementia, psychiatric disease, alcoholism, hepatic or renal dysfunction, postoperative mechanical ventilation dependence, other surgery within the recent 6 months, maintenance of intraoperative anesthesia with combined anesthetics, or incomplete medical record.
Main outcome measures: The primary outcome was the incidence of POD after administration of propofol- and sevoflurane-based anesthesia during hospitalization. Patients were screened for POD regularly by attending nurses using the Nursing Delirium Screening Scale (disorientation, inappropriate behavior, inappropriate communication, hallucination, and psychomotor retardation) during the entirety of the patient’s hospital stay; if 1 or more screening criteria were met, a psychiatrist was consulted for the proper diagnosis and management of delirium. A psychiatric diagnosis was required for a case to be counted toward the incidence of POD in this study. Secondary outcomes included postoperative 30-day complications (angina, myocardial infarction, transient ischemic attack/stroke, pneumonia, deep vein thrombosis, pulmonary embolism, acute kidney injury, or infection) and length of postoperative hospital stay.
Main results: POD occurred in 29 patients (10.3%) out of the total cohort of 281. POD was more common in the sevoflurane group than in the propofol group (15.7% vs 5.0%; P = .003). Using multivariable logistic regression, inhalational sevoflurane was associated with an increased risk of POD as compared to propofol-based anesthesia (odds ratio [OR], 4.120; 95% CI, 1.549-10.954; P = .005). There was no association between choice of anesthetic and postoperative 30-day complications or the length of postoperative hospital stay. Both older age (OR, 1.242; 95% CI, 1.130-1.366; P < .001) and higher pain score at postoperative day 1 (OR, 1.338; 95% CI, 1.056-1.696; P = .016) were associated with increased risk of POD.
Conclusion: Propofol-based anesthesia was associated with a lower incidence of and risk for POD than sevoflurane-based anesthesia in older patients undergoing spine surgery.
Study 2 Overview (Mei et al)
Objective: To determine the incidence and duration of POD in older patients after total knee/hip replacement (TKR/THR) under intravenous propofol or inhalational sevoflurane general anesthesia.
Design: Randomized clinical trial of propofol and sevoflurane groups.
Setting and participants: This study was conducted at the Shanghai Tenth People’s Hospital and involved 209 participants enrolled between June 2016 and November 2019. All participants were 60 years of age or older, scheduled for TKR/THR surgery under general anesthesia, American Society of Anesthesiologists (ASA) class I to III, and assessed to be of normal cognitive function preoperatively via a Mini-Mental State Examination. Participant exclusion criteria included preexisting delirium as assessed by the Confusion Assessment Method (CAM), prior diagnosed neurological diseases (eg, Parkinson’s disease), prior diagnosed mental disorders (eg, schizophrenia), or impaired vision or hearing that would influence cognitive assessments. All participants were randomly assigned to either sevoflurane or propofol anesthesia for their surgery via a computer-generated list. Of these, 103 received inhalational sevoflurane and 106 received intravenous propofol. All participants received standardized postoperative care.
Main outcome measures: All participants were interviewed by investigators, who were blinded to the anesthesia regimen, twice daily on postoperative days 1, 2, and 3 using CAM and a CAM-based scoring system (CAM-S) to assess delirium severity. The CAM encapsulated 4 criteria: acute onset and fluctuating course, agitation, disorganized thinking, and altered level of consciousness. To diagnose delirium, both the first and second criteria must be met, in addition to either the third or fourth criterion. The averages of the scores across the 3 postoperative days indicated delirium severity, while the incidence and duration of delirium was assessed by the presence of delirium as determined by CAM on any postoperative day.
Main results: All eligible participants (N = 209; mean [SD] age 71.2 [6.7] years; 29.2% male) were included in the final analysis. The incidence of POD was not statistically different between the propofol and sevoflurane groups (33.0% vs 23.3%; P = .119, Chi-square test). It was estimated that 316 participants in each arm of the study were needed to detect statistical differences. The number of days of POD per person were higher with propofol anesthesia as compared to sevoflurane (0.5 [0.8] vs 0.3 [0.5]; P = .049, Student’s t-test).
Conclusion: This underpowered study showed a 9.7% difference in the incidence of POD between older adults who received propofol (33.0%) and sevoflurane (23.3%) after THR/TKR. Further studies with a larger sample size are needed to compare general anesthetics and their role in POD.
Commentary
Delirium is characterized by an acute state of confusion with fluctuating mental status, inattention, disorganized thinking, and altered level of consciousness. It is often caused by medications and/or their related adverse effects, infections, electrolyte imbalances, and other clinical etiologies. Delirium often manifests in post-surgical settings, disproportionately affecting older patients and leading to increased risk of morbidity, mortality, hospital length of stay, and health care costs.1 Intraoperative risk factors for POD are determined by the degree of operative stress (eg, lower-risk surgeries put the patient at reduced risk for POD as compared to higher-risk surgeries) and are additive to preexisting patient-specific risk factors, such as older age and functional impairment.1 Because operative stress is associated with risk for POD, limiting operative stress in controlled ways, such as through the choice of anesthetic agent administered, may be a pragmatic way to manage operative risks and optimize outcomes, especially when serving a surgically vulnerable population.
In Study 1, Chang et al sought to assess whether 2 commonly utilized general anesthetics, propofol and sevoflurane, in older patients undergoing spine surgery differentially affected the incidence of POD. In this retrospective, single-blinded observational study of 281 geriatric patients, the researchers found that sevoflurane was associated with a higher risk of POD as compared to propofol. However, these anesthetics were not associated with surgical outcomes such as postoperative 30-day complications or the length of postoperative hospital stay. While these findings added new knowledge to this field of research, several limitations should be kept in mind when interpreting this study’s results. For instance, the sample size was relatively small, with all cases selected from a single center utilizing a retrospective analysis. In addition, although a standardized nursing screening tool was used as a method for delirium detection, hypoactive delirium or less symptomatic delirium may have been missed, which in turn would lead to an underestimation of POD incidence. The latter is a common limitation in delirium research.
In Study 2, Mei et al similarly explored the effects of general anesthetics on POD in older surgical patients. Specifically, using a randomized clinical trial design, the investigators compared propofol with sevoflurane in older patients who underwent TKR/THR, and their roles in POD severity and duration. Although the incidence of POD was higher in those who received propofol compared to sevoflurane, this trial was underpowered and the results did not reach statistical significance. In addition, while the duration of POD was slightly longer in the propofol group compared to the sevoflurane group (0.5 vs 0.3 days), it was unclear if this finding was clinically significant. Similar to many research studies in POD, limitations of Study 2 included a small sample size of 209 patients, with all participants enrolled from a single center. On the other hand, this study illustrated the feasibility of a method that allowed reproducible prospective assessment of POD time course using CAM and CAM-S.
Applications for Clinical Practice and System Implementation
The delineation of risk factors that contribute to delirium after surgery in older patients is key to mitigating risks for POD and improving clinical outcomes. An important step towards a better understanding of these modifiable risk factors is to clearly quantify intraoperative risk of POD attributable to specific anesthetics. While preclinical studies have shown differential neurotoxicity effects of propofol and sevoflurane, their impact on clinically important neurologic outcomes such as delirium and cognitive decline remains poorly understood. Although Studies 1 and 2 both provided head-to-head comparisons of propofol and sevoflurane as risk factors for POD in high-operative-stress surgeries in older patients, the results were inconsistent. That being said, this small incremental increase in knowledge was not unexpected in the course of discovery around a clinically complex research question. Importantly, these studies provided evidence regarding the methodological approaches that could be taken to further this line of research.
The mediating factors of the differences on neurologic outcomes between anesthetic agents are likely pharmacological, biological, and methodological. Pharmacologically, the differences between target receptors, such as GABAA (propofol, etomidate) or NMDA (ketamine), could be a defining feature in the difference in incidence of POD. Additionally, secondary actions of anesthetic agents on glycine, nicotinic, and acetylcholine receptors could play a role as well. Biologically, genes such as CYP2E1, CYP2B6, CYP2C9, GSTP1, UGT1A9, SULT1A1, and NQO1 have all been identified as genetic factors in the metabolism of anesthetics, and variations in such genes could result in different responses to anesthetics.2 Methodologically, routes of anesthetic administration (eg, inhalation vs intravenous), preexisting anatomical structures, or confounding medical conditions (eg, lower respiratory volume due to older age) may influence POD incidence, duration, or severity. Moreover, methodological differences between Studies 1 and 2, such as surgeries performed (spinal vs TKR/THR), patient populations (South Korean vs Chinese), and the diagnosis and monitoring of delirium (retrospective screening and diagnosis vs prospective CAM/CAM-S) may impact delirium outcomes. Thus, these factors should be considered in the design of future clinical trials undertaken to investigate the effects of anesthetics on POD.
Given the high prevalence of delirium and its associated adverse outcomes in the immediate postoperative period in older patients, further research is warranted to determine how anesthetics affect POD in order to optimize perioperative care and mitigate risks in this vulnerable population. Moreover, parallel investigations into how anesthetics differentially impact the development of transient or longer-term cognitive impairment after a surgical procedure (ie, postoperative cognitive dysfunction) in older adults are urgently needed in order to improve their cognitive health.
Practice Points
- Intravenous propofol and inhalational sevoflurane may be differentially associated with incidence, duration, and severity of POD in geriatric surgical patients.
- Further larger-scale studies are warranted to clarify the role of anesthetic choice in POD in order to optimize surgical outcomes in older patients.
–Jared Doan, BS, and Fred Ko, MD
Icahn School of Medicine at Mount Sinai
Study 1 Overview (Chang et al)
Objective: To assess the incidence of postoperative delirium (POD) following propofol- vs sevoflurane-based anesthesia in geriatric spine surgery patients.
Design: Retrospective, single-blinded observational study of propofol- and sevoflurane-based anesthesia cohorts.
Setting and participants: Patients eligible for this study were aged 65 years or older admitted to the SMG-SNU Boramae Medical Center (Seoul, South Korea). All patients underwent general anesthesia either via intravenous propofol or inhalational sevoflurane for spine surgery between January 2015 and December 2019. Patients were retrospectively identified via electronic medical records. Patient exclusion criteria included preoperative delirium, history of dementia, psychiatric disease, alcoholism, hepatic or renal dysfunction, postoperative mechanical ventilation dependence, other surgery within the recent 6 months, maintenance of intraoperative anesthesia with combined anesthetics, or incomplete medical record.
Main outcome measures: The primary outcome was the incidence of POD after administration of propofol- and sevoflurane-based anesthesia during hospitalization. Patients were screened for POD regularly by attending nurses using the Nursing Delirium Screening Scale (disorientation, inappropriate behavior, inappropriate communication, hallucination, and psychomotor retardation) during the entirety of the patient’s hospital stay; if 1 or more screening criteria were met, a psychiatrist was consulted for the proper diagnosis and management of delirium. A psychiatric diagnosis was required for a case to be counted toward the incidence of POD in this study. Secondary outcomes included postoperative 30-day complications (angina, myocardial infarction, transient ischemic attack/stroke, pneumonia, deep vein thrombosis, pulmonary embolism, acute kidney injury, or infection) and length of postoperative hospital stay.
Main results: POD occurred in 29 patients (10.3%) out of the total cohort of 281. POD was more common in the sevoflurane group than in the propofol group (15.7% vs 5.0%; P = .003). Using multivariable logistic regression, inhalational sevoflurane was associated with an increased risk of POD as compared to propofol-based anesthesia (odds ratio [OR], 4.120; 95% CI, 1.549-10.954; P = .005). There was no association between choice of anesthetic and postoperative 30-day complications or the length of postoperative hospital stay. Both older age (OR, 1.242; 95% CI, 1.130-1.366; P < .001) and higher pain score at postoperative day 1 (OR, 1.338; 95% CI, 1.056-1.696; P = .016) were associated with increased risk of POD.
Conclusion: Propofol-based anesthesia was associated with a lower incidence of and risk for POD than sevoflurane-based anesthesia in older patients undergoing spine surgery.
Study 2 Overview (Mei et al)
Objective: To determine the incidence and duration of POD in older patients after total knee/hip replacement (TKR/THR) under intravenous propofol or inhalational sevoflurane general anesthesia.
Design: Randomized clinical trial of propofol and sevoflurane groups.
Setting and participants: This study was conducted at the Shanghai Tenth People’s Hospital and involved 209 participants enrolled between June 2016 and November 2019. All participants were 60 years of age or older, scheduled for TKR/THR surgery under general anesthesia, American Society of Anesthesiologists (ASA) class I to III, and assessed to be of normal cognitive function preoperatively via a Mini-Mental State Examination. Participant exclusion criteria included preexisting delirium as assessed by the Confusion Assessment Method (CAM), prior diagnosed neurological diseases (eg, Parkinson’s disease), prior diagnosed mental disorders (eg, schizophrenia), or impaired vision or hearing that would influence cognitive assessments. All participants were randomly assigned to either sevoflurane or propofol anesthesia for their surgery via a computer-generated list. Of these, 103 received inhalational sevoflurane and 106 received intravenous propofol. All participants received standardized postoperative care.
Main outcome measures: All participants were interviewed by investigators, who were blinded to the anesthesia regimen, twice daily on postoperative days 1, 2, and 3 using CAM and a CAM-based scoring system (CAM-S) to assess delirium severity. The CAM encapsulated 4 criteria: acute onset and fluctuating course, agitation, disorganized thinking, and altered level of consciousness. To diagnose delirium, both the first and second criteria must be met, in addition to either the third or fourth criterion. The averages of the scores across the 3 postoperative days indicated delirium severity, while the incidence and duration of delirium was assessed by the presence of delirium as determined by CAM on any postoperative day.
Main results: All eligible participants (N = 209; mean [SD] age 71.2 [6.7] years; 29.2% male) were included in the final analysis. The incidence of POD was not statistically different between the propofol and sevoflurane groups (33.0% vs 23.3%; P = .119, Chi-square test). It was estimated that 316 participants in each arm of the study were needed to detect statistical differences. The number of days of POD per person were higher with propofol anesthesia as compared to sevoflurane (0.5 [0.8] vs 0.3 [0.5]; P = .049, Student’s t-test).
Conclusion: This underpowered study showed a 9.7% difference in the incidence of POD between older adults who received propofol (33.0%) and sevoflurane (23.3%) after THR/TKR. Further studies with a larger sample size are needed to compare general anesthetics and their role in POD.
Commentary
Delirium is characterized by an acute state of confusion with fluctuating mental status, inattention, disorganized thinking, and altered level of consciousness. It is often caused by medications and/or their related adverse effects, infections, electrolyte imbalances, and other clinical etiologies. Delirium often manifests in post-surgical settings, disproportionately affecting older patients and leading to increased risk of morbidity, mortality, hospital length of stay, and health care costs.1 Intraoperative risk factors for POD are determined by the degree of operative stress (eg, lower-risk surgeries put the patient at reduced risk for POD as compared to higher-risk surgeries) and are additive to preexisting patient-specific risk factors, such as older age and functional impairment.1 Because operative stress is associated with risk for POD, limiting operative stress in controlled ways, such as through the choice of anesthetic agent administered, may be a pragmatic way to manage operative risks and optimize outcomes, especially when serving a surgically vulnerable population.
In Study 1, Chang et al sought to assess whether 2 commonly utilized general anesthetics, propofol and sevoflurane, in older patients undergoing spine surgery differentially affected the incidence of POD. In this retrospective, single-blinded observational study of 281 geriatric patients, the researchers found that sevoflurane was associated with a higher risk of POD as compared to propofol. However, these anesthetics were not associated with surgical outcomes such as postoperative 30-day complications or the length of postoperative hospital stay. While these findings added new knowledge to this field of research, several limitations should be kept in mind when interpreting this study’s results. For instance, the sample size was relatively small, with all cases selected from a single center utilizing a retrospective analysis. In addition, although a standardized nursing screening tool was used as a method for delirium detection, hypoactive delirium or less symptomatic delirium may have been missed, which in turn would lead to an underestimation of POD incidence. The latter is a common limitation in delirium research.
In Study 2, Mei et al similarly explored the effects of general anesthetics on POD in older surgical patients. Specifically, using a randomized clinical trial design, the investigators compared propofol with sevoflurane in older patients who underwent TKR/THR, and their roles in POD severity and duration. Although the incidence of POD was higher in those who received propofol compared to sevoflurane, this trial was underpowered and the results did not reach statistical significance. In addition, while the duration of POD was slightly longer in the propofol group compared to the sevoflurane group (0.5 vs 0.3 days), it was unclear if this finding was clinically significant. Similar to many research studies in POD, limitations of Study 2 included a small sample size of 209 patients, with all participants enrolled from a single center. On the other hand, this study illustrated the feasibility of a method that allowed reproducible prospective assessment of POD time course using CAM and CAM-S.
Applications for Clinical Practice and System Implementation
The delineation of risk factors that contribute to delirium after surgery in older patients is key to mitigating risks for POD and improving clinical outcomes. An important step towards a better understanding of these modifiable risk factors is to clearly quantify intraoperative risk of POD attributable to specific anesthetics. While preclinical studies have shown differential neurotoxicity effects of propofol and sevoflurane, their impact on clinically important neurologic outcomes such as delirium and cognitive decline remains poorly understood. Although Studies 1 and 2 both provided head-to-head comparisons of propofol and sevoflurane as risk factors for POD in high-operative-stress surgeries in older patients, the results were inconsistent. That being said, this small incremental increase in knowledge was not unexpected in the course of discovery around a clinically complex research question. Importantly, these studies provided evidence regarding the methodological approaches that could be taken to further this line of research.
The mediating factors of the differences on neurologic outcomes between anesthetic agents are likely pharmacological, biological, and methodological. Pharmacologically, the differences between target receptors, such as GABAA (propofol, etomidate) or NMDA (ketamine), could be a defining feature in the difference in incidence of POD. Additionally, secondary actions of anesthetic agents on glycine, nicotinic, and acetylcholine receptors could play a role as well. Biologically, genes such as CYP2E1, CYP2B6, CYP2C9, GSTP1, UGT1A9, SULT1A1, and NQO1 have all been identified as genetic factors in the metabolism of anesthetics, and variations in such genes could result in different responses to anesthetics.2 Methodologically, routes of anesthetic administration (eg, inhalation vs intravenous), preexisting anatomical structures, or confounding medical conditions (eg, lower respiratory volume due to older age) may influence POD incidence, duration, or severity. Moreover, methodological differences between Studies 1 and 2, such as surgeries performed (spinal vs TKR/THR), patient populations (South Korean vs Chinese), and the diagnosis and monitoring of delirium (retrospective screening and diagnosis vs prospective CAM/CAM-S) may impact delirium outcomes. Thus, these factors should be considered in the design of future clinical trials undertaken to investigate the effects of anesthetics on POD.
Given the high prevalence of delirium and its associated adverse outcomes in the immediate postoperative period in older patients, further research is warranted to determine how anesthetics affect POD in order to optimize perioperative care and mitigate risks in this vulnerable population. Moreover, parallel investigations into how anesthetics differentially impact the development of transient or longer-term cognitive impairment after a surgical procedure (ie, postoperative cognitive dysfunction) in older adults are urgently needed in order to improve their cognitive health.
Practice Points
- Intravenous propofol and inhalational sevoflurane may be differentially associated with incidence, duration, and severity of POD in geriatric surgical patients.
- Further larger-scale studies are warranted to clarify the role of anesthetic choice in POD in order to optimize surgical outcomes in older patients.
–Jared Doan, BS, and Fred Ko, MD
Icahn School of Medicine at Mount Sinai
1. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. J Am Geriatr Soc. 2006;54(10):1578-1589. doi:10.1111/j.1532-5415.2006.00893.x
2. Mikstacki A, Skrzypczak-Zielinska M, Tamowicz B, et al. The impact of genetic factors on response to anaesthetics. Adv Med Sci. 2013;58(1):9-14. doi:10.2478/v10039-012-0065-z
1. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. J Am Geriatr Soc. 2006;54(10):1578-1589. doi:10.1111/j.1532-5415.2006.00893.x
2. Mikstacki A, Skrzypczak-Zielinska M, Tamowicz B, et al. The impact of genetic factors on response to anaesthetics. Adv Med Sci. 2013;58(1):9-14. doi:10.2478/v10039-012-0065-z
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>1122 JCOM ORR Ko</fileName> <TBEID>0C02B54E.SIG</TBEID> <TBUniqueIdentifier>NJ_0C02B54E</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname>Anesthetic Choices and Postopera</storyname> <articleType>1</articleType> <TBLocation>Copyfitting-JCOM</TBLocation> <QCDate/> <firstPublished>20221117T155806</firstPublished> <LastPublished>20221117T155807</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20221117T155806</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText/> <bylineFull/> <bylineTitleText>Chang JE, Min SW, Kim H, et al. Association between anesthetics and postoperative delirium in elderly patients undergoing spine surgery: propofol versus sevoflurane. Global Spine J. 2022 Jun 22:21925682221110828. doi:10.1177/21925682221110828 Mei X, Zheng HL, Li C, et al. The effects of propofol and sevoflurane on postoperative delirium in older patients: a randomized clinical trial study. J Alzheimers Dis. 2020;76(4):1627-1636. doi:10.3233/JAD-200322 </bylineTitleText> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Objective: To assess the incidence of postoperative delirium (POD) following propofol- vs sevoflurane-based anesthesia in geriatric spine surgery patients. Desi</metaDescription> <articlePDF/> <teaserImage/> <title>Anesthetic Choices and Postoperative Delirium Incidence: Propofol vs Sevoflurane</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi>10.12788/jcom.0116</doi> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>jcom</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">40713</term> </publications> <sections> <term canonical="true">41021</term> </sections> <topics> <term canonical="true">302</term> <term>325</term> <term>215</term> <term>327</term> <term>248</term> <term>258</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Anesthetic Choices and Postoperative Delirium Incidence: Propofol vs Sevoflurane</title> <deck/> </itemMeta> <itemContent> <p class="sub1">Study 1 Overview (Chang et al) </p> <p><strong><em>Objective:</em></strong> To assess the incidence of postoperative delirium (POD) following propofol- vs sevoflurane-based anesthesia in geriatric spine surgery patients. <br/><br/><strong><em>Design:</em></strong> Retrospective, single-blinded observational study of propofol- and sevoflurane-based anesthesia cohorts.<br/><br/><strong><em>Setting and participants:</em></strong> Patients eligible for this study were aged 65 years or older admitted to the SMG-SNU Boramae Medical Center (Seoul, South Korea). All patients underwent general anesthesia either via intravenous propofol or inhalational sevoflurane for spine surgery between January 2015 and December 2019. Patients were retrospectively identified via electronic medical records. Patient exclusion criteria included preoperative delirium, history of dementia, psychiatric disease, alcoholism, hepatic or renal dysfunction, postoperative mechanical ventilation dependence, other surgery within the recent 6 months, maintenance of intraoperative anesthesia with combined anesthetics, or incomplete medical record.<br/><br/><strong><em>Main outcome measures:</em></strong> The primary outcome was the incidence of POD after administration of propofol- and sevoflurane-based anesthesia during hospitalization. Patients were screened for POD regularly by attending nurses using the Nursing Delirium Screening Scale (disorientation, inappropriate behavior, inappropriate communication, hallucination, and psychomotor retardation) during the entirety of the patient’s hospital stay; if 1 or more screening criteria were met, a psychiatrist was consulted for the proper diagnosis and management of delirium. A psychiatric diagnosis was required for a case to be counted toward the incidence of POD in this study. Secondary outcomes included postoperative 30-day complications (angina, myocardial infarction, transient ischemic attack/stroke, pneumonia, deep vein thrombosis, pulmonary embolism, acute kidney injury, or infection) and length of postoperative hospital stay.<br/><br/><strong><em>Main results:</em></strong> POD occurred in 29 patients (10.3%) out of the total cohort of 281. POD was more common in the sevoflurane group than in the propofol group (15.7% vs 5.0%; <em>P</em> = .003). Using multivariable logistic regression, inhalational sevoflurane was associated with an increased risk of POD as compared to propofol-based anesthesia (odds ratio [OR], 4.120; 95% CI, 1.549-10.954; <em>P</em> = .005). There was no association between choice of anesthetic and postoperative 30-day complications or the length of postoperative hospital stay. Both older age (OR, 1.242; 95% CI, 1.130-1.366; <em>P</em> < .001) and higher pain score at postoperative day 1 (OR, 1.338; 95% CI, 1.056-1.696; <em>P</em> = .016) were associated with increased risk of POD.<br/><br/><strong><em>Conclusion:</em></strong> Propofol-based anesthesia was associated with a lower incidence of and risk for POD than sevoflurane-based anesthesia in older patients undergoing spine surgery.</p> <p class="sub1">Study 2 Overview (Mei et al) </p> <p><strong><em>Objective:</em></strong> To determine the incidence and duration of POD in older patients after total knee/hip replacement (TKR/THR) under intravenous propofol or inhalational sevoflurane general anesthesia.<br/><br/><strong><em>Design:</em></strong> Randomized clinical trial of propofol and sevoflurane groups.<br/><br/><strong><em>Setting and participants:</em></strong> This study was conducted at the Shanghai Tenth People’s Hospital and involved 209 participants enrolled between June 2016 and November 2019. All participants were 60 years of age or older, scheduled for TKR/THR surgery under general anesthesia, American Society of Anesthesiologists (ASA) class I to III, and assessed to be of normal cognitive function preoperatively via a Mini-Mental State Examination. Participant exclusion criteria included preexisting delirium as assessed by the Confusion Assessment Method (CAM), prior diagnosed neurological diseases (eg, Parkinson’s disease), prior diagnosed mental disorders (eg, schizophrenia), or impaired vision or hearing that would influence cognitive assessments. All participants were randomly assigned to either sevoflurane or propofol anesthesia for their surgery via a computer-generated list. Of these, 103 received inhalational sevoflurane and 106 received intravenous propofol. All participants received standardized postoperative care.<br/><br/><strong><em>Main outcome measures:</em></strong> All participants were interviewed by investigators, who were blinded to the anesthesia regimen, twice daily on postoperative days 1, 2, and 3 using CAM and a CAM-based scoring system (CAM-S) to assess delirium severity. The CAM encapsulated 4 criteria: acute onset and fluctuating course, agitation, disorganized thinking, and altered level of consciousness. To diagnose delirium, both the first and second criteria must be met, in addition to either the third or fourth criterion. The averages of the scores across the 3 postoperative days indicated delirium severity, while the incidence and duration of delirium was assessed by the presence of delirium as determined by CAM on any postoperative day.<br/><br/><strong><em>Main results:</em></strong> All eligible participants (N = 209; mean [SD] age 71.2 [6.7] years; 29.2% male) were included in the final analysis. The incidence of POD was not statistically different between the propofol and sevoflurane groups (33.0% vs 23.3%; <em>P</em> = .119, Chi-square test). It was estimated that 316 participants in each arm of the study were needed to detect statistical differences. The number of days of POD per person were higher with propofol anesthesia as compared to sevoflurane (0.5 [0.8] vs 0.3 [0.5]; <em>P </em>= .049, Student’s <em>t</em>-test).<br/><br/><strong><em>Conclusion:</em></strong> This underpowered study showed a 9.7% difference in the incidence of POD between older adults who received propofol (33.0%) and sevoflurane (23.3%) after THR/TKR. Further studies with a larger sample size are needed to compare general anesthetics and their role in POD.</p> <p class="sub1">Commentary</p> <p>Delirium is characterized by an acute state of confusion with fluctuating mental status, inattention, disorganized thinking, and altered level of consciousness. It is often caused by medications and/or their related adverse effects, infections, electrolyte imbalances, and other clinical etiologies. Delirium often manifests in post-surgical settings, disproportionately affecting older patients and leading to increased risk of morbidity, mortality, hospital length of stay, and health care costs.<sup>1</sup> Intraoperative risk factors for POD are determined by the degree of operative stress (eg, lower-risk surgeries put the patient at reduced risk for POD as compared to higher-risk surgeries) and are additive to preexisting patient-specific risk factors, such as older age and functional impairment.<sup>1</sup> Because operative stress is associated with risk for POD, limiting operative stress in controlled ways, such as through the choice of anesthetic agent administered, may be a pragmatic way to manage operative risks and optimize outcomes, especially when serving a surgically vulnerable population.</p> <p>In Study 1, Chang et al sought to assess whether 2 commonly utilized general anesthetics, propofol and sevoflurane, in older patients undergoing spine surgery differentially affected the incidence of POD. In this retrospective, single-blinded observational study of 281 geriatric patients, the researchers found that sevoflurane was associated with a higher risk of POD as compared to propofol. However, these anesthetics were not associated with surgical outcomes such as postoperative 30-day complications or the length of postoperative hospital stay. While these findings added new knowledge to this field of research, several limitations should be kept in mind when interpreting this study’s results. For instance, the sample size was relatively small, with all cases selected from a single center utilizing a retrospective analysis. In addition, although a standardized nursing screening tool was used as a method for delirium detection, hypoactive delirium or less symptomatic delirium may have been missed, which in turn would lead to an underestimation of POD incidence. The latter is a common limitation in delirium research. <br/><br/>In Study 2, Mei et al similarly explored the effects of general anesthetics on POD in older surgical patients. Specifically, using a randomized clinical trial design, the investigators compared propofol with sevoflurane in older patients who underwent TKR/THR, and their roles in POD severity and duration. Although the incidence of POD was higher in those who received propofol compared to sevoflurane, this trial was underpowered and the results did not reach statistical significance. In addition, while the duration of POD was slightly longer in the propofol group compared to the sevoflurane group (0.5 vs 0.3 days), it was unclear if this finding was clinically significant. Similar to many research studies in POD, limitations of Study 2 included a small sample size of 209 patients, with all participants enrolled from a single center. On the other hand, this study illustrated the feasibility of a method that allowed reproducible prospective assessment of POD time course using CAM and CAM-S.</p> <p class="sub1">Applications for Clinical Practice and System Implementation</p> <p>The delineation of risk factors that contribute to delirium after surgery in older patients is key to mitigating risks for POD and improving clinical outcomes. An important step towards a better understanding of these modifiable risk factors is to clearly quantify intraoperative risk of POD attributable to specific anesthetics. While preclinical studies have shown differential neurotoxicity effects of propofol and sevoflurane, their impact on clinically important neurologic outcomes such as delirium and cognitive decline remains poorly understood. Although Studies 1 and 2 both provided head-to-head comparisons of propofol and sevoflurane as risk factors for POD in high-operative-stress surgeries in older patients, the results were inconsistent. That being said, this small incremental increase in knowledge was not unexpected in the course of discovery around a clinically complex research question. Importantly, these studies provided evidence regarding the methodological approaches that could be taken to further this line of research. </p> <p>The mediating factors of the differences on neurologic outcomes between anesthetic agents are likely pharmacological, biological, and methodological. Pharmacologically, the differences between target receptors, such as GABAA (propofol, etomidate) or NMDA (ketamine), could be a defining feature in the difference in incidence of POD. Additionally, secondary actions of anesthetic agents on glycine, nicotinic, and acetylcholine receptors could play a role as well. Biologically, genes such as <em>CYP2E1</em>, <em>CYP2B6</em>, <em>CYP2C9</em>, <em>GSTP1</em>, <em>UGT1A9</em>, <em>SULT1A1</em>, and <em>NQO1</em> have all been identified as genetic factors in the metabolism of anesthetics, and variations in such genes could result in different responses to anesthetics.<sup>2</sup> Methodologically, routes of anesthetic administration (eg, inhalation vs intravenous), preexisting anatomical structures, or confounding medical conditions (eg, lower respiratory volume due to older age) may influence POD incidence, duration, or severity. Moreover, methodological differences between Studies 1 and 2, such as surgeries performed (spinal vs TKR/THR), patient populations (South Korean vs Chinese), and the diagnosis and monitoring of delirium (retrospective screening and diagnosis vs prospective CAM/CAM-S) may impact delirium outcomes. Thus, these factors should be considered in the design of future clinical trials undertaken to investigate the effects of anesthetics on POD.<br/><br/>Given the high prevalence of delirium and its associated adverse outcomes in the immediate postoperative period in older patients, further research is warranted to determine how anesthetics affect POD in order to optimize perioperative care and mitigate risks in this vulnerable population. Moreover, parallel investigations into how anesthetics differentially impact the development of transient or longer-term cognitive impairment after a surgical procedure (ie, postoperative cognitive dysfunction) in older adults are urgently needed in order to improve their cognitive health. </p> <p class="sub1">Practice Points </p> <ul class="body"> <li>Intravenous propofol and inhalational sevoflurane may be differentially associated with incidence, duration, and severity of POD in geriatric surgical patients.</li> <li>Further larger-scale studies are warranted to clarify the role of anesthetic choice in POD in order to optimize surgical outcomes in older patients.</li> </ul> <p> <em>–Jared Doan, BS, and Fred Ko, MD Icahn School of Medicine at Mount Sinaidoi:10.12788/jcom.0116</em> </p> <p class="sub1">References</p> <p class="reference">1. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. <em>J Am Geriatr Soc.</em> 2006;54(10):1578-1589. doi:10.1111/j.1532-5415.2006.00893.x</p> <p class="reference">2. Mikstacki A, Skrzypczak-Zielinska M, Tamowicz B, et al. The impact of genetic factors on response to anaesthetics. <em>Adv Med Sci.</em> 2013;58(1):9-14. doi:10.2478/v10039-012-0065-z</p> </itemContent> </newsItem> </itemSet></root>