High-Risk Perioperative Medications in the Chinese Elderly Population

Introduction

With the progress of medical technology, an ever-increasing number of operative procedures are performed in patients, especially in aged patients. Compared with their younger counterparts, the older surgical patients encounter a higher risk of perioperative complications and mortality due to deteriorated physical function and surgical stress.^1,2 Additionally, the elderly are susceptible to multiple comorbid conditions and have to take chronic medications. The inappropriate withdrawal or withholding of chronic medications in perioperative period is associated with an increased risk for drug-related problems (DRPs), including medication errors and adverse events.^3,4 Also, the adverse interactions between chronic medications and medications related to surgeries, for instance, anesthetics, analgesics, antibiotics and contrast agents, jeopardize surgical outcomes for the aged patients.⁵ For these reasons, it is necessary to review the perioperative medications for the elderly all along the care pathway to identify drugs that potentially imperil the safety of the patients.

A medication review refers to the structured evaluation of a patient’s medication regime to provide convenience in minimizing the number of the DRPs and optimizing the patients’ outcomes. A few published studies have established tools for reviewing the elderly patients’ medication regimes and optimizing the patients’ pharmacotherapy. Most of these tools are based on explicit criteria, including the Beers criteria,⁶ The Screening Tool for Older Person’s Prescription (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) criteria,⁷ Priscus List,⁸ Australian Prescribing Indicators Tool,⁹ French Consensus Panel List,¹⁰ Zhan’s criteria¹¹ and Improved criteria in the elderly tool.¹² These criteria were mostly used to assess the elder medical patients’ medication rather than surgical ones’, for they failed to evaluate the interactions between medications and perioperative physical and pathological conditions as well as interactions between chronic medications and surgery-related medications. Whereas, a few clinical studies have researched the chronic medication withdrawal and withholding in the perioperative period.^13–20 These preexisting studies focused on the impact of specific medication categories upon surgical patients yet did not provide an explicit evidence-based medication list to guide prescribing and medication audit.

Under the circumstances, Chinese experts have developed an explicit criterion as the tool for reviewing high-risk perioperative medications (HRPOMs) for the elderly.²¹ The HRPOMs are defined as (i) drugs that easily cause toxicity or adverse reactions due to aging physical function and surgical stress, (ii) drugs whose inappropriate withdrawal or continuation in the perioperative period easily causes more harm than benefit, (iii) drugs that can be replaced with safer alternatives. A few previous studies have demonstrated that HRPOMs can undermine the physical function or worsen the pathological conditions,^13,22 postpone or exacerbate the recovery of the surgical wound,^15,23 and impair the treatment of surgical complications.²⁰

Whereas, there was no literature verifying the HRPOM list, and assessing the prevalence of HRPOMs for the elderly so far. This cross-sectional study aimed to screen the HRPOMs and the association between HRPOM exposure and the demographic and clinical characteristics of the older patients admitted to a Chinese university-affiliated general hospital, and verify the effectiveness of the new-developed HRPOM list.

Methods

The study population comprised consecutive admissions to the surgical wards of a general hospital over a 6-month period (January 2020–June 2020). All patients aged ≥65 years were eligible for inclusion. The medication list for each patient included medications prescribed after the admission and drugs, which were taken before the admission for chronic diseases. The solvents and traditional Chinese medicines were excluded. Demographics and clinical characteristics were obtained using the Hospital Information System, included patient demographics, the number of diagnoses at discharge, day of hospital stay and the magnitude of the surgery. As some patients were admitted more than once to the hospital during the study period, calculations were based on admissions rather than patients. Screening for HRPOMs for the elderly was performed with the Microsoft Excel Visual Basic for Applications and was manually reviewed by 2 clinical pharmacists (Ren and Tan).

Chi-square analysis was used for univariate analysis and multivariate logistic regression analysis was used to establish the association between HRPOM exposure, which is defined as at least one HRPOM, and both demographic and clinical variables (expressed as odds ratio with 95% confidence intervals, [CI]). Statistical analysis was conducted using the SPSS software package version 25 (SPSS, Chicago, IL). Figures were drawn using the GraphPad Prism version 9.00 for Windows, GraphPad Software, San Diego, California, USA.

An ethics committee review was not required as the study was a clinical audit, and the patient data was anonymized to comply with relevant data protection and privacy regulations.

Results

Between January 1st 2020 and June 30th 2020, 810 patients were admitted to Jinshan Hospital of Fudan University to undergo surgery. All patients were included in the study and 618 (76.3%) of them encountered HRPOM exposure. In total, 19,224 medications including chronic medications and medications prescribed after the admission were used by the 810 patients, and 2113 HRPOMs were identified (11.0%).

Table 1 reports the demographics and clinical characteristics and the presence of HRPOM exposure. The mean age (± standard deviation, [SD]) of patients was 73.3 (±6.7, range: 65–95), 50.7% were males. The mean day of hospital stay was 9.9 days (±10.1, range: 0–122). The mean number of distinct diagnoses at discharge was 4.5 (±3.1, range: 1–19). The mean number of medications used during hospitalization was 23.7 (±14.3, range: 1–101). The magnitude of surgery was categorized into 4 groups according to the Surgical Classification Management System of China.²⁴ Figure 1 shows the distribution of the magnitude of the surgery and HRPOM exposure. The type of surgery was classified according to the International Classification of Diseases Clinical Modification of 9^th Revision Operations and Procedures (ICD-9-CM-3), including general surgery (36.3%), ophthalmology (6.9%), otolaryngology (4.7%), gynecology (3.3%), neurosurgery (6.7%), urology (10.1%), orthopedics (23.7%) and thoracic surgery (8.3%).

Table 1 Demographics and Clinical Characteristics of the Study Population in Jinshan Hospital of Fudan University, Shanghai, China, Between Jan 1st and June 30th, 2020

The contribution of HRPOMs identified is showed in Table 2. 2113 HRPOMs which were identified in the study involved 42 medications and 12 categories including of cardiovascular system (20.9%), urinary system (12.6%), hematological system (17.2%), central nervous system (10.9%), endocrine system (17.4%), gastrointestinal system (2.7%), 1st-generation anti-allergic (3.4%), anesthetics or anesthesia-assisted (1.6%), anti-inflammatory and anti-rheumatic (12.4%), anti-infective (0.7%), respiratory (0.1%) and other medications (0%). As shown in Figure 2, the top 20 medications comprised 93.5% of the HRPOMs.

Table 2 HRPOMs and the Concomitant Conditions and Potential Risks Identified in the Study and Recommendations According to the List

Table 3 reports the crude and adjusted odds for the occurrence of HRPOM exposure according to the variables. Upon univariate analysis, patients who were 70 years or older, or stayed in the hospital longer than 7 days were at higher risk of HRPOM exposure. The female patients were more likely to encounter HRPOM exposure than the male patients. Those with HRPOM exposure at discharge were significantly more likely to have more than 2 diagnoses or to use more than 15 medications during their hospitalization. Additionally, patients who underwent surgeries of Grade IV suffered more likelihood of HRPOM exposure than those who underwent surgeries of Grade III or lower.

Table 3 Crude and Adjusted Odds Ratios (95% CI) for HRPOM Exposure in the Study Population in Jinshan Hospital of Fudan University, Shanghai, China, Between Jan 1st and June 30th, 2020

Multivariate analysis showed there were positive associations between HRPOM exposure and age, the number of diagnoses at discharge, days of hospital stay and the number of medications used during hospitalization. Besides, patients who underwent surgeries of Grade IV were at 1.73 times increased odds of HRPOM exposure.

Discussion

The objective of our study was to investigate the previously unidentified prevalence of HRPOM exposure for the elderly in a Chinese university-affiliated general hospital, and verify the new-developed HRPOM list for the elderly. To our knowledge, this study is the first attempt to use a Chinese representative sample regarding the elderly surgical patients admitted to 8 common surgical wards to estimate the prevalence of HRPOMs with the use of a new-developed list of HRPOMs for the elderly. During our study, application of the HRPOM list had not yet been published for any settings.

Our findings revealed a total number of 2113 HRPOMs in a total number of 19,224 medications, and 618 participants encountered HRPOM exposure (76.3%). The preexisting medication review concerning perioperative medication for the elderly is limited. 486 participants in our study encountered HRPOMs related to chronic diseases (60.0%), while the previously reported prevalence of potentially inappropriate medications (PIMs) in Chinese hospitalized older patients ranged from 53.5% to 72.5%,^25,26 whereas few literature showed the prevalence of PIM in surgical patients was from 42.3% to 77.6%.^27–29 The HRPOM list for the elderly complies well with previously published PIM criteria.

HRPOMs generally included two supercategories in our study, drugs related to surgery such as analgesics, anesthetics, sedatives and anti-infective agents and drugs related to chronic non-communicable diseases such as antihypertensives, hypoglycemics and antimyocardial ischemia agents. HRPOMs related to surgery in our study comprised 50.5% while 46.5% for HRPOMs related to chronic non-communicable diseases. Drugs related to surgery usually involve anesthesia, induced anesthesia and post-surgical complications such as pain, delirium, bleeding, thrombosis and infection. In the first place, the HRPOMs referred to non-steroidal anti-inflammatory drugs (NSAIDs, aspirin≤100mg/day excluded) that were used by 257 participants (31.7%). The utilization rate of NSAIDs in our study was much higher than what was reported in previous literature regarding geriatric medication^26,30,31 mainly due to their foundational role in postsurgical analgesic, anti-inflammatory, anti-stress³² and anti-fever. Whereas the short-term use of postsurgical NSAIDs is associated with increased risk of bleeding³³ and acute kidney injury³⁴ especially in the older population and/or patients with related underlying medical conditions. The second-most HRPOM related to surgery was constituted by the glucocorticoids with concomitant NSAIDs (used by 189 participants, 23.3%). Glucocorticoids identified in our study were used to prevent or treat postoperative nausea and vomiting,^35,36 airway hyperresponsiveness,³⁷ allergy and inflammatory complications. The combination of glucocorticoids and NSAIDs increased the risk of gastrointestinal bleeding and ulcer.^16,38,39 HRPOMs related to surgery identified in our study potentially increased the occurrence of postoperative complications and thus increased the day of hospital stay and swelled the treatment cost.

Drugs related to chronic diseases were introduced to treat chronic comorbid conditions such as hypertension, diabetes, heart disease and ischemic stroke. Regarding this supercategory, Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers (ACEI/ARB) for hypertension held the predominant proportion as 220 participants in our study used them (27.2%). Hypertension is the most common chronic disease in Chinese older people, and the incidence was 55.7% for the population aged 65 to 74 years and 60.2% for the population aged 75 years or older.⁴⁰ Our study showed the prevalence of hypertension in the elder surgical patients was 50.2%, which fitted the previous survey. And the utilization rate of ACEI/ARB in our study was 54.1% compared with 27.4% as reported in the survey. Diuretics and calcium channel blockers (CCBs) were reported as the two most frequently used antihypertensive agents in China, while our study revealed the perioperative prescription of diuretics was limited mainly owing to their potential effect on electrolytes and blood volume levels. Moreover, according to the HRPOMs list, perioperative use of CCBs was proved to be safe enough except in vasospastic angina patients^14,41,42 who were not found in this audit. The withholding of ACEI/ARB in the perioperative period was associated with a lower risk of death and postoperative vascular events¹⁹ while a higher prevalence of intraoperative hypotension.⁴³ And when combining with potassium-sparing diuretics, ACEI/ARB raises the risk of hyperkalemia. Note that the withdrawal of the drugs results in fluctuation of blood pressure. HRPOMs related to chronic diseases were contended to mask the predisposing frailty of patients and/or reduce the severity of chronic comorbidities.¹ Take ACEI/ARB for example, inappropriate withholding or withdrawal of HRPOMs easily brings more harm than benefit.

The demographic and clinical variables were carefully grouped to reveal their associations with HRPOM exposure. Age, the number of distinct diagnoses, days of hospital stay and medications used during hospitalization were independent predictors for HRPOM exposure in our study. The elderly are more likely to be assailed by chronic health conditions, the number and severity of which also increase with age. Moreover, poorly managed chronic diseases often result in other organs’ injury and multiple chronic complications, which contributed to the number of distinct diagnoses. Compared with the reference group, patients with 3 or more diagnoses were around 3 times likely to experience HRPOM exposure in our study, which agreed with PIM presence in hospitalized medical patients reported previously.⁴⁴ Medical patients prefer pharmacotherapy rather than non-drug methods to treat each distinct diagnosis and thus receive more high-risk medications,²⁶ whereas surgical patients are more positive to surgical approaches for each distinct diagnosis.

It is noticeable that the occurrence of HRPOM exposure significantly increased with the number of medications in our study. The mean number of drugs used during hospitalization was 23.7, which was far more than the number defined by polypharmacy. Polypharmacy was generally defined as taking five or more medications.⁴⁵ This provides further evidence to previous studies that more medications mean more risks.^4,26–29,31 Given the poor health status and medication adherence, the elderly on polypharmacy are at higher risk of adverse drug events than the population of younger age or/and without polypharmacy.⁴⁶

The days of hospital stay were usually regarded as one of the hospitalization outcomes, while in our study this variable also contributed to HRPOMs. Patients hospitalized over two weeks were about 4 times more odds of HRPOM exposure than those hospitalized within one week. The elderly are susceptible to malnourished status, chronic conditions and surgical complications and thus easily suffered from extended length of hospital stay.⁴⁷ Nevertheless, patients with an excessive length of hospital stay are vulnerable to complications such as stress and deep venous thrombosis,⁴⁸ which increased the presence of high-risk medications as reported in preexisting literature.^27,31

Surgeries were categorized into four groups according to the magnitude of the surgery, and surgeries of Grade IV were of the highest risk of postsurgical complications and mortality. Logistic regression revealed HRPOM exposure was scarcely associated with the magnitude of surgery. Patients who underwent surgeries of Grade IV were at 1.73 times increased odds of HRPOM exposure than those with surgeries of Grade III or lower. Kennedy et al also reported a scarce association between postsurgical complications and the magnitude of surgery.¹ Further, the t-test showed patients with surgeries of Grade IV possessed more diagnoses, used more medications and hospitalized for more days compared with those of the reference population. As discussed above, the magnitude of surgery contributed to HRPOM exposure via the increasing days of hospital stay and the number of distinct diagnoses and medications.

The limitations of this study must be acknowledged. First, this medication audit was conducted from a resource within a single hospital and thus biases preexist in the spectra of surgeries and other clinical variables. Participants from some surgical wards tended to undergo day-surgeries or lower magnitude of surgeries and thus used fewer medications. HRPOM exposure of these participants was relatively fewer. Second, information from this analysis was limited because hospital records are not designed for research purposes, and their diagnostic quality may vary depending upon each surgeon and clinical unit, as data on surgical outcomes including postsurgical complications and mortality was not recorded. Thus, the impact of HRPOMs upon surgical outcomes remains unclear.

Even though this is the first study to reveal the high-risk medications used in the perioperative period for elderly patients in China, further research is necessary. Studies that use data from multiple medical centers would avoid static biases. And well-designed prospective studies including postsurgical complications and other clinical characteristics that we failed to collect would help to elucidate the impact of HRPOMs on the older surgical patients and further validate the HRPOMs list for the elderly.

Conclusion

We have uncovered the prevalence of HRPOMs for the elderly in a Chinese general hospital, and verified the HRPOM list for the elderly. HRPOMs were found to be more common in patients of 70 years or older, and those with more diagnoses, medications and days of hospital stay were at more odds to expose to HRPOMs. The magnitude of surgery was scarcely associated with HRPOM exposure. HRPOMs identified in our study comprehensively comprised not only chronic medications but also medications related to surgery. The effectiveness of the HRPOM list for the elderly was thus verified. Our study may provoke prospective research to assess the adverse effects of high-risk medications on the elderly’s surgical outcomes. And pharmaceutical care should be applied to monitor drug-related complications of elderly surgical patients and optimize their surgical outcomes.

Figure 1 The distribution of the number of diagnosis and medications, hospital stay per week and HRPOM exposure according to the magnitude of surgery. Notes: Hospital stay/week: 1: ≤7 days, 2: 8~14 days, 3: ≥15 days. The occurrence of HRPOM exposure of patients with surgeries of Grade IV was 91.7% compared with 66.3% for those with surgeries of GradeI, 62.8% for those with surgeries of GradeIIand 74.0% for those with surgeries of Grade III.

Figure 2 The distribution of the top 20 HRPOMs, which comprised 93.5% of the HRPOMs identified in the study.Abbreviations: NSAIDs, non- steroidal anti-inflammatory drugs; ACEI, angiotensin-converting enzyme Inhibitor; ARB, angiotensin receptor blocker.