Impact of the COVID‐19 pandemic on outcomes of cholecystectomy for acute cholecystitis: a national cohort study

The COVID‐19 pandemic was associated with significant disruptions to healthcare provision globally and in Aotearoa New Zealand. It remains unclear how this disruption affected the surgical management of acute cholecystitis and whether there are ongoing impacts.


Introduction
][5][6][7] On the 11 March 2020, the World Health Organisation (WHO) declared the COVID-19 outbreak a global pandemic, 8 leading to significant shifts in healthcare resource allocation. 9From late 2019 to early 2020, the CHOLECOVID Collaborative conducted an international observational study of 9783 patients with acute cholecystitis before and after the onset of the COVID-19 pandemic, and reported that the pandemic was associated with significant disruptions in healthcare delivery and staffing, greater disease severity, and reduced rates of cholecystectomy. 10A multicentre analysis of 16 hospitals in Madrid also found that morbidity, rates of failed conservative treatment, and hospital length of stay increased during the COVID-19 pandemic for patients with acute cholecystitis. 11n 2023, the WHO reported that essential health services appeared to be recovering from COVID-19-related disruptions internationally, 12 and declared on the 5 May 2023 that the COVID-19 pandemic was no longer a public health emergency of international concern. 13][14][15][16] In Aotearoa New Zealand, hospital admissions for gallbladder disease and cholecystectomy increased by 5.8% and 6.6% respectively between 2004 and 2019. 17Further, it is known that risk factors for acute cholecystitis (such as obesity 18 and type 2 diabetes mellitus 19 ) are more prevalent among M aori, and some data suggest that acute cholecystitis likely disproportionately affects M aori patients. 20Ethnic inequities in aetiologies of benign biliary disease remain understudied.
Therefore, given the societal and healthcare disruptions caused by the COVID-19 pandemic, it is prudent to assess the longitudinal impacts of the pandemic on surgical healthcare within Aotearoa New Zealand.It is of interest if these system burdens have affected the management of acute cholecystitis, which is poorly understood, common, and known to affect diverse cohorts of individuals globally. 10,17Surgical management of acute cholecystitis, is, therefore, a potentially valuable and generalizable marker of surgical system resilience.
The overall objective was to evaluate the management and postoperative outcomes of patients treated with cholecystectomy for acute cholecystitis before and during the COVID-19 pandemic in Aotearoa New Zealand.The aims were to determine whether the COVID-19 pandemic was associated with changes in patient demographics, disease severity and the incidence of short-term postoperative complications in Aotearoa New Zealand.

Methods
This study is a comparative secondary analysis of the CHOLENZ study 2 and the Aotearoa New Zealand subset for the CHOLECOVID study, 10 both of which were observational cohort studies conducted using the student-and trainee-led collaborative research model. 21Ethical approval for both studies were obtained from the Auckland

Participants
The CHOLECOVID study analysed 9783 adult patients (>18 years) with acute cholecystitis from 247 hospitals across 40 countries from September-November 2019 to March-May 2020, of which four sites were within Aotearoa New Zealand (Auckland City, Christchurch, Waikato, and Whang arei hospitals).The CHOLENZ study recruited 1171 adult patients (>18 years) undergoing cholecystectomy for benign gallbladder disease from 19 centres in Aotearoa New Zealand from August-October 2021.For this analysis, all patients with acute cholecystitis who were managed with cholecystectomy as their initial treatment within Aotearoa New Zealand were included.Patients initially managed with non-operative intent, including those that ultimately required an operation, were excluded to align the cohort between the CHOLECOVID and CHOLENZ datasets.

Time periods
Participants were classified into three phases: pre-pandemic, pandemic, and late-pandemic (i.e., prior to, during the initial stages of, and during the later stages of the COVID-19 pandemic respectively).Pre-pandemic and pandemic phase participants comprised the CHOLECOVID participants within the Aotearoa New Zealand subset who were recruited from September-November 2019 to March-May 2020, respectively.Late-pandemic phase participants comprised CHOLENZ participants who were recruited from August-October 2021.

Data collection
Both studies collected data on participant demographics, preoperative blood and imaging investigations, and operative characteristics.Comorbidity status was assessed using the Charlson Comorbidity Index (CCI) total score 22 and acute cholecystitis severity was graded according to the Tokyo severity grade. 23Information on postoperative complications during 30-days was collected, including readmission to hospital, death, and postoperative (including biliary) complications (using Clavien-Dindo classification (CD)). 24rioritized ethnicity was categorized according to the Ministry of Health 2017 Ethnicity Data Protocols. 25

Statistical analysis
Data were analyzed in JMP Pro 17.0.0(SAS Institute Inc., Cary, NC, USA) and are presented as n (%), mean (SD), median (interquartile range, IQR), or odds ratios (OR) with associated 95% confidence intervals (CI).Continuous data were visually assessed for normality and analysed using one-way ANOVA (if normally distributed) or Kruskall-Wallis one-way ANOVA (if non-normally distributed).Categorical data were analysed using chi-squared-test.During analysis, the MELAA and Other ethnic groups were combined to "Other" due to small sample sizes.Multivariable binary logistic regression analyses were conducted to explore the relationship between phases (pre-pandemic, pandemic, and late-pandemic) and readmission to hospital, any minor CD complications (defined as CD I-II), and any major CD complications (defined as CD III-V) by 30-day follow-up using OR (95% CI).Covariates included in the model included age, sex, ethnicity, CCI total score, and Tokyo severity grade.Forest plots were used to visualize the OR (95% CI).Death and postoperative biliary complications were not assessed as outcome variables due to insufficient event counts but were described.A subgroup analysis was conducted comprising Values are mean (SD) or n (%) unless otherwise indicated.P-values are for comparisons across all groups and assessed using one-way ANOVA or chi-squared-test unless otherwise indicated.†Values are median (IQR) and P-values calculated using Kruskal-Wallis one-way ANOVA.MELAA, Middle Eastern/Latin American/ African.only hospitals that had been included in both the CHOLENZ and CHOLECOVID studies.A pre-specified analysis comparing rates of readmission, any minor CD complications, and any major CD complications across different ethnicities using chi-squared-test and univariable logistic regression analysis was also performed.

Participants demographics, preoperative blood results, and clinical management
There were no significant differences in age or Tokyo severity grade across pandemic phases (Table 1).However, there were significant differences in participant ethnicity, with the proportion of M aori participants decreasing three-fold from pre-pandemic to pandemic phases (29% and 11%, respectively) despite the proportion of European participants remaining unchanged (58%).Rates of obesity or severe obesity (body-mass index, BMI >30) were nearly twice as high in the pandemic and late-pandemic phases than prepandemic cohorts (54% and 53% vs. 28%, respectively).Bloods are summarized in Table 2. Nearly all cholecystectomies were performed laparoscopically (98%), with only one (0.2%) open cholecystectomy, and 11 (2%) converted to open (Table 3).There was no difference in time from admission to preoperative investigations (ultrasound, computed tomography, or magnetic resonance cholangiopancreatography) or surgery, or length of admission between pandemic phases (P>0.05).

Adjusted analysis
On univariable regression, pandemic participants were more likely to experience minor CD complications (OR 4.95, 95% CI 1.94-13.9),although this difference was no longer significant after multivariable adjustment (OR 2.24, 95% CI 0.740-6.81)(Table 5).In contrast, both univariable and multivariable analyses demonstrated that cholecystectomy during the late-pandemic phase was associated with fewer major CD complications than the pre-pandemic phase (univariable OR 0.11, 95% CI 0.016-0.59;multivariable OR 0.05, 95% CI 0.00-0.470).There was no association between pandemic phase and readmission to hospital.Forest plots summarize these findings in Fig. 2. Similar findings were obtained in the subgroup analysis (Table S1).

Outcomes across ethnic groups
Overall, rates of minor CD complications differed significantly across ethnic groups (P = 0.027), with Asians and Other having the highest rates (31% and 28%, respectively), followed by Pacific Peoples (19%), European (16%), and M aori (11%).Univariable logistic regression confirmed that Asians were more likely to develop minor CD complications than Europeans (OR 2.32, 95% CI 1.20-4.50)(Table 5).Rates of readmission and major CD complications did not differ across ethnic groups (Table S2).

Discussion
We conducted a secondary analysis of two multicentre collaborative studies to assess the impact of the COVID-19 pandemic on outcomes of cholecystectomy for acute cholecystitis in Aotearoa New Zealand.Our main findings are that participants receiving cholecystectomy tended to be more comorbid and physiologically impaired and have higher rates of obesity during both the early and late phases of the COVID-19 pandemic when compared to the pre-pandemic population, yet did not have increased delays to timely management or worse clinical outcomes during or after the COVID-19 pandemic.
The COVID-19 pandemic response in Aotearoa New Zealand during 2020 and 2021 was structured around a four-tiered Alert system, which ranged from level 1 (used during times of isolated COVID-19 community transmission and marked by an absence of societal restrictions) to level 4 (used during times of uncontrolled and intense COVID-19 community transmission with closure of all non-essential services). 268][29] In contrast, August to October 2021 (classified in our analysis as the "late-pandemic phase") was characterized by a brief escalation of Alert levels secondary to new-onset community transmission of the Delta variant of COVID-19, followed by a stepwise loosening of Alert level restrictions throughout the majority of Aotearoa New Zealand and gradual restoration of pre-pandemic healthcare service delivery. 26,30As such, our multicentric and longitudinal analysis assesses three critical timepoints of Aotearoa New Zealand's national pandemic response and so is well-positioned to explore how surgical management of acute cholecystitis was impacted by the COVID-19 pandemic.
Surgical priorities changed during the COVID-19 pandemic, with greater emphasis placed on deferring surgery or trialling conservative management for uncomplicated cases and maximising theatre availability for acute/emergency procedures. 31Previous research has demonstrated that Aotearoa New Zealand experienced a lower incidence of COVID-19 infection and mortality than other highincome countries during the initial stages of the pandemic, 32,33 and so may also have experienced less healthcare disruption than areas with higher rates of infection.Nevertheless, the findings of this Of note, patients operated on during the pandemic tended to have increased BMI which has been associated with greater operative difficulty 34 and higher anaesthetic risk. 35This is overlaid by the fact that obesity is a known risk factor for symptomatic gallstone disease 34,36,37 and therefore may explain their higher prevalence amidst the cohort when access to an operation was more restricted.This finding is also consistent with a recent systematic review of 74 studies that reported increases in weight gain and the prevalence of obesity during the COVID-19 pandemic, and suggested that this may reflect deleterious pandemic-associated changes in physical activity, mental health, diet, and socioeconomic factors. 38e found that rates of major complications were lower in the late-pandemic phase compared to pre-pandemic phase, but that there was otherwise no significant difference in time to treatment, length of stay, or rates of readmission or minor complications between participants in the pre-pandemic and pandemic phases.This finding is broadly consistent with other surgical studies conducted overseas.Siegel et al. 39 performed a retrospective analysis of 5604 patients in Germany with acute cholecystitis between prepandemic and pandemic phases and found no significant difference in mortality, length of stay, or postoperative complications across time periods.Further, Hillebrandt et al. 40 conducted a large cross-sectional study comprising 10 723 German patients undergoing surgery and reported that while the COVID-19 pandemic was associated with a slighter higher rate of mortality and specific postoperative complications, these findings were likely secondary to changes in indication for surgery (i.e., more urgent or major operations being done during the pandemic) rather than poorer quality or accessibility of healthcare.Early data has also suggested that postcholecystectomy outcomes during later stages of the pandemic are comparable with pre-pandemic outcomes.Demetriou et al. 41 reported in a single-centre analysis of 159 patients undergoing elective laparoscopic cholecystectomies in the United Kingdom that patients operated on after the acute phase of the pandemic did not have significantly higher rates of postoperative complications, readmission to theatre, or length of stay than pre-pandemic patients, although acknowledged that their analysis may have been underpowered due to small sample size.Overall, our data and the wider literature suggests that despite the system-level disruption generated by the COVID-19 pandemic, and the ongoing potential for future waves, cholecystectomy remains safe for patients with acute cholecystitis.
The main strength of this study is its multicentric and collaborative design which enabled large sample sizes and detailed assessment of three separate timepoints relevant to different stages of the COVID-19 pandemic in Aotearoa New Zealand.Nevertheless, sample sizes during the primary pandemic period in Aotearoa New Zealand were relatively low (n = 52) which may increase risk of selection bias and temporal variations in the prevalence of cholecystectomy across these phases.Further, since the CHOLENZ study did not collect data on COVID-19 infection status, we were unable to explore the impact of a COVID-19 infection on patient management and outcomes before and after the pandemic.Additionally, non-operative management of cholecystitis was not captured in the CHOLENZ data set, hence the proportion, outcomes, and changes across pandemic phases for patients managed nonoperatively remain unquantified.

Impact of the COVID-19 pandemic
In conclusion, we found that patients undergoing cholecystectomy during the pandemic tended to be more comorbid and physiologically impaired than those in pre-pandemic phase.However, cholecystectomy for acute cholecystitis remained safe during these times of significant healthcare disruption as compared to the preand late-pandemic phases.

Table 1
Baseline demographics

Table 2
Preoperative blood results Values are mean (SD) or n (%) unless otherwise indicated.P-values are for comparisons across all groups and assessed using one-way ANOVA or chi-squared-test unless otherwise indicated.†Values are median (IQR) and p-values calculated using Kruskal-Wallis one-way ANOVA.ALP, alkaline phosphate; ALT, alanine transaminase; IU, international units.

Table 3
Clinical management during initial admission Clinical management