Perioperative Complications in Patients with Systemic Sclerosis: A Comparative Cohort Analysis

Background: Systemic sclerosis (SSc) is a rare autoimmune disorder with pathological manifestations affecting multiple organ systems. Few studies have examined perioperative outcomes in patients with this disorder. The primary aim of this retrospective single-center comparative cohort analysis was to estimate the incidence of select perioperative complications in a population of SSc patients. In an exploratory analysis, we analyzed the relationship between SSc and susceptibility to select perioperative complications when treated at a large quaternary-care institution. Methods: We conducted a single-center retrospective, comparative cohort study to compare perioperative outcomes in a SSc (n=258) and a frequency matched control cohort (n=632). We analyzed for the presence of major composite infection (MCI), major adverse cardiac events (MACE), 30-day readmission, 30-day mortality, in-hospital complications, length of stay and airway management outcomes. Results: MCI was higher in the SSc compared to the control cohort [adjusted odds ratio (ORadj)=5.02 (95%CI: 2.47-10.20) p<0.001]. Surgical site infection (3.5% vs. 0%, p<0.001), and other infection types (5% vs. 0%, p<0.001) were higher in the SSc cohort. MACE was not significantly different between SSc vs. Control groups [6.2% vs. 7.9%, ORadj=1.33 (95%CI: 0.61-2.91) p=0.48]. Higher rates of limited cervical range of motion (13.6% vs. 3.5%, p<0.001), microstomia (11.5% vs. 1.3%, p<0.001) and preoperative difficult airway designation (8.7% vs. 0.5%, p<0.001) were observed in the SSc cohort. Bag mask ventilation grade was similar between groups (p=0.44). After adjustment, there was no between-group difference in Cormack-Lehane grade 3 and 4 view on direct laryngoscopy in SSc patients [ORadj = 1.86 (95%CI: 0.612 −5.66) p=0.18] but evidence of higher rates of video laryngoscopy [ORadj= 1.87 (95%CI:1.07 - 3.27) p=0.03]. Length of stay [median: 0.2 vs. 0.3 days, p=0.08], 30-day mortality [1.2% vs. 0.6%, ORadj=2.79 (95%CI: 0.50-15.6) p=0.24] and readmission [11.5% vs. 8.1%, ORadj=1.64 (95%CI: 0.96 - 2.82) p=0.07] were not statistically significant. Conclusions: SSc patients demonstrate mostly similar rates of MACE, 30-day mortality, length of stay intraoperative and airway complications. There is evidence of increased risk of overall 30-day MCI risk and readmission after endoscopic procedures.


Introduction
Systemic sclerosis or scleroderma (SSc) is a rare immune-mediated disease characterized by cutaneous and organ-based fibrosis with an overall incidence of approximately 20 per million per year in the United States and a global prevalence of 150-300 cases per million 1 .Likely precipitated by complex environmental and genetic triggers, it is believed that injury to endothelial cells results in dysfunctional activation of fibroblasts, abnormal extracellular matrix deposition, and scarring in the integumentary and other organ systems 2 .Diagnosis is complex and based on clinical, radiological, and biomarker findings on a weighted scale with major criteria centered on findings of proximal cutaneous sclerosis and minor criteria including nail fold capillary pattern, the presence of pulmonary fibrosis, and SSc selective autoantibodies 3 .The four major variants of SSc are diffuse cutaneous, limited cutaneous SSc, overlap syndrome, and sine.
Limited cutaneous SSc also includes the subset of patients with Calcifications, Raynaud's Phenomenon, Esophageal Hypomotility, Sclerodactyly, and Telangiectasia (CREST) syndrome.Diffuse cutaneous SSc is characterized by proximal limb involvement and higher rates of interstitial lung disease (ILD), and renal and cardiac involvement.All variants of SSc can result in a wide range of progressive end-organ dysfunction that carries significant perioperative implications.SSc patients may present with microstomia or limited cervical extension, with intermittent reports of difficulties with airway management. 4,5Autonomic dysfunction is common in SSc, and we previously identified reports of perioperative dysrhythmias in the literature 6. SSc-related myocardial fibrosis may increase the risk for myocardial infarction in the perioperative time period 7 .ILD, pulmonary hypertension (PH), and pulmonary arterial hypertension (PAH) are frequent complications of SSc 8 .Gastrointestinal involvement results in high rates of gastroesophageal reflux disease, esophageal dysmotility, dysphagia, and malnutrition [9][10][11] .
There is a paucity of studies that have explored the perioperative outcomes of patients with SSc.The primary aim of this retrospective singlecenter comparative cohort analysis was to estimate the incidence of perioperative complications in a population of SSc patients.Secondly, we sought to explore the relationship between SSc and susceptibility to select perioperative complications when treated at a large quaternary-care institution.Our outcomes included the presence of a 30-day composite measure of major postoperative infection (MCI), 30-day major adverse cardiovascular events (MACE), 30-day readmission, 30-day mortality, length of stay (LOS), intraoperative complications and airway management outcomes.

STUDY DESIGN
We conducted a matched cohort study using patients undergoing surgery at Yale-New Haven Hospital, a non-profit, 1,541-bed tertiary medical center located in New Haven, Connecticut, USA.This single-center retrospective study (Study #200028645) was approved by the Yale University School of Medicine Institutional Review Board with a waiver of informed consent.This manuscript adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement guidelines for observational studies in epidemiology 12 .
The study cohort consisted of adult patients undergoing elective surgical or endoscopic procedures at YNHH between January 1, 2010, and January 1, 2020.Inclusion criteria for the study cohort included all patients aged >18 years old with the diagnosis of SSc based on the International Classification of Disease (ICD-10).The following ICD-10 codes were used: M34, M34.0, M34.1, M34.2, M34.8, M34.81, M34.82, M34.83, M34.83, M34.89 and M34.9 to initially screen for SSc patients.After screening by ICD-10 coding, individual charts were manually reviewed to confirm the rheumatologist's diagnosis of systemic sclerosis (diffuse cutaneous, limited cutaneous, overlap syndrome, and sine variants only) 3 .Using frequency matching, a control cohort without the diagnosis of SSc was extracted with similar age, gender, and procedure.The final analysis included the first surgical encounter of 632 control subjects and 258 SSc subjects.
Pulmonary hypertension (PH) was defined as a pulmonary artery mean pressure of >25mmHg by right heart catheterization within 2 years of the procedure.Elevated right ventricular systolic pressure (eRVSP) was defined as >40mmHg by echocardiography within 1year of the procedure.Procedures were categorized by anatomical location and defined as major, or minor based on the following standardized criteria.Major surgery was defined as a surgical procedure with deep tissue, abdominal, thoracic, or cranial surgical penetration, and minor surgery was defined as minimally invasive or superficial procedures.
Anaesthesia type was characterized into nine categories (general endotracheal anaesthesia, general laryngeal mask anaesthesia, neuraxial anaesthesia, regional anaesthesia only, regional anaesthesia and general endotracheal anaesthesia (ETT), regional anaesthesia and general laryngeal mask airway (LMA), general anaesthesia with a natural airway, conscious sedation, and not recorded).
We collected select in-hospital respiratoryrelated complications (composite reintubation, non-invasive positive pressure ventilation, mechanical ventilation, and intensive care admission) and LOS (in days).30

STATISTICAL ANALYSIS
We summarized patient characteristics using means and standard deviations (SD) and/or median and interquartile range (IQR) for continuous variables and frequencies and percentages for categorical variables.Baseline characteristics for SSc and control subjects were compared using chi-square tests or Fisher's exact tests for categorical variables and t-tests or Wilcoxon Rank Sum tests for continuous variables.We visually inspected for normal distribution of the data.We removed emergency procedures from the control and SSc cohorts prior to analysis.For the binary perioperative outcomes, multivariable logistic regression analyses were used to compare the odds of complication between cohorts and also to assess the factor of SSc with the selected outcomes after controlling for clinically relevant confounders.For the continuous perioperative outcomes, multivariable linear regression analyses were used.Confounding variables were identified by clinical experience, prior clinical validation or physiological rationale and availability.Adjustments performed for the postoperative 30day outcomes included: Age, BMI, Elixhauser comorbidities, procedural category, ASA physical status.For airway management (Incidence of video laryngoscopy, incidence of Cormack-Lehane Classification grade 3 and 4 on direct laryngoscopy), adjustments performed included: age, BMI, ASA physical status.For the purposes of regression model stability, procedural categories were collapsed into 5 anatomically similar and clinically relevant groups.Upon collapse, no significant difference was observed between groups [p=0.71].Statistical significance was established at 0.05 level.No correction was made for multiple comparison given the exploratory nature of the analysis.All analyses were performed using SAS version 9.47.

Results
We identified 632 control patients and 258 SSc patients who underwent surgery and had followup for a minimum of 30 days.The CONSORT flowchart of research subject inclusion is provided in Figure 1.
Demographic data for the SSc and control cohorts are summarized in Table 1.

**by right heart catheterization within 2 years of surgical encounter (% of entire SSc cohort). † % describes proportion w/in variant type
We observed an incidence of preoperative diagnosis of interstitial lung disease (ILD) of 32.9% in our SSc cohort [diffuse cutaneous: N=37 (66.7%), limited cutaneous: 37 (

Discussion
Our aim for this study was to contribute baseline estimates of perioperative complications in an SSc population that has been previously neglected in the literature.In our literature review, we found a number of case reports and series describing airway management difficulties, intraoperative cardiac arrest, and other perioperative adverse events that warranted larger scale analysis 4,[15][16][17][18][19][20] .
Data on 30-day perioperative complications, airway management, and complications in SSc patients are, to our knowledge, not readily available in the literature.Microstomia (1.3% vs. 11.5%,p<0.001) and limited cervical range of motion (3.5% vs. 13.6%,p<0.001) were both very common in the SSc cohort.Microstomia has been previously identified as an important cause for difficult airway but was only documented in 11.5% of our SSc cohort.Microstomia is reported to affect 52-80% of SSc patients, suggesting that it may be under-recognized at the time of preoperative physical examination 21,22 .Incidence of difficult mask ventilation (Grade 3 or 4) was not significantly different between cohorts (1.1% vs. 3.1%, p=0.44).Although direct laryngoscopy first-pass success was lower in the SSc cohort (91.8% vs. 95.8%,p=0.18) it was not statistically significant.We analyzed VL use and found a significantly higher incidence of use in SSc patients when compared to controls.Increased VL use (30% vs. 17.4%, p=0.027) and similar rates of failed intubation (1.1% vs. 0%, p=1), suggest that preoperative identification of potential difficult airway and pre-emptive use of VL may have reduced the excess risk of difficult airway instrumentation in SSc patients 23 .
Intraoperative complications were similar between cohorts with the exception of inductionrelated bradycardia (16.3% vs. 1.3%, p<0.0001).This is an interesting finding and may be associated with case reports of cardiac arrest related to sinoatrial arrest observed in the literature.Fortunately, in our SSc cohort, these bradycardic events resolved uneventfully, and intraoperative cardiac arrests (0% vs. 1%, p=1) and intraoperative cardiac arrhythmia (2.3% vs. 0.9%, p=0.12) were similar between cohorts 24,25 .This also may suggest that the current management of SSc-related cardiac conditions are well managed prior to presentation for surgery 25 .
In our exploratory analysis, we were able to report that a composite infection measure using meaningful grouping, MCI, was significantly higher in postoperative SSc patients when compared to a control cohort.This significance was predominately contributed by the development of higher rates of 30-day postoperative surgical site infection, urinary tract infection, bloodstream infection or sepsis when compared to controls.SSc patients with skin ulcers secondary to microcirculatory vasculopathy have been perceived to have higher rates of impaired wound healing [26][27][28] .Secondly, all-cause mortality studies in SSc populations have observed that 33% of deaths due to non-SSc-related causes were attributed to infections, particularly septicemia and pneumonia 29 .Thus, our observation of higher postoperative infection is likely consistent with prior findings of increased infection risk in SSc populations.Due to the rarity of the disorder, the SSc cohort was not adequately powered to provide observations into individual respiratory complications though a higher incidence was observed in 30-day postoperative pneumonia (1.7% vs. 4.0% p=0.12).Surprisingly, despite the common presence of esophageal dysmotility disorders in SSc, no statistically significant relationship was observed in intraoperative aspiration (0.5% vs. 1.2%, p=0.36) nor 30-day aspiration pneumonitis/pneumonia (1% vs. 1.2%, p=0.72) in our SSc cohort.However, MCI and readmission was higher in SSc compared to controls after endoscopic procedures, largely driven by a larger incident in other infection (urinary tract infection, bloodstream infection or unspecified sepsis).This may suggest that infectious complications are being underdiagnosed after endoscopic procedures in these high-risk patients.Overall, the SSc cohort's higher rate of postoperative infection suggest that improved post-procedure vigilance and a higher level of suspicion for infection is warranted.
Luo et al. did not observe an association between perioperative MACE but did present evidence suggestive that perioperative myocardial infarction may be higher in SSc populations 7 .We similarly observed that MACE was not statistically different between control and SSc cohorts.eRVSP (12.0%) and diagnosed PH (8.5%) were relatively common in our SSc cohort.This is consistent with the published prevalence of pulmonary hypertension in SSc populations (5-12%) but a much higher prevalence when compared to the general surgical population (0.81% for noncardiac surgery, 10.72% for cardiac surgery) [30][31][32] .Furthermore, the presence of eRVSP has been observed to increase overall mortality 33 .SSc-related PH has demonstrated lower response rates to targeted therapy and poorer prognosis, thus identifying and optimizing these patients may improve perioperative outcomes 34 .Furthermore, we were interested in the association of PH or eRVSP and 30-day pneumonia given recent data that has suggested a pathophysiological relationship between dysregulated immune responses in pulmonary hypertension and increased risks of respiratory complications 35,36 .Although 30-day pneumonia was higher in the SSc cohort, subcohort analysis of eRVSP and PH SSc sub-cohorts failed to achieve statistical significance, but this finding is limited by small sample size.
The possibility of selection bias exists, given the retrospective and exploratory nature of the study.Furthermore, as a retrospective study, these observations can only provide association, rather than causation.We cannot rule out the possibility that unmeasured confounding affected our findings, particularly changing medical practice over the decade of data collection.Given the complexity of SSc diagnoses, we were heavily reliant on rheumatologist expertise for inclusion during manual chart review of ICD-10 identified research subjects.In regard to observations of airway management, it is important to acknowledge that significant inter-proceduralist variability exist regarding standard of care and technique.We acknowledge that this increases the likelihood of type II error, and that multiple testing increases the probability of type I errors in our observations.We utilized a composite measure of highly related and common postoperative infectious and cardiovascular endpoints to better control for Type I errors in our statistical analysis.

Conclusion
In conclusion, we provided detailed estimates of the incidence of perioperative complications within a large cohort of SSc patients.First-pass success with direct laryngoscopy appears to be statistically similar to control cohort and there is no significant increased frequency of difficult bag mask ventilation.We found that VL use is more frequent in SSc and has possibly contributed to reduced airway instrumentation risk in this population.We observed significantly higher incidences of induction-related bradycardia in our SSc cohort, but this did not lead to a statistically significant increased risk of persistent intraoperative cardiac arrhythmia or arrest when compared to the control population.Secondly, we observed that a 30-day composite measure of infection (MCI) was significantly higher when compared to a control cohort although 30-day MACE, 30-day mortality, readmission and length of stay were similar to the control cohort.This observed higher risk of 30-day perioperative infection should be considered during perioperative care of SSc patients.To improve the precision of these exploratory findings, further corroboration with larger multi-center cohorts is warranted.

Figure 1 .
Figure 1.A CONSORT diagram of patient selection for the study and control cohort.Table1.Demographical and clinical characteristics of the SSc and control cohorts.

Table 2 .
Demographical Data.Selected Elixhauser covariates at time of surgical encounter

Table 2 .
Elixhauser covariates at time of surgical encounter for systemic sclerosis vs. control cohorts.

Table 3 .
Airway management & intraoperative characteristics of the systemic sclerosis vs. control cohort.

Table 4 .
Prevalence and features of pulmonary hypertension in the systemic sclerosis cohort.

Table 5 .
Univariate and multivariable regression analysis of selected in-hospital and 30-day clinical outcomes.

Table 2 .
Detailed description of systemic sclerosis surgical site infections.Pulmonary Function Test n (%) or mean (SD) within one year of procedure †