Additive Risk of Surgical Site Infection from More than One Risk Factor Following Craniotomy for Tumor

doi:10.21203/rs.3.rs-2596453/v1

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Additive Risk of Surgical Site Infection from More than One Risk Factor Following Craniotomy for Tumor

https://doi.org/10.21203/rs.3.rs-2596453/v1

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published 29 Mar, 2023

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Purpose

This study seeks to expound upon risk factor etiologies for surgical site infection (SSI) and investigate their combinatorial effects on infection rate following craniotomy for neuro-oncologic pathology.

Methods

Patients who underwent neuro-oncologic craniotomy between 2006-2020 were included. Medical records were reviewed to identify the occurrence of wound infection at ≤3 months postoperatively. Potential risk factors for infection included tumor pathology, location, anesthesia type, indication, ventricular entry, foreign body, brachytherapy, lumbar drain, prior operation, prior cranial radiation, prior infection, bevacizumab, and medical comorbidities (hypertension, obesity, hyperlipidemia, other cancer, cirrhosis). Logistic regression was implemented to determine risk factors for SSI. Chi-square tests were used to assess whether the number of risk factors (e.g., 0, ≥1, ≥2, ≥3, ≥4) increases the risk of SSI compared to patients with fewer risk factors. The relative increase with each additional risk factor was also evaluated.

Results

A total of 1209 patients were included. SSI occurred in 42 patients (3.5%) by 90 days after surgery. Significant risk factors on binary logistic regression were bevacizumab (OR 40.84; p<0.001), cirrhosis (OR 14.20, p=0.03), foreign body placement (OR 4.06; P<0.0001), prior radiation (OR 2.20; p=0.03), and prior operation (OR 1.92; p=0.04). Infection rates in the combinatorial analysis were as follows: ≥1 risk factor = 5.9% (OR 2.74; p=0.001), ≥2 = 6.7% (OR 2.28; p=0.01), ≥3 = 19.0% (OR 6.5; p<0.0001), ≥4 = 100% (OR 30.2; p<0.0001).

Conclusions

Risk factors in aggregate incrementally increase the risk of postoperative SSI after craniotomy for tumor.

craniotomy

surgical site infection

risk factors

The incidence of surgical site infection (SSI) after craniotomy ranges from 2.2–19.8% [1]. SSI significantly contributes to patient morbidity and has been associated with increased health care expenditures, reoperations, antibiotic treatments, and prolonged hospital stays [1,2]. Numerous studies have attempted to identify pre- and intraoperative risk factors for SSI in order to develop preventative strategies for these potentially avoidable complications. Several previously described risk factors include age, operative duration, number of surgical sites, mode of antibiotic prophylaxis, and American Society of Anesthesiologists (ASA) score [1,3]. However, studies examining these risk factors have solely evaluated their independent association with SSI, irrespective of their effect when present simultaneously. Likewise, the diversity of sample sizes, inclusion criteria, and subpopulations assessed render it difficult to draw consistent conclusions and highlight the need to more precisely define risk factors for postoperative SSI in neurosurgical patients [2,4,5]. The present study therefore seeks to further expound upon risk factor etiologies and investigate their combinatorial effect on infection rate among patients undergoing craniotomy for tumor.

After obtaining Institutional Review Board approval, a prospective database of consecutive neuro-oncologic craniotomies performed by a single surgeon (THS) between January 2006 and June 2020 at a single institution (NewYork-Presbyterian Hospital-Weill Cornell Medicine) was retrospectively reviewed. Patient consent was not required (IRB 0606008601). Cases involving burr holes, endoscopic procedures, epilepsy surgeries, or transsphenoidal and decompressive craniectomies were excluded.

Medical records were reviewed to identify potential risk factors for infection. These included tumor pathology, tumor location (intraparenchymal versus extraparenchymal), cranial location (supratentorial versus infratentorial), anesthesia type (general versus awake), indication (biopsy versus resection), and potential risk factors for infection including: ventricular entry, presence of a foreign body (ventriculoperitoneal shunts (VPS), external ventricular drains (EVD), brachytherapy, intracranial pressure (ICP) monitors), lumbar drains, prior operation/biopsy, prior cranial radiation, prior infection, use of bevacizumab, and medical comorbidities including hypertension, obesity, hyperlipidemia/hypercholesterolemia, other cancer (not neuro-oncologic), and cirrhosis.

The first step was to determine which patients developed wound infections. Both outpatient and inpatient medical records were reviewed to establish the occurrence of postoperative wound infections at either 1- or 3-months after surgery. Infection was established through reoperation and confirmed with subsequent bacterial cultures. All patients with suspected SSIs were taken for immediate reoperation and no patients were managed with antibiotics alone. All patients received prophylactic intravenous antibiotics consisting of cefazolin (or vancomycin if allergic to penicillin and its derivates).

A logistic regression model was subsequently implemented to determine which potential risk factors incurred a statistically significant risk of wound infection. The next step was to evaluate whether the number of risk factors (e.g., none, one or more, two or more, three or more, four or more) increases the risk of SSI. The relative increase with each additional risk factor was also assessed. Given the decrease in sample size that occurs when assessing patients with greater numbers of concomitant risk factors, we opted to establish groups based on the overall quantity of these variables, rather than their particular etiologies. Risk factor groups were therefore compared to corresponding groups with fewer risk factors (e.g., ≥ 1 vs none, ≥ 2 vs ≤ 1, ≥3 vs ≤ 2, ≥4 vs ≤ 3). All p-values are two-sided with statistical significance evaluated at the 0.05 alpha level. Analyses were performed in SAS Version 9.4 (SAS Institute, Inc., Cary, NC).

Of note, wounds were intraoperatively irrigated with either antibiotics alone (cefazolin 1 g or gentamicin 80 mg if allergic, diluted in 1-liter normal saline; 2 X 60 cc irrigation bulbs), antibiotic irrigation combined with dilute betadine (50:50 mixture 7.5% povidone iodine and normal saline; 2 X 60 cc irrigation bulbs), or a combination of antibiotic irrigation, betadine irrigation, and vancomycin powder (~ 0.5 g) prior to closure.

A total of 1375 cases were reviewed, of which 148 cases were excluded due to the operative report not being available (n = 16), use of a burr hole (n = 98), or lack of a cranial operation (n = 34). The final cohort was comprised of 1209 cases.

The most common histology was meningioma (25.6%), followed by glioblastoma (24.2%) and metastasis (20.8%). A total of 1070 patients (88.5%) presented with supratentorial tumors, and 794 tumors (69.2%) were intraparenchymal in origin. Among all cases, 322 (26.6%) were reoperations and 173 procedures (14.3%) were preceded by radiation therapy. The ventricle was opened in 143 cases (11.8%), lumbar drains were placed in 32 cases (2.7%), and a foreign body (VPS, brachytherapy seeds, ICP monitors, or EVD) was placed in a total of 142 cases (11.8%). The most common patient comorbidities included hypertension (n = 402, 33.3%), other cancers (n = 299, 24.73%), and hyperlipidemia/hypercholesterolemia (n = 213, 17.6%) (Table 1).

Table 1

Patient Characteristics and Operative Variables
Characteristics, n (%)
Age, mean ± sd, yrs	57.56 ± 15.27
Prior Operation	322 (26.63%)
Prior Radiation	173 (14.31%)
Prior Infection	25 (2.07%)
Hypertension	402 (33.25%)
Diabetes Mellitus	123 (10.17%)
Obesity	41 (3.39%)
Hyperlipidemia/Hypercholesterolemia	213 (17.62%)
Cirrhosis	3 (0.25%)
Other Cancer	299 (24.73%)
Indication, n (%)
Biopsy	51 (4.23%)
Resection	1158 (95.77%)
Pathology, n (%)
Meningioma	310 (25.64%)
Glioblastoma Multiforme	293 (24.23%)
Metastasis	252 (20.84%)
Lymphoma	24 (1.99%)
Oligodendroglioma	58 (4.8%)
Astrocytoma	68 (5.62%)
Operative Variables, n (%)
Intraparenchymal	794 (65.67%)
Extraparenchymal	353 (29.20%)
Non-Tumor	62 (5.13%)
Surpratentorial	1063 (87.92%)
Infratentorial	139 (11.5%)
Both Supratentorial and Infratentorial	7 (0.58%)
Ventricle Opened	143 (11.83%)
Foreign Body	142 (11.75%)
Lumbar Drain	32 (2.65%)
Post-Operative CSF Leak	27 (2.23%)
Bevacizumab	7 (0.58%)

Significant independent risk factors on binary logistic regression were bevacizumab (OR 40.84; p < 0.001), cirrhosis (OR 14.20, p = 0.03), foreign body placement (OR 4.06; P < 0.0001), prior radiation (OR 2.20; p = 0.03), and prior operation (OR 1.92; p = 0.04) (Table 2).

Table 2

Logistic Regression of Suspected Risk Factors for Infection
Risk Factor	Odds Ratio	95% Confidence Interval	P-Value
Bevacizumab	40.84	8.83–188.88	< 0.0001
Cirrhosis	14.20	1.26–159.87	0.032
Foreign Body	4.09	2.10–7.98	< 0.0001
Prior Radiation	2.20	1.09–4.47	0.029
Prior Operation	1.92	1.02–3.61	0.042
Lumbar Drain	1.90	0.44–8.21	0.39
Ventricle Opened	1.80	0.82–3.97	0.15
Hypertension	1.69	0.91–3.14	0.1
Prior Infection	1.21	0.16–9.20	0.85
Other Cancer	0.71	0.32–1.55	0.39
Obesity	0.69	0.09–5.12	0.71
Hyperlipidemia	0.62	0.24–1.60	0.33
Diabetes Mellitus	0.21	0.03–1.53	0.12

Overall, 787 patients (65%) did not have any risk factors, 422 patients (35%) had ≥ 1 risk factor, 180 patients (15%) had ≥ 2 risk factors, 42 patients (3.5%) had ≥ 3 risk factors, and 2 patients (0.2%) had ≥ 4 risk factors (Table 3). A total of 380 patients (31.4%) were given antibiotic irrigation alone, 485 patients (40.1%) were treated with betadine alone, and 344 patients (28.5%) were given a combination of antibiotic irrigation, betadine irrigation, and vancomycin powder. The distribution of prophylactic regimens among patients with no risk factors (antibiotic irrigation alone: 31%, antibiotic plus betadine irrigation: 40%, antibiotic plus betadine irrigation plus vancomycin powder: 29%) was comparable to the distribution in patients with one or more risk factors (antibiotic irrigation alone: 32%, antibiotic plus betadine irrigation: 40%, antibiotic plus betadine irrigation plus vancomycin powder: 28%). Since we previously demonstrated that these maneuvers were only helpful at reducing infection among patients with no significant preoperative risk factors, differentiation by prophylactic modality was not considered in the present study [6]. Overall, postoperative SSI occurred in 20 patients (1.7%) within 30 days and 42 patients (3.5%) by 90 days.

We subsequently assessed whether patients with multiple risk factors in combination exhibited an increased infection rate compared to those with fewer risk factors. Although CSF leak was significantly associated with SSI (OR 7.03, p < 0.001), we herein classified it as a postoperative risk factor, excluding it form the combinatorial analysis of potential pre- and intraoperative risk factors.

Patients with one or more risk factors exhibited an infection rate of 5.9% and were 2.74 times more likely to develop an infection than patients without risk factors (p = 0.001). Patients with two or more risk factors had an infection rate of 6.7% and were 2.28 times more likely to develop and infection compared to patients with either one or no risk factors (p = 0.01). Patients with three or more risk factors had an infection rate of 19.0% and were 6.5 times more likely to develop an infection than patients with two or fewer risk factors (p < 0.0001). Patients with 4 or more risk factors had a 100% infection rate and were 30.2 times more likely to develop an infection compared to patients with 3 or fewer risk factors (p < 0.0001) (Table 3, Fig. 1).

Table 3. Risk of Infection Among Groups with Increasing Numbers of Risk Factors
Number of Risk Factors	Number of Patients (%)	Number of Infections (%)	Risk Ratio (Versus Fewer Risk Factors)	95% Confidence Interval	P-Value
0	787 (65.0)	17 (2.2)	-	-	-
≥ 1	422 (34.9)	25 (5.9)	2.74	1.50–5.02	0.001
≥ 2	180 (14.9)	12 (6.7)	2.28	1.19–4.38	0.01
≥ 3	42 (3.5)	8 (19.0)	6.54	3.23–13.25	< 0.0001
≥ 4	2 (0.2)	2 (100.0)	30.18	22.25–40.93	< 0.0001

Precisely defining preoperative and intraoperative risk factors for wound infection in neurosurgical patients is crucial for mitigating associated health care expenditures, developing individualized prevention strategies, and maximizing patient quality of life [2,4]. However, prior literature has primarily focused on individual demographics, comorbidities, and perioperative characteristics, without considering the influence of multiple risk factors in combination. The present study is the first, to our knowledge, investigating the relative increase in risk of SSI caused by the presence of more than one risk factor. Notwithstanding etiology, we herein show that patients with a greater number of risk factors may have a higher incidence of infection due to risk factor quantity alone, and that this incidence increases as more risk factors are added.

Factors associated with increased risk of infection in our study had some overlap but were not identical to those identified in prior literature. A systematic review and meta-analysis of 26 studies reported the following risk factors for SSI among craniotomy patients: CSF leak (OR 7.82), > 1 operation (OR 2.35), operation duration > 4 hours (OR 1.77), venous sinus entry (OR 4.02), ASA score (OR 1.40), and male sex (OR 1.47). Age, operative site, antibiotic prophylaxis, ICP monitoring, foreign body placement, hypertension, and diabetes were not associated with increased risk of wound infection [4]. Importantly, these studies solely investigated the association of individual risk factors with SSI and did not account for any relative increase in risk caused by the presence of more than one risk factor.

Patients with a foreign body in our cohort exhibited 4-times greater odds of postoperative infection. Buchanan et. al. likewise found placement of a foreign body to be a significant predictor of 30-day readmission for SSI (OR 1.47; p = 0.02) [7]. The presence of external ventricular drains or ventricular shunts has been shown to predispose neurosurgical patients to colonization and subsequent infiltration of bacteria into the CSF [8]. Ventricular entry intraoperatively did not increase the risk of infection among our patients. Further prospective studies exploring the duration of ventricular opening, foreign body placement, and utility of CSF surveillance would be beneficial. Of note, current neurocritical care guidelines suggest no more than a single dose of prophylactic antibiotics at the time of drain or shunt insertion, as well as limiting postoperative antibiotic duration to < 24 hours [7,9].

The association of bevacizumab with infection and wound breakdown is also well documented. Clark et. al. show that patients receiving bevacizumab developed significantly more healing complications relative to non-bevacizumab treated patients [10]. Saran et. al. report greater infection rates among glioblastoma patients treated with bevacizumab (54.4% vs 39.1%), citing myelotoxicity as a likely underlying cause [11]. It is reasonable to posit that prior radiation and brachytherapy compromise healing via a similar mechanism [11–13].

Fang et. al. [4] and Hussein et. al [14] both report CSF leak as the most significant risk factor observed for SSI. Our group determined that CSF leak was significantly associated with SSI (OR 7.03; p < 0.0001). However, CSF leak was not included in our current analysis as it is a postoperative risk factor that cannot be identified preoperatively. Literature investigating the underlying mechanism suggests that CSF leak leads to retrograde movement of bacteria through the peritubular gap or lumen [15]. Thus, while not beneficial for predicting SSI risk preoperatively, the need to prevent CSF leak through careful surgical planning and early definitive management is evident.

Opening of the ventricle, lumbar drain placement, prior infection, as well as comorbidities including hypertension, diabetes, additional non-neurologic cancer, hyperlipidemia/hypercholesterolemia, and obesity were not significant independent risk factors for SSI in our cohort. Aside from the lack of literature investigating the additive risk of multiple risk factors, these findings also suggest that there is substantial variability in regard to the assessment of individual risk factors for SSI. We now show that the presence of more than one risk factor may confer an additive risk of postoperative SSI that is dependent on risk factor quantity alone. Overall, by assessing risk factors as composites rather than individual entities, health care professionals will have the capacity to better identify patients at greater risk for surgical site infections and tailor care accordingly [16].

The study has several limitations. The retrospective, single-center design reduces the level of evidence and generalizability of our findings. Additionally, the limited sample size of patients with each potential combination of risk factors required us to investigate the additive effect of risk factor quantity overall, rather than particular risk factor etiologies.

To the best of our knowledge, this study is the first to investigate the combinatorial influence of risk factors on SSI. Our results suggest that risk factors in aggregate incrementally increase the risk of post-operative SSI. Additional multi-center prospective studies investigating the combinatorial influence of risk factors on SSI are needed to create more effective risk stratification systems that can individualize prevention strategies and operative planning among patients undergoing craniotomy for neuro-oncologic pathology.

Funding:

Jason Chua, MPH and Paul Christos, DrPH, were partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (1-UL1-TR002384-01).

Competing Interests:

The authors report no conflict of interest concerning the materials, methods, or findings specified in this study.

Author Contributions:

All authors contributed to study conception, material preparation, and data collection/analysis. The manuscript was written by OM and THS. All authors commented on previous versions of the manuscript, as well as approved the final manuscript.

Data Availability:

The datasets generated or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Patient Consent:

This is a retrospective cohort study. The Institutional Review Board at NewYork-Presbyterian Hospital-Weill Cornell Medicine has confirmed that no ethical approval or patient consent was required (IRB 0606008601).

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No competing interests reported.

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published 29 Mar, 2023

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Additive Risk of Surgical Site Infection from More than One Risk Factor Following Craniotomy for Tumor

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