Antibiotic Prophylaxis in Endoscopic Endonasal Pituitary and Skull Base Surgery

Accepted Manuscript Antibiotic prophylaxis in endoscopic endonasal pituitary and skull base surgery Laura Milanese, MD, Matteo Zoli, MD, Giacomo Sollini, MD, Chiara Martone, MD, Corrado Zenesini, MS, Carmelo Sturiale, MD, Paolo Farneti, MD, Giorgio Frank, MD, Ernesto Pasquini, MD, Diego Mazzatenta, MD PII:

S1878-8750(17)31175-0

DOI:

10.1016/j.wneu.2017.07.075

Reference:

WNEU 6137

To appear in:

World Neurosurgery

Received Date: 9 April 2017 Revised Date:

12 July 2017

Accepted Date: 13 July 2017

Please cite this article as: Milanese L, Zoli M, Sollini G, Martone C, Zenesini C, Sturiale C, Farneti P, Frank G, Pasquini E, Mazzatenta D, Antibiotic prophylaxis in endoscopic endonasal pituitary and skull base surgery, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.07.075. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Milanese 1

ACCEPTED MANUSCRIPT

Antibiotic prophylaxis in endoscopic endonasal pituitary and skull base surgery.

Laura Milanese1, MD, Matteo Zoli1,MD, Giacomo Sollini2,3, MD, Chiara Martone2, MD, Corrado Zenesini4, MS, Carmelo Sturiale1, MD, Paolo Farneti5, MD, Giorgio Frank1, MD, Ernesto

1

RI PT

Pasquini2, MD, Diego Mazzatenta1,6 , MD.

Center of surgery for pituitary tumors and endoscopic skull base surgery. Department of

SC

Neurosurgery - IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. ENT Department, Ospedale Bellaria, Bologna, Italy.

3

Department of Otorhinolaryngology - Head and Neck surgery, University of Genova, Genova,

M AN U

2

Italy. 4

Epidemiology and Biostatistics Service - IRCCS – Istituto delle Scienze Neurologiche, Bologna.

5

Department of Experimental, Diagnostic and Specialty Medicine, Bologna University of Bologna,

6

TE D

Bologna, Italy.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

EP

Correspondence to: Laura Milanese, M.D.,

AC C

IRCCS Istituto delle Scienze Neurologiche, Center of surgery for pituitary tumors and endoscopic skull base surgery. Department of Neurosurgery

Bellaria Hospital 40139, Bologna, Italy. Tel. +39 051 6225514 Fax + 39 051 6225347 e-mail: [email protected] Keywords: antibiotic prophylaxis; endoscopic endonasal approach; meningitis. Abbreviations: CSF= cerebrospinal fluid

Milanese 2

ACCEPTED MANUSCRIPT Abstract

Objective: Postoperative infection is a potentially dramatic consequence in endoscopic endonasal surgery. The aim of this study is to assess the efficacy of our intraoperative antibiotic prophylaxis, analyzing the risk factors of postoperative meningitis in our series.

RI PT

Methods: Each endoscopic endonasal procedure performed since 1998 in patients with no preoperative infections and a follow-up longer than 30 days have been included and retrospectively reviewed. Antibiotic protocol consisted in single antibiotic administration of ampicillin/sulbactam 3

SC

g or cefazolin 2 g on induction, no postoperative administrations have been performed after 2005. All cases of CSF leak, meningitis, and systemic infection were recorded.

M AN U

Results: Two thousand thirty-two procedures matched the inclusion criteria (median age 50; range: 1-89, male/female ratio: 1:1.12). Intraoperative CSF leak occurred in 32.8% of the cases and postoperative CSF leak in 3.4%. The rate of meningitis was 0.69%, other systemic infections were observed in 0.44% of cases. Meningitis was statistically associated with intra- and postoperative

TE D

CSF leak (p<0.001). Other risk factors were the intradural extension of the tumors and their malignant histology. Extended approaches producing wide osteo-dural defects were correlated with a higher risk of meningitis (p<0.001).

EP

Conclusions: All surgical maneuvers to prevent, detect and quickly repair intra- and postoperative CSF leak are crucial to avoid postoperative meningitis. The proposed prophylaxis protocol is

AC C

comparable in safety to those recommended in literature as assessed by the low rate of meningitis.

Milanese 3

ACCEPTED MANUSCRIPT Introduction

Postoperative infection is a serious complication in endoscopic endonasal surgery that can lead to permanent neurological deficits or, in a restricted number of cases, can be fatal. Antibiotic prophylaxis has a crucial role in clean/contaminated procedures including endoscopic endonasal

RI PT

surgery to reduce the risk of postoperative infections.1-4 Indeed, in this approach contaminated nasal space and sinuses are the natural corridors to reach extradural or intradural pituitary and skull base lesions.5-6 This could expose to the risk of developing postoperative meningitis.7-9 Therefore, a

SC

proper antibiotic prophylaxis with particular attention to all the routine maneuvers of sterilization of the surgical instrumentation and disinfection of the surgical field are crucial to reduce the risk of

M AN U

infection.10-12 In the literature, different antibiotics with different dosages and times of administrations have been proposed.2,4,13-16The aim of this study is to analyze our surgical experience with a short/ultra-short antibiotic prophylaxis protocol, evaluating its efficacy and

Materials and Methods

TE D

assessing the risk factors of postoperative meningitis.

EP

Each endoscopic endonasal procedure performed at the Neurosurgical Department of IRCCS Institute of Neurological Sciences of Bologna and ENT Department of Bellaria Hospital, Bologna,

AC C

for pituitary or skull base lesions between 1998 and May 2016 was retrospectively considered in this study. This series included sellar and suprasellar hypothalamic-pituitary tumors, such as pituitary adenomas, Rathke cleft cysts, craniopharyngiomas and hypothalamic glioma, skull base pathologies, such as clivus chordoma, meningiomas, craniocervical junction abnormalities, spontaneous or post-traumatic CSF leak, and finally malignant tumors of the nasal cavity and paranasal sinuses. Cases with preoperative suspicion of CSF infection have been excluded by the final analysis, as well as patients who died within the first month after surgery (Fig.1).

Milanese 4

ACCEPTED MANUSCRIPT

A short-term intraoperative antibiotic protocol (usually given every 3 hours from induction with a further dose 6 hours after the end of the surgery) was adopted from 1998 to 2005. Conversely, ultrashort term (single intraoperative administration on induction) was adopted after 2005. In both time spans, if surgery lasted more than 3 hours a further antibiotic administration was given. We

RI PT

preferred a gram-positive prophylaxis: from 2013 iv ampicillin/sulbactam 3 g has been the first-line antibiotic, while until that year we usually used cefazolin 2 g (if the patient was allergic: clindamycin 600 mg or clarithromycin 500 mg).

SC

All cases of meningitis and localized infection (i.e., sinusitis, pneumonia, cystitis, etc.) or systemic infections (sepsis) were recorded on the basis of clinical reports of the patients, as well as the

leak, have been considered.

M AN U

duration of the surgery. Postoperative non-infectious complications, with special attention to CSF

The surgical endoscopic approaches were divided into: standard midline trans-sphenoidal, ethmoido-pterygo-sphenoidal,

transtuberculum-transplanum,

transclival,

transcribiform

and

TE D

endonasal (including in this last group transethmoidal approaches and surgical procedures to pterygopalatine or infratemporal fossa).

Intraoperative CSF leak at the time of surgery was considered in this study as well as the need of

EP

reconstruction and its technique, distinguishing between unilayer overlay (using abdominal fat or mucoperiostium from septum or turbinates), multilayer technique with fascia lata and pedicled

AC C

nasoseptal flap (with or without multilayer plastic beneath). Multilayer reconstruction consists in various combination of autologous free graft or vascularized flap and it’s tailored on extension and site of the defect. Usually for large anterior skull base defects the technique consists in placing first an intradural intracranial layer of fascia lata, followed by a second extradural layer in the epidural space. Finally a third layer of mucoperiostium or nasoseptal flap is positioned overlay. Pieces of fat previously harvested from the thigh are placed on the contour of the bony resection to eliminate any dead space and flatten the residual bony of the skull base. Multilayer reconstruction in extended transsphenoidal approaches (e.g. extended to the tuberculum sellae or the posterior planum

Milanese 5

ACCEPTED MANUSCRIPT

sphenoidalis) differs, because of the difficult in dissecting the dura from the bone near the parasellar structures. For this reason usually one single intracranial layer is placed followed by fat and mucoperiostium graft or local flap.

RI PT

Statistical analysis

Continuous variables are presented as mean ± standard deviation (SD), while categorical variables as absolute frequency (relative frequency). Fisher’s exact test was used to evaluate the association

SC

between meningitis rate and the other variables, namely intra- or postoperative CSF leak, type of pathology, surgical approach adopted, plastic repair performed, type of antibiotic prophylaxis and

M AN U

duration of the surgery. The unit of analysis was the procedure.

Univariate and multivariate logistic regression models (95% confidence interval) were used to investigate meningitis-related risk factors and to determine independent risk factors related to meningitis.

TE D

Model 1 was evaluated for the following variables: age, sex, CSF leak, plastic, prophylaxis and surgical approach. In Model 2 we replicated the analyses omitting the surgical approach and adding the pathology. The surgical approach and the pathology were highly correlated and caused a

EP

multicollinearity problem in the same model.

All p-values are based on 2-sided tests and p < 0.05 were considered significant. Statistical analysis

Results

AC C

was performed using the statistical package Stata SE 14.0.

A total of 2,082 procedures were included in the study. Fifty cases (2.4%) were excluded because they presented clinical and bio-humoral signs of CSF infection before surgery or were deceased within the first 30 days from surgery. (Fig. 1) Among the remaining 2,032 procedures, mean age of patients was 50 years old (SD 16.8) and male/female ratio was 1:1.12.

Milanese 6

ACCEPTED MANUSCRIPT

In Tab. 1 the type of pathologies treated through pure endoscopic endonasal approaches are summarized, as well as the surgical approach and CSF leak repair technique adopted. Surgery duration was less than 3 hours in 1,680 (82.7%) surgical procedures and exceeded this time in 352 (17.3%) procedures. Intraoperative CSF leak occurred in 666 (32.8%) procedures, while

RI PT

postoperative CSF leak in 69 cases (3.4%).

The rate of meningitis in our study was 0.69% (14/2032), as illustrated in Table 2. Postoperative CSF leak was strongly associated with the development of meningitis. Indeed, in case of

SC

postoperative CSF leak 10.14% of cases suffered from meningitis, while this rate was 0.36% when no CSF leak after surgery occurred (p<0.001). In case the patient with postoperative CSF leak had

M AN U

also an intraoperative leak, the risk of meningitis raised to 13.3% vs. 7.1% of patients with only postoperative fistula and 1.3% of patients with only intraoperative leak (p<0.001). Other systemic infections were observed in nine cases (0.4%), all consisted in respiratory or urinary pathologies.

TE D

On the univariate analysis, malignant nasal and paranasal tumors (3/133, 2.3%) and the pathologies with a more common intradural location, such as craniopharingiomas (3/114; 2.6%), chordomas (2/85, 2.4%), meningiomas (2/52, 3.9%) were the most frequently associated with postoperative

EP

meningitis (p=0.001). Furthermore, cases undergone to extended approaches to anterior fossa, suprasellar region and posterior fossa accounted for 85% of meningitis in our series (p<0.001)

AC C

(Tab.2), while only 2/1,379 and 1/104 cases of CSF infection were associated respectively with a midline transsphenoidal or ethmoido-pterygo-sphenoidal approach. Finally, among the different techniques of plastic repair, the nasoseptal flap, which has been used selectively for cases with wider osteo-dural opening, proved to be more associated with meningitis accounting for 5.7% of cases (p<0.001) (Tab.2). Although our prophylaxis protocol changed over time, we observed no statistically significant rate of meningitis in spite of the introduction of an ultra-short antibiotic prophylaxis (p=0.539). Conversely, the duration of surgery proved to be an influential parameter on univariate analysis,

Milanese 7

ACCEPTED MANUSCRIPT

indeed 10 (2.8%) cases with longer duration of surgery developed meningitis, while it occurred in only 4 cases (0.2%) for procedures lasting less than 3 hours (p<0.001). The multivariate analysis confirmed that the factors associated with a higher risk of developing

RI PT

postoperative meningitis were postoperative CSF leak and surgical approach. (Tab. 3)

Discussion

This retrospective study investigated the experience of a large single-center cohort of endoscopic

SC

endonasal procedures over a period of 18 years with a short or ultra-short antibiotic prophylaxis using a common and inexpensive drug. The most relevant result is the low rate of meningitis (<1%)

M AN U

achieved. This complication was more significantly associated with the presence of postoperative and/or intraoperative CSF leak. Also malignant sinonasal tumors and pathologies requiring extended approaches proved to be at higher risk of developing this infection. The very low rate of meningitis is in line with previous studies and confirms that endoscopic endonasal procedures are

TE D

safe, although this kind of surgery should be considered as clean/contaminated.14-18 Indeed, in a recent review, 82 studies were analyzed and the overall rate of meningitis was 1.7%.17 Moreover, Orlando et al., similarly to our experience, reported a rate of meningitis of 0.59% (1/170), which

EP

decreased to 0% (0/235) as reported in a consecutive study of the same group after experiencing ultra-short single agent prophylaxis.15,18

AC C

Indeed, according to the international guidelines for prevention of surgical site infection, antimicrobial prophylaxis should reduce the microbial load to prevent intraoperative contamination and avoid affecting patient immunological defenses.19 The right antibiotic drug selection has an important role in the intraoperative prophylaxis but it represents only the last phase of the multiple steps needed to prepare an adequate environment for surgery: surgical site, operating room and personnel antiseptic management. Indeed, face and nasal disinfection, positioning of external devices such as lumbar drainage and postoperative course in the ICU may be concomitant factors to take into account.

20

Moreover, the antibiotic of choice should be safe, low-price and active on the

Milanese 8

ACCEPTED MANUSCRIPT

most probable bacterial contaminants considering the site of the surgery. Based on these recommendations, we have employed ampicillin/sulbactam or cefazolin in all cases of endoscopic endonasal approach, even in case of extended skull base surgical procedures requiring dural opening. Since 2005, the ultra-short term antibiotic administration protocol has been routinely

RI PT

employed after these procedures in our Institution. It has been reported that an incorrect use of antibiotic prophylaxis increases the risk of systemic infections.19,21In fact, even if nasal packing is necessary postoperatively , we prefer not to continue antibiotic administration, which is also spared

SC

in case of intra- and/or postoperative CSF leak if no clinical and laboratory signs of infection have been developed. It is also remarkable that the rate of other localized or systemic infections is

M AN U

particularly low in our series, confirming the effectiveness and safety of our protocol. In this study, the most relevant factor associated with the risk of postoperative meningitis was the presence of a postoperative CSF leak (p<0.001), although the intraoperative finding of CSF leak also increased the risk of developing postoperative CSF infection (p<0.001). This result is similar to

TE D

the experience of Kono et al., who reported the presence of a postoperative CSF leak as the most important risk factor for the development of meningitis.16 Therefore, a careful inspection at the end of the surgery, including simple tricks such as the Valsalva maneuver if necessary, might be useful

EP

to avoid a missing leakage.

It is well known that the incidence of infection increases with the duration of the leakage.22 Thus, an

AC C

aggressive strategy to detect and to repair the postoperative CSF leak as soon as possible is crucial to reduce this risk. In our center, we performed a complete assessment in case of suspicion of postoperative CSF leak consisting in the evaluation of CSF beta trace protein, CT scan to detect the presence or increased of intracranial air, and finally an endoscopic nasal inspection with eventual plastic repair if needed.23 Conservative treatment with lumbar drain positioning is not considered as the first option in cases of postoperative rhinoliquorrhea, although sometimes it revealed to be useful in some cases of post-traumatic or spontaneous CSF leak either perioperative or before surgery.

Milanese 9

ACCEPTED MANUSCRIPT

As already reported, our CSF leak repair strategy consists in the simple placement of Gelfoam if no CSF oozing is observed and, for midline approaches, when the diaphragm sellae is well preserved (Fig. 2). If it appears thin or the arachnoid layer is exposed, even in the absence of a frank CSF leak, abdominal fat and septal or middle turbinate mucoperiostium is placed in a unilayer overlay

RI PT

fashion as well as in case of evident CSF leak for sellar approaches or for small skull base defects (Fig.3). Moreover, for extended approaches a multilayer technique with fat, fascia lata and mucoperiostium and fascia lata or nasoseptal flaps are preferred (Fig.4). Plastic repair with

SC

nasoseptal flap was more associated with CSF infection in this series. This result might be explained by the use of this technique in our Institution in selected cases with large osteo-dural

M AN U

defects after extended approaches such as those performed for intradural chordomas or suprasellar and third ventricle craniopharingiomas. Noteworthy, we believe that the use of autologous material for plastic repair after endoscopic endonasal surgery is better to prevent infectious and immunogenic complications.24,25

TE D

Although the rate of meningitis is low and in line with others reported in the literature, the change of antibiotic prophylaxis protocol in 2005 might be considered a limit of this study. Moreover, the pathologies more frequently associated with postoperative development of meningitis were

EP

craniopharingiomas, chordomas, meningiomas and endonasal malignant tumors, which are particularly rare pathologies and mostly require a more extended approach (i.e., transclival,

AC C

transtuberculum-transplanum, ethmoido-pterygo-sphenoidal or transcribriform) affecting also the length of surgery.17

Conclusions Although the endoscopic endonasal approach is considered a clean/contaminated surgery with higher risk of postoperative infective sequelae, in our center, since 2005 the ultra-short antibiotic prophylaxis with common and inexpensive drug such as ampicillin/sulbactam and cefazolin was employed. However, a careful inspection after the removal of the lesion to assess intraoperative

Milanese 10

ACCEPTED MANUSCRIPT

leakage and, when necessary, a watertight plastic closure at the end of surgery are the most relevant maneuvers for the prevention of post-operative meningitis. Whenever a postoperative CSF leak is documented or strongly suspected, its rapid, effective and aggressive surgical management, avoiding antibiotic treatments if no clear signs of meningitis are present, is required to avoid

RI PT

subsequent infections.

SC

Acknowledgments: thanks to Cecilia Baroncini for English revision.

This research did not receive any specific grant from funding agencies in the public, commercial, or

M AN U

not-for-profit sectors.

References

1. Weber RS, Callender DL. Antibiotic prophylaxis in clean-contaminated head and neck

TE D

oncologic surgery. Ann OtolRhinolLaryngol Suppl. 1992;155:16-20. 2. Rodrigo JP, Alvarez JC, Gómez JR, Suárez C, Fernández JA, Martínez JA. Comparison of three prophylactic antibiotic regimens in clean-contaminated head and neck surgery. Head

EP

Neck 1997;19(3):188-93.

3. Saleh AM, Torres KM, Murad MH, et al. Prophylactic perioperative antibiotic use in

AC C

endoscopic sinus surgery: A systematic review and meta-analysis. Otolaryngol Head Neck Surg 146:533–538, 2012. 4. Rosen SA, Getz AE, Kingdom T, Youssef AS, Ramakrishnan VR. Systematic review of the effectiveness of perioperative prophylactic antibiotics for skull base surgeries. Am J Rhinol Allergy2016;30(2):e10-6. 5. Kassam A, Snyderman CH, Mintz A, Gardner P, Carrau RL. Expanded endonasal approach: the rostrocaudal axis. Part I. Crista galli to the sellaturcica. Neurosurg Focus. 2005;19(1):E3.

Milanese 11

ACCEPTED MANUSCRIPT

6. Kassam A, Snyderman CH, Mintz A, Gardner P, Carrau RL. Expanded endonasal approach: the rostrocaudal axis. Part II. Posterior clinoids to the foramen magnum.Neurosurg Focus. 2005;19(1):E4. 7. Horowitz G, Fliss DM, Margalit N, Wasserzug O, Gil Z. Association between cerebrospinal

RI PT

fluid leak and meningitis after skull base surgery.Otolaryngol Head Neck Surg. 2011;145(4):689-93.

8. Daudia A, Biswas D, Jones NS. Risk of meningitis with cerebrospinal fluid rhinorrhea. Ann

SC

OtolRhinolLaryngol. 2007;116(12):902-5.

9. Lai LT, Trooboff S, Morgan MK, and Harvey RJ. The risk of meningitis following expanded

M AN U

endoscopic endonasal skull base surgery: A systematic review. J NeurolSurg B Skull Base 75:18–26, 2014.

10. Harvey RJ, Nogueira JF, Schlosser RJ, Patel SJ, Vellutini E, Stamm AC. Closure of large skull base defects after endoscopic transnasal craniotomy. Clinical article. J Neurosurg.

TE D

2009;111(2):371-9.

11. Hadad G, Bassagasteguy L, Carrau RL, Mataza JC, Kassam A, Snyderman CH, Mintz A. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular

EP

pedicle nasoseptal flap. Laryngoscope.2006;116(10):1882-6. 12. Kassam AB, Thomas A, Carrau RL, Snyderman CH, Vescan A, Prevedello D, Mintz A,

AC C

Gardner P. Endoscopic reconstruction of the cranial base using a pediclednasoseptal flap. Neurosurgery. 2008;63(1 Suppl 1):ONS44-52; discussion ONS52-3. 13. Kraus DH, Gonen M, Mener D, et al. A standardized regimen of antibiotics prevents infectious complications in skull base surgery. Laryngoscope 115:1347–1357, 2005. 14. Brown SM, Anand VK, Tabaee A, and Schwartz TH. Role of perioperative antibiotics in endoscopic skull base surgery. Laryngoscope117:1528–1532, 2007.

Milanese 12

ACCEPTED MANUSCRIPT

15. Orlando R, Cappabianca P, Tosone G,Esposito F, Piazza M, de Divitiis E. Retrospective analysis of a new antibiotic chemoprophylaxis regimen in 170 patients undergoing endoscopic endonasaltranssphenoidal surgery. SurgNeurol 2007; 68:145–148. 16. Kono Y, Prevedello DM, Snyderman CH, et al. One thousand endoscopic skull base surgical

RI PT

procedures demystifying the infection potential: incidence and description of postoperative meningitis and brain abscesses. Infect Control HospEpidemiol 32:77–83, 2011.

17. Borg A, Kirkman MA, Choi D. Endoscopic endonasal anterior skull base surgery: a

SC

systematic review of complications over the past 65 years. World Neurosurg. 2016 pii: S1878-8750(16)00327-2.

M AN U

18. Somma T, Maraolo AE, Esposito F, Cavallo LM, Tosone G, Orlando R, Cappabianca P. Efficacy of ultra-short single agent regimen antibiotic chemo-prophylaxis in reducing the risk of meningitis in patients undergoing endoscopic endonasaltranssphenoidal surgery. Clinical neurology and neurosurgery 2015;139: 206-209.

TE D

19. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR, Hospital Infection Control Practices Advisory Committee. Guideline for prevention of surgical site infection. American journal of infection control 1999; 27: 97-134.

EP

20. Lobo BC, D'Anza B, Recinos PF, Kshettry VR, Snyderman CH, Woodard TD, Sindwani R. Trends in Perioperative Management of Endoscopic Skull Base Surgery Patients. J Neurol Surg B 2017; 78(S 01): S1-S156

AC C

21. Burke JP. Infection control - a problem for patient safety. N Engl J Med. 2003; 348:651-6. 22. Friedman JA, Ebersold MJ, Quast LM. Persistent posttraumatic cerebrospinal fluid leakage. Neurosurg Focus 2000;9(1):e1. 23. Banu MA, Szentirmai O, Mascarenhas L, Salek AA, Anand VK, Schwartz TH. Pneumocephalus patterns following endonasal endoscopic skull base surgery as predictors of postoperative CSF leaks.J Neurosurg. 2014;121(4):961-75.

Milanese 13

ACCEPTED MANUSCRIPT

24. Malliti M, Page P, Gury C, Chomette E, Nataf F, Roux FX. Comparison of deep wound infection rates using a synthetic dural substitute (neuro-patch) or pericranium graft for dural closure: a clinical review of 1 year. Neurosurgery. 2004;54(3):599-603; discussion 603-4. 25. Schick B, Wolf G, Romeike BF, Mestres P, Praetorius M, Plinkert PK. Dural cell culture. A

RI PT

new approach to study duraplasty. Cells Tissues Organs.2003;173(3):129-37.

Captions

SC

Fig. 1

Fig. 2

M AN U

Diagram showing the exclusion criteria of the study population.

Intraoperative endoscopic endonasal images. 0° scope. A. Intraoperative inspection of the surgical field after the removal of a macroadenoma: no CSF leak was detected. B. Plastic repair with Gelfoam in the surgical field.

TE D

Fig. 3

Intraoperative endoscopic endonasal images. 0° scope. A. Ethmoidal spontaneous CFS leak

Fig. 4

EP

(black circle). B. Unilayer overlay closure with mucoperiostium.

Intraoperative endoscopic endonasal images. 0° scope. Multilayer plastic repair with nasoseptal

AC C

flap. A. Osteodural defect after posterior fossa meningioma resection. B. Plastic repair is performed in a multilayer fashion: fascia lata is placed intradurally intracranially. C. Abdominal fat is placed intradurally. D-E. A second graft of fascia lata is positioned in the epidural space (intracranial extradural layer). F. Finally, the nasoseptal flap is positioned overlay to protect the underlying reconstruction. Tab. 1 Features of the series. Tab. 2

Milanese 14

ACCEPTED MANUSCRIPT Association between meningitis and the risk factors. Tab. 3

Univariate and multivariate Logistic Regression model between meningitis and the considered

AC C

EP

TE D

M AN U

SC

RI PT

variables.

ACCEPTED MANUSCRIPT n (%)

Characteristics

F 1075 (52.9%)

Sex

M 957 (47.1%)

50.1 ± 16.8 years

Pathology

Pituitary adenoma 1416 (69.7%)

RI PT

Age (years)

Craniopharyngioma 114 (5.6%)

CSF leak 137 (6.7%) Meningioma 52 (2.6%)

SC

Chordoma 85 (4.2%)

M AN U

Rathke cleft cyst 84 (4.1%)

Malignant tumors 133 (6.5%)

Craniocervical junction abnormalities 5 (0.2%) Hypothalamic glioma 6 (0.3%)

Transsphenoidal 1379 (67.9%)

TE D

Surgical approaches

Supradiaphragmatic 148 (7.3%) Ethmoido-pterygo-sphenoidal 104 (5.1%)

EP

Transtuberculum-transplanum 42 (2%) Transclival 88 (4.3%)

AC C

Transcribriform 59 (2.9%)

Plastic repair

Endonasal and extended approaches 212 (10.4%)

No plastic 1275 (62.8%) Unilayer overlay 416 (20.5%) Multilayer with fascia lata 287 (14.1%) Nasoseptal flap 54 (2.7%)

Table 1: Features of the series

ACCEPTED MANUSCRIPT

CSF LEAK Postoperative:

p-value

yes

12/666 (1.8)

< 0.001

no

2/1366 (0.2)

yes

7/69 (10.1)

no

7/1963 (0.4)

< 0.001

CSF LEAK Combined 1/1292 (0.1)

SC

Nothing

M AN U

6/449 (1.3)

Intraoperative only

1/14 (7.1)

Postoperative only Intraoperative and Postoperative PATHOLOGY

6/45 (13.3)

0.001

4/1416 (0.3)

TE D

Pituitary adenoma

3/114 (2.6)

Craniopharyngioma

AC C

EP

Chordoma CSF leak

< 0.001

RI PT

CSF LEAK Intraoperative:

Meningitis/Total (%)

2/85 (2.4)

0/137 (0.0)

Meningioma

2/52 (3.9)

Rathke cleft cyst

0/84 (0.0)

Malignant tumors

3/133 (2.3)

Craniocervical junction abnormalities

0/5 (0.0)

Hypothalamic glioma

0/6 (0.0)

SURGICAL APPROACH

< 0.001

ACCEPTED MANUSCRIPT 2/1379 (0.2)

Transsphenoidal

5/148 (3.4)

Ethmoido-pterygo-sphenoidal

1/104 (1.0)

Transtuberculum-Transplanum

2/42 (4.8)

Transclival

2/88 (2.3)

Transcribrifrom

2/59 (3.4) 0/212 (0.0)

No plastic

2/1275 (0.2) 5/416 (1.2)

Unilayer overlay

4/287 (1.4)

Short

AC C

Ultra-short

EP

PROPHYLAXIS

TE D

Multilayer with fascia lata Nasoseptal flap

< 0.001

M AN U

PLASTIC

SC

Transnasal

RI PT

Supradiafragmatic

3/53 (5.7) 0.539 2/487 (0.4)

12/1545 (0.8)

Table 2: Association between meningitis and the risk factors.

ACCEPTED MANUSCRIPT

Age (years)

Sex:

OR crude (95% CI)

p

OR adjusted* (95% CI)

p

OR adjusted** (95% CI)

p

1.02 (0.99 – 1.05)

0.267

1.02 (0.99 – 1.05)

0.233

1.01 (0.98 – 1.04)

0.638

female male

ref. 0.67 (0.23 – 1.93)

ref. 0.453

0.77 (0.25 – 2.34)

CSF LEAK

yes

ref. 12.51 (2.79 – 56.09)

ref. 0.001

CSF LEAK Postoperative: no

31.55 (10.74 – 92.71) 0.001

Plastic: No plastic

ref. 7.74 (1.50 – 40.08)

Multilayer

9.00 (1.64 – 49.38)

Nasoseptal flap

37.44 (6.11 – 229.1)

1.90 (0.42 – 8.51)

AC C

0.85 (0.29 – 2.45)

0.757

ref.

7.05 (2.10 – 23.65)

0.002

ref.

<

ref.

<

18.00 (4.48 – 72.38)

0.001

20.79 (5.64 – 76.63)

0.001

ref.

0.015

0.40 (0.09 – 1.68)

0.210

0.80 (0.20 – 3.24)

0.755

0.011

0.51 (0.11 – 1.95)

0.282

0.54 (0.13 – 2.33)

0.409

0.001

0.72 (0.11 – 4.58)

0.726

2.31 (0.44 – 12.21)

0.324

ref.

EP

Ultra-short

0.005

ref.

TE D

Unilayer overlay

Prophylaxis: Short

<

5.87 (1.72 – 20.01)

M AN U

yes

ref.

0.646

SC

Intraoperative: no

ref.

RI PT

Variables

0.403

ref. 0.70 (0.13 – 3.76)

ref. 0.676

0.56 (0.11 – 2.81)

0.484

ACCEPTED MANUSCRIPT

Surgic. Approach:

ref.

Transsphenoidal Supradiafragmatic Ethmoido-pterygo-

ref.

24.07 (4.63 – 125.26) 0.001 6.68 (0.60 – 74.38)

sphenoidal

10.67 (1.16 – 98.08)

0.036

0.122 10.47 (0.70 – 157.19)

0.089

< 34.43 (4.73 – 250.72) 0.001 18.21 (1.57 – 211.92)

0.020

Transplanum

16.01 (2.23 – 115.11) 0.006 13.38 (1.71 – 104.92)

0.014

Transclival

24.16 (3.34 – 174.68) 0.002 15.72 (1.82 – 135.99)

RI PT

Transtuberculum-

SC

Transcribrifrom

0.012

ref.

Pituitary adenoma

9.54 (2.11 – 43.18)

Chordoma

8.51 (1.54 – 47.13)

Meningioma

14.12 (2.53 – 78.94)

Malignant tumors

8.15 (1.80 – 36.81)

ref.

0.003

2.30 (0.28 – 18.61)

0.436

0.014

5.15 (0.77 – 34.29)

0.090

0.003

4.22 (0.53 – 33.45)

0.173

0.006

8.31 (1.80 – 36.81)

0.020

TE D

Craniopharyngioma

M AN U

Phatology:

EP

Table 3: Univariate and multivariate Logistic Regression model between meningitis and the considered variables

AC C

*Mode1 1: Transnasal omitted (212 observation) because predicts outcome perfectly **Model 2: CSF leak, Rathke cleft cyst, Craniocervical junction abnormalities, Hypothalamic glioma

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT The rate of meningitis in endoscopic endonasal approach is still debated Ultra-short antibiotic prophylaxis is associated with a low rate of meningitis Meningitis is more associated with postoperative CSF leak

AC C

EP

TE D

M AN U

SC

RI PT

Quick postoperative CSF leak repair is crucial to reduce the risk of meningitis

ACCEPTED MANUSCRIPT Disclosure- Conflict of interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

AC C

EP

TE D

M AN U

SC

RI PT

The authors have no funding, financial relationships, or conflicts of interest to disclose.