Reposted with permission from ©AANS, 2014
J Neurosurg Pediatrics (Suppl) 14:60–71, 2014
AANS, 2014
(Original text of the guideline was edited to reflect the update.  Please click here for the original publication.)

Pediatric hydrocephalus: systematic literature review and evidence-based guidelines

Part 8: Management of cerebrospinal fluid shunt infection

UPDATE

Mandeep S. Tamber, MD,1  Paul Klimo, Jr., MD, MPH,2,3 Catherine A. Mazzola, MD,4  Ann Marie Flannery, MD5

¹Department of Pediatric Neurological Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; ²Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, and ³Le Bonheur Children’s Hospital, Memphis, Tennessee; ⁴Division of Pediatric Neurological Surgery, Goryeb Children’s Hospital, Morristown, New Jersey; and ⁵Department of Neurological Surgery, Saint Louis University, St. Louis, Missouri

Object. The objective of this systematic review was to answer the following question: What is the optimal treatment strategy for CSF shunt infection in pediatric patients with hydrocephalus?

Methods. The US National Library of Medicine and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I–III). Evidentiary tables were constructed that summarized pertinent study results, and based on the quality of the literature, recommendations were made (Levels I–III).

Results. A review and critical appraisal of 27 studies that met the inclusion criteria allowed for a recommendation for supplementation of antibiotic treatment using partial (externalization) or complete shunt hardware removal, with  a moderate degree of clinical certainty. However, a recommendation regarding whether complete shunt removal is favored over partial shunt removal (that is, externalization) could not be made owing to severe methodological deficiencies in the existing literature. There is insufficient evidence to recommend the use of intrathecal antibiotic therapy as an adjunct to systemic antibiotic therapy in the management of routine CSF shunt infections. This also holds true for other clinical scenarios such as when an infected CSF shunt cannot be completely removed, when a shunt must be removed and immediately replaced in the face of ongoing CSF infection, or when the setting is ventricular shunt infection caused by specific organisms (for example, gram-negative bacteria).

Conclusions. Supplementation of antibiotic treatment with partial (externalization) or complete shunt hardware removal are options in the management of CSF shunt infection. There is insufficient evidence to recommend either shunt externalization or complete shunt removal as the preferred surgical strategy for the management of CSF shunt infection. Therefore, clinical judgment is required. In addition, there is insufficient evidence to recommend the combination of intrathecal and systemic antibiotics for patients with CSF shunt infection when the infected shunt hardware cannot be fully removed, when the shunt must be removed and immediately replaced, or when the CSF shunt infection is caused by specific organisms. The potential neurotoxicity of intrathecal antibiotic therapy may limit its routine use.

Recommendation: Supplementation of antibiotic treatment with partial (externalization) or with complete shunt hardware removal is an option in the management of CSF shunt infection. Strength of Recommendation: Level II, moderate degree of clinical certainty.

Recommendation: There is insufficient evidence to recommend either shunt externalization or complete shunt removal as a preferred surgical strategy for the management of CSF shunt infection. Therefore, clinical judgment is required. Strength of Recommendation: Level III, unclear degree of clinical certainty.

Recommendation: There is insufficient evidence to recommend the combination of intrathecal and systemic antibiotics for patients with CSF shunt infection in whom the infected shunt hardware cannot be fully removed or must be removed and immediately replaced, or when the CSF shunt infection is caused by specific organisms. The potential neurotoxicity of intrathecal antibiotic therapy may limit its routine use. Strength of Recommendation: Level III, unclear degree of clinical certainty.

(http://thejns.org/doi/abs/10.3171/2014.7.PEDS14328)

 Key Words: cerebrospinal fluid shunt, infection, therapy, pediatrics,  evidence-based guidelines, practice guidelines, hydrocephalus

 Abbreviations used in this paper: EVD = external ventricular drain; VA = ventriculoatrial; VP = ventriculoperitoneal.

 Cerebrospinal fluid shunt infection is one of the most common and serious complications of CSF shunt therapy. Infection admissions number approximately 2300 per year in the United States and, in aggregate, account for more than 50,000 hospital days.¹ Total hospital charges related to the management of CSF shunt infection were nearly $250 million in 2003 adjusted dollars.¹

Within 24 months after insertion, infections complicate approximately 11% of initial CSF shunt placements.² Despite the high incidence of this complication, the optimal management of CSF shunt infection has yet to be defined. The existing evidence regarding the management of CSF shunt infection is of poor methodological quality. As such, current management is dictated not by evidence, but rather by physician preference and other possibly relevant patient-level factors (for example, patient surgical risk, ventricle size, and complexity of the shunt system). It is not surprising that there is significant variation in CSF shunt infection treatment protocols between centers.³

The objective of this systematic review was to answer the following question: What is the optimal treatment strategy for CSF shunt infection in pediatric patients with hydrocephalus? The successful treatment of CSF shunt infection aims to cure the infection (that is, minimize the probability of reinfection or relapse) while maintaining functional CSF diversion and minimizing morbidity, mortality, and the cost of therapy. The alternative paradigms for the management of ventricular shunt infection are illustrated well if one considers important historical milestones in the treatment of hydrocephalus. The evidentiary tables are structured somewhat accordingly (Fig. 1). The development of the Holter-Pudenz valve in 1957 and the ability to insert the distal end of a ventricular shunt into the right atrium was a major development in the treatment of hydrocephalus. Although ventriculoatrial (VA) shunts facilitated continuous and regulated CSF diversion, the fact that the distal catheter entered the heart posed logistical problems when these shunts inevitably became infected. A major issue with VA shunts was loss of limited venous access if these shunts were removed and not immediately replaced. In light of this limitation, the predominance of literature examining the treatment of CSF shunt infections in the era of VA shunts documented the outcomes of treatment with systemic antibiotics alone (Table 1) and whether the elevated CSF antibiotic concentrations achieved by intrathecal therapy conferred any additional benefit in managing the ventriculitis that often accompanied CSF shunt infection—both while leaving the infected shunt in situ or after removing the shunt and immediately replacing it in infected cerebrospinal fluid (Table 2).

A decade later, Ames developed a technique for placement of the distal catheter in the peritoneal space, and as such, made shunt removal and later replacement a feasible surgical strategy in the management of CSF shunt infection. Over time, the combined medical and surgical treatment of ventricular shunt infection became more accepted, in part because of the gradual phase-out of VA shunts and their associated limitations with respect to repeated surgical access to the heart, but perhaps more significantly because of the realization that an infected ventricular shunt, as an infected foreign body, was difficult if not impossible to sterilize using antibiotics alone. This management philosophy accepts not only that shunt removal (and eventual replacement once CSF sterility is achieved) requires multiple surgeries, but also the risk of introducing secondary infection during a variable period of external drainage. Therefore, although more contemporary literature examining the treatment of CSF shunt infection consists of studies that incorporate some form of shunt removal, variations in whether the infected shunt was partially removed (that is, externalized) (Table 3) or completely removed (see Table 4), and whether supple- mental intrathecal antibiotics were administered contribute to significant between-study heterogeneity.

A lack of rigorous comparative effectiveness studies leads to uncertainty regarding the preferred therapeutic strategy for a particular clinical circumstance. Decision analytical modeling attempts to apply statistical simulation techniques to preexisting data to rank competing therapeutic options in terms of their relative effective- ness. A decision analysis examining the treatment of CSF shunt infection using data from published studies (most included in evidentiary Tables 1–4) came to the conclusion that the best treatment modality for CSF shunt infection was antibiotic administration (systemic, with or without intrathecal administration) and complete removal of the infected shunt, with intercurrent external ventricular drainage or ventricular taps, followed by placement of a new shunt when CSF sterility is achieved. Sensitivity analyses revealed that this treatment option had the highest cure rate, the lowest failure rate, and the lowest mortality rate when compared with treatment consisting of antibiotic therapy with shunt removal and immediate replacement, or antibiotic treatment alone, over a wide range of assumptions.⁴

Multiple review articles on the topic also conclude that shunt infection should be ideally managed with antibiotics, complete shunt removal, and placement of a temporary external ventricular drain (EVD), followed by reimplantation after CSF sterilization.^5-9 Although intrathecal administration of antibiotics appears to make theoretical sense because of enhanced CSF antibiotic concentrations, its practical application is controversial, owing in large part to the potential adverse effects of intrathecal therapy, including neurotoxicity. The indications for intrathecal therapy are not well established and presently range from use in any shunt infection, use in only those infections in which the CSF cannot be sterilized by systemic antibiotics alone (for example, persistent positive cultures), or use in those ventricular shunt infections caused by specific organisms (for example, gram- negative infections). A practice survey of board-certified members of the American Society of Pediatric Neurosurgeons revealed that most surgeons treat ventricular shunt infection with antibiotics, removal of the infected CSF shunt, and placement of an EVD, followed by delayed shunt replacement—a management paradigm that can be supported by the available evidence, as detailed below.

Fig. 1. Organization of evidentiary tables based on alternative paradigms for the management of CSF shunt infection.

Methods

Search Criteria

We searched the US National Library of Medicine (PubMed/MEDLINE) database and the Cochrane Data- base of Systematic Reviews for the period January 1966 through March 2012 using the following MeSH subject headings: (CSF shunts) AND (bacterial infection OR prosthesis-related infection OR catheter-related infection) AND (treatment OR outcome) AND (antibacterial agents OR injections OR antibiotics OR device removal OR ventriculostomy OR combined modality therapy). Searches were limited to studies in patients younger than 18 years of age, the management of initial (not repeat) CSF shunt infection, and to the English language.

Authors performed an updated literature search (in PubMed and Cochrane Central) for this guideline chapter through a medical librarian at the Congress of Neurological Surgeons Guidelines office using the below-mentioned existing search terms to update the original search through November 30, 2019.

Search Results

A total of 342 abstracts were screened and 69 full- text articles were retrieved for review. The details of this process are described in Part 1, the introduction and methodology section of these guidelines.5 An examination of the reference lists of these 69 full-text articles yielded an additional 24 articles that warranted full-text review (Fig. 2). Subsequent review of the full texts of these 93 articles led to the exclusion of 66 articles based on predefined criteria, leaving 27 articles as the basis for the evidentiary tables for this particular recommendation. Reasons for exclusion of full-text articles included the following: literature review (n = 19); no treatment outcomes given (n = 14); pediatric patients not reported separately (n = 6); wrong target population (n = 1); small sample size (n = 19); not a full report of a clinical study (n = 2); not relevant to the study question (n = 3); and other (n = 2).

An additional 2 studies out of the 62 new studies yielded by the 2020 underwent full text review, but were excluded.  No new studies met inclusion criteria from the original guideline. (Fig 3)

Results

In general, the methodological quality of the evidence related to this recommendation was poor. The studies that met our inclusion criteria were typically descriptive series of small numbers of patients and were vulnerable to the biases and limitations of a retrospective study design. Because the studies relied on the accuracy and completeness of the medical record, the control of potentially confounding variables was nonexistent. Although most studies did compare outcomes between patient groups treated under alternative management protocols, the rationale behind why a particular treatment was assigned to a particular patient group was not clearly described, leading to significant issues with selection bias. For those studies describing the outcomes of a single management protocol, between-study comparisons of results was hampered by widely disparate management protocols and the use of nonuniform outcome measures (and definitions thereof). These limitations precluded, for the most part, any meaningful quantitative synthesis of the data; what follows is a largely qualitative review of the evidence relevant to this recommendation.

Despite the overall predominance of Class III data, the 13 studies presented in evidentiary Tables 1^10-16 and 2^17-22 are quite suggestive of the notion that in the management of CSF shunt infection, supplementation of antibiotic treatment with partial (externalization) or complete shunt hardware removal should be considered. Two Class II studies provide particularly compelling evidence in favor of a combined medical and surgical management of CSF shunt infection, and deserve to be elaborated on further.

In 1980, James et al¹⁹ published the results of a moderate-quality randomized controlled trial in which 10 patients with evidence of CSF shunt infection were randomized to each of 3 different treatment arms: 1) complete shunt removal, systemic antibiotics, and either external ventricular drainage or ventricular taps for decompression and intrathecal antibiotic administration, with delayed shunt replacement; 2) complete shunt removal and immediate shunt replacement with intrashunt and systemic antibiotics; or 3) intrashunt and systemic antibiotics without shunt removal. The outcome was negative ventricular CSF cultures 48 hours after cessation of antibiotic therapy and again within 4 months of completion of therapy. All 10 patients who underwent complete shunt removal, systemic antibiotics, and either external ventricular drainage or ventricular taps for decompression and intrathecal antibiotic administration were successfully treated. Nine of 10 patients treated with complete shunt removal and immediate shunt replacement with intrashunt and systemic antibiotics achieved therapeutic trast, only 3 of 10 patients who received systemic and intrathecal antibiotics without shunt removal were successfully treated. The treatment results in this latter group rather clearly demonstrate that shunt removal, rather than antibiotic therapy (including intrathecal therapy), was responsible for the improved outcomes seen in the comparison groups. Secondary outcomes also were consistent with a benefit toward surgical removal of the shunt, as length of hospital stay was lowest in those patients who underwent complete shunt removal with delayed shunt re placement after a course of systemic and intrathecal antibiotics. The only deaths occurred in those patients who received medical management alone. Because of the convincing inferiority of medical management alone, further randomization to this group was halted, but the study was continued as a prospective nonrandomized comparison of treatment outcomes between those patients receiving intrathecal and systemic antibiotics in conjunction with complete shunt removal and delayed versus immediate shunt replacement.¹⁸ The principal conclusions remain unchanged.

Fig. 2a. Flowchart showing the process involved in identifying relevant literature

Fig. 2b. Flowchart showing the process involved in identifying relevant literature for the 2020 Update. The criteria for “records excluded” and “full text articles excluded with reasons” are detailed in Part 1 of the Guidelines.

The nearly equivalent treatment outcomes of shunt removal followed by immediate shunt replacement (that is, shunt replacement in infected CSF) versus delayed shunt replacement (that is, shunt replacement after the CSF has been sterilized) in the aforementioned studies by James and colleagues^18,19 was suggestive of the potential utility of intrathecal antibiotics in those clinical circumstances in which the shunt must be removed and immediately replaced. As such, these studies provide some evidence applicable to the intrathecal antibiotic recommendation as well. As outlined earlier, it appears that most of the treatment effect comes from shunt removal, making the relative contribution of intrathecal antibiotics to improved outcomes in this scenario rather uncertain. Hence, elevating the recommendation for intrathecal antibiotics to a Level II recommendation, based on these relatively high quality data alone, appears unwarranted.

Additional evidence pertaining to the intrathecal antibiotic recommendation comes largely from  Class III studies that examined the results of treatment of ventricular shunt infection in those clinical circumstances  in which the infected shunt components are not removed (Table 2)^17-22 or only partially removed (that is, externalized) (Table 3)^23-26. There was a Class III study that documented a fairly large proportion of patients who achieved therapeutic success—comparable to the success seen in patients who underwent shunt removal—when the patients were treated with intrathecal antibiotics but their shunts were left in situ.16 In addition, Bayston and Rickwood¹⁷ documented eradication of staphylococcal VA or VP shunt infection in 5 of 43 patients who underwent antibiotic treatment alone; 4 of the 5 patients who were successfully treated received intrathecal antibiotics. In cases in which ventricular shunt infection was treated with systemic and intrathecal antibiotics along with shunt externalization, either because of the complexity of the shunt infection scenario (for example, multiloculated hydrocephalus) or surgeon preference, a prospective non-randomized study by James and Bradley²⁴ and a Class III study by Arnell et al²³ were both able to demonstrate positive treatment outcomes in all patients in their respective case series. Finally, another retrospective case series by James and Bradley²⁷ showed convincingly high cure rates with a significantly shorter length of stay in those patients with an uncomplicated shunt infection (that is, a single shunt system) treated with complete shunt removal together with systemic and intrathecal antibiotics (Table 4). Unfortunately, the absence of a concurrent control group treated with shunt removal and systemic antibiotics alone in this and other studies listed in Table 4 limits the impact of these data to the overall body of evidence.

When examining the studies presented in evidence in Table 3^23-26 and Table 4^27-36 it is difficult to say with any degree of clinical certainty whether complete shunt removal leads to better shunt infection treatment outcomes than partial shunt removal. This is due, in part, to the paucity of outcome data comparing the 2 treatment options within the same study population, but also to the confounding effect of intrathecal antibiotic therapy, as described above.

After a full-text review of the contents of papers that were initially identified through our search strategy or our scrutiny of reference lists, predefined criteria led to the exclusion of multiple studies from the evidentiary tables. The recommendations provided above are not materially changed by the exclusion of these studies.

2020 Update

After examining these additional abstracts, two full text articles were assessed for their potential inclusion into the evidence tables.  Yakut et al³⁷ was excluded because there was non-consecutive enrollment of patients, and a study by von der Brelie et al³⁸ did not meet inclusion criteria as pediatric patients represented less than 80% of the overall cohort that was reported. 

Conclusions

Recommendation: Supplementation of antibiotic treatment with partial (externalization) or with complete shunt hardware removal is an option in the management of CSF shunt infection. Strength of Recommendation: Level II, moderate degree of clinical certainty.

Recommendation: There is insufficient evidence to recommend either shunt externalization or complete shunt removal as a preferred surgical strategy for the management of CSF shunt infection. Therefore, clinical judgment is required. Strength of Recommendation: Level III, unclear degree of clinical certainty.

Recommendation: There is insufficient evidence to recommend the combination of intrathecal and systemic antibiotics for patients with CSF shunt infection in whom the infected shunt hardware cannot be fully removed or must be removed and immediately replaced, or when the CSF shunt infection is caused by specific organisms. The potential neurotoxicity of intrathecal antibiotic therapy may limit its routine use. Strength of Recommendation: Level III, unclear degree of clinical certainty.

It appears that the optimal management of CSF shunt infection requires a multimodality approach. Re- view and critical appraisal of the available evidence regarding the management of ventricular shunt infection allow for a recommendation for the supplementation of antibiotic treatment with partial (externalization) or complete shunt hardware removal with a moderate degree of clinical certainty. However, a recommendation regarding whether complete shunt removal is favored over partial shunt removal (that is, externalization) cannot be made, owing to severe methodological deficiencies in the existing literature. Furthermore, there is insufficient evidence to recommend the use of intrathecal antibiotic therapy as an adjunct to systemic antibiotic therapy in the management of routine CSF shunt infections, or in other clinical scenarios, such as when an infected CSF shunt cannot be completely removed, must be removed and immediately replaced in the face of ongoing CSF infection, or in the setting of ventricular shunt infection caused by specific organisms (for example, gram-negative bacteria).

Deficiencies in the existing literature regarding the management of CSF shunt infection provide a strong rationale for further prospective research into the subject. Key questions that remain unanswered include, but are certainly not limited to the following:

• Defining the optimal duration of antibiotic therapy in the management of CSF shunt infection, with the aim of simultaneously maximizing the probability of successful treatment without reinfection or relapse, and minimizing the length of hospital stay and over-all cost to the health care system
• Refining the indications for intrathecal antibiotic therapy and ascertaining the risk/benefit profile of such therapy (potential adverse effects vs potential reduction in relapse/reinfection rates and shorter hospital stays).
• Definition and validation of standardized treatment outcome measures, based on microbiological or other biomarker-based criteria. This would not only facilitate a comparison of results across studies, but also potentially yield objective criteria that facilitate decision making in other contentious areas of CSF shunt infection management, such as the optimal timing of shunt reimplantation.

Perhaps the best strategy to treat ventricular shunt infection is to continue our focus on the prevention of this significant complication of CSF shunt therapy.

Based on the assessments made in the 2020 update, the authors concluded that no new literature exists to support any change or revision to the current guideline.

Acknowledgments

We acknowledge the American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Guidelines Committee for the members’ reviews, comments, and suggestions; Laura Mitchell, Guidelines Project Manager for the CNS, for her contributions; Pamela Shaw, research librarian, for her assistance with the literature searches; Kevin Boyer for his assistance with data analysis; and Sue Ann Kawecki for her assistance with editing. We also acknowledge the following peer reviewers for their contributions to review the update to the guidelines: Jennifer Sweet, MD, Brandon Rocque, MD, Christoph Greissenauer, MD, Jeffrey Olson, MD.

Disclosure

The systematic review and evidence-based guidelines were funded exclusively by the CNS and AANS Pediatric Section, which received no funding from outside commercial sources to support the development of this document.

Conflict(s) of Interest: None. All members of the Pediatric Hydrocephalus Systematic Review and Evidence-Based Guidelines Task Force declared any potential conflicts of interest prior to beginning work on this evidence review.

Conflict(s) of Interest: None. All Pediatric Hydrocephalus Systematic Review and Evidence-Based Guidelines Update Task Force members declared any potential conflicts of interest prior to beginning work on this systematic review and evidence-based guidelines.

Author contributions to the study and manuscript preparation include the following. Conception and design: AANS/CNS Joint Section on Pediatrics. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Tamber. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Flannery. Administrative/technical/material support: all authors. Study supervision: Flannery.

Evidence Tables

Table 2. Systemic and Intrathecal Antibiotic Treatment with Shunt Left In Situ or Removed and Immediately Replaced

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