Upload
others
View
8
Download
0
Embed Size (px)
Citation preview
J Neurosurg Pediatrics 8:000–000, 2011
600 J Neurosurg: Pediatrics / Volume 8 / December 2011
HydrocepHalus is one of the most common prob-lems faced by neurosurgeons. Despite the appli-cation of endoscopic procedures for treatment,
most adults and children with hydrocephalus will require the implantation of a permanent CSF diversion device. Shunts have been used since the 1950s but continue to be plagued with complications, including infection. The rate of infection generally ranges from 5% to 15% but can be much higher in certain patient subgroups, such as neo-nates with posthemorrhagic hydrocephalus.15,17,21,32,42,56 Shunt infection comes with obvious undesirable burdens to the patient, family, neurosurgeon, other health care providers, and the health care system, with both short- and long-term consequences. Infection often causes shunt
J Neurosurg Pediatrics 8:600–612, 2011
Antibiotic-impregnated shunt systems versus standard shunt systems: a meta- and cost-savings analysis
Clinical article
Paul Klimo Jr., m.D., m.P.H.,1–3 Clinton J. tHomPson, m.s.,4 Brian t. ragel, m.D.,5 anD FreDeriCK a. BooP, m.D.1–3
1Semmes-Murphey Neurologic & Spine Institute; 2Department of Neurosurgery, University of Tennessee Health Science Center; 3St. Jude Children’s Research Hospital, Memphis, Tennessee; 4School of Public Health and Health Services, George Washington University, Washington, DC; and 5Department of Neurosurgery, Oregon Health & Science University, Portland, Oregon
Object. Infection is a serious and costly complication of CSF shunt implantation. Antibiotic-impregnated shunts (AISs) were introduced almost 10 years ago, but reports on their ability to decrease the infection rate have been mixed. The authors conducted a meta-analysis assessing the extent to which AISs reduce the rate of shunt infection compared with standard shunts (SSs). They also examined cost savings to determine the degree to which AISs could decrease infection-related hospital expenses.
Methods. After conducting a comprehensive search of multiple electronic databases to identify studies that evaluated shunt type and used shunt-related infection as the primary outcome, 2 reviewers independently evaluated study quality based on preestablished criteria and extracted data. A random effects meta-analysis of eligible studies was then performed. For studies that demonstrated a positive effect with the AIS, a cost-savings analysis was con-ducted by calculating the number of implanted shunts needed to prevent a shunt infection, assuming an additional cost of $400 per AIS system and $50,000 to treat a shunt infection.
Results. Thirteen prospective or retrospective controlled cohort studies provided Level III evidence, and 1 pro-spective randomized study provided Level II evidence. “Shunt infection” was generally uniformly defined among the studies, but the availability and detail of baseline demographic data for the control (SS) and treatment (AIS) groups within each study were variable. There were 390 infections (7.0%) in 5582 procedures in the control group and 120 infections (3.5%) in 3467 operations in the treatment group, yielding a pooled absolute risk reduction (ARR) and relative risk reduction (RRR) of 3.5% and 50%, respectively. The meta-analysis revealed the AIS to be statistically protective in all studies (risk ratio = 0.46, 95% CI 0.33–0.63) and in single-institution studies (risk ratio = 0.38, 95% CI 0.25–0.58). There was some evidence of heterogeneity when studies were analyzed together (p = 0.093), but this heterogeneity was reduced when the studies were analyzed separately as single institution versus multiinstitutional (p > 0.10 for both groups). Seven studies showed the AIS to be statistically protective against infection with an ARR and RRR ranging from 1.7% to 14.2% and 34% to 84%, respectively. The number of shunt operations requiring an AIS to prevent 1 shunt infection ranged from 7 to 59. Assuming 200 shunt cases per year, the annual savings for converting from SSs to AISs ranged from $90,000 to over $1.3 million.
Conclusions. While the authors recognized the inherent limitations in the quality and quantity of data available in the literature, this meta-analysis revealed a significant protective benefit with AIS systems, which translated into substantial hospital savings despite the added cost of an AIS. Using previously developed guidelines on treatment, the authors strongly encourage the use of AISs in all patients with hydrocephalus who require a shunt, particularly those at greatest risk for infection. (DOI: 10.3171/2011.8.PEDS11346)
Key WorDs • antibiotic • cerebrospinal fluid shunt • infection • meta-analysis
Abbreviations used in this paper: ACC = American College of Cardiology; AHA = American Heart Association; AIS = anti-biotic-impregnated shunt; ARR = absolute risk reduction; ATS = American Thoracic Society; EVD = external ventricular drain; GRADE = Grades of Recommendation, Assessment, Development, and Evaluation; NNT = number needed to treat; RR = risk ratio; RRR = relative risk reduction; SS = standard shunt.
J Neurosurg: Pediatrics / Volume 8 / December 2011
Meta-analysis of shunt systems
601
malfunction, placing the patient at risk for the potential consequences. It can also lead to scarring and loculation of the ventricles, making the patient’s hydrocephalus more complex, and may result in a lower IQ, an increased risk of seizures, and psychomotor retardation.13,36,44,69,71 Furthermore, the purported cost of treating a shunt in-fection is upward of $50,000 in the US, making it one of the most costly implant-related infections.18 As such, the prevention of shunt infection should be paramount. A shunt-related infection, by definition, is any infection associated with the implantation of a shunt, with the most serious in terms of potential morbidity and mortality be-ing infected CSF or ventriculitis. A wide range of prac-tices has been designed to prevent shunt infection,30 and rigid adherence to a shunt surgery protocol has repeatedly been shown to decrease shunt infection rates.14,40,41,49,55
The most common pathogens in shunt infections are gram-positive skin organisms acquired at the time of sur-gery, namely Staphylococcus epidermidis and S. aureus. Although antibiotic-impregnated silastic catheters were first introduced by Roger Bayston in 1977 and then were considered more specifically with shunts in 1989,10 these devices did not become available for clinical use until about 10 years ago. The first, and still the only available, AIS was introduced in 2002. This AIS is impregnated with 0.054% rifampin and 0.15% clindamycin (Bactiseal, Codman, Johnson & Johnson). Although it does not re-duce bacterial adherence, this combination of antibiotics kills bacteria and thus prevents colonization by the most common pathogens for up to 56 days in in vitro studies and up to 127 days in vivo.9,11,46 The AIS has also been shown to be nonepileptogenic.1
Since the introduction of the AIS, there have been a number of studies evaluating its effectiveness compared with SSs. Some investigators have shown that the use of AISs decreases the risk of shunt infection, but oth-ers have not. Our primary objective in the present study was to combine data from existing studies to maximize their power to determine whether a difference in shunt infection rates truly exists, that is, to minimize the chance of incorrectly concluding that there is no difference. Secondly, in this era of escalating health care expendi-tures, we believe it is important to present cost-savings data on AIS systems. We hope to clarify whether AISs can lower the infection risk and identify the added costs and potential savings, so that surgeons can best determine whether it is clinically and economically indicated to use the AIS at their institutions.
MethodsSearch Strategy
Our systematic search strategy involved an electronic database search, a manual search of journals, examina-tion of bibliographies of relevant articles, and consulta-tion with the senior author (F.A.B.). We electronically searched MEDLINE (via NLM Gateway), PubMed, The Cochrane Library, Web of Knowledge, and Scopus to find English-language articles published from January 2000 to April 2011 while using the following terms in various
combinations: “antibiotic-impregnated,” “shunt,” “cathe-ter,” “system,” “infection,” and “hydrocephalus.” Articles were also searched using the “Related Articles” function on PubMed and by reviewing the references from articles identified in the aforementioned searches. We excluded so-called grey literature, such as conference proceedings, abstracts, and trial registries.
Inclusion Criteria, Data Extraction, End Points, and Definitions
The goal of the search strategy was to identify stud-ies published in the English language that satisfied the following criteria: 1) the study had a group of patients (adult or pediatric) that was treated with an AIS (treat-ment group); 2) the study had a group of patients (adult or pediatric) that was treated with an SS (control group); 3) the chosen implanted shunt system represented the only intentional treatment difference between the 2 patient groups (that is, no other changes were indicated, such as a difference in surgical technique); and 4) the minimum data included the total number of procedures performed in each group (treatment and control) and the number of shunt infections. Studies were excluded if they contained data that had been previously published (duplicated data) or if the authors used an AIS system other than the Codman Bactiseal system.
Two individuals (P.K. and B.T.R.) independently screened all potential articles and extracted data from eligible articles. For all studies, we collected the follow-ing data (for the AIS and SS groups) if available, in ad-dition to what was stated in the inclusion criteria above: study type, study population, number of patients, number of patients younger than 1 year, number of shunt opera-tions, average age, age range, initial or revision operation, recent shunt infection (usually within the last 6 months), type of hydrocephalus (communicating, obstructive, or unclear), and cause of hydrocephalus (congenital; post-hemorrhagic, including postsubarachnoid hemorrhage and germinal matrix hemorrhage of prematurity; spina bifida; normal pressure hydrocephalus; posttraumatic; tu-mor; and postmeningitic).
Although the primary outcome for the purpose of this meta-analysis was shunt infection, its definition was, of course, determined by the authors of the studies that met our entry criteria. In general, a CSF shunt/catheter-related infection was present if a patient had signs and symptoms of shunt malfunction or infection with an or-ganism cultured from the CSF, shunt apparatus, purulence from the shunt wound(s), or abdominal fluid/pseudocyst. Some investigators also included patients in whom the clinical suspicion was very high (for example, raised CSF white blood cell count, clinical improvement after shunt removal, and treatment with antibiotic therapy) but posi-tive CSF cultures were lacking.33,38 The shunt infection rate was calculated per procedure, rather than per patient, for 2 reasons. First, we judged that it was more clinically relevant because some patients undergo multiple shunt re-visions, and second, in some studies, the total number of patients was not provided.
Each study that met our inclusion criteria was careful-ly reviewed independently, and the authors’ conclusions
P. Klimo Jr. et al.
602 J Neurosurg: Pediatrics / Volume 8 / December 2011
were verified based on the data provided. Disagreements in study selection and data abstraction were resolved through discussion. The quality of the evidence provided in each study was then graded I–IV (Table 1).4 We used 2 classification systems to grade the strength of our recom-mendations on the use of AISs based on the results of our meta-analysis (Tables 2 and 3).58,68
The Meta-AnalysisFor each study, we identified the number of infections
resulting from SSs and AISs and then computed the risk of an infection with the AIS relative to the SS, yielding an RR. An RR < 1 indicates protection against infection with the AIS. The overall risk ratio was computed using the method of DerSimonian and Laird.20
We conducted a random effects meta-analysis of the selected studies. A random effects model—as opposed to a fixed effects model—does not assume that the measure of association (that is, the RR) is uniform across strata (that is, among studies) and consequently yields a more conserva-tive estimate of the effect. We assessed heterogeneity us-ing the chi-square test of heterogeneity and the I2 statistic, where the former returns a chi-square distributed test sta-tistic and corresponding p value and the latter returns a value bound between 0% and 100%, with higher values de-noting increasing heterogeneity. We regarded a chi-square test of heterogeneity p value less than α = 0.10 and an I2 value in the range of 30%–60% as suggestive of moderate heterogeneity.16,19 To examine the source of heterogeneity, we categorized the studies based on their institutional sta-tus (single vs multiinstitutional) and analyzed each group separately (sensitivity analysis). We hypothesized that this stratification would account for some of the observed het-erogeneity. We initially excluded studies that presented pooled data from multiple institutions because we judged that single-institution data were “cleaner,” that is, any dif-ference in the infection rate between the treatment and control groups was more likely a result of the intervention (switching from an SS to an AIS) than a result of any one or more of the large number of variables that could posi-tively or negatively affect the primary outcome (that is, confounders). Nonetheless, we reasoned that the data from the multiinstitutional studies were important enough to be
included, although we elected to analyze them separately (see Results). We also assessed the presence of publication bias via a funnel plot.22,66,67 All statistical analysis was con-ducted using Stata/SE 11.2 software.
The Cost-Benefit AnalysisFor each study in which a statistically significant re-
duced infection rate was demonstrated for the AIS, we calculated an ARR and RRR. The number of AISs that would need to be implanted to prevent 1 shunt infection, or the number needed to treat (NNT), was calculated for each study as the inverse of the ARR. We then calculated the cost of preventing 1 shunt infection as the NNT mul-tiplied by the additional cost of an AIS system, which is approximately $400. Next, assuming a cost of $50,000 to a treat shunt infection, we calculated the savings per NNT and the savings per annum, assuming that the institution performs 200 shunt operations per year.
ResultsThe initial search strategy identified 22 studies, but
several articles were disqualified from analysis. Izci et al.34 used a silver-impregnated polyurethane ventricular catheter that has not been evaluated by others and is not commercially available in the US. Two groups of authors presented similar data in multiple publications; we chose the publication that provided the most detailed data. The group from Johns Hopkins University has published at least 8 studies that detail their experience with AIS over different but overlapping time periods.8,26,27,45,59–62 Two publications were selected for this analysis because they had a large number of patients over extended time peri-ods, with each study focusing on pediatric or adult pa-tients only.26,45 Likewise, Eymann and colleagues24,25 had 2 publications with shared data, and the one used for this meta-analysis was selected because it included both adult and pediatric patients and also had a cost-benefit analysis. Thus, 14 studies met our inclusion criteria. 2,7,24,26,29,31,33,37,
38,45,47,53,54,65 Note, however, that the study by Eymann et al.24 had separate data for adult and pediatric patients, and thus each population was analyzed and listed separately.
TABLE 1: Levels for classification of evidence
Level Definition
I prospective, randomized, controlled clinical trial w/ masked outcome assessment in representative population; requires clearly defined primary outcome(s), clearly defined exclusion/inclusion criteria, adequate accounting for dropouts & crossovers w/ numbers sufficiently low to have minimal potential for bias, & relevant baseline characteristics presented & substantially equivalent among treatment groups or appropriate statistical adjustment for differences
II prospective matched group cohort study in representative population w/ masked outcome assessment that meets re- quirements listed above OR a randomized controlled trial in representative population that lacks 1 of the criterion listed above
III all other controlled trials including well-defined natural history controls or patients serving as own controls in representa- tive population in which outcome assessment is independently assessed or independently derived by objective out- come measures (that is, an outcome measure that is unlikely to be affected by an observer’s (patient, treating physi- cian, or investigator) expectation or bias (for example, blood tests or administrative outcome data)
IV evidence from uncontrolled studies, case series, case reports, or expert opinion
J Neurosurg: Pediatrics / Volume 8 / December 2011
Meta-analysis of shunt systems
603
Characteristics of Eligible StudiesThere were 2 prospective studies (1 controlled cohort
and 1 randomized), 2 ambidirectional cohort studies (data collected both retro- and prospectively), and 10 retrospec-tive cohort studies (Table 4). Eleven studies involved pa-tients from a single institution, and 3 studies included data from multiple institutions. Two of these multiinstitutional studies were from the United Kingdom. Although the study by Richards et al.53 used data from the UK Shunt Registry in which “all major neurosurgery centers” in the British Isles contribute, we could not confidently assume that the data from the 3 neurosurgery units presented in the Kandasamy et al.38 study were also used in the Richards et al. study. Furthermore, Kandasamy et al. only reported on pediatric patients. Therefore, it was decided
to include both studies. Seven studies contained both adult and pediatric patients, 5 had just pediatric patients, and 2 had only adults. All studies except 1 were graded as having Level III data. The study by Govender et al.29 was a prospective randomized trial but was downgraded to Level II data quality because of serious methodological and data interpretation flaws, including the lack of clearly defined primary outcome and demographic data for the treatment and control groups (see Discussion). The demo-graphic data for patients in the SS and AIS groups within each study are detailed in Tables 5 and 6.Tests for Evidence of Publication Bias
There is a trend toward a modest publication bias in our analysis, although this bias was not statistically sig-nificant (p = 0.103). The absence of studies in the lower
TABLE 2: Strength of recommendation used by ACC and AHA
Class Definition
I conditions for which there is evidence &/or general agreement that given procedure or treatment is useful & effectiveII conditions for which there is conflicting evidence &/or divergence of opinion about usefulness/efficacy of procedure or
treatment a weight of evidence/opinion in favor of usefulness/efficacy b usefulness/efficacy less well established by evidence/opinionIII conditions for which there is evidence &/or general agreement that the procedure/treatment is not useful/effective & in
some cases may be harmful
TABLE 3: Strength of recommendation used by the ATS and the GRADE system
Grade of Recommendation Clarity of Risk/Benefit Implications
strong recommendation w/ benefit clearly outweighs harms & burdens or vice versa
high-quality evidence recommendation can apply to most patients in most circumstances; further research very unlikely to change confidence in estimate of effect
moderate-quality evidence recommendation can apply to most patients in most circumstances; further research (if performed) likely to have important impact on our confidence in estimate & may change estimate
low-quality evidence recommendation may change when higher-quality evidence becomes avail- able; further research (if performed) likely to have important impact on confidence in estimate & may change estimate
very-low-quality evidence recommendation may change when higher-quality evidence becomes avail- able; any estimate of effect, for at least 1 critical outcome, very uncertain
weak recommendation w/ high-quality evidence benefits closely balanced w/ harms &
burdensbest action may differ depending on circumstances or patients or societal values; further research very unlikely to change confidence in estimate of effect
moderate-quality evidence benefits closely balanced w/ harms & burdens
alternative approaches likely better for some patients under some circum- stances; further research (if performed) likely to have important impact on confidence in estimate of effect & may change estimate
low-quality evidence uncertainty in estimates of benefits, harms, & burdens; benefits may be closely balanced w/ harms & burdens
other alternatives may be equally reasonable; any estimate of effect, for at least 1 critical outcome, very uncertain
very-low-quality evidence major uncertainty in estimates of bene- fits, harms, & burdens; benefits may or may not be balanced w/ harms & burdens
other alternatives may be equally reasonable; any estimate of effect, for at least 1 critical outcome, very uncertain
P. Klimo Jr. et al.
604 J Neurosurg: Pediatrics / Volume 8 / December 2011
right quadrant of the funnel plot (Fig. 1) indicates that small, negative studies have not been published and thus are not included in this meta-analysis.
Meta-Analysis: Shunt Infection and Sensitivity AnalysisAmong the 14 studies, 7 showed AISs to be protective
in preventing a shunt malfunction and 7 documented no statistical benefit (Table 7). There were 5582 procedures involving a standard catheter system and 390 infections, yielding a pooled infection rate of 7.0%. In the population receiving AISs, there were 120 infections among 3467 shunt operations, for an overall infection rate of 3.5%.
When analyzing only the single-institution studies (12 study populations), the overall RR was 0.38 (95% CI 0.25–0.58, p < 0.001; Fig. 2). In other words, a shunt in-fection was 2.63 times more likely when using an SS than an AIS. If all studies were included (15 studies, includ-ing both data sets from Eymann et al.24), then the over-all RR was 0.46 (95% CI 0.33–0.63, p < 0.001), making shunt infection 2.18 times more likely with an SS system. There was evidence of some heterogeneity when all of the studies were analyzed together (Q = 21.33, df = 14, p = 0.093), but when we examined the studies according to their institutional status, the heterogeneity was reduced to statistically nonsignificant levels (p > 0.10 for both single- and multiinstitutional studies). The stratification of our analysis—a sensitivity analysis according to study institutional status—indicated that the observed hetero-geneity was partially explained by institutional status. Furthermore, the I2 statistic decreased from 34.4% for all studies to 29.0% for single-institution studies, suggest-ing that the institutional status accounted for some of the overall heterogeneity, with the remaining heterogeneity attributable to differences between the single-institution studies. Our recommendation on the use of AISs is strong evidence with low- to moderate-quality evidence based on the GRADE system/ATS guidelines and Class IIa evi-dence based on the ACC/AHA guidelines.
Cost-Savings AnalysisAs the difference in infection rates between patients
who had an SS and those who had an AIS increases, the NNT to prevent 1 shunt infection consequently decreases (Table 8). For example, the study by Gutiérrez-González et al.31 showed a decrease in the infection rate from 17% to 2.8%, yielding an NNT of 7. A lower NNT translates into a lower additional cost for switching to the AIS (as-suming an additional hospital cost of $400 per AIS kit). Assuming a cost of $50,000 to treat a shunt infection, the cost savings per shunt infection prevented for the various studies is shown in Table 8. The estimated annual sav-ings, assuming 200 shunt operations performed, ranges from just under $90,000 to well over $1.3 million.
DiscussionLiterature Review
Of the 14 studies that satisfied our inclusion and ex-clusion criteria, 7 revealed AISs to be statistically protec-tive,24,26,31,38,45,47,53 whereas 7 did not.2,7,29,33,37,54,65 Among the studies with negative statistical findings, one2 had such a small number of patients (18 patients, 6 with AISs) that no conclusion could be made, although the authors believed that the “AIS could be effective.” The authors of 2 studies29,33 made somewhat misleading comments in their respective abstracts that required us to classify them as finding no benefit with the AIS. Hayhurst et al.33 stated that “AIS catheters can reduce the number of shunt infections” and “had a significant impact on the neona-tal hydrocephalic population,” when in fact their results showed no difference in the shunt infection rate overall and within any subgroup, including neonates. Proponents of AISs have given much credence to the prospective randomized trial by Govender et al.29 These authors pro-vided a definition of shunt infection, even differentiating between an “internal” and an “external” infection, and described their inclusion and exclusion criteria, surgical
TABLE 4: Summary of studies used in meta-analysis
Authors & Year Study Design Study Population Study SiteData Level
Farber et al., 2011 retrospective adult single institution IIISteinbock et al., 2010 prospective pediatric + adult multiinstitutional, multinational IIIGutiérrez-González et al., 2010 retrospective pediatric + adult single institution IIIKandasamy et al., 2011 ambispective pediatric multiinstitutional, uninational IIIRichards et al., 2009 retrospective matched pair pediatric + adult multiinstitutional, uninational IIIParker et al., 2009 retrospective pediatric single institution IIIAlbanese et al., 2009 retrospective adult single institution III Eymann et al., 2008 retrospective pediatric + adult single institution IIIHayhurst et al., 2008 retrospective pediatric single institution IIIPattavilakom et al., 2007 ambispective pediatric + adult single institution IIIRitz et al., 2007 retrospective pediatric + adult single institution IIIKan & Kestle, 2007 retrospective pediatric single institution IIIAryan et al., 2005 retrospective pediatric single institution IIIGovender et al., 2003 prospective, randomized, blinded pediatric + adult single institution II
J Neurosurg: Pediatrics / Volume 8 / December 2011
Meta-analysis of shunt systems
605
TABL
E 5:
Cha
ract
eris
tics o
f pat
ient
s who
rece
ived
an S
S*
Pt A
geSe
x (no
.)No
. of S
hunt
Proc
edur
es
Type
of H
ydro
ceph
alus
(no.)
Etiol
ogy o
f Hyd
roce
phalu
s (no
.)
Auth
ors &
Yea
r
No.
of
Pts
No. o
f Sh
unt
Ops
Mea
n (y
rs)No
. <1
Yr
Rang
e M
FIn
itial
Revi-
sio
n
No. o
f Prio
r Sh
unt
Infec
tions
Non-
comm
Comm
Un-
clear
Cong
en-
ital
PHH
Spina
Bi
fida
NPH
Tumo
rTr
auma
Men
in-
gitis
Farb
er et
al., 2
011
250
250
61NA
NANA
NA18
070
2NA
NANA
NANA
NA19
5NA
NANA
Stein
bock
et al
., 201
0 38
738
732
.821
NANA
NANA
NANA
NANA
NA5
9534
1912
123
14Gu
tiérre
z-Go
nzále
z
et al.
, 201
047
47NA
8†NA
3017
2720
10NA
NANA
NA8
NA16
6 0
NA
Kand
asam
y et a
l., 20
11NA
1963
465
NA1 d
–16 y
rsNA
NA79
811
65NA
NANA
NANA
NANA
NANA
NANA
Rich
ards
et al
., 200
999
499
4NA
NANA
501
493
780
214
NANA
NANA
4929
768
8529
531
74Pa
rker e
t al.,
2009
NA57
06.4
NA1 d
–20 y
rs31
425
615
741
3NA
281
289
021
511
592
047
NA36
Alba
nese
et al
., 200
912
1261
.30
44–7
9 yrs
57
120
02
100
010
00
2 0
0Ey
mann
et al
., 200
8‡98
9870
028
–85 y
rs50
48NA
NANA
871
19NA
NANA
71NA
NANA
Eyma
nn et
al., 2
008‡
2222
1.5NA
1 d–7
2 mos
1111
NANA
NANA
NANA
85
20
5NA
NAHa
yhur
st et
al., 2
008
6577
NA11
NANA
NA30
47NA
NANA
NANA
NANA
0NA
NANA
Patta
vilak
om et
al.,
20
07NA
551
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
Ritz
et al.
, 200
717
240
842
.4NA
NA77
95NA
NANA
50/17
211
4/172
8/172
NANA
NANA
NANA
NAKa
n & K
estle
, 200
765
806.
818
NA40
25NA
NA8
NANA
NA15
2712
0NA
NANA
Arya
n et a
l., 20
05NA
46NA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NAGo
vend
er et
al., 2
003
6077
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
* Co
mm =
comm
unica
ting;
d = da
y; NA
= no
t ava
ilable
; Non
comm
= no
ncom
munic
ating
; NPH
= no
rmal
pres
sure
hydr
ocep
halus
; PHH
= po
sthem
orrh
agic
hydr
ocep
halus
; Pt =
patie
nt.†
Less
than
or eq
ual to
6 mo
nths o
f age
.‡
Data
are f
rom
a sing
le pa
per, b
ut th
e aut
hors
analy
zed p
ediat
ric an
d adu
lt pati
ents
sepa
ratel
y, an
d so t
he da
ta ar
e list
ed se
para
tely.
P. Klimo Jr. et al.
606 J Neurosurg: Pediatrics / Volume 8 / December 2011
TABL
E 6:
Cha
ract
eris
tics o
f pat
ient
s who
rece
ived
an A
IS
Pt A
geSe
x (no
.)No
. of S
hunt
Proc
edur
es
Type
of H
ydro
ceph
alus
(no.)
Etiol
ogy o
f Hyd
roce
phalu
s (no
.)
Auth
ors &
Yea
r
No.
of Pts
No. o
f Sh
unt
Ops
Mea
n (y
rs)No
. <1
Yr
Rang
eM
FIn
itial
Revi-
sio
n
No. o
f Prio
r Sh
unt
Infec
tions
Non-
co
mmCo
mmUn
clear
Cong
en-
ital
PHH
Spina
Bi
fida
NPH
Tumo
rTr
auma
Men
in-
gitis
Farb
er et
al., 2
011
250
250
60NA
NANA
NA19
654
1NA
NANA
NANA
NA18
3NA
NANA
Stein
bock
et al
.,
2010
4646
18.3
16NA
NANA
NANA
NANA
NANA
NA17
21
70
0
Gutié
rrez-
Gonz
ález
et
al., 2
010
7272
NA6*
NA38
3455
1716
NANA
NANA
12NA
1721
4NA
Kand
asam
y et a
l.,
20
1148
758
1NA
153
1 d–1
6 yrs
NANA
218
363
NANA
NANA
NANA
NANA
NANA
NA
Rich
ards
et al
., 200
999
499
4NA
NANA
501
493
780
214
NANA
NANA
4929
768
8529
531
74Pa
rker e
t al.,
2009
NA50
26.7
NA1 d
–19.8
yrs
267
235
142
360
NA25
025
2 0
175
159
640
30NA
32Al
bane
se et
al.,
20
096
662
.80
40–7
7 yrs
33
60
00
6 0
06
00
00
0
Eyma
nn et
al.,
20
08†
171
171
71.3
033
–84 y
rs97
74NA
NANA
813
528
NANA
NA13
5NA
NANA
Eyma
nn et
al.,
20
08†
2626
1.1NA
0.03–
84 m
os11
15NA
NANA
NANA
NA13
108
02
NANA
Hayh
urst
et al.
,
2008
150
214
NA33
1 d–1
6 yrs
NANA
4716
7NA
NANA
NANA
NANA
0NA
NANA
Patta
vilak
om et
al.,
20
0717
824
3NA
23NA
NANA
123
120
NANA
NANA
53/17
833
/178
0/178
14/17
839
NA4
Ritz
et al.
, 200
786
190
32.8
NANA
3749
NANA
NA17
/86
68/8
61/8
6NA
NANA
NANA
NANA
Kan &
Kes
tle, 2
007
6480
7.922
NA35
29NA
NA16
NANA
NA26
1616
0NA
NANA
Arya
n et a
l., 20
0531
324.5
NA6 m
os–1
7 yrs
NANA
1121
NANA
NANA
NANA
NANA
NANA
NAGo
vend
er et
al.,
20
0350
60NA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NANA
NA
* Le
ss th
an or
equa
l to 6
month
s of a
ge.
† Da
ta ar
e fro
m a s
ingle
pape
r, but
the a
utho
rs an
alyze
d ped
iatric
and a
dult p
atien
ts se
para
tely,
and s
o the
data
are l
isted
sepa
ratel
y.
J Neurosurg: Pediatrics / Volume 8 / December 2011
Meta-analysis of shunt systems
607
procedure, sample size calculation, and follow-up proto-col. Nevertheless, their study suffered from a number of critical flaws. The investigators failed to provide a clear definition of their primary end point; they did not discuss the method of randomization and whether any known shunt infection risk factors, such as prematurity, would be controlled for in the randomization process or data analy-sis; and they did not provide the demographic makeup of the treatment or control groups to demonstrate whether they were balanced. They focused their conclusion on their finding of a decreased shunt infection rate in the first 2 months in the AIS group, but the overall shunt infection rate, which we believe is more clinically relevant, was
not statistically different between the AIS (5%) and SS (13.3%) groups. Furthermore, this study was conducted in a region of South Africa where the prevalence of HIV is the highest, and the patients, as stated by the authors, often have an extremely poor socioeconomic status, are severely malnourished, and have poor immunocompe-tency. These factors, therefore, limit the external validity, or generalizability, of this study as compared with other studies in the literature from more socioeconomically ad-vanced countries.
There was a mild publication bias in the articles used in the meta-analysis, as depicted by the lack of uniform distribution within the inverted V of the funnel plot (Fig. 1), which suggests that small, negative studies have not been published in the literature. Furthermore, as mentioned in the Results, authors from Johns Hopkins University have published multiple articles with duplicate data, all of which have revealed a positive effect with AISs.8,26,27,45,59–62 This duplication has the effect of flooding the literature with results that could have been coalesced into fewer studies. To control for this effect, we selected only those studies that had distinct data—1 study that had adult patients and 1 study that contained only pediatric patients. Even more concerning is the fact that 2 authors who are associated with all of the studies are self-admitted paid consultants for Codman, which could raise questions regarding the unbi-ased nature of the studies and results.
Meta-Analysis and LimitationsOur meta-analysis showed AISs to be protective
against shunt infection. The pooled infection rate de-
Fig. 1. Funnel plot with pseudo 95% confidence limits showing un-equal distribution of studies, indicative of a lack of small negative stud-ies within the literature. S.E. = standard error.
TABLE 7: Number of shunt infections and rates per study
SS AIS
Authors & YearNo. of Pts Infected
% Infected Per Procedure
No. of Pts Infected
% Infected Per Procedure Study Conclusions*
Farber et al., 2011 10 4 3 1.2 AIS reduced shunt infection rateSteinbock et al., 2010 14 3.6 0 0 no difference in shunt infection rateGutiérrez-González et al., 2010 8 17 2 2.8 AIS reduced shunt infection rateKandasamy et al., 2011 155 7.9 30 5.2 AIS reduced shunt infection rateRichards et al., 2009 47 4.7 30 3 AIS reduced shunt infection rateParker et al., 2009 64 11.2 16 3.2 AIS reduced shunt infection rateAlbanese et al., 2009 7 58.3 0 0 no difference in shunt infection rate Eymann et al., 2008† 4 4 1 0.5 AIS reduced shunt infection rate & resulted in significant
hospital cost savingsEymann et al., 2008† 3 13.6 1 3.8 AIS reduced shunt infection rate & resulted in significant
hospital cost savingsHayhurst et al., 2008 8 10.4 21 9.8 no difference in shunt infection ratePattavilakom et al., 2007 36 6.5 3 1.2 AIS reduced shunt infection rateRitz et al., 2007 10 2.5 5 2.6 no difference in shunt infection rateKan & Kestle, 2007 7 8.8 4 5 no difference in shunt infection rateAryan et al., 2005 7 15.2 1 3.1 no difference in shunt infection rateGovender et al., 2003 10 13 3 5 no difference in shunt infection rate
* Conclusions put forth by authors of the individual papers were not automatically accepted and were verified by 2 authors (P.K. and B.T.R.) of the present paper.† Data are from a single paper, but the authors analyzed pediatric and adult patients separately, and so the data are listed separately.
P. Klimo Jr. et al.
608 J Neurosurg: Pediatrics / Volume 8 / December 2011
creased from 7.0% in the patients in the SS group to 3.5% in those in the AIS group—ARR and RRR of 3.5% and 50%, respectively. Regardless of whether all studies were included or only those from a single institution, the odds of a shunt infection developing was more than 2 times greater in patients with an SS than in those who received an AIS.
Since a meta-analysis is a summation of trials, it is only as good as the trials that are combined within it. Although the trials used in this meta-analysis shared cer-tain core components, as defined by our inclusion and ex-clusion criteria, and all had Class III data, with the excep-tion of 1 study with Class II data, there was a considerable degree of heterogeneity among them. For example, some
studies included only adult patients, others had only chil-dren, and still others included both. Surgical technique is obviously a factor that cannot be controlled for in such an analysis and, as discussed previously, may be somewhat more ”standardized” in a study from a single institution than in a multiinstitutional study. Even the definition of a shunt infection was not identical from study to study. The availability of composition data for the control and treat-ment groups within each of the studies varied consider-ably, even for seemingly basic data such as sex and age (Tables 5 and 6). Some studies gave little to no compo-sitional data for the treatment or control groups.7,47,54 The most important implication regarding group composition
Fig. 2. Forest plots of all studies (multi- and single-institution) with their respective RRs, events (infections), treatments (pro-cedures), and cumulative RRs.
TABLE 8: Cost analysis for studies that demonstrated a benefit in switching from an SS to an AIS
Authors & YearSS Infection
Rate (%)AIS Infection
Rate (%)ARR (%)
RRR (%) NNT
Cost to Prevent 1 Shunt Infection (US$)*
Cost Savings Per NNT (US$)†
Cost Savings Per Annum (US$)‡
Farber et al., 2011 4 1.2 2.8 70 36 14,400 35,600 199,360Gutiérrez-González et al., 2010 17 2.8 14.2 84 7 2,800 47,200 1,349,920Kandasamy et al., 2011 7.9 5.2 2.7 34 37 14,800 35,200 190,080 Richards et al., 2009 4.7 3 1.7 36 59 23,600 26,400 89,760 Parker et al., 2009 11.2 3.2 8 71 13 5,200 44,800 689,920 Eymann et al., 2008§ 4 0.5 3.5 88 29 11,600 38,400 264,960 Eymann et al., 2008§ 13.6 3.8 9.8 72 10 4,000 46,000 920,000 Pattavilakom et al., 2007 6.5 1.2 5.3 82 19 7,600 42,400 445,200
* NNT × $400.† $50,000 − (NNT × $400).‡ (200/NNT) × [$50,000 − (NNT × $400)].§ Data are from a single paper, but the authors analyzed pediatric and adult patients separately, and so these data are listed separately.
J Neurosurg: Pediatrics / Volume 8 / December 2011
Meta-analysis of shunt systems
609
is whether collectively the treatment and control groups are balanced for some of the known prognostic factors (that is, confounders) for shunt infection.
Various primarily nonmodifiable preoperative pa-tient characteristics are thought to be risk factors for shunt infection. Newborns (younger than 6–12 months of age) and premature infants in particular (< 40 weeks gestation), with their immature immune systems, thin skin, and high bacterial skin flora, have frequently been shown in the literature to be high-risk groups, with infec-tion rates of 10%–15% or higher.3,23,28,43,50,63,70 A few re-ports have not shown age to be a risk factor.42,65 Simon et al.63 also identified female sex, African-American race, public insurance, cause of intraventricular hemorrhage, and respiratory complex chronic condition as risk factors. Kestle et al.39 found an alarmingly high overall reinfec-tion rate of 26% in patients who were treated for a recent CSF shunt infection and 29% in those infected with S. epidermidis. Ritz et al.54 “assumed” a number of shunt in-fection risk factors as part of their data analysis, including age (< 1 and > 80 years), premature birth, EVD, former shunt infection, former systemic infection, disturbance of consciousness, and former radiation or chemotherapy. Prusseit et al.51 listed a number of “confirmed” risk fac-tors, which included among others low gestational age and preterm birth, young age at shunt placement, and cause of hydrocephalus (increased risk after intraventricular hem-orrhage, infectious etiology, or children with malignant disease, chemotherapy-associated immunosuppression, or long-term application of steroids). High-risk subgroups as defined by Parker et al.45 were characterized by prema-turity (< 35 weeks gestational age), placement of shunts immediately after meningitis, conversion of an EVD to a shunt, and shunt replacement due to nosocomial infection in patients requiring prolonged hospital stays (> 1 month). Pattavilakom et al.47 listed similar risk factors such as cause of hydrocephalus, previous revisions, extended hos-pital stay, positive CSF cultures prior to implantation, and the preoperative occurrence of CSF leakage or the use of an EVD.
What this demonstrates is that there are undoubtedly a number of known and unknown preoperative risk fac-tors or confounders for shunt infection, with varying de-grees of agreement among neurosurgeons collectively. It is impossible based on the studies that qualified for our meta-analysis to know whether the SS and AIS groups were balanced with respect to even the more commonly cited risk factors simply because such data were not avail-able in all studies. Our hope is that with so many patients and procedures in each treatment group (5582 and 3467 procedures in the SS and AIS groups, respectively), the influence that any differences between the groups as re-gards known and unknown confounders would be less-ened, and thus the statistically significant and substantial reduction in the infection rate that we demonstrated is a true finding and not a false positive or a Type I error.
Steps may be taken at the design stage or in the analy-sis stage of a clinical study to reduce the impact of dispro-portionately distributed confounders. Matching groups on certain key confounders, as done in the study by Richards et al.,53 can eliminate the impact of only those confounders
that were matched, but matching on multiple confounders in a large cohort trial can be economically and logistically impracticable. Although some authors have called for a prospective, blinded, randomized controlled trial,37 such an analysis would require, as correctly stated by Richards et al.,53 very large patient numbers, which would necessitate multicenter cooperation, the establishment of a standard protocol, and considerable funding. For example, if we as-sumed that the shunt infection rates in our meta-analysis were true, with a b of 20% and an α of 5%, more than 500 patients would be needed in each group. More importantly, it may be difficult to recruit centers into such a trial be-cause, anecdotally, some neurosurgeons and centers have developed a strong bias toward using the AIS (that is, lack of clinical equipoise). It is easy to understand why. For the neurosurgeon, converting to the AIS requires no change in surgical technique or added surgical time and may re-duce the risk of what is arguably one of the most adverse complications of shunt surgery. Furthermore, there have been no reported deleterious consequences of implanting an AIS. Although there has been some concern that AIS systems may ”mask” or delay shunt infections or even in-crease the rate or virulence of such an infection, Sciubba et al.60 showed that AISs did not increase the incidence of late CSF shunt infection. There have been no reports of postsurgical hypersensitivity, and Abed et al.1 demon-strated that AISs are nonepileptogenic. Nonetheless, the Hydrocephalus Clinical Research Network developed and implemented a standardized shunt surgery protocol that excluded the use of AISs in 4 centers with 21 neurosur-geons.41
In the absence of a well-designed prospective cohort trial or randomized trial, we believe that our meta-analysis provides the best evidence-based appraisal of the current literature. Using the ATS/GRADE system, we strongly recommend the use of AISs based on low- to moderate-quality evidence (Class II and III data). Similarly, we give our findings a Grade IIb on the ACC/AHA scale, which indicates that, although there is some conflicting evi-dence, the weight of the evidence favors AIS use.
Cost Analysis and LimitationsThe implantation of shunts is a very common proce-
dure and thus uses tremendous monetary resources. Each year, more than $2 billion dollars are spent treating pedi-atric hydrocephalus, with an estimated cost of $36,000–$40,000 per admission.48,64 The cost to treat a shunt infec-tion may be upward of $50,000 or more.18 Therefore, the impact of a measure to decrease the risk of shunt infec-tion can translate into substantial health care savings.
The greater the risk reduction with a conversion to AISs, the lower the number of AIS implants needed to prevent 1 infection and thus the less additional cost to prevent 1 shunt infection, assuming the commonly quot-ed additional cost of $400 for an AIS system (at the pri-mary author’s hospital [P.K.], the difference is $412.48). With a lower NNT and thus lower additional expenditure to prevent 1 shunt infection, the cost savings per NNT (assuming a cost of $50,000 to treat a shunt infection) and cost savings per annum (assuming 200 shunt opera-tions/year) increases accordingly. The savings per annum
P. Klimo Jr. et al.
610 J Neurosurg: Pediatrics / Volume 8 / December 2011
in trials that showed a benefit with AIS systems ranged from just less than $90,000 to over $1.3 million (Table 8).
The cost savings are dependent on several factors and assumptions. The biggest factor is the decrease in the shunt infection rate with a change to the AIS (ARR). In some institutions, the shunt infection rates are so low that converting to AISs would not be financially worthwhile. Choux et al.14 reported a per-procedure rate of 0.17% af-ter the introduction of a strict protocol for shunt surgery. With the addition of intrathecal vancomycin and genta-mycin at the time of surgery, Ragel et al.52 saw their infec-tion rate fall to 0.4%. Pirotte et al.49 reported the lowest infection rate in the literature, 0%, in a consecutive series of 100 patients undergoing 115 surgeries with the imple-mentation of their own perioperative protocol. Thus, if an institution’s shunt infection rate is already well be-low 5% with the use of standard catheters, converting to AISs may not be cost effective or may best be limited to patients at greatest risk for shunt infection (for example, premature infants).
A significant assumption in our analysis was the cost of treating a shunt infection. Darouiche18 estimated the medical and surgical cost of treating a shunt infection to be $50,000. Attenello et al.8 recently reported the average hos-pital cost per shunt infection for AIS and SS catheters as $46,640 and $49,397, respectively. At the primary author’s institution (P.K.), the average cost in 2010 was $51,741. The cost to treat a shunt infection is dependent on 2 primary variables: how the shunt infection is treated and the health care system under which the patient is treated. There is no uniform method or duration of treatment for shunt infec-tion,6,39 but one of the more common procedures involves the removal of all hardware at the time of diagnosis, place-ment of an EVD for a period of several days or weeks while the patient is treated with intravenous (and possibly intra-ventricular) antibiotics until the infection clears, and reim-plantation of a new shunt.35,39,57 Other authors have reported successful outcomes with externalization of the shunt and treatment with systemic and intraventricular antibiotics fol-lowed by implantation of a new shunt5 or in situ treatment with systemic and intraventricular antibiotics in patients with coagulase-negative staphylococci without external-ization or replacement of the hardware.12 As an example of the difference in hospital costs between markedly different health care systems, Eymann et al.24 reported a much lower average cost of $17,300 and $13,000 for children and adults, respectively, under the socialized government-run German health care system. Even with a much lower cost in treating a shunt infection, they still saved approximately $50,000 with nearly 200 shunt operations. We chose $50,000 as the total cost because we believe it most likely reflects the cost of a shunt infection in the US. Annual cost savings were calculated based on 200 shunt operations being performed during that year, a number we thought was reasonable for a typical high-volume children’s hospital where the impact of savings would be the greatest.
ConclusionsShunt infections can have long-term consequences to
the patient and impose significant burdens on the family,
neurosurgeon, and health care system. The prevention of shunt infection is therefore critically important. The AIS system has been a welcome addition to the treatment of patients with hydrocephalus, but its effectiveness remains unclear. While recognizing the variable quality of exist-ing literature, the lack of a uniform definition of “shunt infection,” and a possible publication bias, we have none-theless shown in our meta-analysis the protective effect of AISs. The infection rate decreased from 7.0% with SSs to 3.5% with AISs. When all 14 studies were included in our analysis, the risk of developing a shunt infection with an SS was 2.18 times greater than that with an AIS. The pro-tective effect of the AIS translated into a significant per annum cost savings, ranging from $90,000 to over $1.3 million. Economically, the decision to convert to an AIS system must be institution-based and is dependent on the baseline shunt infection rate, the estimated change with conversion to an AIS, the average hospital costs for the treatment of a shunt infection, and the number of shunt operations performed at the institution. Unless an institu-tion’s shunt infection rate is already well below 5%, we believe that an AIS should strongly be considered in all patients, especially in those who have the highest risk of shunt infection.
Disclosure
The authors report no conflict of interest concerning the mate-rials or methods used in this study or the findings specified in this paper.
Author contributions to the study and manuscript preparation include the following. Conception and design: Klimo, Thompson. Acquisition of data: Klimo, Ragel. Analysis and interpretation of data: Klimo, Thompson. Drafting the article: Klimo. Critically revis-ing the article: all authors. Reviewed submitted version of manu-script: all authors. Approved the final version of the manuscript on behalf of all authors: Klimo. Statistical analysis: Thompson. Study supervision: Boop.
References
1. Abed WT, Alavijeh MS, Bayston R, Shorvon SD, Patsalos PN: An evaluation of the epileptogenic properties of a rifampicin/clindamycin-impregnated shunt catheter. Br J Neurosurg 8:725–730, 1994
2. Albanese A, De Bonis P, Sabatino G, Capone G, Marchese E, Vignati A, et al: Antibiotic-impregnated ventriculo-peritoneal shunts in patients at high risk of infection. Acta Neurochir (Wien) 151:1259–1263, 2009
3. Ammirati M, Raimondi AJ: Cerebrospinal fluid shunt infec-tions in children. A study on the relationship between the eti-ology of hydrocephalus, age at the time of shunt placement, and infection rate. Childs Nerv Syst 3:106–109, 1987
4. Armon C, Evans RW: Addendum to assessment: Prevention of post-lumbar puncture headaches: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 65:510–512, 2005
5. Arnell K, Enblad P, Wester T, Sjölin J: Treatment of cerebro-spinal fluid shunt infections in children using systemic and in-traventricular antibiotic therapy in combination with external-ization of the ventricular catheter: efficacy in 34 consecutively treated infections. J Neurosurg 107 (3 Suppl):213–219, 2007
6. Arthur AS, Whitehead WE, Kestle JR: Duration of antibiotic therapy for the treatment of shunt infection: a surgeon and patient survey. Pediatr Neurosurg 36:256–259, 2002
7. Aryan HE, Meltzer HS, Park MS, Bennett RL, Jandial R, Levy ML: Initial experience with antibiotic-impregnated sili-
J Neurosurg: Pediatrics / Volume 8 / December 2011
Meta-analysis of shunt systems
611
cone catheters for shunting of cerebrospinal fluid in children. Childs Nerv Syst 21:56–61, 2005
8. Attenello FJ, Garces-Ambrossi GL, Zaidi HA, Sciubba DM, Jallo GI: Hospital costs associated with shunt infections in pa-tients receiving antibiotic-impregnated shunt catheters versus standard shunt catheters. Neurosurgery 66:284–289, 2010
9. Bayston R, Ashraf W, Bhundia C: Mode of action of an an-timicrobial biomaterial for use in hydrocephalus shunts. J Antimicrob Chemother 53:778–782, 2004
10. Bayston R, Grove N, Siegel J, Lawellin D, Barsham S: Prevention of hydrocephalus shunt catheter colonisation in vi-tro by impregnation with antimicrobials. J Neurol Neurosurg Psychiatry 52:605–609, 1989
11. Bayston R, Lambert E: Duration of protective activity of ce-rebrospinal fluid shunt catheters impregnated with antimicro-bial agents to prevent bacterial catheter-related infection. J Neurosurg 87:247–251, 1997
12. Brown EM, Edwards RJ, Pople IK: Conservative manage-ment of patients with cerebrospinal fluid shunt infections. Neurosurgery 58:657–665, 2006
13. Chadduck W, Adametz J: Incidence of seizures in patients with myelomeningocele: a multifactorial analysis. Surg Neurol 30:281–285, 1988
14. Choux M, Genitori L, Lang D, Lena G: Shunt implantation: reducing the incidence of shunt infection. J Neurosurg 77: 875–880, 1992
15. Cochrane DD, Kestle J: Ventricular shunting for hydrocephalus in children: patients, procedures, surgeons and institutions in English Canada, 1989-2001. Eur J Pediatr Surg 12 (Suppl 1): S6–S11, 2002
16. Crowther M, Lim W, Crowther MA: Systematic review and meta-analysis methodology. Blood 116:3140–3146, 2010
17. Dallacasa P, Dappozzo A, Galassi E, Sandri F, Cocchi G, Masi M: Cerebrospinal fluid shunt infections in infants. Childs Nerv Syst 11:643–649, 1995
18. Darouiche RO: Treatment of infections associated with surgi-cal implants. N Engl J Med 350:1422–1429, 2004
19. Deeks JJ, Higgins JPT, Altman DG: Chapter 9: Analysing data and undertaking meta-analyses, in Higgins JPT, Green S (eds): Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. (http://www.cochrane-handbook.org) [Accessed September 1, 2011]
20. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 7:177–188, 1986
21. Drake JM, Kestle JR, Milner R, Cinalli G, Boop F, Piatt J Jr, et al: Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus. Neurosurgery 43:294–305, 1998
22. Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634, 1997
23. Enger PO, Svendsen F, Wester K: CSF shunt infections in children: experiences from a population-based study. Acta Neurochir (Wien) 145:243–248, 2003
24. Eymann R, Chehab S, Strowitzki M, Steudel WI, Kiefer M: Clinical and economic consequences of antibiotic-impregnat-ed cerebrospinal fluid shunt catheters. J Neurosurg Pediatr 1:444–450, 2008
25. Eymann R, Steudel WI, Kiefer M: Infection rate with applica-tion of an antibiotic-impregnated catheter for shunt implanta-tion in children—a retrospective analysis. Klin Padiatr 221: 69–73, 2009
26. Farber SH, Parker SL, Adogwa O, McGirt MJ, Rigamonti D: Effect of antibiotic-impregnated shunts on infection rate in adult hydrocephalus: a single institution’s experience. Neu rosurgery 69:625–629, 2011
27. Farber SH, Parker SL, Adogwa O, Rigamonti D, McGirt MJ: Cost analysis of antibiotic-impregnated catheters in the treat-ment of hydrocephalus in adult patients. World Neurosurg 74:528–531, 2010
28. Fulkerson DH, Vachhrajani S, Bohnstedt BN, Patel NB, Patel AJ, Fox BD, et al: Analysis of the risk of shunt failure or infection related to cerebrospinal fluid cell count, protein level, and glucose levels in low-birth-weight premature in-fants with posthemorrhagic hydrocephalus. Clinical article. J Neurosurg Pediatr 7:147–151, 2011
29. Govender ST, Nathoo N, van Dellen JR: Evaluation of an an-tibiotic-impregnated shunt system for the treatment of hydro-cephalus. J Neurosurg 99:831–839, 2003
30. Gruber TJ, Riemer S, Rozzelle CJ: Pediatric neurosurgical practice patterns designed to prevent cerebrospinal fluid shunt infection. Pediatr Neurosurg 45:456–460, 2009
31. Gutiérrez-González R, Boto GR, Fernández-Pérez C, del Prado N: Protective effect of rifampicin and clindamycin im-pregnated devices against Staphylococcus spp. infection after cerebrospinal fluid diversion procedures. BMC Neurol 10:93, 2010
32. Hanlo PW, Cinalli G, Vandertop WP, Faber JA, Bøgeskov L, Børgesen SE, et al: Treatment of hydrocephalus determined by the European Orbis Sigma Valve II survey: a multicenter prospective 5-year shunt survival study in children and adults in whom a flow-regulating shunt was used. J Neurosurg 99: 52–57, 2003
33. Hayhurst C, Cooke R, Williams D, Kandasamy J, O’Brien DF, Mallucci CL: The impact of antibiotic-impregnated catheters on shunt infection in children and neonates. Childs Nerv Syst 24:557–562, 2008
34. Izci Y, Secer H, Akay C, Gonul E: Initial experience with sil-ver-impregnated polyurethane ventricular catheter for shunt-ing of cerebrospinal fluid in patients with infected hydroceph-alus. Neurol Res 31:234–237, 2009
35. James HE, Bradley JS: Aggressive management of shunt in-fection: combined intravenous and intraventricular antibiotic therapy for twelve or less days. Pediatr Neurosurg 44:104–111, 2008
36. Jamjoom AB, Mohammed AA, al-Boukai A, Jamjoom ZA, Rahman N, Jamjoom HT: Multiloculated hydrocephalus re-lated to cerebrospinal fluid shunt infection. Acta Neurochir (Wien) 138:714–719, 1996
37. Kan P, Kestle J: Lack of efficacy of antibiotic-impregnated shunt systems in preventing shunt infections in children. Childs Nerv Syst 23:773–777, 2007
38. Kandasamy J, Dwan K, Hartley JC, Jenkinson MD, Hayhurst C, Gatscher S, et al: Antibiotic-impregnated ventriculoperi-toneal shunts—a multi-centre British paediatric neurosurgery group (BPNG) study using historical controls. Childs Nerv Syst 27:575–581, 2011
39. Kestle JR, Garton HJ, Whitehead WE, Drake JM, Kulkarni AV, Cochrane DD, et al: Management of shunt infections: a multicenter pilot study. J Neurosurg 105 (3 Suppl):177–181, 2006
40. Kestle JR, Hoffman HJ, Soloniuk D, Humphreys RP, Drake JM, Hendrick EB: A concerted effort to prevent shunt infec-tion. Childs Nerv Syst 9:163–165, 1993
41. Kestle JR, Riva-Cambrin J, Wellons JC III, Kulkarni AV, White head WE, Walker ML, et al: A standardized protocol to reduce cerebrospinal fluid shunt infection: the Hydrocephalus Clinical Research Network Quality Improvement Initiative. Clinical article. J Neurosurg Pediatr 8:22–29, 2011
42. Kontny U, Höfling B, Gutjahr P, Voth D, Schwarz M, Schmitt HJ: CSF shunt infections in children. Infection 21:89–92, 1993
43. Kulkarni AV, Drake JM, Lamberti-Pasculli M: Cerebrospinal fluid shunt infection: a prospective study of risk factors. J Neurosurg 94:195–201, 2001
44. Mapstone TB, Rekate HL, Nulsen FE, Dixon MS Jr, Glaser N, Jaffe M: Relationship of CSF shunting and IQ in children with myelomeningocele: a retrospective analysis. Childs Brain 11:112–118, 1984
P. Klimo Jr. et al.
612 J Neurosurg: Pediatrics / Volume 8 / December 2011
45. Parker SL, Attenello FJ, Sciubba DM, Garces-Ambrossi GL, Ahn E, Weingart J, et al: Comparison of shunt infection inci-dence in high-risk subgroups receiving antibiotic-impregnated versus standard shunts. Childs Nerv Syst 25:77–83, 85, 2009
46. Pattavilakom A, Kotasnas D, Korman TM, Xenos C, Danks A: Duration of in vivo antimicrobial activity of antibiotic-impregnated cerebrospinal fluid catheters. Neurosurgery 58: 930–935, 2006
47. Pattavilakom A, Xenos C, Bradfield O, Danks RA: Reduction in shunt infection using antibiotic impregnated CSF shunt catheters: an Australian prospective study. J Clin Neurosci 14: 526–531, 2007
48. Patwardhan RV, Nanda A: Implanted ventricular shunts in the United States: the billion-dollar-a-year cost of hydrocephalus treatment. Neurosurgery 56:139–145, 2005
49. Pirotte BJ, Lubansu A, Bruneau M, Loqa C, Van Cutsem N, Brotchi J: Sterile surgical technique for shunt placement re-duces the shunt infection rate in children: preliminary analy-sis of a prospective protocol in 115 consecutive procedures. Childs Nerv Syst 23:1251–1261, 2007
50. Pople IK, Bayston R, Hayward RD: Infection of cerebrospi-nal fluid shunts in infants: a study of etiological factors. J Neurosurg 77:29–36, 1992
51. Prusseit J, Simon M, von der Brelie C, Heep A, Molitor E, Volz S, et al: Epidemiology, prevention and management of ventriculoperitoneal shunt infections in children. Pediatr Neurosurg 45:325–336, 2009
52. Ragel BT, Browd SR, Schmidt RH: Surgical shunt infection: significant reduction when using intraventricular and systemic antibiotic agents. J Neurosurg 105:242–247, 2006
53. Richards HK, Seeley HM, Pickard JD: Efficacy of antibiotic-impregnated shunt catheters in reducing shunt infection: data from the United Kingdom Shunt Registry. Clinical article. J Neurosurg Pediatr 4:389–393, 2009
54. Ritz R, Roser F, Morgalla M, Dietz K, Tatagiba M, Will BE: Do antibiotic-impregnated shunts in hydrocephalus therapy reduce the risk of infection? An observational study in 258 patients. BMC Infect Dis 7:38, 2007
55. Rotim K, Miklic P, Paladino J, Melada A, Marcikic M, Scap M: Reducing the incidence of infection in pediatric cerebro-spinal fluid shunt operations. Childs Nerv Syst 13:584–587, 1997
56. Schmidt K, Gjerris F, Osgaard O, Hvidberg EF, Kristiansen JE, Dahlerup B, et al: Antibiotic prophylaxis in cerebrospinal fluid shunting: a prospective randomized trial in 152 hydroce-phalic patients. Neurosurgery 17:1–5, 1985
57. Schreffler RT, Schreffler AJ, Wittler RR: Treatment of cere-brospinal fluid shunt infections: a decision analysis. Pediatr Infect Dis J 21:632–636, 2002
58. Schünemann HJ, Jaeschke R, Cook DJ, Bria WF, El-Solh AA, Ernst A, et al: An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guide-lines and recommendations. Am J Respir Crit Care Med 174:605–614, 2006
59. Sciubba DM, Lin LM, Woodworth GF, McGirt MJ, Carson B, Jallo GI: Factors contributing to the medical costs of cerebro-
spinal fluid shunt infection treatment in pediatric patients with standard shunt components compared with those in patients with antibiotic impregnated components. Neurosurg Focus 22(4):E9, 2007
60. Sciubba DM, McGirt MJ, Woodworth GF, Carson B, Jallo GI: Prolonged exposure to antibiotic-impregnated shunt catheters does not increase incidence of late shunt infections. Childs Nerv Syst 23:867–871, 2007
61. Sciubba DM, Noggle JC, Carson BS, Jallo GI: Antibiotic-impregnated shunt catheters for the treatment of infantile hy-drocephalus. Pediatr Neurosurg 44:91–96, 2008
62. Sciubba DM, Stuart RM, McGirt MJ, Woodworth GF, Samdani A, Carson B, et al: Effect of antibiotic-impregnated shunt cath-eters in decreasing the incidence of shunt infection in the treat-ment of hydrocephalus. J Neurosurg 103 (2 Suppl):131–136, 2005
63. Simon TD, Hall M, Riva-Cambrin J, Albert JE, Jeffries HE, Lafleur B, et al: Infection rates following initial cerebrospinal fluid shunt placement across pediatric hospitals in the United States. Clinical article. J Neurosurg Pediatr 4:156–165, 2009
64. Simon TD, Riva-Cambrin J, Srivastava R, Bratton SL, Dean JM, Kestle JR: Hospital care for children with hydrocephalus in the United States: utilization, charges, comorbidities, and deaths. J Neurosurg Pediatr 1:131–137, 2008
65. Steinbok P, Milner R, Agrawal D, Farace E, Leung GK, Ng I, et al: A multicenter multinational registry for assessing ventricu-loperitoneal shunt infections for hydrocephalus. Neurosurgery 67:1303–1310, 2010
66. Sterne JA, Egger M: Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol 54: 1046–1055, 2001
67. Sterne JA, Egger M, Smith GD: Systematic reviews in health care: Investigating and dealing with publication and other bi-ases in meta-analysis. BMJ 323:101–105, 2001
68. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr: Scientific evidence underlying the ACC/AHA clinical prac-tice guidelines. JAMA 301:831–841, 2009
69. Vanaclocha V, Sáiz-Sapena N, Leiva J: Shunt malfunction in relation to shunt infection. Acta Neurochir (Wien) 138:829–834, 1996
70. Vinchon M, Dhellemmes P: Cerebrospinal fluid shunt infec-tion: risk factors and long-term follow-up. Childs Nerv Syst 22:692–697, 2006
71. Walters BC, Hoffman HJ, Hendrick EB, Humphreys RP: Cerebrospinal fluid shunt infection. Influences on initial man-agement and subsequent outcome. J Neurosurg 60:1014–1021, 1984
Manuscript submitted May 20, 2011.Accepted August 25, 2011.Address correspondence to: Paul Klimo Jr., M.D., M.P.H.,
Semmes-Murphey Neurologic & Spine Institute, 6325 Humphreys Boulevard, Memphis, Tennessee 38120. email: [email protected].