External ventricular drains (EVD, ventriculostomy catheters) are used to monitor the intracranial pressure (ICP) and to drain CSF. They are particularly helpful for the management of patients with elevated ICP, secondary to acute hydrocephalus caused by subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) (1). Compared to other methods of ICP monitoring, however, EVDs are associated with an increased risk of ventriculostomy-related infection (VRI)(2). Several risk factors for VRI have been identified. These include the presence of intraventricular hemorrhage, SAH, duration of catheterization, basilar cranial fracture with CSF leak, and EVD irrigation (3). The VRI is a serious complication, which has been associated with an increased rate of morbidity, mortality, length of hospital stay, and health care costs (3–5). The reported incidence of VRI varies largely from 2 up to 27% (6–10), mostly depending on the different criteria used for its diagnosis. Due to CSF contamination with blood, CSF pleocytosis, glucose, (11) and protein levels need to be carefully interpreted for the diagnosis of VRI.

Previous studies have tried to tackle the issue of the benefit of laboratory values for VRI diagnosis. Most commonly, CSF's WBC was found to be sensitive for the diagnosis of VRI (8, 12). In certain cases, however, even CSF's WBC was found to be unable to distinguish patients with and without positive CSF cultures (11). On the topic of plasma-derived markers, a recent review found that only around 30% of studies found differences in WBC within plasma, as well as C-reactive protein (CRP) between patients with and without VRI (12), with some more positive reports for the use of procalcitonin (PCT) (13, 14). Most studies, however, primarily compared patients with and without VRI excluding those with infections of another origin.

In this study, we aimed to characterize the value of CSF and plasma-derived inflammatory markers for the diagnosis of VRI in patients with hemorrhagic stroke (either non-traumatic SAH or spontaneous ICH) by comparing patients with VRI, patients with non-cerebral infection, and patients without any infection.

The study was approved by the local ethics committee (Kantonale Ethikkommission Zürich, BASEC-Number: PB_2017_00093) and was in accordance with the ethical standards laid down in the 2013 Declaration of Helsinki for research involving human subjects.

Of 329 patients with hemorrhagic stroke and an EVD in situ admitted to the NCCU of the University Hospital Zurich, 263 patients met the inclusion criteria. One hundred eighty-seven patients (71.1%) suffered from SAH and 76 patients (28.9%) from ICH. Of these patients, 36% (n = 68) with SAH, as well as 17% (n = 13) with ICH, were diagnosed with VRI. Patients' demographics and severity of disease comparing the cohorts with no infection, with non-cerebral infection, and with VRI for the different hemorrhagic stroke types are shown in Table 1. The duration of catheterization was longer in patients with VRI (18 ± 14.7) than in patients with non-cerebral infection (16 ± 12.4) or without infection (11 ± 7.4). Furthermore, the neurocritical care unit and hospital length of stay were longer in patients with VRI than the other cohorts. The severity of disease (radiographic and clinical), as well as proportion with the entricular extension of the hemorrhage, did not differ between the three cohorts.

The laboratory parameters of CSF and plasma are presented in Table 2. The course of WBC in CSF and plasma, as well as of CRP and PCT, are shown in Figure 1. Figure 2 shows the distributions at their respective peak. Overall, patients with non-cerebral infection had significantly higher inflammatory markers in plasma compared to patients without any infection. Similarly, patients with non-cerebral infection had higher CRP and PCT than patients with VRI. No differences in plasma inflammatory markers could be found between patients with VRI and patients without any infection. The WBC in CSF was higher in patients with VRI compared both to other groups. Considering patients with SAH and ICH separately, WBC in plasma did not differ in patients with SAH among patients with VRI, with non-cerebral infection, and without any infection. Overall, WBC in plasma and CSF was higher in patients with VRI following SAH than in patients with VRI following ICH.

Considering patients with VRI (Table 3), a VRI was diagnosed on average on day 9 ± 6.2 after EVD insertion. The time duration between EVD insertion and VRI diagnosis did not differ among patients with SAH and ICH (8 ± 5.5 vs. 11 ± 8.9, p = 0.114). Furthermore, the WBC peak in CSF occurred at similar time points in SAH and ICH (8 ± 6.3 vs. 7±6.3 for SAH and ICH respectively) (p = 0.874). Neutrophils were the most frequent subtype of WBC at the day of the peak in both patients with SAH (55 ± 25.5%) and ICH (59 ± 32.1%). Fourteen (17.2%) patients presented positive CSF culture (N = 3 Escherichia coli, N = 3 Klebsiella pneumoniae; N = 1 Enterococcus faecalis; N = 1 Enterococcus cloacae; N = 1 Klebsiella aerogenes; N = 1 Pseudomonas aeruginosa; N = 1 Serratia marcescens; N = 2 Staphylococcus epidermidis; and N = 1 Streptococcus pyogenes). No differences in CSF or plasma-derived factors, as well as the timing of peak and date of diagnosis, could be found comparing patients diagnosed with VRI, either with or without a positive CSF culture.

Patients with non-cerebral infection most commonly suffered from pneumonia (n = 76, 78%), followed by urinary tract infections (n = 12, 12%), with another 4 (4%), 3 (3%), and 2 (2%) suffering from gastrointestinal, intravenous catheter-related, and other infections, respectively; Furthermore, patients without infection commonly presented with fever (n = 25, 29.4%) or neurological deterioration during their stay (n = 29, 34.1%).

The purpose of our study was to evaluate the benefit of the plasma inflammatory markers WBC, CRP, and PCT for the diagnosis of VRI and its differentiation from patients with non-cerebral infection and patients without infection. While patients with infection of non-cerebral origin had higher systemic inflammatory markers within plasma than patients with VRI, there were no significant differences in levels of CRP, PCT, or plasma WBC between patients with VRI and controls without infections.

The finding that plasma-derived laboratory values do not differentiate patients with VRI and controls without infections is of interest. However, this study has several limitations. Firstly, this is a single-center retrospective study limiting the generalizability of the results. Furthermore, the true incidence of VRI is unknown. At our institution, VRI is diagnosed by the presence of two or more signs/symptoms of VRI after exclusion of alternative infectious source, and earliest 48 h after EVD insertion. This definition follows the criteria by the Centers for Disease Control and Prevention (CDC) (15). Due to the retrospective design of this study, the exact combination of symptoms and signs are unknown. Positive CSF culture was not necessary. Thus, some patients without VRI might have been wrongly grouped. While this definition allows for early diagnosis, it comes with its benefits and drawbacks that we describe below.

The VRI currently lacks universally accepted reliable diagnostic criteria with over 16 unique definitions reported (16). The reported frequency of VRI ranges between 2% and 27%. Simple definitions rely purely on one or more positive CSF cultures with or without concomitant change within the CSF laboratory values (6–10). Due to the high mortality and morbidity associated with VRI (3–5), antibiotic therapy is (also in our cohort) commonly started empirically in the absence of positive bacterial CSF cultures, as the achievement of negative results from cultures requires at least 72 h (17, 18). On the other hand, even though CSF culture remains the gold standard, false-negative tests occur in up to 20% (12, 19). Patients with positive PCR and CSF-negative cultures have been described, suggesting some “aseptic” infections to have a bacterial origin (19). Increasing the frequency of CSF sampling is also not a viable solution as sampling itself increases the positive rate of cultures (20, 21).

More lenient criteria only require clinical signs of VRI, as well as a plasma or CSF-derived laboratory values, in different combinations. Hemorrhagic stroke per se may cause headache, impaired level of consciousness, fever, and nuchal stiffness leading to a difficult interpretation of these clinical parameters (22). Furthermore, blood contamination of CSF hampers the interpretation of cell count, glucose, protein, and lactate levels (23). The SAH of aneurysmal origin itself causes a systemic inflammatory response that includes an increase of WBC, CRP, and PCT within plasma in the absence of a microbial origin (24–26).

The rise of plasma-derived laboratory markers allows for the detection of an infection. However, in our cohort of patients with hemorrhagic stroke, CRP, PCT, and WBC did not prove to be reliable parameters for the diagnosis of VRI. In case of increased inflammatory markers in plasma, a non-cerebral infection is more likely. In the setting of an ICU, patients are critically ill and have several invasive devices and lines (e.g., endotracheal arterial catheters, central venous, and arterial lines) and are, thus, more prone to associated infections (bloodstream infection, pneumonia, or urinary tract infection), which affect the systemic inflammatory response. Furthermore, SAH itself leads to a systemic inflammatory response rendering this patient cohort at risk of overdiagnosing and overtreatment in comparison to ICH. Better diagnostic criteria for VRI are, thus, needed in this specific patient group.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Kantonale Ethikkommission Zürich, BASEC-Number: PB_2017_00093. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

SB, SW, and GB conceived the study. EP, AM, and AE acquired some of the data. Statistical analysis was performed by SB. SB and GB drafted the manuscript. EK reviewed the manuscript for intellectual content. All authors agreed with the publication and the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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