Effectiveness of Silver-Impregnated EVD in Clinical Practice

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1		Sylvain Diop	--	1728	2023-03-14 19:06:45	\|
2	layout	Camila Xu	Meta information modification	1728	2023-03-15 01:28:27	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms24054819

External ventricular drain(EVD) are widely used in neurosurgery to control cerebral hypertension mainly related to subarachnoid hemorrhage (SAH) or traumatic brain injury. It consists of a catheter inserted through the skull into the ventricles by a neurosurgeon, allowing the drainage of the cerebrospinal fluid (CSF) and the monitoring and control of the intracranial pressure. It also exposes the patient to ventriculostomy-related infection (VRI) leading to higher morbidity and economic burden.

external ventricular drain biofilm bacteria silver nanoparticles ventriculostomy-related infection

1. Background

External ventricular drain(EVD) are widely used in neurosurgery to control cerebral hypertension mainly related to subarachnoid hemorrhage (SAH) or traumatic brain injury ^[1]. It consists of a catheter inserted through the skull into the ventricles by a neurosurgeon, allowing the drainage of the cerebrospinal fluid (CSF) and the monitoring and control of the intracranial pressure ^[1]. It also exposes the patient to ventriculostomy related infection (VRI) leading to higher morbidity and economic burden ^[2]. The pooled incidence of VRI is 11.4 per 1000 catheters per day and the main risk factors identified are SAH, intraventricular hemorrhage, and CSF leakage at the point of insertion ^[2]. Duration of EVD catheterization remained a debated risk factor, but in the majority of the studies, VRI occurred around day 10 ^[3]^[4]. The most frequent bacteria implicated in VRI are Gram-positive cocci (GPC) belonging to the head skin flora (Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus spp., Streptococcus spp.) ^[3]. It has been postulated that VRI involves prior colonization of the surface devices by bacterial biofilm originating from the skin microbiota ^[5]. Periprocedural prophylactic and prolonged intravenous antibiotics failed to demonstrate convincing evidence to prevent VRI ^[3]^[6]. Consequently, EVD impregnated with an antimicrobial agent has been developed to reduce the risk of bacterial adhesion, biofilm formation, and VRI development.

2. Silver-Impregnated External Ventricular Drain(EVD)

Currently, numerous medical devices impregnated or coated with silver nanoparticles have been developed such as urinary catheters, central venous catheters (CVC), or EVD. The most studied and worldwide available silver-impregnated EVD is the Silverline^TM EVD. The catheter is made in polyurethane recovered with 1% of silver nanoparticles and 1% of insoluble silver salt. According to the manufacturers (Spielberg KG), it allows a continuous release of silver ions with a broad-spectrum activity of up to 32 h ^[7].

2.1. Antimicrobial Effect of Silver

The antimicrobial properties of silver have been known for thousands of years. Ancient Egyptians were familiar with the use of various metals, such as lead or silver, to treat or prevent infectious diseases ^[8]. Silver has good biocompatibility with mammalian cells and a broad-spectrum antimicrobial activity against both GPC, Gram-negative rods (GNR), and fungi even at low concentrations. The antimicrobial action is mediated by the direct toxicity of silver ions on bacteria through several mechanisms such as the generation of reactive oxygen species, damage of intracellular structure and proteins, alteration of signal transduction pathway, or electron chain transport ^[8]. Silver ion has a high affinity to peptidoglycan. It seems less effective in GPC because the large peptidoglycan wall could prevent the silver ion from reaching the bacteria cytoplasm ^[9]. Silver ions also demonstrated an anti-biofilm activity in vitro against both GPC and GNR. The antibacterial activity is very short because, in vivo, the silver ion quickly binds an anion (such as chloride) and precipitates ^[10]. Thus, to be effective, silver must be released continuously from the biomaterial surface. The antimicrobial effect of silver nanoparticles also depends on several factors such as size, shape, colloidal state, and the concentration of silver ions generated over time ^[11]. It leads to the development of numerous impregnation methods on biopolymer allowing the release of a small concentration of silver ions over time.

2.2. Synthesis of Silver-Impregnated Biomaterial and Experimental Results

Numerous synthesis methods for silver nanoparticles are available such as chemical (i.e., chemical reduction, electrochemical synthesis, pyrolysis method) or physical methods (i.e., arc discharge, laser irradiation). Recently a green synthetic process has also been developed, limiting the use of toxic chemical compounds ^[10]. The challenge associated with the synthesis of silver nanoparticles-impregnated biomaterial is multi-faceted: It must allow the synthesis of small-size nanoparticles (<100 nm) homogeneously distributed along the catheter and released continuously at a predictable rate over time, without local or systemic toxic effect. Polyurethane is a biopolymer with wide application in the medical field because of its biocompatibility and its advantageous physical properties ^[12].

Saveleyev et al. experimentally tested the synthesis and effectiveness of silver nanoparticles-impregnated polyurethane catheters ^[12]. The nanoparticles synthesized had a spherical shape and a size of 10 to 110 nm without changing the nature of the biomaterial. The impregnated material demonstrated bactericidal and bacteriostatic activity against S. aureus, GNR (Pseudomonas aeruginosa, Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis, and Escherichia coli), and fungi ^[12]. Another study tested the impregnation of silver nanoparticles on polyurethane CVC grafted with acrylic acids. Scanning electron microscopy (SEM) showed that silver nanoparticles had a mean size of 45 nm, however, the concentration of silver in the biomaterial was very low. The antimicrobial effect was observed against E coli and methicillin-resistant S. aureus (MRSA) strains ^[13]. The data from the Manufacturer showed that Silverline^TM catheters have antimicrobial activity on GPC, GNR, and Candida (with a concentration of 10⁷ to 10⁸ cfu/mL according to the strain considered) when assessed with the roll culture plate method ^[7].

Bayston et al. investigated specifically in vitro Silverline^TM EVD effectiveness against different strains of Staphylococci and Escherichia coli at a concentration of 10⁴ cfu/mL during in and out flow conditions and found a rapid decrease of the antimicrobial activity over time, presumably due to the large size and the low density of the silver nanoparticles. Indeed, SEM observation showed that the silver nanoparticles had a diameter of 500 nm and were not uniformly disposed onto the catheter. Silverline^TM EVD were unable to kill 100% of the bacteria attached during flow conditions ^[14]. The application of a conditioning film on the catheter, mimicking in vivo conditions did not influence the antimicrobial effect of the EVD ^[14].

Galiano et al. investigated the concentration of silver by atomic absorption spectroscopy on an artificial CSF fluid crossing continuously (10 mL per hour at 37 °C) polyurethane ventricular shunt (VS) impregnated with silver nanoparticles (Silverline^TM) and sampled every 24 h. They found no silver in each sample and expressed concerns about the effective delivery of silver by the catheter over time ^[15]. Moreover, they found no difference in bacterial growth when S. aureus and E. coli strains were exposed to Silverline^TM and a control catheter ^[15].

3. Effectiveness of Silver-Impregnated EVD in Clinical Practice

The Infectious Disease Society of America (IDSA) guidelines regarding the prevention of healthcare-associated ventriculitis and meningitidis, published in 2017, recommend the use of antimicrobial-impregnated EVD, but Silverline^TM EVD are not specifically mentioned, whereas antibiotics-impregnated EVD (AI-EVD) are ^[2]. Results of the SILVER randomized clinical trial (RCT), including 325 patients, found a significant decrease in EVD infection with Silverline^TM compared to unprocessed EVD (12.3 % and 21.4%, p = 0.043; respectively). VRI was defined as bacteria identified on Gram stain or isolated by culture in a CSF sample ^[16]. Another RCT assessing the effectiveness of silver-impregnated lumbar drains compared to unprocessed drains included 48 patients and found a similar rate of infection-related devices in both groups (4.2% and 16.7%, p = 0.16; respectively). Infection was defined as a positive CSF culture or at least one sign of meningitidis and (1) increased CSF white blood cell count, proteins level, or decreased glucose level or (2) microorganisms seen on Gram stain or (3) colonization of catheter tip ^[17]. A large prospective study comparing 146 silvers-impregnated EVD with 188 AI-EVD and 161 unprocessed EVD, found no difference in the incidence of CSF infection ^[18]. A meta-analysis of one RCT and four cohort studies (two retrospective and two prospective) for a total of 943 patients found that silver-impregnated EVD were associated with a lower risk of infection (RR = 0.60; 95% CI [0.40–0.90]). The authors also reported that there was no difference in mortality whatever the type of catheter used (RR = 1.17; 95% CI [0.76–1.81]) ^[19]. In a meta-analysis including one RCT and one prospective study, there was no difference in the incidence of VRI between silver-impregnated EVD and unprocessed EVD (OR = 0.33; 95% CI [0.07–1.69]; p = 0.18) ^[20]. Another meta-analysis of six observational studies found no significant benefice of silver EVD on the rate of VRI (OR = 0.71; 95% CI [0.46–1.08]; p = 0.11) ^[21]. Similarly, in a large meta-analysis of 12 studies comparing silver-impregnated and unprocessed CVC: there was no difference in the rate of colonization (OR = 0.907; 95% CI [0.758–1.087]; p = 0.290) and in the rate of catheter-related bloodstream infection (CRBSI) (OR = 0.721; 95% CI [0.476–1.094]; p = 0.124) ^[22]. Clinical results of silver compared to unprocessed EVD are resumed in Table 1.

Table 1. Effectiveness of silver impregnated compared to unprocessed EVD in clinical practice.

Comparison between Silver Impregnated and Unprocessed EVD
Years of Publication/Authors	Type of Study	Catheter	Number of Patients	Incidence of VRI/Infection Rate According to the Type of EVD
Keong et al., 2012 ^[16]	Randomized controlled trial	Silver-impregnated EVD (Silverline^TM) vs. unprocessed EVD	278 patients (138 vs. 140)	12.3% vs. 21.4% p = 0.043
Jakobs et al., 2018 ^[17]	Randomized controlled trial	Silver-impregnated ELD (Silverline^TM) vs. unprocessed ELD	48 patients (24 in each group)	4.2% vs. 16.7% p = 0.16
Jamjoom et al., 2018 ^[18]	Prospective cohort	Silver-impregnated EVD (Silverline^TM) vs. unprocessed EVD	307 patients (146 vs. 161)	13.7% vs. 7.5% p = 0.09
Wang et al., 2013 ^[20]	Meta-analysis (1 RCT, 1 prospective study)	Silver-impregnated EVD (Silverline^TM) vs. unprocessed EVD	317 patients (157 vs. 160)	OR = 0.33; 95% CI [0.07–1.69]; p = 0.18
Konstantelias et al., 2015 ^[19]	Meta-analysis (1 RCT, 2 prospective, and 2 retrospective studies)	Silver-impregnated EVD (Silverline^TM) vs. unprocessed EVD	943 patients (491 vs. 452)	RR = 0.60; 95% CI [0.40–0.90]
Atkinson et al., 2016 ^[21]	Meta-analysis (2 prospective and 4 retrospective studies)	Silver-impregnated EVD (Silverline^TM) vs. unprocessed EVD	1057 patients (504 vs. 553)	OR = 0.71; 95% CI [0.46–1.08]; p = 0.11

ELD: External Lumbar Drain. EVD: External Ventricular Drain. OR: Odds Ratio. RCT: Randomized Controlled Trial. RR: Relative Risk.

Adverse Effect

The toxicity of silver ions is a function of their concentration. Silver toxicity seems to be low in the human body. Chronic exposition or ingestion of silver leads to a deposit in tissue and organs which usually are not life-threatening ^[23]. In the case of EVD, silver is directly delivered into the cerebral parenchyma and ventricles. An animal study showed a cerebral inflammatory response when the brain was exposed to a silver clip ^[24]. An experimental study assessing the potential toxic effect of VS impregnated with silver nanoparticles showed reassuring results. The concentration of silver ions, in a fluid sampled after crossing the catheter, was negligible, thus, limiting the potentiality of adverse effects ^[15]. Another experimental study on silicone catheters impregnated with silver nanoparticles inserted in mice found that most of the silver remained on the catheter (approximately 16% of the silver was released after ten days). There was no accumulation of silver in the major organs. However, silver accumulated locally in the tissue surrounding the catheter, but its concentration remained far below the toxic level in humans ^[25]. Clinical results are also reassuring with no reported adverse effect linked to the accumulation of silver ions in organs and tissue ^[26].

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Sylvain Diop

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