Issue: Volume 65 - Issue 6 - June 2019 ISSN 2640-5245
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The inspiration for this column comes from audience response to my presentation at the Symposium on Advanced Wound Care (SAWC) Spring, May 7–11, 2019, in San Antonio, Texas. Attendees from the United States, Brazil, Canada, and Mexico all had the same question at the end of my session: What antiseptics should we be using in pediatrics, specifically in neonates?
Immature neonates (ie, babies born before 32 weeks’ gestation) have a significant cutaneous disadvantage, starting with an immature, thin, underdeveloped epidermis; few layers of stratum corneum; and insufficient intercell lamellar fat. Cohesiveness between the epidermis and dermis is weak due to short and few fibrils; the dermis is thin, less dense, prone to edema (especially with minimal subcutaneous tissue support), and provides inadequate subcutaneous fat support. Neonates have a propensity for edema, increased percutaneous absorption, and immature anti-inflammatory defenses, increasing their risk for systemic toxicity from certain cutaneous substances. In addition, the prenatal environment in which neonates develop and are exposed to during labor is not sterile as previously thought. Depending on maternal diet, health, and route of delivery, neonates might be colonized with commensal bacteria; pathogenic gram-positive and gram-negative colonization may occur, especially during caesarian section birth. This initial colonization is always followed/potentiated by “neonatal colonization” in the next 24 to 48 hours, often with coagulase-negative staphylococci and sometimes by pathogenic Staphylococcus aureusand gram-negative microbes. The lack of the acidic mantle predisposes a fetus to pathogenic microbial colonization; warmth and humidity inside isolettes can contribute to bacterial proliferation.
The biggest enemy to newborn skin is the number of percutaneous procedures neonates endure during their hospital stay. Catheter-related bloodstream infection (CRBSI) is the most common nosocomial neonatal infection. Neonatal sepsis is devastating; delayed neurodevelopment and white brain matter injury have been linked to blood-stream infections. Many believe CRBSI is caused by organisms colonizing skin at the catheter insertion site, migrating along the catheter surface to the tip; or by pathogens introduced when the hub is accessed that migrate along inner lumen of the catheter. In addition, neonatal catheters are kept in place longer than adult versions, making hematogenous spread possible as well. Because the true cause of the infection usually is unknown, all possibilities have to be considered.
To mitigate CRBSI, care bundles comprising actionable items are compiled, including recommendations for the use of antiseptics to decolonize skin. The Centers for Disease Control and Prevention (CDC) have made specific recommendations for skin preparation before cannulation in adults and older children, but no specific recommendations have been endorsed by the CDC, the US Food and Drug Administration, European societies, surgical societies, the American Academy of Pediatrics, or Cochrane reviews with regard to the safety, efficacy, and use of various antiseptics in preterm neonates. In fact, most guidelines and published protocols advise against or at least recommend cautious use of antiseptics in premature or low birth weight infants or children <2 month of age. Despite such advisories, multiple surveys reveal widespread use of antiseptics (chlorhexidine gluconate [CHG] in alcohol or aqueous solution, povidone-iodine ([PI], and isopropyl alcohol) in the US and globally. Approximately 80% of US neonatal intensive care units (NICUs) use CHG for central line maintenance, 70% of NICUs use it for central line insertion, 50% to 60% use it for peripheral intravenous (PIV) line insertion (50% use alcohol), and many use PI, especially in babies <1500 g or <2 weeks old. Recently, owing to the epidemic of methicillin-resistant S aureus (MRSA) in ICUs and ongoing concern about postsurgical infection, 7% of NICUs have been shown to use CHG for MRSA decolonization and 1.5% use it for routine bathing.
The Question: Do We Know What We Are Doing?
Skin antisepsis is an essential component of sepsis prevention in neonatal care units, yet guidelines on product utilization and safety are scarce. Various interventions have been considered and rejected in the recent past as a mandate for skin decolonization, such as CHG umbilical cord cleansing, post-birth whole body CHG washes, vaginal CHG use, topical emollients, and antibiotics. Many units do not have an antiseptic guideline, and many providers are totally unaware of product risks and toxicities. What is known has been extrapolated from recently published studies involving adult and older children and a few neonatal papers. The dilemma comes from the fact that few data support neonatal safety, some raise toxicity concerns, and few are the type of research (ie, strong level of evidence, randomized controlled trials [RCTs], one is on the way]) that show superiority of one product over the other or ensure lack of harm.
Isopropyl alcohol. Several alcohols have been shown to be effective antimicrobials against both gram-positive and gram-negative organisms, as well as against fungi and enveloped viruses. Optimal microbicidal concentration activity ranges from 60% to 90%, which decreases significantly if <50% is inactive in the presence of organic materials. Alcohol denatures proteins, interferes with cell metabolism, and causes bacterial cell membrane lysis. It has a synergistic antiseptic activity when combined with CHG and for a long time was blamed for skin irritation, burns, and necrosis as well as concern for alcohol intoxication.
CHG. A cationic biguanide antiseptic, CHG is produced in both aqueous and alcohol-based forms; 0.05%, 0.25%, 1%, 2%, and 4% solutions are available. CHG works at the membrane level, damaging outer and inner bacterial membranes, causing leakage and disruption of membrane potential critical for adenosine triphosphate generation. CHG is more effective against gram-positive than gram-negative bacteria and has less activity against fungi. In adults, CHG is minimally absorbed through the skin and has low skin irritant potential, but it should not be placed near eyes, mucous membranes, ears, or meninges. Systemic percutaneous absorption in neonates has been demonstrated in multiple studies, with the greatest concentrations occurring at 24 to 48 hours after application, especially in preterm neonates. CHG inhibition of L1 cell adhesion of molecule-mediated neurite growth of cerebellar granule neurons has been demonstrated; this fact, along with hexachlorophene’s previous history of association with vacuolar encephalopathy (1970 through 1980), has neonatal practitioners wondering whether CHG can cross the blood-brain barrier and/or cause neurotoxicity and, if so, at what level. In vitro studies from Europe have demonstrated dose-dependent, statistically significant reduction in glutathione peroxidase, superoxide dismutase, and catalase activity with systemic CHG absorption in human blood, which is concerning considering preterm neonates are deficient in anti-inflammatory enzymes early in life. Odontoblasts, fibroblasts, human epithelial cells, and erythrocytes all have shown dose-dependent toxicity in vitro, with concentrations as low as 0.04%. In animals, direct intraocular exposure to CHG demonstrated adrenergic neuron toxicity and lethal outcomes with oral ingestion. However, no correlation with human blood levels is available. In addition, the levels are difficult to compare because no standard CHG assay exists. Cutaneous side effects, including irritation, dermatitis, and burns, have been clearly documented in preterm neonates (see Figure 1 and Figure 2). Both aqueous and alcohol-based solutions have been implicated, eliminating the claim that alcohol was the main cause of skin injuries.
Iodine. Considered one of the most efficacious antiseptics and topical antimicrobials (for biofilm) among current topical products, ionophores are composed of elemental iodine and a polymer carrier of high molecular weight. This combination increases solubility, provides sustained release, and reduces skin irritation. PI solution is the most common form used in neonatal units. The PI complex attacks proteins, nucleotides, and fatty acids in the organisms, leading to cell death. Iodine is a broad-spectrum antiseptic, effective against gram-positive and gram-negative bacteria, fungi, viruses, and protozoa. However, its systemic absorption is a concern for pregnant and lactating mothers as well as preterm neonates as a potential cause of transient hypothyroidism. Studies in the US show very low incidence of PI-induced hypothyroidism. The concern for cytotoxicity is less than that of CHG, but skin irritation and occasional burns have been described in preterm neonates. When iodine’s efficacy is compared with CHG, studies show different outcomes in adults/children and neonates.
Antiseptics for central venous catheter (CVC) insertion. Various concentrations, solutions, and types of antimicrobials are used in neonates, but they are difficult to compare and do not have a clear superiority such as what CHG has demonstrated in the adult population (eg, CHG was more effective at lowering catheter colonization in an adult ICU but made no difference in catheter-related bacteremia, and surgical site infection was lower in the CHG 2% alcohol group than in the 70% isopropyl alcohol group in adults). Adult studies may utilize either stronger (4%) CHG and/or a combination of CHG with alcohol, which enhances the germicidal properties of CHG. Pediatric studies show use of both solutions and no clear efficacy of one type. Few neonatal studies have compared CHG and iodine products.
Comparative research. Garland et al conducted multiple trials involving infants. A pilot study that evaluated PI versus .2% CHG/alcohol solution found a slightly higher, but statistically insignificant bacterial colonization rate at the tip of catheters in the CHG group, no CRBSI, and no dermatitis. These authors also conducted a study comparing 10% PI to 0.5% CHG for peripheral intravenous catheter colonization (CHG had significantly reduced colonization rates, but neither group developed an infection) and a multicenter RCT to compare the effect of CHG-impregnated dressing and PI on CRBSI, central line-associated bloodstream infection, and catheter colonization. The CHG-impregnated dressing was superior in reducing CVC tip colonization rates; no infections occurred in either group, but dermatitis occurrence was significant in the CHG dressing group. Majidipour et al found PI more efficacious than CHG for skin disinfection in neonates. Kieran et al found no difference between PI or 2% CHG/alcohol in the CRBSI rate in preterm neonates before CVC insertion. Anderson et al reported improved reduction in bloodstream infection with CHG versus PI dressings, although other interventions might have skewed the results; the CHG group reported a 10% dermatitis rate versus none in the PI group. Malathi et al compared 0.5% CHG/70% alcohol to PI for antisepsis before venipuncture or intravenous (IV) placement; both decreased colonization by 99% and showed no differences in bloodstream infections or mortality. Linder et al compared PI to 0.5% CHG/70% alcohol for CVC insertions and found no difference in the rate of CRBSI. A study by McCord of Canadian neonatal antiseptic practices involving CHG with/without alcohol reported skin breakdown and burns in 96% and 68%, respectively. Only 23% of providers were aware of risks and poor safety profile.
An ongoing RCT by Clarke et al is exploring insertion of catheters (the ARCTIC study) in neonates using 2% aqueous CHG versus a 70% CHG/alcohol combination for skin disinfection before percutaneous CVC insertion.
Effects of CHG bathing on targeted skin decolonization in the NICUs. In adults and older children, daily bathing with CHG washcloths has demonstrated significant reduction in nosocomial infections and reduced skin colonization with multidrug-resistant organisms. Large RCT trials from developing countries performed among neonates did not show any benefit to using CHG. Sankar and Paul published a systematic review of the efficacy and safety of whole-body skin cleaning with CHG in neonates that found no conclusive evidence of beneficial effect after single skin cleaning with a particular product.
Johnson et al demonstrated that 2% CHG bathing for MRSA decolonization decreased the gram-positive bacterial burden (on the arm more than the groin) after the first bath, but bacteria returned to baseline by 72 hours. This raises the concern of “adequate” interval to suppress bacterial growth without “too much” systemic absorption. Johnson et al described twice-weekly baths if babies were >36 weeks’ gestational age and older than 72 hours; baths were started after 4 weeks of life in babies <36 weeks gestational age. Residual skin CHG concentration was inversely related to colonization burden. I am concerned that residual concentration may enhance systemic CHG concentration and potentiate toxicity (if such exists).
In conclusion, as CHG and PI use continues to increase as the need to prevent CRBSI grows, we need to acknowledge that we do not know whether what we are using is really safe and/or whether more studies are needed. Is CHG absorption in preterm neonates harmful? Can it cross the blood-brain barrier? Can neurotoxicity and a poor neurodevelopmental outcome (a common sequela of preterm birth) be attributed to CHG use? Is PI safer, given its lack of cytotoxicity and the associated low incidence of transient hypothyroidism? Is PI as efficacious as CHG in the preterm population, despite small but statistically significant advantages of using CHG for decontamination in adults and a few neonatal studies?
Until answers become available, we need to be wary. Personally, I cannot recommend PI over CHG or vice versa. In my experience, both have done the job. I have not seen burns or clinically/laboratory significant hypothyroidism in my unit from PI use. I have seen few cutaneous burns and multiple cases of dermatitis from CHG; all eventually healed. I would encourage spot-specific, minimal application. Practitioners should avoid pooling under the skin and dripping on the skin; excess should be wiped with nonsterile saline as soon as procedures are completed. Avoid placing any dressings on moist skin, especially skin prepared with antiseptics; the skin must be completely dry. Based on current evidence, dressings impregnated with antiseptics are contraindicated in neonates; personally, I encourage caution in smaller pediatric patients as well.
CHG use for baths for MRSA decolonization needs to be individualized. If the NICU has relatively low MRSA and CRBSI rates, are additional antiseptic baths necessary? Given the unknown potential harm and known risks of skin irritation and burns, as well as the short-lived decolonization effect, we need to reconsider what implies standard use. Patient-by-patient individual evaluation makes more sense.
