NHMRC Public Consultations

Teleflex Medical Australia (Teleflex) has carefully reviewed Draft Australian Guidelines for the Prevention and Control of Infection in Healthcare, v7.0 published on 13.04.2018 (the draft Guidelines), and would like to thank the National Health and Research Council (NHMRC) for the opportunity to provide feedback and comments.

As a major supplier of vascular access products in Australia, Teleflex appreciates and supports a coordinated approach to the prevention of health care associated infections (HAIs) including device-related infections in Australia and appreciates the NHMRC’s ongoing commitment and effort towards these goals. Teleflex shares NHMRC’s concerns regarding patient safety and in particular makes this submission to the NHMRC in the hope that suggested revision of the draft Guidelines will include rewriting of those sections concerning risk management and chlorhexidine use and use of chlorhexidine central venous catheters.  

Prior to making this submission Teleflex reviewed relevant literature, research, evidence and guidelines regarding chlorhexidine use and anaphylaxis including the 2017 literature review undertaken by the University of South Australia What is the impact of chlorhexidine use on the incidence of anaphylaxis?  

Teleflex’s review of the literature concurred with that of the University of South Australia who throughout their literature review highlight the rarity of true anaphylaxis, the limitations including the retrospectivity, of several reviews, the lack of generalisability of findings outside of the perioperative setting, the variability in defining anaphylaxis attributable to chlorhexidine and the multiple reports of anaphylaxis occurring in patients previously known to be sensitive to chlorhexidine and yet still being exposed subsequently to chlorhexidine. 

In particular Teleflex recommends NHMRC consider some additional information before proceeding with the following specific recommendations and text. To assist NHMRC Teleflex has provided references and/or alternative views to support their eight recommended revisions which are in order according to the current guideline draft.

I.          Use and management of sharps, safety engineered devices and medication vials (Subsection 3.1.3; Needleless devices) page 66 of 294.

The current draft guideline includes four paragraphs about “needleless devices” without actually defining them in a way that is consistent with much of the literature and international guidelines. The draft guideline’s glossary includes an explanation of “needle-free devices” which is somewhat similar but not identical to the universal accepted definition. The glossary term “needle-free devices” is not identical to the text which uses the term “needleless devices”. The ambiguity in these two sections needs to be clarified so that the terminology used in the guideline is identical to the terminology used in the glossary and is familiar to readers.  

Teleflex recommends replacing all the current text describing needleless intravenous connectors and instead using the term “needleless connectors” [1-3] to refer to those needleless devices used to allow connection of catheters, administration sets, and syringes. Sub-classification of these devices based on their design and the type of displacement they cause is common. Teleflex encourages NHMRC to modify the draft guideline as per the terminology recommended by Hadaway [2] and subsequently reaffirmed by its use in robust guidelines including those from the Centers for Disease Control and Prevention (CDC),[1, 4], The Society for Healthcare Epidemiology of America[5] and the Australian and New Zealand Intensive Care Society.[6]  

Although the 3rd and 4^th paragraphs under “Needleless Devices” mention the risk of “inadequate disinfection procedures” and “contamination risk” the draft guideline fails to mention two critical elements of needleless connector or hub disinfection, the use of friction for a specific period as per manufacturer instructions and the need for the decontaminated connector or hub to dry before access.[1, 4-8] Despite Australian recognition of the need to improve maintenance of intravenous catheters [9] neither of these recommendations are made in section 3.4.2.3 page 153 onwards which would be the logical place for them to be included not under Subsection 3.1.3.

 II.          Intravascular access devices (Subsection 3.4.2.3) page 153 of 294 in particular Device selection page 155 of 294.

The draft guideline currently includes the following statement at Device selection page 155 of 294:  

“There is evidence to suggest that antimicrobial coated or impregnated catheters can reduce the risk of bloodstream infection. However, the magnitude of the benefits differs according to the healthcare setting, and significant benefits have only been shown in intensive care units [258]” NHMRC’s reference #258 used to substantiate this statement is not research but a 3-year old 2015 Queensland Health authored document “Guideline for peripherally inserted central venous catheters (PICC).” downloadable from https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases-infection/infection-prevention/intravascular-device-management  

Teleflex whilst appreciative of the evolving nature of research and evidence attempting to clarify the efficacy of antimicrobial catheters refers the NHMRC to a recent 2017 research report which compared and clarified the efficacy of the chlorhexidine/silver sulfadiazine (CSS) and minocycline/rifampin (MR)-impregnated CVCs against the most frequent yeasts isolated from CLABSIs.[10] In this in vitro study investigators differentiate between two generations of CSS-CVCs with the first generation being those coated on the external luminal surface and second-generation CSS-CVCs, (coated on both the external and internal surfaces). They report CSS-CVCs had a superior anti-Candida activity compared to MR-CVCs. The authors also raise the issue that whilst the second-generation CVCs show significant reduction in catheter colonisation, to date, the low power of randomised studies has resulted in no clear difference in central line associated bloodstream infection (CLABSI) being demonstrated.  

Teleflex also wishes to bring the 2016 Cochrane Collaboration’s Intervention Review to the NHMRC’s attention.[11] This updated review found that antimicrobial CVCs were effective in reducing rates of CRBSI and catheter colonisation. It noted however that the magnitude of benefit for reducing catheter colonisation varied by setting with significant benefit shown only in those studies conducted in intensive care units (ICUs). This statement differs greatly from that currently contained in the guideline which Teleflex disputes as being incorrect, easily misinterpreted and failing to distinguish between CRBSI and catheter colonisation. For those reasons Teleflex recommends that the NHMRC re-write the current statement  regarding consideration of an impregnated or coated CVC to be in accordance with the 2012 ANZICS Central Line Insertion and Maintenance Guidelines[6], the 2016 Cochrane findings[11] and multiple other high-level guidelines recommending routine use of coated or impregnated CVCs expected to remain insitu for > 5 days[1, 4, 7, 8] or where patients are at a heightened risk of CLABSI or where an institution or specific units within an institution are experiencing unacceptably high rates of CLABSI.[5]

 Teleflex would also like to highlight the potential long-term delay that negative statements such as that in the current draft may have on trialling and adopting novel technologies. As the NHMRC would appreciate, the Australian Therapeutic Goods Administration (TGA) rightly encumbers device manufacturers seeking medical device or goods registration with substantial manufacturing, safety, efficacy and performance requirements. The human and financial investments are also substantial. Accordingly, Teleflex requests further consideration by the NHMRC and its expert Infection Control Guidelines Advisory Committee (ICGAC) as to the likely negative consequences of NHMRC recommendation which are written either in ambiguous, negative or incorrect language. By their very nature clinicians aim to avoid unintended consequence or harm to patients in their care, they are risk adverse and often over-react conservatively when guidelines are unclear, convoluted, contradictory or ambiguous. Additionally, negatively written guidelines potentially limit user consideration of novel and new technologies. The extended periods between guideline publication and updates are a further compelling reason that agencies must ensure their recommendations are clear, conducive to easy adoption and not so inflexible to retard and halt consideration of emerging technologies. To this end and in consideration of future CLABSI-prevention technologies likely to be marketed by Teleflex and its peer manufacturers Teleflex again requests very careful reconsideration by NHMRC of the existing tone, language and accuracy of its recommendations and by default, non-recommendation of antimicrobial treated CVCs outside of ICUs.

III.          Intravascular access devices (Subsection 3.4.2.3) page 156 of 294 in particular Maintenance page 156 of 294.

The 4^th point under Maintenance (Subsection 3.4.2.3) page 156 of 294 currently recommends   "Using chlorhexidine-impregnated sponges at the catheter insertion site for all devices significantly reduces IVD-related bloodstream infection and device colonisation rates. The safety of these sponges has not been established in low birth- weight neonates who may be at risk for skin or systemic toxicity”. There is no reference supporting this recommendation.                                                

In 2017 the CDC updated their guidelines for the use of chlorhexidine – impregnated dressings. It states “with an FDA-cleared label that specifies a clinical indication for reducing CRBSI or CABSI recommended to protect the insertion site of short term non-tunnelled central venous catheters in patients over 18 years of age.” [4] These updated recommendations extend the choice of product but limit the recommendations to adult patients. The level of evidence to support the claim was also increased to the same level as the recommendation for the use of specific antimicrobial central venous catheters.   

https://www.cdc.gov/infectioncontrol/guidelines/bsi/c-i-dressings/index.html  

Given the current debate among experts and contradictory recommendations in the scientific literature[12, 13] and guidance[1, 4, 5, 7] regarding use of chlorhexidine-impregnated sponges Teleflex is curious to better understand how the ICGAC and NHMRC can support such a statement so vehemently particularly where in earlier and subsequent sections of the draft guideline recommendations question the safety of chlorhexidine and recommend against its routine use? Teleflex concurs with the NHMRC’s recommendation and requests that the ICGAC carefully review every mention of chlorhexidine so as to remove mixed messages and instead ensure internal consistency for recommendations regarding chlorhexidine in the final guideline. In particular Teleflex requests the use of clearer, less sensational and ambiguous language in those sections where chlorhexidine safety and sensitivity are considered. These issues are addressed in more detail in the following section. (4 Organisational Support)   

IV.          Risk Management and Chlorhexidine (Subsection 4.1.4; Practice Statement 37 – Practical Info Page 170 of 294)

Section 4.1.4 Risk Management (page 16) Practice Statement 37 is currently written as “It is good practice to only use chlorhexidine in appropriate situations and when clinically indicated. Healthcare professionals should consider the appropriateness of using chlorhexidine in every clinical situation.” Teleflex is concerned that as it is currently written without reference, a clear definition of an “appropriate situation” or a clinical indication or detail regarding the many, current, safe and beneficial prophylactic and therapeutic uses of chlorhexidine including as a common ingredient in hand hygiene solutions, oral care solutions, as a skin prep solution, in impregnated dressings and in impregnated intravascular devices including central venous catheters (CVCs), readers will interpret this statement as a recommendation not to use chlorhexidine containing solutions, devices or dressings and in doing so potentially increase the overall risk of HAIs in Australia.  

To reduce ambiguity and the potential of misinterpretation Teleflex suggests that Practice Statement 37 be rewritten to read.  

37. Appropriate clinical use of chlorhexidine includes and should be limited to hand hygiene solutions, oral care solutions, as a skin prep solution, in impregnated dressings and in high risk settings and at-risk populations in impregnated or coated central venous catheters (CVCs) as detailed in the relevant sections of this Guideline. Chlorhexidine-containing products, devices or solutions should never be used in patients with known chlorhexidine sensitivity.  

The current first two points/ paragraphs under Practical Info should be deleted. The 3^rd paragraph should remain as is and stand alone. 

 V.          Risk Management and Chlorhexidine (Subsection 4.1.4; Practice Statement 37 – Benefits and harms Page 171 of 294)

This section currently reads “Despite the paucity of clinical evidence, it is suggested that healthcare workers limit the use of chlorhexidine and consider the appropriateness of using chlorhexidine in every clinical situation as this can assist in preventing chlorhexidine resistance.”  

As per the reasons discussed in point V above, Teleflex recommends the existing wording be deleted and replaced with “Appropriate clinical use of chlorhexidine includes and should be limited to hand hygiene solutions, oral care solutions, as a skin prep solution, in impregnated dressingsand in high risk settings and at-risk populations in impregnated or coated central venous catheters (CVCs) as detailed in the relevant sections of this Guideline.” 

 V1.          Risk Management and Chlorhexidine (Subsection 4.1.4; Practice Statement 37 – Rationale Page 171 of 294)

Teleflex recommends the existing wording “This advice is based on limited empirical evidence, but on sound theoretical principles and supported by expert opinion. The use of chlorhexidine when clinically indicated and appropriate is justified to reduce HAI.” be retained only if the clinical indications i.e. to hand hygiene solutions, oral care solutions, as a skin prep solution, in impregnated dressings and in high risk settings and at-risk populations in impregnated or coated central venous catheters (CVCs) are included in (Subsection 4.1.4; Practice Statement 37 – Practical Info Page 170 of 294) as suggested above.  

V11.          Risk Management and Chlorhexidine (Subsection 4.1.4; Practice Statement 38 – Practical Info 171 of 294)

Subsection 4.1.4; Practice Statement 38 – Practical Info 171 of 294) of the draft guideline currently reads “Increasing chlorhexidine usage by consumers and healthcare workers has resulted in a number of different adverse reactions including allergic contact dermatitis, photosensitivity, anaphylaxis and septic shock [296] [297] [298] [299]. Anaphylactic reactions to chlorhexidine are rare but are potentially life-threatening complications. Greater recognition of the potential for chlorhexidine-related anaphylaxis is needed, and patients should be prompted for any chlorhexidine reactions/anaphylaxis during the 'allergy history' subjective assessment.  

Whilst information is limited, it seems the severity of allergic reactions is greatest when the exposure is a result of a chlorhexidine impregnated CVC.  

Teleflex agrees in principle with this statement but is concerned that its current structure does not accurately reflect the known degree of risk. Teleflex refers the review by Sharp et al[14]to the NHMRC noting Sharp’s observation that: “Literature exists of patients with known allergy and even previous anaphylactic reactions to CHL being exposed again to CHL resulting in repeated anaphylaxis. Most of these occur during CVC insertion.” Sharp p. 240.  

Accordingly, Teleflex recommends that the section be restructured to read: “Anaphylactic reactions to chlorhexidine are rare but are potentially life-threatening complications. Increasing chlorhexidine usage by consumers and healthcare workers has resulted in a number of different adverse reactions including allergic contact dermatitis, photosensitivity, anaphylaxis and septic shock [296] [297] [298] [299]. Greater recognition of the potential for chlorhexidine-related anaphylaxis is needed, and patients should be prompted for any chlorhexidine reactions/anaphylaxis during the 'allergy history' subjective assessment. Chlorhexidine containing solutions, dressings or impregnated devices should never be used with patients known or suspected to be sensitive to chlorhexidine.  

Chlorhexidine is an excellent antiseptic agent that may very infrequently cause anaphylaxis. Though anaphylactic reactions to chlorhexidine are uncommon, it is an increasingly prevalent allergen in the perioperative setting. Exposure to chlorhexidine in the clinical environment is routine. Avoidance of recurrent anaphylactic reactions must begin with the identification and substitution of all products containing chlorhexidine. Careful planning and implementation is required to prevent inadvertent exposure to chlorhexidine in the sensitised patient as they move throughout the hospital system.

Teleflex recommends deletion of the current line “Whilst information is limited, it seems the severity of allergic reactions is greatest when the exposure is a result of a chlorhexidine impregnated CVC” as this risk is more accurately described by the proposed replacement reproduced from the Australian and New Zealand College of Anaesthetists (ANZCA)recommendations[15, 16]  “Chlorhexidine is an excellent antiseptic agent that may occasionally cause anaphylaxis. Though anaphylactic reactions to chlorhexidine are uncommon, it is an increasingly prevalent allergen in the perioperative setting.”   

In the period 2015 – 2017 Teleflex sold 9.6 million Chlorhexidine impregnated central venous catheters globally with 8 reports of chlorhexidine hypersensitivity. In that same period Teleflex Australia sold 150,000 units of Chlorhexidine impregnated central venous catheters with 1 report of chlorhexidine hypersensitivity. [18] Chlorhexidine hypersensitivity is relatively rare, but it can be serious & even life-threatening. Central Line Associated Bloodstream Infection (CLABSI) remains an issue and is a life threatening risk. The CDC reports a 25% mortality rate in patients with confirmed CLABSI. [1]  The CDC & SHEA guidelines gave select antimicrobial catheters, including the Teleflex / Arrow Chlorhexidine & SSD impregnated catheters their highest evidential rating for effectiveness & recommend they be considered as a method for CLABSI prevention.[1,5]   

2017 saw the Federal Drug Administration (FDA) release a safety communication about hypersensitivity reactions to Chlorhexidine Gluconate used as a skin antiseptic. There were 52 cases of anaphylaxis with Chlorhexidine Gluconate being used as a skin antiseptic in the period 1969 – June 2015. With the majority of reports being since 2010. [19] https://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm539575.htm This safety alert would support the deletion of the line “Whilst information is limited, it seems the severity of allergic reactions is greatest when the exposure is a result of a chlorhexidine impregnated CVC”

 V111.          Risk Management and Chlorhexidine (Subsection 4.1.4; Practice Statement 38 – Key Info Quality of evidence 172 of 294)

This section in the draft currently reads “A recent literature review found that chlorhexidine-related anaphylaxis appears to be a relatively rare event in healthcare. However, the evidence in this area is limited, and the studies available tend to be retrospective and focused specifically in perioperative settings. The limited nature of the evidence makes it difficult to determine the clinical significance of these findings, and it is possible that larger acute care healthcare facilities might encounter one or more anaphylactic events each year.”  

Having reviewed the 2017 literature review undertaken by the University of South Australia What is the impact of chlorhexidine use on the incidence of anaphylaxis?[17] Teleflex is concerned that the comment “It is possible that a large acute care hospital might encounter one or more chlorhexidine-related anaphylactic events each year.” is unsubstantiated by the authors of the literature review and repeated verbatim and without reference in the quality of evidence following Practice Statement 38. For these reasons Teleflex recommends that the ICGAC and NHMRC review this statement and remove it. Should a substitute comment be required we would recommend reviewing Sharp et al & the ANZCA Chlorhexidine practice guidelines and replacing with Chlorhexidine is an excellent antiseptic agent that may very infrequently cause anaphylaxis. Though anaphylactic reactions to chlorhexidine are uncommon, it is an increasingly prevalent allergen in the perioperative setting.”   

Please be assured that Teleflex appreciates the need for recommendations regarding infection control and prevention generally and specifically regarding vascular access and safe, appropriate chlorhexidine use. To facilitate ICGAC and NHMRC’s review of Teleflex’s comments research used in this submission can be downloaded from https://www.dropbox.com/sh/cpikwlyvx3ccyuh/AACqCKCSKBxYiWhAXvPkZLH4a?dl=0

References

1.         O'Grady, N.P., et al., Guidelines for the prevention of intravascular catheter-related infections. American Journal of Infection Control, 2011. 39(4 Suppl 1): p. S1-34.

2.         Hadaway, L. and D. Richardson, Needleless connectors: a primer on terminology. J Infus Nurs, 2010. 33(1): p. 22-31.

3.         Hadaway, L., Needleless Connectors: Improving Practice, Reducing Risks. Journal of the Association for Vascular Access, 2011. 16(1): p. 20-33.

4.         O'Grady, N.P., et al. Guidelines for the prevention of intravascular catheter-related infections: Recommendation Updates. 2017 July 2017 [cited 2018 9th May 2018];                Available from: https://www.cdc.gov/infectioncontrol/guidelines/bsi/updates.html.

5.         Marschall, J., et al., Strategies to prevent central line-associated bloodstream infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol, 2014.                  35(7): p. 753-71.

6.         Australian and New Zealand Intensive Care Society. Central Line Insertion and Maintenance Guideline. 2012  [cited 2017;                                                                              Available from: http://www.anzics.com.au/Downloads/ANZICS_Insertion%26maintenance_guideline2012_04.pdf.

7.         Loveday, H.P., et al., epic3: national evidence-based guidelines for preventing healthcare-associated infections in NHS hospitals in England. J Hosp Infect, 2014. 86                   Suppl 1: p. S1-70.

8.         Royal College of Nursing, Standards for infusion therapy. 2016, Royal College of Nursing.: London.

9.         Rickard, C.M., J. Webster, and E.G. Playford, Prevention of peripheral intravenous catheter-related bloodstream infections: the need for a new focus. Med J Aust,                      2013. 198(10): p. 519-20.

10.       Cobrado, L., et al., Anti-Candida activity of antimicrobial impregnated central venous catheters. Antimicrobial Resistance and Infection Control, 2017. 6: p. 110.

11.       Lai, N.M., et al., Catheter impregnation, coating or bonding for reducing central venous catheter-related infections in adults. Cochrane Database of Systematic                          Reviews, 2016(3).

12.       Ullman, A.J., et al., Dressing and securement for central venous access devices (CVADs): A Cochrane systematic review. Int J Nurs Stud, 2016. 59: p. 177-96.

13.       Marsh, N., et al., Devices and dressings to secure peripheral venous catheters: A Cochrane systematic review and meta-analysis. Int J Nurs Stud, 2017. 67: p. 12-19.

14.       Sharp, G., S. Green, and M. Rose, Chlorhexidine-induced anaphylaxis in surgical patients: a review of the literature. ANZ J Surg, 2016. 86(4): p. 237-43.

15.       Australian and New Zealand College of Anaesthetists (ANZCA), Guidelines on the Perioperative Management of Patients with Suspected or Proven Hypersensitivity to                Chlorhexidine, in PS60. 2016, ANZCA.

16.       Australian and New Zealand College of Anaesthetists (ANZCA), Guidelines on the Perioperative Management of Patients with Suspected or Proven Hypersensitivity to                Chlorhexidine: Background Paper, in PS60BP. 2016, ANZCA.

17.       University of South Australia, What is the impact of chlorhexidine use on the incidence of anaphylaxis?, D.o.H.S. School of Nursing and Midwifery, Editor. 2017,                        National Health and Medical Research Council (NHMRC): Canberra.

18.       Teleflex 2018 SAP Data on File

19.       Federal Drug Administration. Safety Communication. FDA warns about rare but serious reactions with the skin antiseptic chlorhexidine gluconate. Feb 2017 FDA