Oral immune therapy (OIT) has really taken off at least in our units. The notion here is that provision of small amounts (0.2 mL intrabucally q2or 24 hours) can prime the immune system. Lymphoid tissue present in the oropharynx and intestine exposed to this liquid gold in theory will give the immune system a boost and increase levels of IgA. Such rises in IgA could help improve the mucosal defence barrier and therefore lessen the incidence of late onset sepsis. Rodriguez et al described this in their paper Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives in 2009. They followed it up the next year with a pilot study demonstrating how to actually administer such therapy. The fact that this approach has been adopted so quickly I think speaks to the principle that this kind of therapy falls into the category of “can’t hurt and might help”. The real question though is does it actually make a difference?
Recently, authors from Brazil presented their findings from a single centre double blind RCT entitled Randomized Controlled Trial of Oropharyngeal Colostrum Administration in Very-low-birth-weight Preterm Infants. This authors are commended for studying this practice in such a fashion and included infants <34 weeks who were <1500g at birth to receive the above mentioned intervention. These infants were compared to placebo who received the same intervention except instead of mother’s own colostrum they were given sterile water. In total there were 149 infants randomized with 81 receiving OIT vs 68 who received a placebo. The primary outcome of interest on which a power calculation was performed was the incidence of late onset sepsis. Other typical outcomes including NEC, ROP, BPD, IVH and death were also followed.
Did they find a difference?
Sadly to many of you I am sure they did not as is shown in the table below.
Surprisingly the authors also looked at levels of IgA in infants in both arms and also found no difference.
There is a big problem with this study however that no doubt will lead to a repeat version at some point. While the authors enrolled the numbers above, the numbers that were analyzed in the table are 34 lower in the OIT arm and only 2 lower in the placebo group. In essence, a large number of mothers after enrollment were not able to provide the colostrum that was needed for the study. The study called for 48 applications over a 48 hour period and a little more than half of the mothers were able to do it.
Do not be dismayed then that no difference was found here. There is no need to “throw the baby out with the bathwater” and abandon OIT based on this one study. I think what is needed in the future though is a study that enrolls far more than needed to account for attrition due to loss of mothers who can complete the study. Without another study I think the practice will continue but does it really make a difference to rates of sepsis? Who knows but there is no doubt it helps parents who are feeling that they have lost control of a pregnancy that has gone wrong, a positive experience and the feeling that they are doing something for their child.
I had the pleasure of meeting the author of a paper I am about to comment on this week while at the 99 NICU conference in Stockholm. Dr. Ohlin from Orebro University in Sweden presented very interesting work on their unit’s “scrub the hub” campaign. As he pointed out, many places attempt to reduce coagulase negative staphylococcal infections by introducing central line bundles but seldom is there one thing that is changed in a bundle that allows for a before and after comparison like his team was able to do. I was so impressed by this work and at the same time concerned about another strategy to reduce infection that I felt compelled to make a comment here.
Scrub the hub!
Dr. Ohlin and the first author Dr. Bjorkman published Scrubbing the hub of intravenous catheters with an alcohol wipe for 15 sec reduced neonatal sepsis back in 2015. They compared a 16.5 month period in their unit when they rolled out a CLABI reduction bundle to a period of 8.5 months afterwards when they made one change. Nurses as is done in the units I work in were commonly scrubbing the hub before they injected the line with a medication but in the second epoch the standard changed to be a specified 15 second scrub instead of being left up to the individual nurse. With permission from Dr. Ohlin here is a picture of the hubs highlighting bacterial growth without scrubbing, then for a duration less than 15 seconds and then with 15 seconds.
In the first epoch they had 9 confirmed CLABSIs and 0 confirmed in the second after their intervention. The rate of CLABSI then in the first epoch was 1.5% vs 0% in the second group. As with any study looking at sepsis, definitions are important and while they didn’t do paired cultures to rule out contamination (one positive and one negative as is the definition in our hospitals) they did refer each patient to a senior Neonatologist to help determine whether each case should be considered a true positive or not. Given that they made no changes to practice or other definitions in diagnosing infections during that time perhaps the results were indeed real. Presumably if they had missed an infection and not treated it in the second epoch the patient would have declared themselves so I think it is reasonable to say that 8.5 months without a CLABSI after their intervention is a success. As Dr. Ohlin points out the scrub duration may also help due to the abrasion of the hub surface removing a bacterial film. Regardless of the reason, perhaps a 15 second scrub is a good idea for all?
The lazy person’s solution – the SwabCap
One way to get around human nature or people being distracted might be to cover each luer lock with a cap containing 70% isopropyl alcohol. In this way when you go to access the line there should be no bacteria or labour required to scrub anything since the entry of the line is bathed in alcohol already. This was the subject of a systematic review from the Netherlands entitled Antiseptic barrier cap effective in reducing central line-associated bloodstream infections: A systematic review and meta-analysis. The reviews ultimately examined 9 articles that met their inclusion criteria and found the following; use of the antiseptic barrier cap was effective in reducing CLABSIs (IRR = 0.59, 95% CI = 0.45–0.77, P < 0.001). Moreover, they concluded that this was an intervention worth adding to central-line maintenance bundles. Having said that, the studies were mostly adult and therefore the question of whether minute quantities of isopropyl alcohol might be injected with medications was not a concern when they made their conclusion.
What about using such caps in ELBW infants
Sauron et al in St. Justine Hospital in Montreal chose to look at these caps more carefully after they were implemented in their NICU. The reason for taking a look at them was due to several luer valves malfunctioning. The authors created an in-vitro model to answer this question by creating a closed system in which they could put a cap on the end of a line with a luer lock and then inject a flush, followed by a simulated medication (saline) and then a flush and collect the injected materials in a glass vial that was sealed to prevent evaporative loss of any isopropyl alcohol. They further estimated the safe amount of isopropyl alcohol from Pediatric studies would be 1% of the critical threshold of this alcohol and using a 500g infant’s volume of distribution came up with a threshold of 14 mmol/L. The study then compared using the SwabCap over two different valve leur lock systems they had in their units (SmartSite and CARESITE valves) vs. using the strategy of “scrub the hub”.
The results were quite concerning and are shown below.
SwabCap on Smart Site Valve
Incubator 35 degrees
SwabCap on CARESITE valve
Incubator 35 degrees
Isopropyl alcohol pad on CARESITE Valve
Certainly, the Smart Site valve allowed considerable amounts of isopropyl alcohol to enter the line but the CARESITE while better still allowed entry compared to the control arm which allowed none. Beyond the introduction of the alcohol into the system in all cases considerable clouding of the valves occurred with repeated capping of the system with new caps as was done with each med injection since each was single use. In lines that were not accessed contact with the cap was left for 96 hours as per recommendations from the manufacturer and these changes occurred as well.
While a reduction in CLABSI is something we all need to strive to obtain, it is better to take the more difficult path and “scrub the hub” and by that for 15 seconds which incidentally is the same recommended duration for hand hygiene in both of our units. Perhaps in larger term infant’s seepage of isopropyl alcohol into the lines would not be as concerning as their larger volume of distribution would lead to lower levels but I would ask the question “should any isopropyl alcohol be injected into any baby?”. I think not and perhaps by reading this post you will ask the same thing if your unit is using these caps.
Thank you to Örebro University Hospital for their permission in using the photo for the post
As I sit drinking my morning coffee and feeling a little sense of heartburn I began to reflect on the fact that I can’t recall the last time I prescribed ranitidine or a PPI in an infant for anything other than an acute upper GI bleed. I know I had done so after moving to Winnipeg in 2010 at a few time points but that practice has certainly died at least for me. You know what? I don’t think it has made one iota of difference but based on the results from this post I think it is for the best. What has inspired my republishing of this post is my question as to whether or not you think your units practice has changed as well since the revelation that these medications are not only ineffective but harmful. Read on and enjoy your Sunday
Choosing wisely is an initiative to “identify tests or procedures commonly used whose necessity should be questioned and discussed with patients. The goal of the campaign is to reduce waste in the health care system and avoid risks associated with unnecessary treatment.”
The AAP Section on Perinatal Pediatrics puts the following forth as one of their recommendations.
“Avoid routine use of anti-reflux medications for treatment of symptomatic gastroesophageal reflux disease (GERD) or for treatment of apnea and desaturation in preterm infants.
Gastroesophageal reflux is normal in infants. There is minimal evidence that reflux causes apnea and desaturation. Similarly, there is little scientific support for the use of H2 antagonists, proton-pump inhibitors, and motility agents for the treatment of symptomatic reflux. Importantly, several studies show that their use may have adverse physiologic effects as well as an association with necrotizing enterocolitis, infection and, possibly, intraventricular hemorrhage and mortality.”
How strong is the evidence?
The evidence for risk with acid suppression is largely based on either retrospective or in the case of Terrin G et al a prospective observational cohort study Ranitidine is Associated With Infections, Necrotizing Enterocolitis, and Fatal Outcome in Newborns. In this study the authors compared a group of premature infants with birth weights between 401 – 1500g or 24 – 32 weeks gestation who received ranitidine for reflux symptoms to those who did not. All told 91 were exposed while 183 were not. The authors are to be commended for standardizing the feeding protocol in the study so that when comparing NEC between groups one could not blame differences in formula consumption or rate of feeding advancement. Additionally, bias was controlled by having those not involved in care collect outcome data without knowing the purpose of the study. Having said that, they may have been able to ascertain that ranitidine was used and have been influenced in their assessments.
The patients in terms of risk factors for poor outcome including CRIB and apgar scores, PDA etc were no different to explain an increased risk for adverse outcome.
From the above table, rates of infections were clearly higher in the ranitidine group but more concerning was the higher rate of mortality at 9.9% vs 1.6% P=0.003 and longer hospitalization median 52 vs 36 days P=0.001.
I can say this much. Although small in number, the studies that are available will make it very difficult to ever have a gold standard RCT done on this topic. This scant amount of evidence, backed by the biologic plausibility that raising the gastric pH will lead to bacterial overgrowth and potential aspiration of such contents provides the support for the Choosing Wisely position.
Why do we continue to see use of such medications though? It is human nature I suspect that is the strongest motivator. We care for infants and want to do our best to help them through their journey in neonatal units. When we hear on rounds that the baby is “refluxing” which may be documented by gulping during a brady, visible spit ups during A&Bs or through auscultation hearing the contents in the pharynx we feel the need to do something. The question invariably will be asked whether at the bedside or by the parents “Isn’t there something we can do?”.
My answer to this is yes. Wait for it to resolve on its own, especially when the premature infants are nowhere close to term. I am not sure that there is any strong evidence to suggest treatment of reflux episodes with gastric acid suppression helps any outcomes at all and as we see from the Terrin study length of stay may be prolonged. I am all in favour of positional changes to reduce such events but with respect to medications I would suggest we all sit on our hands and avoid writing the order for acid suppression. Failure to do so will likely result in our hands being very busy for some infants as we write orders to manage NEC, pneumonia and bouts of sepsis.
I don’t know about you but I have deeply rooted memories from the 1990s of donning a yellow gown and gloves before examining each and every patient on my list before rounds. This was done as we firmly believed such precautions were needed to prevent the spread of infections in the NICU. As time went on though the gowns were removed and not long after so went the gloves as priority was placed on performance of good hand hygiene to reduce rates of infection in our units.
Essentially the authors hypothesized that the use of non-sterile gloves after performing hand hygiene (compared to hand hygiene alone) would reduce late-onset invasive infection (>72 hours after birth), defined as 1 or more episodes per patient of a BSI, urinary tract infection,meningitis, and/orNEC associated with clinical signs and symptoms of infection and treated with antimicrobials. When determining the size of study needed, they used a baseline incidence of 60% and looked to find a 25% reduction in their outcome. Unfortunately for them (although very fortunate for their patients, the incidence of LOS in the experimental arm was 32% with a 45% incidence in the control group (hand hygiene alone). What does this mean when your expected rate is higher than your observed? In short you need more patients to show a difference and indeed they failed to show a significant difference between the two groups. They did however find a difference in gram positive infections being 15 vs 32% p=0.03 and seem to take some comfort in this finding. If you were to give the paper a quick read you might be impressed with the finding and might even shrug your shoulders and say the common expression “Can’t hurt but might help” Maybe we should adopt this?
Not so Fast
There is a significant potential source of error here that needs to be addressed. The definition of a proven blood stream infection as per the CDC is two positive cultures for the same organism. In this study only one culture was required to be positive so the potential for diagnostic error is high. In our own centre although unpublished we have noted since adopting a mandatory two culture collection approach for LOS that there have been a significant number of occasions where one culture was noted to be positive and the other negative. Antibiotics in these cases have been stopped (for gram positive organisms) after 48 hours without consequence. In this study however the findings of increased rates of positive cultures in the hand hygiene only group is heavily influenced by the presence of only one positive culture as is seen in this table.
When looking at the numbers of times there were greater than or equal to 2 positive cultures in the CoNS group one sees the vast majority were only based on one culture. Furthermore, of the 20 infections in the hand hygiene only group, 19 were gram positve CoNS of which only 4 had more than one culture. Based on this finding and the lack of any other significant difference in infectious outcomes the proof that gloves add anything to reducing infection rates is tough to argue.
It certainly was a shock to see such a paper as I saw flashes of my past yellow gowned self coming back to haunt me. Based on my take of this paper however I would say that at least for the time being I will take my time, wash my hands before and after every patient encounter and keep the gloves around for handling those yet unbathed newborns. Spend your energy where it counts and that is ensuring your hands are properly cleaned before touching your patient or lines.
The scenario is often the same. Faced with a child born to a mother with risk factors for sepsis you decide to start antibiotics. The time comes closer to 36 – 48 hours when you must decide whether or not to continue. Each time we examine our results and look at cultures and try to do what is right. Yet defining right is sometimes hard for so many. If we had 100% sensitivity and specificity for all our tests it would be easy but we don’t. So what can we do?
If I had to have one wish though it would be that we could improve upon our diagnostic accuracy when it comes to treating suspected infections in the newborn. As health care providers we have an extremely loud inner voice trying to tell us to minimize risk when it comes to missing a true bacterial infection. On the other hand so much evidence has come forth in the last few years demonstrating that prolonging antibiotics beyond 48 hours is not just unwise in the absence of true infection but can be dangerous. Increased rates of necrotizing enterocolitis is just one such example but other concerns due to interfering with the newborn microbiome have arisen in more recent years. What follows are some general thoughts on septic workups that may help you (and myself in my own practice) as we move ahead into the New Year and may we cause less harm if we consider these.
The Role of Paired Blood Cultures
Although not published by our centre yet, we adopted this strategy for late onset sepsis a couple years back and have seen a significant reduction in work-ups deemed as true infections since adoption. While the temptation to do only one blood culture is strong as we have a desire to minimize skin breaks consider how many more there will be if you do one culture and get a CONS organism back. There will be several IV starts, perhaps a central line, repeat cultures etc. If you had done two at the start and one was positive and the other negative you could avoid the whole mess as it was a contaminant from the start. On my list of do no harms I think this may have the greatest benefit.
The Chest X-Ray Can Be Your Friend
While I am not a fan of routine chest x-rays I do believe that if you are prepared to diagnose an opacification on a chest x-ray as being due to a pneumonia (VAP or in those non-ventilated) that you need to follow this up with a repeat x-ray 24 – 48 hours later. If the opacity is gone it was atelectasis as a true pneumonia will not clear that easily. Well worth the radiation exposure I say.
If You Are Going To Do a Work-up Make It A Complete One
We hear often in rounds the morning after a septic work-up that the baby was too sick to have an LP and that we can just check the CSF if the blood is positive. There are two significant problems to this approach. The first which is a significant concern is that in a recent study of patients with GBS meningitis, 20% of those who had GBS in the CSF had a negative blood culture. Think about that one clearly… relying on a positive culture to decide to continue antibiotics may lead to partially treated GBS meningitis when you discontinue the antibiotics prematurely. Not a good thing. The second issue is that infants with true meningitis can have relatively low CSF WBC counts and may drift lower with treatment. Garges et al in a review of 95 neonates with true meninigits found that CSF WBC counts >21 cells per mm3 had a sensitivity of 79% and specificity at 81%. This means that in those with true meningitis 19% of the time the WBC counts would be below 21 leading to the false impression that the CSF was “fine”. If antibiotics were effective it could well be by 48 hours that the negative CSF culture you find would incorrectly lead you to stop antibiotics. Message: Do the CSF sampling at the time of the septic work-up whenever possible.
If We Aren’t Prepared To Do a Supra Pubic Aspirate Should We Not Collect Urine At All?
This provocative question was asked by a colleague last week and is based on the results of a study which was the topic of the following post: Bladder Catherterizations for UTI: Causing more harm than good? The gist of it is that it would appear that in many cases the results of a catheter obtained urine cannot be trusted. If that is the case then are we ultimately treating infections that don’t actually exist when the only positive culture is from a urine. I believe using point of care ultrasound to obtain specimens from a SPA will be the way to go but in the meantime how do we address the question of whether a UTI is present or not? May need to rely on markers of inflammation such as a CRP or procalcitonin but that is not 100% sensitive or specific either but may be the best we have at the moment to determine how to interpret such situations.
Lastly, Slow Down And Practice Good Hand Hygiene
So much of what I said above is important when determining if an infection is present or not. The importance of preventing infection cannot be understated. Audits of hand hygiene practice more often than not demonstrate that physicians are a group with some of the lowest rates of compliance. Why is that? As a physician I think it has nothing to do with ignorance about how to properly perform the procedure but rather a tendency to rush from patient to patient in order to get all the things done that one needs to do well on service or call. If we all just slow down a little we may eventually have less need to run from patient to patient as the rate of infections may drop and with it demand for our time.
If slowing down is something that you too think is a good idea you may want to have a look at the book In Praise of Slowness by Carl Honore (TED Talk by Carl Below) which may offer some guidance how to do something that is more easily said than done. Here is hoping for a little slower pace in the new year. We could reap some fairly large benefits!