Call me prescient, OK, you won’t, but I will. Two recent observational studies suggest that the recent NICE guidelines have had adverse effects on infants evaluated for potential early neonatal sepsis. ‘NICE’ of course is not an adjective for how good the guidelines are, but the acronym for the National Institute of Health and Care Excellence in the UK.
Any long time neonatalresearch watchers will remember vividly my perceptive analysis and critique of those guidelines. Which included the good (to stop antibiotics at 36 hours if no signs of sepsis) and the questionable; universal measurement of CRP at the start, with a repeat at 18 to 24 hours, and stopping the antibiotics if the trend is ‘reassuring’. My concern being that CRPs are relatively sensitive but with low specificity. Infants exposed to many different stressors, infectious and not, may have increased CRP. As early onset sepsis in term infants is relatively uncommon in most of the at-risk situations outlined, the proportion of babies who have unnecessary prolongation of antibiotic therapy solely for a CRP which is not ‘reassuring’ might be substantial.
You have, of course, to balance that against the theoretical benefit of continuing antibiotics in an infant who is truly septic, in whom the antibiotics would have been stopped were it not for the non-reassuring CRP. A benefit which is likely to occur much less often.
Two recent studies have sought to quantify these impacts.
Mukherjee A, Davidson L, Anguvaa L, Duffy DA, Kennea N. NICE neonatal early onset sepsis guidance: greater consistency, but more investigations, and greater length of stay. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014.
This is a before-after study which investigated the impacts on babies evaluated for possible sepsis.
I think this is from a single hospital in London (it is a short report so some details are missing, also weirdly there is not a single reference, not even to the NICE guidelines), and it appears that about 8-9% of babies had sepsis work-ups, with around 70 babies affected in each of the 2 month cohorts, before and after the NICE guidelines.
They looked at how many babies stayed in the hospital less than 72 hours, this decreased from 38.1% to 18.4%. More babies stayed over 5 days, from 20.9% up to 27.7%. They found that 58% of the repeat CRPs were used to change management, including leading to more LPs (14% up to 23%). In all of their babies there were no positive cultures.
We envisaged shorter hospital stays with new NICE standards, particularly, with the aim of 36 h blood culture reporting. However, repeat CRP led to further investigations, increased LPs and longer durations of treatment and stay. This, in turn, impacted on workload and cost, and influenced parental experience in the first few days of life
This experience, published as a letter in Archives, recounts what happened with about 40 babies, before and after the guidelines. 1 of 40 before the guidelines had an LP, compared to 8 afterward. Entirely because the CRP was raised. Hospital stay increased after the guidelines, and duration of antibiotic use increased. None of the babies had positive cultures.
Our results indicate that babies in group B had prolonged hospital stay requiring longer duration of intravenous antibiotics without much clinical benefit.
I think there should be a rapid re-evaluation of these guidelines, which seem to be only having negative effects, at least from these 2 experiences. I think the reason that the NICE guidelines are not very nice is that the data being used to support the recommendation are based largely upon a single study from 1998, a good study from Bill Benitz in California, unfortunately (for the NICE guidelines) that study was not among asymptomatic babies, but only babies who had symptoms, the list of which includes shock, new apnea, lethargy, respiratory distress and so on, and also includes preterm infants down to 550 grams birth weight. It only included babies treated for sepsis in one of 3 NICUs. (See evidence table 10.3 in the guideline that you can find here). So it is of no relevance to the healthy full term baby with risk factors alone, in whom the false positives are clearly going to be much more frequent.
In the more recent study by Thierry Lacaze and colleagues, which only included asymptomatic infants being evaluated because of signs of sepsis, a single CRP at 18 hours of age had a PPV of 14% for proven or probable sepsis. I discussed the article when it first came out, and I think the suggestion of those authors, that a low CRP at 18 hours of age, using a method which gave a result immediately to the medical team, could lead to earlier stopping of antibiotics and earlier discharge is reasonable. The implication being that a non-reassuring CRP would then mean waiting until 36 hours and making a decision independent of the CRP.
For asymptomatic babies CRPs are too sensitive, being elevated for all sorts of reasons unrelated to sepsis requiring treatment.