Antibiotics are dangerous, unless you actually need them.

In response to my previous post Claus Klingenberg wrote a comment in which he mentioned a recent systematic review that he had published with a group of colleagues. This review of a small number of RCTs (9) and a larger number of observational studies (38) examined the effects of prolonging or broadening the spectrum of antibiotic therapy on individual risks such as NEC and later fungal sepsis, and how those complications impact mortality. (Esaiassen E, et al. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1858-70).

The RCTs were generally comparisons of different antibiotic regimes, apart from one of routine antibiotics vs no antibiotics. The observational studies were also mostly short vs long courses, and narrow vs broad spectrum. They found:

Prolonged antibiotic exposure in uninfected preterm infants is associated with an increased risk of NEC and/or death, and broad-spectrum antibiotic exposure is associated with an increased risk of IFI.

The authors of the review appropriately did not calculate a pooled Odds Ratio, as the studies are too heterogeneous, but the individual ORs for NEC and/or death range from 1.3 to 7.7, they include numerous observational studies with over 5,000 babies. The studies of invasive fungal infection show in most instances, and particularly in larger studies, an association with the use of third generation cephalopsorins or carbapenems. Specifically among preterm infants, there is an increase in all-cause mortality when antibiotics are given for longer periods in babies with negative cultures.

 

 

 

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A negative view of culture-negative sepsis

I have now posted quite a few times about ways to reduce antibiotic use in the NICU, and in the term baby nursery.

One thing that would help to reduce unnecessary usage is to abandon the idea that culture-negative sepsis is an entity that needs to be treated with antibiotics. I well remember a pair of mono-chorionic twins from several years ago that had identical presentations of early-onset sepsis with shock in the first few hours of life. One had a blood culture positive for E. Coli, the other had negative cultures. Presumably the cytokine/inflammatory response in the bacteremic twin had been shared with his brother through anastomotic channels. Treating such an inflammatory response syndrome with antibiotics is unlikely to improve outcome.

A great perspectives article recently published on-line in Pediatrics (Cantey JB, Baird SD. Ending the Culture of Culture-Negative Sepsis in the Neonatal ICU. Pediatrics. 2017) reviews the reasoning many people use to continue antibiotics in the face of negative cultures. They note the following:

1. if a culture of at least 1 mL is obtained before starting antibiotics, the sensitivity of detecting organisms down to a bacterial density of 4 CFU/mL is close to 100%, and is probably even better with the newest culture techniques.

2. Infants with negative cultures at 36 to 48 hours who have their antibiotics stopped virtually never need further treatment.

3. Infants who have negative cultures after maternal antibiotic therapy were either not infected or have been adequately treated. This is not a reason for continuing antibiotics.

4. Ancillary tests (CRP, procalcitonin, and the like) are of no use for deciding if a baby is septic, they have poor positive predictive value, and are non-specific.

5. Our clinical opinion as to the likelihood of sepsis is very poorly predictive of true sepsis.

“Culture negative sepsis” may indeed exist, the example I gave above is one situation which you could call by that name, viral infections, leading to an inflammatory response, are another. Neither situation is likely to benefit from prolonged antibiotic therapy.

The authors conclude that we need to learn to trust our blood cultures

Put simply, if the bacteria cannot grow in the blood culture bottle (an ideal medium at an ideal temperature, free of antibiotics, complement, or phagocytes), then why would they grow effectively in the infant’s bloodstream? As we learn more about the adverse effects of antibiotic exposure on short- and long-term neonatal outcomes, it becomes increasingly clear that prolonged antibiotic therapy for suspected sepsis is a luxury our infants cannot afford.

If you have access, I urge you to read this well-reasoned and well-written piece, and take its message to heart. Prolonged antibiotic therapy in the face of negative cultures increases the risk of later sepsis, and of necrotizing enterocolitis. Killing probiotic organisms in the gut with antibiotics allows the overgrowth of pathogens which can then wreak havoc.

I think we should have a rule that antibiotics are always stopped after 36 hours. Continuing them would then need a definitive decision, which would be easy if the cultures are positive, and should almost always be a decision to not restart in the face of negative blood cultures.

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Volume guarantee, does it guarantee volume?

I published an abstract somewhere, a while a go, that was called “Volume guarantee does not guarantee volume”. It was a summary of the results of a short-term cross-over trial which showed that tidal volumes stays quite variable when you switch from pressure limited ventilation to volume-guarantee, using the Babylog.

The reason of course is that respiratory efforts vary from breath to breath, so a system designed to measure the tidal volume delivered and then adjust the pressures for the next breath, is bound to be always playing catch-up. Sometimes the variability is small, sometimes, when the baby is irritable or crying, for example, the variability can be quite substantial.

In true volume-controlled ventilation the machines deliver a fixed volume into the ventilator circuit for each breath; there actually was at one time a neonatal ventilator that did this, the old Bourns LS104, which I am old enough to have actually used (in my animal lab). The problem with such machines is that the compressible volume of the ventilator circuit is substantially greater than the volume of a baby’s lungs, so any minor change in lung compliance (the ventilator circuit has, of course, an unchanging compliance) can lead to dramatic changes in the actual pulmonary tidal volume received by the infant. If compliance deteriorates significantly you can end up ventilating just the ventilator circuit, and not the baby. In contrast improvements in compliance can lead to dramatic increases in the volumes delivered to the baby, and excessive, damaging inhalational volumes. The Bourns LS104 was associated with worse pulmonary outcomes and went off the market.

Safe volume ventilation in newborns must be determined by the volume actually entering (or leaving) the lungs of the baby, and measured at the endotracheal tube. Some of the trials of “volume targeted ventilation” (including the 2 of the largest ones included in the Cochrane review) in the newborn have used the Siemens Servo 300c in PRVC mode, which measured the volume delivered at the ventilator end of the circuit. Volumes selected for those trials were determined by watching the babies chest move and selecting a volume which gave good chest movement, which varied between 5 and 15 ml/kg. You really cannot call that volume targeted ventilation, and such studies should be considered separately in systematic reviews of volume targeted ventilation in the newborn. In fact if you take those trials out of the systematic reviews, the evidence base for a clinically significant benefit of volume targeted ventilation is rather weak with not many more than 100 patients on volume ventilation and 100 with pressure limited ventilation (even though I personally think it is likely to be an improvement over pressure limited ventilation).

So a system that adjusts pressures in order to get the target volume, will always have tidal volumes which are variable (unless your patient is apneic or paralyzed). In contrast, a system which targets a particular pressure (standard neonatal ventilators that is) will likely have even higher variations in volume, including potentially damaging breaths with excessive inspiratory volumes.

Overall, volume guarantee systems should therefore have fewer breaths which are seriously excessive (or indeed breaths which are much too small). Is that really true? There are numerous small short-term cross-over studies that demonstrate that indeed there are fewer excessive tidal volumes with the babylog or VN500 systems. In part this is also likely to be due to another safety feature in VG ventilation, at least with the Drager systems, that once the volume passes a particular threshold (for the babylog/VN500 that is 130% of the set tidal volume) the inhalation is terminated, and circuit pressure returns to the set PEEP.

How good are the machines at consistently delivering the desired tidal volume? A new publication from David Tingay and his group from the children’s hospital in Melbourne examined this with the SLE 5000.

Farrell O, et al. Volume guaranteed? Accuracy of a volume-targeted ventilation mode in infants. Archives of disease in childhood Fetal and neonatal edition. 2017.

They showed with an extensive data collection in 100 babies, with millions of inflations recorded, that tidal volumes were close to the desired tidal volumes with narrow confidence intervals.

One thing I noted that seemed a bit strange however, is from their figure 1.

(A) Bland-Altman plot of VTset and expiratory tidal volume (VTe) . Solid black line denotes the bias, dashed black lines denote the 95% CI of the limits of agreement. (B) Relationship between VTset and VTe; y=0.736x+1.073 (r=0.34, p<0.0001; linear regression). Solid black line represents the line of best fit and dotted black lines represent 95% CI bands. To ease visual interpretation of figures, and after seeking statistical advice, symbols represent the average values for each infant rather than all values analysed (maximum 90 000/infant)

The dots on the graphs represent the average values from individual patients, who had a median of over 80,000 inflations per patient. Therefore over a large number of inflations some babies had average delivered tidal volumes that were up to 3 mL/kg less, or nearly 2 mL/kg more, than the desired tidal volume, if I interpret graph A correctly. I can understand that sometimes the pressure limit is being hit frequently, limiting the administered pressures and therefore the tidal volume, and that this could lead to smaller average tidal volumes than the set volume; but I find it hard to understand why tidal volumes would be consistently larger than the set volume over a large number of inflations, shouldn’t the ventilator have reduced the pressures to lead to smaller tidal volume? I guess it is possible that the ventilator had reduced the peak pressure down to a minimum (PEEP) and the baby was spontaneously generating volumes higher than the set volume. It would be nice to know if these explanations are correct.

Other findings were that it seems that CO2 is probably truly more stable during volume targeted ventilation, and that the latest algorithm for leak adjusting the inflations seemed to work better that the older algorithm, and indeed worked quite well up to an ETT leak of 30%.

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When good journals print nonsense. (And good doctors too).

It is hard to believe the drivel some people are prepared to countenance just because it is supposed to be very old drivel. Chen KL, et al. Acupuncture in the neonatal intensive care unit-using ancient medicine to help today’s babies: a review. J Perinatol. 2017;37(7):749-56.

Starting with the questionable premise that acupuncture has been in use for ‘thousands’ of years (a brief summary of the recent history of Acupuncture can be found here)., the authors of this article promote its investigation for pain control in the newborn’. Even if the earliest known possible references to acupuncture (which date from about 100 BCE) do really refer to what we now know as acupuncture, the fact that it is an old system is not necessarily in its favour. For it is based on pre-scientific theories of how bodies work, and the manipulation of non-existent energies (Xi) that flow through non-existent meridians, we would be better to remain extremely sceptical that sticking needles anywhere in the body would have distant effects on specific illnesses, or indeed any reproducible effect at all.

Fortunately we have ditched just about all of “traditional western medicine”, which was also based on a similarly profound lack of understanding of anatomy and of physiology.

What is clear from published research is that there are sometimes small effects of acupuncture, which are reproduced regardless of the site that the needles are stuck into, and that you can get the same effects without sticking the needle in at all. The better a study is designed, the lesser the effects of acupuncture. In studies with complete blinding, using sham acupuncture at random sites in control groups, the small effects of acupuncture are usually identical to the small effects of sham controls. (See here for a review of systematic reviews of acupuncture for pain control which concludes “Numerous reviews have produced little convincing evidence that acupuncture is effective in reducing pain. Serious adverse events, including deaths, continue to be reported”).

Some people have promoted these small effects as evidence that acupuncture harnesses the “placebo effect” (as if that was a good thing) what it really is, is evidence that it does not have a real effect.

Using acupuncture, of any variety, including shining lights on “acupuncture points”, is a totally unethical thing to do in an investigation of pain control in the newborn. To perform a painful procedure and test acupuncture against a known effective analgesic is an idea that should horrify anyone who cares about pain in babies.

The articles quoted in this review include ridiculous nonsense such as the “demonstration of active acupuncture points” in the ears of babies with neonatal abstinence syndrome. The demonstration of these non-existent points is often made with a “machine that goes ping”,

which is what was done in the study they refer to. These are galvanometers of various designs, which are used as  supposed identifiers of acupuncture points, they have never been shown to do anything except go “ping”. It is hard to believe that anyone could swallow the idea that there is a specific point in the ear that can be needled to create specific effects elsewhere in the body, based on totally imaginary “homunculi” like this one.

Far from being thousands of years old, auricular acupuncture was made up in France in the 1950’s. The “machines that go ping” measure electrical conductivity of the skin, which varies according to the angle of the implement, the pressure applied, and how much the skin is stretched: such machines have never been demonstrated to detect any real structure or phenomenon.

Despite its total lack of scientific justification there are unfortunately a couple of studies in newborn infants that have been performed. They, not surprisingly, showed no effect of laser acupuncture or of acupuncture accompanied by electrical stimulation. One of the studies, examining the analgesic effect of laser acupuncture, compared laser acupuncture alone to sucrose alone before heel lancing in newborns, the infants in the sucrose group had less pain; that is a truly unethical trial.

We must not start exposing newborn infants to painful procedures in order to investigate the impact of this nonsense. Acupuncture is nothing more than a theatrical placebo, which is unlikely to impress a newborn infant. As Colquhoun and Novella note “A small excess of positive results after thousands of trials is most consistent with an inactive intervention. The small excess is predicted by poor study design and publication bias…The best controlled studies show a clear pattern, with acupuncture the outcome does not depend on needle location or even needle insertion. Since these variables are those that define acupuncture, the only sensible conclusion is that acupuncture does not work.”

If you can get this nonsense published in a normally high quality journal, maybe I should write a review article about ear candling, or the benefits of homeopathy: or maybe I should set up an “alternative medicine NICU”, it would probably be as effective as Mitchell and Webb’s emergency room.

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Not neonatology; trip to Western Canada.

I have just returned from summer vacation, we were very fortunate with the weather and with the wildlife viewing. I have put 2 new pages up of my photos under the “Photos” item on the menu at the top of this page. Wildlife of the Canadian Rockies, and Wildlife of the West Coast, Vancouver Island.

One photo I am quite pleased with is of a Purple Martin mother feeding her chick, that had grown to be a similar size to her. It was the first time I had seen Purple Martins, (unfortunately there were no males around), and I caught the moment when the mother deposited the meal right at the back of the young ones mouth. In this sequence  you can see her approaching the noisily demanding chick, then, with the nictitating membrane over her eye, plunging her beak into the chick’s mouth, and then, without pausing, she flew off again to find more food for her hungry charge. Exhausting being a new parent.

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Using less antibiotics

Most newborns who receive antibiotics are not infected. This is true of full term babies in normal newborn care, and preterms in the NICU. For most infants antibiotics can be stopped after 36 hours if cultures are negative at that point (for the few which are positive between 36 and 48 hours, antibiotics can be restarted without missing a dose). Duration of treatment of those with positive cultures, or of those who are thought to have culture negative sepsis, is quite arbitrary.

Stocker M, et al. Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). Lancet. 2017.

In this large international RCT of infants who had antibiotics started for suspected early onset sepsis (<72 hours of age) and who were term or late-preterm were randomized. Infants were evaluated with a reasonably objective risk scoring system, and could score 1 point for risk factors, 1 point for clinical findings, and 1 point for lab values.

The 2 randomized groups either had duration of therapy determined by Procalcitonin levels, or by an arbitrary duration, as shown in the figure. Babies who had positive cultures had at least 7 days of antibiotics, regardless of procalcitonin levels.

The group who used procalcitonin levels had shorter duration of antibiotics, a mean of 55 hours versus 65 hours. But of the 1710 babies included in the trial 47% were determined to be “infection possible”, and 41% were “infection unlikely”.  Only 27 babies had proven infections or about 1.5%.

My main problem with this trial is that the duration of antibiotic use in infants who are not infected is much too long. Any infant with a risk factor, even with no clinical signs, no other supportive evidence and with negative cultures at 36 hours receives between 36 and 72 hours of antibiotics. Any infant with a risk factor and one other point on the risk scale (for example for respiratory distress, or an elevated CRP) will receive 5 to 7 days of antibiotics. So any infant born before 37 weeks who has respiratory distress will have got at least 5 days of antibiotics in the non-procalcitonin group.

A baby with a history of chorioamnionitis or 20 hours ruptured membranes, respiratory distress, and an elevated CRP would be considered to be “infection probable” and would get 7 to 21 days of antibiotics, even if they improved rapidly, and had negative cultures. The clinical sign that was the most frequent was indeed respiratory distress.

I think that the authors have not shown that procalcitonin reduces duration of antibiotic use compared to a more reasonable approach, in which they would be stopped in the large majority of infants at 36 hours if cultures are negative.

I think most babies in this study should have had their antibiotics stopped at 36 hours, so the results of 55 and 65 hours of treatment that they found are both too long.

Overuse of antibiotics is a big problem, when less than 2% of treated babies can be proven to have an infection. Under-treating a baby who is truly infected is the concern that drives these numbers; the authors tried to evaluate that by looking also at deaths within the first month of life, and re-infection with 72 hours of stopping antibiotics. However, the numbers of those events was tiny (less than 1%) so there is no significant difference between the groups, the actual numbers are identical between the groups.

Many of the infants enrolled in this study, especially those in the ‘infection unlikely” group would not even have qualified for antibiotics if the evidence-based neonatal sepsis risk calculator, that I discussed previously, had been used. (It obviously wasn’t available when these authors were planning theire trial, but it is easily available now!)

Mukhopadhyay S, Puopolo KM. Clinical and Microbiologic Characteristics of Early-Onset Sepsis Among VLBW Infants: Opportunities for Antibiotic Stewardship. Pediatr Infect Dis J. 2017.

There is clearly room for improvement among preterm babies also. It has long been my practice to not perform cultures or give antibitoics to preterm babies born by Cesarean delivery with intact membranes to mothers who were not in labour.If there isn’t a route for a baby to get infected they aren’t likely to be infected!

This new publication confirms that practice to be safe. They reviewed over 5000 VLBW infants admitted to the Brigham and Women’s hospital, of which 109 had culture positive sepsis. There was only 1 case of a positive culture among an infant delivered with the characteristics that I mentioned, and that was almost certainly a contaminant (1 of 2 bottles grew a coagulase negative staph, which was negative on repeat culture despite the antibiotics not covering the germ).

The study also confirmed that cultures were very often positive before 36 hours, and 98% before 48h, so a 36 duration of initial antibiotic prescription is appropriate.

Being preterm is not an infectious disease. Some babies are at very low risk of actually being septic and we can avoid giving them antibiotics.

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Life, and medicine, with a disability

I met the author of this article at a CPS meeting a few years ago, she immediately impressed me with her unique perspective. Paige is a developmental pediatrician who does long-term follow-up of preterms, and is involved in developmental evaluation and intervention of children with other challenges, including Spina Bifida.

Church P. A personal perspective on disability: Between the words. JAMA Pediatrics. 2017.

As you will see if you read the article, Paige has a form of Spina Bifida herself, a Lipomyelomeningocele, with a neurogenic bladder and neurogenic bowel, requiring life-long interventions. She discusses the poor tolerance many medical people have of disability, and such how things are often discussed as black or white, whereas having a profound personal experience of disability has made her much more nuanced.

She recounts being involved in a discussion regarding a “selective reduction” of a twin pregnancy where the twin being considered for “reduction”, i.e. abortion, had a similar lesion to her own.

That is an experience that I can barely understand: how would I react if a family was considering terminating  a pregnancy because of a condition that I had? Paige recounts the episode with tact and humanity.

I can imagine, as I have heard them many times, the words of the other physicians involved in such a decision, I am sure they talked about handicaps and limitations, poor quality of life, pain, and restrictions on family life. Most of which is said with good intentions but with no real knowledge of the literature, or of the range of experiences of families living with the challenges.

Just as with similar discussions regarding extreme preterm infants, a list of complications, interventions, disabilities, and long-term problems is often presented, but with no similar list of benefits, achievements, abilities, long-term adaptation, and happiness.

Near the end of her moving piece Paige writes:

Like most things in life, and medicine, disability is sharp, painful, humbling, as well as tremendous, giving, awe-inspiring. It is human. It is not easily distilled to an all or none discussion. Medicine sets the tone for this discussion and, to date, has done a miserable job. More is needed to appreciate the incredible opportunities that disability poses. More education is needed to provide the counselling families deserve: balanced, sensitive, thoughtful, and individualized rather than “objective.”

I sincerely hope that this piece by Paige will be part of a new discussion about these issues.

(Of note, even though the article is behind a paywall, JAMA lets you see the first page of the article before buying, in this case there is only one page, so you can read the whole thing for free!)

Posted in Advocating for impaired children, Neonatal Research | 1 Comment