Cochrane Neonatal Reviews #EBNEO

Cochrane Neonatal Reviews are now freely available full text at

Thanks to the Vermont Oxford Network for making this possible.

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Ethical issues in the NICU

Two new articles by John Lantos address ethical issues, one is explicitly about the NICU, the other is relevant to our issues, but uses an older child case as the example. The article in the FPNEJM is 8 pages long plus 2 pages of references, rarely seen in that journal!

Lantos JD. Ethical Problems in Decision Making in the Neonatal ICU. NEJM 2018;379(19):1851-60.

The central argument of this review is that an important and necessary shift is occurring in the focus of neonatal bioethics. The focus used to be on empowering parents by giving them information and on rule making to define the zone of parental discretion. Today, the focus is shifting toward an ethics of relational autonomy. Doctors need to develop new communication skills to help parents clarify their values. Doctors must also be aware of their own values as they design the choice architecture within which parents will be empowered to make choices. This self-awareness and these communication skills will be especially important as pediatrics changes and decisions become even more complex and value-laden.

He presents the following schema, which includes and expands on ideas and empirical research from several sources, including Annie Janvier, Antoine Payot and Nathalie Gauthier from our hospital, Marlyse Haward from Albert Einstein College of Medicine, several parents, including Barbara Farlow and Jason Baardsness, the POST group of neonatology professionals who have also been NICU parents, and of course, from John Lantos himself.

John Lantos also points out some relatively recent research that points out the limitations with the current paradigms of ethical decision making in the NICU, which he tabulates as shown below.

If you can get access to the full text it is worth the half an hour of your time that an initial read will take, and then several hours of thoughtful reflection.

Also very much worth the read is an article with the thought-provoking title “Tell Parents the Truth, but Tell It Slant” Lantos JD. Pediatrics. 2018;142(Suppl 3):S199-S204 (appears to be open access). Which might suggest at first that he is suggesting that we should bend the truth when talking with parents about difficult decisions. However, in reality he is quoting is from a poem of Emily Dickinson, and he is making a case for ambiguity, for gently revealing the truth when things are not going well, for humility.

He notes that discussions about redirecting active intensive care to comfort care often incorporate a formal request to write a DNR order, but that we do not request a “Do Not Dialyze” order or a “Do Not ECMO” order. That our discussions should incorporate more listening, and more attempts to understand the values and preferences of the family,  “to respect those values and honor those preferences, doctors need to listen carefully to understand what parents are saying, what they are not saying, what they mean, and what they need. Sometimes they may be saying that there are things that they prefer not to discuss or decisions that they prefer not to affirm”.

The quote incorporated into the title is from the first line of the poem (tell all the truth but tell it slant), and I think the last 3 lines of the poem say a lot about what John is talking about:

With explanation kind

The Truth must dazzle gradually

Or every man be blind —-


Who can hear that their child is dying and not react against it? Who can say “no thanks” when given an option of cardiac massage for their critically ill infant? We do violence to the families of our patients to offer them extreme measures which will not work. Rather than demanding explicit agreement to limit or withdraw care, we can often gradually, with explanation kind, let the truth gradually become dazzlingly clear.

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The 2018 Apgar award, and the 2018 Bartholome Award

Virginia Apgar Award

The most prestigious award given to an individual who has made major contributions to neonatology, by the AAP, is the Virginia Apgar award. This year the deserving recipient is Saroj Saigal. Saroj has worked for most of her career at McMaster University, in Hamilton Ontario, after a fellowship in Montreal. She has always performed very high quality work, particularly in neonatal follow-up. In the early 1990’s she realised that all the measurements that we do of the outcomes of extremely preterm babies do not capture their lived experiences, or how they feel about the quality of their lives.

Her seminal publication on the issue studying a cohort of extremely low birth weight babies was Saigal S, et al. Comparison of the health-related quality of life of extremely low birth weight children and a reference group of children at age eight years. Journal of Pediatrics. 1994;125(3):418-25. That publication started a whole area of neonatal research, investigating how our patients experience their lives, and the attitudes of healthcare workers, parents and former patients. Here is a selection of her early publications in this area

Streiner DL, et al. Attitudes of parents and health care professionals toward active treatment of extremely premature infants. Pediatr. 2001;108(1):152-7.
Saigal S, et al. Parental perspectives of the health status and health-related quality of life of teen-aged children who were extremely low birth weight and term controls. Pediatrics. 2000;105(3):569-74.
Saigal S, et al. Impact of extreme prematurity on families of adolescent children. The Journal of pediatrics. 2000;137(5):701-6.
Saigal S, et al. Parental perspectives of the health status and health-related quality of life of teen-aged children who were extremely low birth weight and term controls. Pediatrics. 2000;105(3):569-74.
Saigal S, et al. Self-perceived health status and health-related quality of life of extremely low-birth-weight infants at adolescence. JAMA. 1996;276(6):453-9.
Saigal S, et al. Differences in preferences for neonatal outcomes among health care professionals, parents, and adolescents. JAMA. 1999;281(21):1991-7.

Saroj continues her ground-breaking work, with publications just about every month this year. One of her many important contributions to our field is her book preemie voices, which you can buy at the website, where you can also watch videos that give you an idea of some of the stories in the book.

William G Bartholome Award

This award is given, again by the AAP, for an individual who has a significant impact on the public discussion of ethical issues in pediatrics. It would be hard to think of anyone who has done more for that than John Lantos. He has published several hundred articles and several books (seven I think), and now edits the series in “Pediatrics” of case based discussions of thorny ethical problems.

I remember reading my first John Lantos article in the New England Journal in 1988, Lantos JD etal. Survival After Cardiopulmonary Resuscitation in Babies of Very Low Birth Weight; Is CPR Futile Therapy? NEJM 1988;318:91-5 (one of his first contributions noted on PubMed). He and his group noted that among VLBW infants who had a cardiac arrest and received cardiac massage after admission to the NICU, none of those who received CPR in the first 72 hours of life survived, suggesting that maybe CPR in the NICU for such babies is a futile therapy, in the sense of the term that it never works. I don’t think there is a recent study that examines the same issues, but I would not be surprised if the results were similar.

Since then of course, John’s career has been marked by the clarity of his thinking and the lucidity of his prose. He is now director of the Center for Bioethics at the Children’s Mercy Hospital in Kansas City.  I am currently writing a blog post about 2 of his recent publications, which will appear very shortly; he continues to make me think, which is getting harder as I get older!

Congratulations to Saroj and to John.

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“The war to end all wars” 100 years on

Among the many moving ceremonies to mark the centenary of the Armistice, a series of portraits of casualties of the first world war were stencilled in the sand around Britain, the project is called “Pages of the Sea”, which is a quotation from a poem from the Caribbean poet Derek Walcott, and now incorporated in a new commemorative poem by Carol Ann Duffy. You can read it on the website for the project, which is here, and see many photographs.

This is a portrait of Wilfrid Owen.

A sand portrait of the poet Wilfred Owen on Folkestone beach

Wilfrid Owen left from Folkestone, the beach where this portrait is found, twice, to go to the front.

He was killed after his second departure, on the 4th of November 1918 just a few days before the declaration of the end of the war, his mother could hear the bells ringing in celebration of the Armistice when she received the telegram one week later informing her that her son was dead. In high school in England we were set a Wilfrid Owen poem to study, much of which I still remember:

Dulce et Decorum Est

Bent double, like old beggars under sacks,
Knock-kneed, coughing like hags, we cursed through sludge,
Till on the haunting flares we turned our backs,
And towards our distant rest began to trudge.
Men marched asleep. Many had lost their boots,
But limped on, blood-shod. All went lame; all blind;
Drunk with fatigue; deaf even to the hoots
Of gas-shells dropping softly behind.
Gas! GAS! Quick, boys!—An ecstasy of fumbling
Fitting the clumsy helmets just in time,
But someone still was yelling out and stumbling
And flound’ring like a man in fire or lime.—
Dim through the misty panes and thick green light,
As under a green sea, I saw him drowning.
In all my dreams before my helpless sight,
He plunges at me, guttering, choking, drowning.
If in some smothering dreams, you too could pace
Behind the wagon that we flung him in,
And watch the white eyes writhing in his face,
His hanging face, like a devil’s sick of sin;
If you could hear, at every jolt, the blood
Come gargling from the froth-corrupted lungs,
Obscene as cancer, bitter as the cud
Of vile, incurable sores on innocent tongues,—
My friend, you would not tell with such high zest
To children ardent for some desperate glory,
The old Lie: Dulce et decorum est
Pro patria mori.
* This is a quotation from Horace “it is sweet and decorous to die for one’s country”


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Under Pressure…

This post “under pressure” isn’t about the classic collaboration between David Bowie and Queen at Live Aid, rather it is about how to wean CPAP. Should we trial preterm babies off for a period every day, or either progressively reduce the distending pressure or just stop it? If we do any of those things, the details of how to do it might make a difference. Is weaning to high-flow cannulae better than just stopping the CPAP and using low flow, if O2 is still required?

A few recent studies are relevant to these questions. The best outcome for such studies would probably be something like clinical pulmonary disease at 2 years of age, and, as an important secondary, some metric of respiratory support use, such as in hospital costs, or total duration of CPAP use. It is unlikely we will ever have adequately powered studies to show that stopping CPAP by weaning pressures, compared to progressively weaning off-CPAP time (as an example of a study that could be done) will change the number of infants who are re-admitted for respiratory decompensation during the first year of life.

I guess you could do a study with enough power to show whether one way of weaning, compared to another, led to fewer infants being on oxygen at 36 weeks (i.e. classical “BPD”) but I am increasingly sceptical about this as a measure of pulmonary injury. Acutely reducing lung inflammation with steroids (for example) might decrease the numbers of babies with “BPD” without actually improving the long-term pulmonary health of any of them. Similarly maintaining good lung volume might do a similar thing, whereas overdistension might do the opposite, but the consequences for long term pulmonary health might still be unclear. Despite the limitations of this definition, however, it is still usually collected as the primary variable reflecting lung injury in the preterm.

The Cochrane review of CPAP weaning methods hasn’t been updated since 2011, so the studies below are not included in that review.

Here is a selection of recent publications, starting with the most recent:

Jensen CF, et al. Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation: A Randomized Clinical Trial. JAMA Pediatr. 2018;172(9):824-31. This Danish group enrolled 372 babies, less than 32 weeks gestation, at least 29 weeks Post-Menstrual Age (PMA), on CPAP for at least 24 hours, <8 cmH2O and <30% O2. They were randomized to either suddenly stopping the CPAP, or decreasing by 1 cmH2O every 24 hours until they reached 4, then stopping. The primary outcome was weight gain, which wasn’t different, and all of the secondary outcomes, including those related to lung function and respiratory support duration, were similar between groups. According to the way the manuscript is written a baby on CPAP of 4 would have been eligible for the study, in which case the intervention in the 2 groups would have been identical. A baby on a CPAP of 5 would have frequently only had 1 day difference in duration of CPAP support, unless the reduction to 4 was not tolerated. The median CPAP at randomization was actually 6 in each group. Overall there were no differences in any outcome when the whole group was analyzed. In a subgroup analysis of babies <28 weeks gestation (n=58), more babies were weaned at the first attempt with the gradual pressure wean than the sudden wean, but they had just as long on oxygen, just as many on oxygen at 36 weeks etc.

Yang CY, et al. A randomized pilot study comparing the role of PEEP, O2 flow, and high-flow air for weaning of ventilatory support in very low birth weight infants. Pediatr Neonatol. 2018;59(2):198-204. In a study from Taiwan, babies < 1500g and <30 wk GA on CPAP 5 to 7 cmH2O, were randomized when they weighed at least 750g and on no more than 25% O2. There were about 180 babies in 3 groups: 5 days of CPAP 4-6 cmH2O; progressively increasing time on 0.2 L/Min O2; progressively increasing time on 1.5 L/min of air. They showed a shorter duration of CPAP in the 2nd group, but no other relevant differences, and the 2nd group may well have been unnecessarily hyperoxic, and had more RoP and BPD than the other groups.

Eze N, et al. Comparison of sprinting vs non-sprinting to wean nasal continuous positive airway pressure off in very preterm infants. J Perinatol. 2017;38:164. In Los Angeles/ Orange county, 80 babies of 23 to 30 weeks GA, who had reached at least 26 weeks PMA, and were on CPAP for at least 24 hours, at 5 to 6 cmH2O were randomized to progressively increasing times off CPAP versus reducing CPAP to 5 cmH2O for at least 96h, then stopping the CPAP. In either group they could have nasal cannulae up to 2 L/min if needed and up to 30% O2. The primary outcome was succesful weaning on 1st attempt, and there were no differences in any outcome between groups.

Amatya S, et al. Sudden versus gradual pressure wean from Nasal CPAP in preterm infants: a randomized controlled trial. J Perinatol. 2017;37(6):662-7.   A group from New York studied 70 babies on a CPAP 5 and 21% O2, who either had CPAP reduced by 1 cm every 8h down to 3 cmH2O, or just stopped. The primary outcome was the success of the first attempt to wean, which was more frequent in the gradual pressure wean group, but no other outcomes were different including total duration of oxygen therapy, and duration of CPAP, or weight gain.

Nair V, et al. Effect of Nasal Continuous Positive Airway Pressure (NCPAP) Cycling and Continuous NCPAP on Successful Weaning: A Randomized Controlled Trial. Indian J Pediatr. 2015;82(9):787-93. A study from Calgary studied babies of 25 to 28 weeks GA who had been extubated and were on CPAP for at least 72 hours and were down to 4 cmH2O. They were either left on for another 72 hours then taken off, or they were placed on nasal cannulae at 1 L/min for progressively increasing periods. The primary outcome was succesful weaning at the first attempt, and it did not differ between groups. None of the secondary outcomes differed either.

Tang J, et al. Randomised controlled trial of weaning strategies for preterm infants on nasal continuous positive airway pressure. BMC pediatrics. 2015;15(1):147. In Sydney, 60 babies who were on CPAP of 5 or less, were studied in a 2X2 factorial design, HFNC vs no HFNC after wean, and sudden wean versus gradually increasing time off CPAP (starting at 6h on and 1 h off). Primary outcomes were 1) BPD (O2 at 36 wk); 2) days pf respiratory support; 3) days of hospital stay; and 4) days to achieve full suck feeds. None of the primary outcomes differed between comparisons, (high flow vs no high flow, or abrupt wean compared to progressively prolonging time off. But the abrupt wean group  had fewer days CPAP (10.5 vs 16.5 d; p = 0.02), lower PMA when CPAP was stopped (33.1 vs 34.6 wks; p = 0.05), and fewer days pressure support (21.5 vs 27.5 d; p = 0.04).

Rastogi S, et al. Gradual Versus Sudden Weaning From Nasal CPAP in Preterm Infants: A Pilot Randomized Controlled Trial. Respiratory Care. 2013;58(3):511-6. This study, from the same group in New York, studied a progressive increase in time off compared to sudden stopping of the CPAP in 56 babies of 32 weeks GA or less who had been on CPAP at least 48 hours. The primary outcome was success of the first weaning attempt, which was not different between groups, none of the secondary outcomes was significant either.

Todd DA, et al. Methods of weaning preterm babies <30 weeks gestation off CPAP: a multicentre randomised controlled trial. Archives of disease in childhood Fetal and neonatal edition. 2012;97(4):F236-40. This is the CICADA trial, in which 177 babies on 4 to 6 CPAP and <25% O2 were randomized to one of 3 methods, sudden wean, progressively increasing time off CPAP, and progressively increasing time off combined with moderate flow nasal cannulae (0.5 litres/min, variable FiO2). Babies in the sudden wean group had shorter time on CPAP, came off CPAP at an earlier post-menstrual age, were less likely to be on oxygen at 36 weeks and went home earlier.

What to make of all that? Well it seems that there is no advantage of weaning by progressively increasing time off in any of the studies, and it may well lead to more failures and a longer duration of O2 therapy. It may be that a progressive weaning of pressure to 3 or 4 cmH2O leads to fewer failures in the short term, but there doesn’t seem to be a big advantage, compared to just stopping from 5 cmH2O when the baby satisfies readiness criteria, which were different among studies, but generally required a low stable FiO2 and little respiratory distress, without significant tachypnea.

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More about platelets

The recent RCT comparing transfusion thresholds of 25,000 per mm3 to 50,000 in very preterm babies has generated a great deal of discussion. The result was somewhat unexpected, I think. I would not have been surprised to find that there was no impact on hemorrhage, but the increase in mortality surprised me.

Curley A, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. NEJM. 2018. The PlaNet2 MATISSE trial.

We should always be circumspect when evaluating trials that have a composite primary outcome, in this case “death or serious bleeding’. Does it make sense to put the different parts of the outcome together? Are they likely to be of approximately similar frequency, and of approximately similar importance to families? Are they likely to change in the same direction, and if they do not, then how will we interpret the results?

I think this composite outcome has some validity, especially if the definition of serious bleeding is restricted to bleeds that are potentially life-threatening.

When we examine the results there were fewer babies with the primary outcome in the low threshold group, 19%, compared to the high threshold group, 26%. This outcome was made up of death (low threshold 33/330 (10%), versus higher threshold 48/326 (15%) OR, 1.56 (95% CI 0.95–2.55)) and major bleeding episodes (low threshold 35/330 (11%) versus higher threshold 45/328 (14%) Hazard Ratio, 1.32 (95% CI 1.00–1.74))

Remember, however, that that is only mortality up to 28 days after study enrolment, we don’t know if mortality by the time of discharge was different between groups. We do know from the data in table 2 that by 36 weeks, when the outcome of BPD was determined, there were 50 deaths in the low threshold group, and 60 deaths in the high transfusion group, which is probably consistent with a chance effect. It shows also that between 28 days of age, and 36 weeks postmenstrual age (if we assume that the deaths were among babies less than 32 weeks gestation) there were 17 deaths in the low threshold, 25,000, group, and 12 deaths in the higher threshold, 50,000, group.

There are one or two other things about the trial that are a little confusing, only 90% of the babies in the high threshold group actually had a transfusion, whereas to be in the trial the babies had to have a platelet count under 50,000, so surely 100% of them should have had a transfusion, in the article it is noted that the platelet counts increased to above 50,000 while they were waiting for the platelets, but, once I have decided to give platelets we almost always have them in the NICU to be given within an hour, so it is very unusual to have another platelet count between ordering the platelets and giving them, so I find that a little confusing. In the article it is noted that there were 94 platelet transfusions in the high threshold group that should have been given and were not (and 30 in the low threshold group). There is a per-protocol analysis in the online supplementary materials, which shows almost identical differences between the 2 groups when only those babies who actually followed the protocol are included: mortality 10% vs 14%, and major bleed 9% vs 14%.

Another question to ask is whether or not this is biologically plausible. I think it is, platelet transfusions are pro-inflammatory, they have been associated with TRALI (transfusion related lung injury) in adults, and platelets prepared for transfusion release CD40 ligand (whatever that is) which activates cyclo-oxygenase. So there are potential pathways for adverse effects, which could be diverse and could potentially increase lung injury and other complications. In adults platelet transfusions for thrombocytopenia have also been associated with excess thrombotic complications, again a potential risk for our preterm patients.

My final question is the following : what is MATISSE? I understand the acronym PLaNEt2, even though I can’t remember which letters are capitalised, but what on earth is MATISSE doing there?

In the supplementary data we can see that infants who were IUGR did not have any difference in their incidence of the primary outcome (18% vs 20%) between thresholds, but beware, the p-value for the interaction was 0.3, so we shouldn’t make too much about that as a subgroup analysis, also the overall incidence of the primary outcome was not much different from the babies who were not growth restricted. Of course IUGR babies can get sepsis and NEC also, so those babies weren’t necessarily in the trial because of early onset thrombocytopenia associated with IUGR. Those babies with IUGR, maternal hypertension, and/or placental insufficiency are often thrombocytopenic in the first days of life, and have a reduced proportion of immature platelets. Those with consumptive coagulopathy and an increased proportion of immature platelets often have other derangements of coagulation, and I think are probably at higher risk of bleeding. If the authors have the data it would be fascinating to see whether babies with low production of platelets, due to placental insufficiency, have a different incidence of complications, and a different response to platelet transfusions, to those with platelet consumption.

I think we should be careful making excessive claims for a study with a result like this, especially when the 2 parts of a composite outcome are both barely at the threshold of what is classically considered to be statistically “significant”. On the other hand, as I mentioned before, these are the only reliable data we have, and there is no sign at all of a benefit to transfusion at a higher threshold. So for preterm babies who are not actively bleeding, I for one will no longer transfuse unless they fall below 25,000.

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Platelet transfusions don’t prevent bleeding (and may increase mortality).

When do you give a platelet transfusion? You could easily ask 10 different neonatologists and get 15 different answers. I would be one of those who gave several different answers depending on the clinical situation, believing that thrombocytopenia of different aetiologies probably should be transfused at different thresholds, but not knowing the right threshold for any condition. I thought that platelet transfusions were pretty safe, however, so if a colleague transfused at 50,000 a baby that I would have let fall to 30,000, it didn’t bother me very much.

Questionnaire studies have highlighted the differences in transfusion approaches and practices have been analyzed in studies such as this one,  in which 1/3 of transfusions were given to babies with a count over 50,000 (per cubic millimeter, I won’t repeat the units after this). There was never, however an appropriate evidence base to decide on thresholds.

To answer the question I think you should, first of all, study separately the babies with early thrombocytopenia due to alloimmunization, and the few due to maternal auto-immune thrombocytopenia. Maybe you should also eliminate those with thrombocytopenia associated with placental failure/IUGR, and then randomize the remaining babies, many of whom would have sepsis, or NEC, or CMV, to receive platelets at different thresholds, and see if the higher threshold reduces bleeding compared to a lower one. I would probably leave out the IUGR babies as they almost never seem to bleed, but that may not be true, and we certainly need to know.

That is just about exactly what was done in the just-published PLaNeT-2 trial, which just appeared on-line at the formerly prestigious NEJM. Curley A, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. New England Journal of Medicine. 2018.

This trial enrolled babies of less than 34 weeks gestation and included babies with IUGR: (the protocol has previously been published (Curley A, et al. Platelets for Neonatal Transfusion – Study 2: A Randomised Controlled Trial to Compare Two Different Platelet Count Thresholds for Prophylactic Platelet Transfusion to Preterm Neonates. Neonatology. 2014;106(2):102-6) and the whole protocol is available as a supplementary file on the

Babies with a platelet count of less than 50,000 who had a head ultrasound less than 6 hours previously were randomized. I guess they did this by screening babies with a platelet count of less than 100,000, and performing a head ultrasound if they thought they would become eligible. Babies who had a hemorrhage within the previous 3 days were not eligible.

The primary outcome variable was survival to 28 days (after randomization) without a major hemorrhage : “The outcome of “major bleeding” included intracranial hemorrhage (leading to neurosurgical intervention or radiologic imaging showing midline shift), intraventricular hemorrhage filling 50% or more of the cerebral ventricle, pulmonary hemorrhage (fresh bleeding through an endotracheal tube with increased ventilatory requirements), frank rectal bleeding, and severe bleeding (fatal bleeding, life-threatening bleeding associated with shock, or bleeding requiring fluid boluses or red-cell transfusion). Our definition of rectal bleeding was pragmatic; we defined any amount of fresh visible blood as rectal bleeding”.

660 babies were enrolled in 43 trial sites in the UK, Ireland, and Holland. When transfused babies received 15 mL/kg of platelets. Study size was determined from an expected 20% incidence of major bleeds in the low threshold group, and a desire to detect a reduction to 12% with a higher threshold

The 329 babies in the 25,000 threshold group had 61 major bleeds or deaths prior to 28 days, similar to the hypothesized rate at 19%, and the 324 babies in the high transfusion group had 85 bleeds or deaths which is 26%, for an Odds Ratio of 1.57 (95% confidence intervals 1.06, 2.32).

As you can see from the table with the maine results below, the difference was mostly in survival, although there were a few fewer bleeds in the 25,000 threshold group.

Most of the babies were several days old when enrolled, and many were septic or had NEC. There is really no evidence at all of any benefit of transfusing at a higher threshold from these numbers.

I can’t find in the publication or supplemental data the numbers of babies who survived to discharge, which is much more relevant to me than survival to 28 days after enrolment, if the differences disappear over the subsequent few weeks to discharge (the babies were on average 26 and a half weeks gestation, and about 750 g birth weight so they would have been around for several weeks after the trial) then the implications might be different.

Despite that, I think the lack of any apparent benefit, and possible harm, from transfusing more liberally, and given that this is the only prospective reliable data on outcomes of different platelet transfusion thresholds in the premature, babies at risk of bleeding from thrombocytopenia should be left to fall to 25,000 unless they are actively bleeding. Or maybe even lower.

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