Feeding patterns and NEC

Posted on 6 November 2012 by Keith Barrington

I have discussed before evidence about whether the pattern of introduction or advancement of feeds affects NEC.  I noted that there is only one out of a large number of trials of feeding introduction and advancement which has shown an effect on necrotising enterocolitis, the large preponderance of the literature shows no such effect.

Two new studies also fail to show an effect. One is a historical cohort study, (Maas C, Mitt S, Full A, Arand J, Bernhard W, Poets CF, Franz AR: A historic cohort study on accelerated advancement of enteral feeding volumes in very premature infants. Neonatology 2013, 103(1):67-73.) the authors increased the starting feed volume and the feeding advancement volume, and compared GI complications before and after, the new protocol being to start at 20 mL/kg/d and advance at between 25 and 30 mL/kg/d, for all babies less than 1500g and less than 32 weeks gestation, during both time periods feeds were started on the first day of life. The results showed that full feeds were achieved more quickly in the later group, (6 days vs 8 days on average) and there was no increase in GI complications.

The other study is from Columbia, it is in Spanish, but with the English abstract and a smattering of Spanish, I think I have the gist, (I tried Google translate, but it kept telling me the page was already in English! Perez LA, Pradilla GL, Diaz G, Bayter SM: [necrotizing enterocolitis among preterm newborns with early feeding]. Biomedica : revista del Instituto Nacional de Salud 2011, 31(4):485-491.) The authors randomized 239 babies between 750 and 1500 grams birth weight to start their feeds either at 24 to 48 hours of age or on the 5th day. Both groups had an increase of about 20 mL/kg/d thereafter.  There was no difference in complications, but better nutrition in the early group.

Now I don’t think that routinely waiting to start feeds until after 24 hours is necessary, but the authors performed a nice trial to show that you certainly don’t need to wait 5 days, which they note was their usual practice before the study.

This is yet more data to show that the way that we feed preterm babies has no effect on NEC. So why is the belief so prevalent? I think that NEC is a serious, sometimes devastating disease, and we humans are always trying to find reasons and patterns in what happens to us. NEC usually presents after feeds are started, being relatively uncommon in babies who have never been fed, so the impact of feeds, and how they are given is a reasonable issue of concern. So if you see a baby who has NEC, and notice that the day before they had the NEC they had their feeds increased, it starts to make you think; then if you have a little run of cases, and you change your feeding protocol to become more conservative it is likely (regression to the mean) that NEC will be less frequent afterward. So confirming to you that you did the right thing. The next time you have an outbreak you become even more conservative, and low and behold, the NEC goes away again. This way you end up with some centers with extremely slow feed advancement, and others, who never bought into the association, who feed much more quickly, and year by year, no consistent relation between feeding patterns and NEC in large databases.

One further point, both of the studies above used gastric residuals to determine if the feeds were tolerated, but they used very different guidelines, one tolerated 1-2 mL and less than 30% of the feeds, the other tolerated between 25 to 50%. I previously worked in a center where we stopped measuring residuals; during a period of 8 years I was never bothered by the report of a residual, the only measurable effect was a reduction in periods of feed interruptions. Here at Sainte Justine, since our new feeding protocol was introduced we have also stopped routine measurement of residuals, and again the only obvious effect is to reduce the number of interruptions of feeds.

What would the best evidence based feeding schedule look like for a very immature infant?

1. Start feeds on day 1, at 20 mL/kg/d (should there be exceptions? I think babies in shock could wait a day or 2, otherwise probably not)

2. Use breast milk, with probiotics.

3. Increase by 30 mL/kg/d

4. Add breast milk fortifier immediately (we add after the baby is to receive 25 mL a day, as we prepare the milk every 24 hours and we don’t want to waste precious breast milk. I sachet of fortifier is mixed with 25 mL of breast milk)

5. Don’t measure residuals.

6. Don’t measure abdominal circumference.

The problem comes on day 1 if the Mother has not yet produced breast milk, what do you do? Donor milk, wait for mother’s milk, or give a couple of days of formula? We have opted to wait for mother’s milk (colostrum) as we don’t currently have a source of donor milk, but of course donor milk is not colostrum… Food for another study I think.

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Opioids and Cerebral Development in the Newborn

Posted on 31 October 2012 by Keith Barrington

An extremely interesting “ratling” study from the latest “Neonatology” (Dührsen L, Simons SHP, Dzietko M, Genz K, Bendix I, Boos V, Sifringer M, Tibboel D, Felderhoff-Mueser U: Effects of repetitive exposure to pain and morphine treatment on the neonatal rat brain. Neonatology 2013, 103(1):35-43.) The authors took baby rats on day 1 and looked at the effects  of pain and morphine treatment on cell death in their brains.

The study design is a bit complicated, they had 7 different experimental models, each of which was divided into 3 groups, 1 with severe pain, another with mild pain and a 3rd control. The 7 different models are 3 pairs of protocols, one with and one without morphine, as well as a 7th protocol performed at a later postnatal age, without morphine. All the morphine injections were given 30 minutes prior to the heelpad injections which were used to create the painful stimulus.

What they showed was that pain is bad for your brain! There was substantial neuronal cell death, mostly apoptosis in association with 3 days of severe pain, which was much worse than 3 days of mild pain, after 5 days of injections the apoptosis was equally important in the two groups. When the studies were done later in life (day 13) there wasn’t any detectable effect.

When morphine was given before the painful stimulus it substantially reduced the apoptosis, the figure below is from the publication and shows the preventive effect of morphine against apoptosis in the group that received painful injections for 3 days.


This is important because there is a lot of concern about the potential long term toxicity of various analgesic or anesthetic agents in the newborn, and previous studies of the effects of morphine in the absence of pain have shown adverse effects.

Although you obviously can’t extrapolate from this to what happens in newborn infants, it points out that the effects of various analgesic agents might be very different if the model has a painful stress or not.

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The Preemie Toolkit

Posted on 29 October 2012 by Keith Barrington

If you haven’t seen this and you are involved in NICU and/or follow up, I think this could be a very valuable resource. The preemie toolkit is a series of forms and web links for professionals and families designed to aid in a smooth transition from hospital to home. It includes check-lists for follow up visits, and information about everything from apnea monitors to hand washing.

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Chloride is toxic

Posted on 29 October 2012 by Keith Barrington

I think we have given too little attention to the nature of the crystalloid solutions we use. Not just in neonatology, but apparently in the adult ICU also,  (Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M: Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA : the journal of the American Medical Association 2012, 308(15):1566-1572) I’m a bit surprised this was published in JAMA, although it is interesting, it is not methodologically the best study, in fact it is not even a trial, it is a cohort study where the authors changed their practice in a very strict fashion, and recorded patient outcome data. They did this for a 6 months control period, then a 6 month intervention period.

First a bit about the results and the potential implications in neonatology, I will come back to the study design later.

Background: We know that normal saline has far more chloride than normal plasma, and that it’s use can lead to hyperchloremic acidosis for exactly this reason. Older patients often receive Ringers lactate, Hartmann solution or other lower chloride solutions, but there is very little use of these solutions in newborns. In my unit very often arterial lines in the past were filled with normal or half normal saline. I think neither of these are optimal, saline has relatively far too much chloride, and in fact we should avoid sodium in the first 3 or 4 days of life, as RCTs have shown worse outcomes when more sodium is administered.

Half normal saline is probably not a good idea, you give less sodium, but hypotonic solutions are problematic as when the blood is withdrawn into the catheter and syringe, there is a mixture created of the hypotonic solution and the blood which leads to lysis of the red cells. So although you give less sodium you end up giving more potassium and free hemoglobin when you re-infuse the dead space. We now often use a solution of sodium acetate in the arterial lines, which may be variably hypotonic, this has the advantage of giving less chloride and giving a buffer in its place, but there has been little study of acetate in the newborn.

To get back to this new study, the authors noted that high chloride administration in experimental animals causes renal dysfunction. So during the intervention period they changed their usual fluid administration practices, eliminating normal saline and 4% albumin and using lower chloride solutions (Hartmanns solution, plasma-lyte and 20% albumin) instead. They found significantly less acute kidney injury, and less need for renal replacement therapy (dialysis and the like).

I think this does not have direct implications for our practice, but should stimulate us to think a bit more about the fluids that we use, and whether they are optimal or not.

Finally to return to the study design, I think this is the worst of both worlds. I know it is a pain to design randomized controlled trials, and it can be horrendous getting them through the ethics review committees, but this study (which was approved by the ethics committee without the need for consent) could have been much more important, had much more impact and saved (or not depending on the findings) many future adults in ICU from kidney failure if they had randomized the subjects. As it is, people will discount this because they didn’t do it right; the patients were exposed to exactly the same risks as if they had been in an RCT, and people will go on using high chloride solutions, or will change to lower chloride when we really don’t know the probable effects.

An editorial in JAMA accompanying this study noted “A more definitive study examining the composition of intravenous fluids is now justified and necessary to scientifically test for potential adverse effect” how much better if they had done that straight away.

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Abort all the bankers!

Posted on 29 October 2012 by Keith Barrington

I just heard a great quote from Francesca Martinez on the BBC News Quiz. Francesca Martinez is a stand up comic with a disability (she is often a sit-down comic in fact as you can see here), she is very witty, and often pokes fun at the preconceptions of her audience, she often notes that she has cerebral palsy, but prefers to call herself “wobbly”.

On the News Quiz she recounted doing her show at a doctors conference, after which, during a question and answer session with the audience, someone told her that they were a doctor involved in antenatal counseling and that they felt part of their duty, when counseling about aborting a disabled fetus, was to “reduce the suffering in the world”.

I loved her response to this, first of all she said that the room was very quiet (I imagine that many people present were super embarrassed by the question, and also fascinated to hear how a disabled comedian would answer) her retort was that if they really wanted to reduce the suffering in the world, they should abort all the  bankers, arms dealers, politicians and Rupert Murdoch!

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Weekly Updates #12

Posted on 27 October 2012 by Keith Barrington

Welzing L, Oberthuer A, Junghaenel S, Harnischmacher U, Stützer H, Roth B: Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: a randomized controlled trial. Intensive Care Medicine 2012, 38(6):1017-1024. A small RCT (n=23) comparing fentanyl to remifentanil (both with midazolam). Both regimes gave good sedation and analgesia, but the remifentanil babies were able to be extubated much faster. Fentanyl has an average half life of about 10 hours in the newborn; remifentanil is metabolised by circulating esterases and has an extremely short half-life of about 3 to 6 minutes (this has not been confirmed in small neonates)

Bennett NJ, Tabarani CM, Bartholoma NM, Wang D, Huang D, Riddell SW, Kiska DL, Hingre R, Rosenberg HF, Domachowske JB: Unrecognized Viral Respiratory Tract Infections in Premature Infants during their Birth Hospitalization: A Prospective Surveillance Study in Two Neonatal Intensive Care Units. The Journal of Pediatrics 2012, 161(5):814-818.e813. If you look for respiratory viral infections routinely, you will find them. Not only will you find them, but they seem to prolong assisted ventilation and are associated with bronchopulmonary dysplasia, even though they usually do not cause any obvious symptoms.

 Martinez-Biarge M, Bregant T, Wusthoff CJ, Chew ATM, Diez-Sebastian J, Rutherford MA, Cowan FM: White Matter and Cortical Injury in Hypoxic-Ischemic Encephalopathy: Antecedent Factors and 2-Year Outcome. The Journal of Pediatrics 2012, 161(5):799-807. Follow up of 84 infants with HIE who did not have basal ganglia or thalamic injury. They not that few infants had cerebral palsy, and none very severe CP, but that a wide range of other disabilities were prevalent, cognitive, language, behavioural and seizures.

Katheria A, Rich W, Finer N: Electrocardiogram Provides a Continuous Heart Rate Faster Than Oximetry During Neonatal Resuscitation. Pediatrics 2012. Again challenging our standard practice during resuscitation, Neil Finer and his group measured how long it takes during resuscitation to get a reliable heart rate using the standard (which has become pulse oximetry) to sticking on ECG electrodes like we do everywhere else in medicine. It was faster to put the probes in place (26 vs 38 secs), and much faster to get an audible heart rate signal when you stick the ECG leads on (2 seconds) versus the oximeter probe (24 seconds).

Carr R: The role of colony stimulating factors and immunoglobulin in the prevention and treatment of neonatal infection. Arch Dis Child Fetal Neonatal Ed 2012. A very nice review of the current state of the art.

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Glutamine supplementation, just when you thought it was solved…

Posted on 24 October 2012 by Keith Barrington

Glutamine is one of the most abundant amino acids in our bodies, but there is relatively little in TPN as it is poorly soluble. During the first few days of limited enteral nutrition preterm babies receive little glutamine from any source, and this probably contributes to gut atrophy and perhaps to later feeding intolerance. So a number of studies have tried to supplement glutamine either enterally or in TPN. The Cochrane review shows no overall effect of either mode of supplementation (the latest version from earlier this year, has changed authors apart from Bill McGuire, and includes 11 RCTs with 2800 babies; pretty good evidence for the field of neonatology, and almost entirely negative).

Just published on-line in Pediatrics is a long term outcome study of one of the trials, with some elegant analysis of MRI data from the participants at about 8,5 years (de Kieviet JF, Oosterlaan J, Vermeulen RJ, Pouwels PJW, Lafeber HN, van Elburg RM: Effects of Glutamine on Brain Development in Very Preterm Children at School Age. Pediatrics 2012.). Only 53 of the 89 surviving infants were imaged, but the study shows some differences favouring the glutamine group. They did however perform 15 statistical comparisons between the groups, with no apparent adjustment for the multiple testing; and showed a larger hippocampus in the glutamine supplemented babies.

Now if you go back to their original publication, (van den Berg A, van Elburg RM, Westerbeek EA, Twisk JW, Fetter WP: Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial. The American Journal of Clinical Nutrition 2005, 81(6):1397-1404.) You find that the primary outcome variable was feeding tolerance. In a study with a total of about 100 babies of less than 32 weeks and less than 1500 grams they showed no effect on feeding tolerance. A secondary outcome of serious infections was however different between groups. They actually had an enormously high rate of serious culture positive infections, 75% in the controls and 50% in the glutamine supplemented group, despite  mean birth weight which was over 1.1 kg.

This new follow up study was therefore analyzed with infections as an important co-variate, and all of the differences in MRI findings are explained by the associations between infection and adverse brain development. Importantly the Cochrane review mentioned above does not show any effect of glutamine on infections. So this study was somewhat of an outlier, it does add weight to the importance of infection as an indicator for future cerebral developmental abnormalities, but does not mean that we should re-open the question of supplemental glutamine supplementation in the preterm. I still think that question is settled. Unless perhaps you have a 75% incidence of serious bacterial infections in your VLBW infants….

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Tocolytics and Network meta-analysis

Posted on 22 October 2012 by Keith Barrington

What do you do if you want to know what is the best treatment for a condition, and treatment A and treatment B have both been compared to placebo, but have never been compared to each other in RCTs? If there are multiple options, rather than just 2, then it is usual that several have not been directly compared to each other.

One way to approach this is to do what is called a network meta-analysis, where you try and calculate the relative efficacy of each treatment, and then estimate whether A is better or worse than B. Is this valid? I am not sure… (and I am not alone Li T, Puhan MA, Vedula SS, Singh S, Dickersin K: Network meta-analysis-highly attractive but more methodological research is needed. BMC Med 2011, 9:79.) If the samples were very homogeneous and many details of the research protocols, such as timing and duration of intervention, timing and nature of outcome measures etc etc were identical, then a network meta-analysis might be enticing. Unfortunately that is not often the case.

A new network meta-analysis has been published (Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ: Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ 2012, 345) examining the efficacy of tocolytics to suppress preterm labour and prevent preterm delivery. The analysis is interesting, but rather complex.  They first did systematic reviews of all of the pairwise comparisons for which there was trial data, then performed the network thing. The final evaluation gives a probability that a particular agent is the best, 2nd best, 3rd best and so on, for delaying delivery for a least 48 hours, for maternal side effects etc. They indicate that antiprostaglandin agents (mostly indomethacin, but 4 others have been studied and are lumped together as one category in this meta-analysis) are probably the most effective for delaying delivery for at least 48 hours, and oxytocin receptor antagonists are probably the safest (although the antiprostaglandin agents came close). The authors also confirmed that there is no clear evidence of clinical benefit, in terms of reduction in mortality or the risk of acute lung disease in the baby. A skeptical editorial accompanies the article (skeptical of the benefits of tocolytics, not of the systematic review). Having said that the evidence that these agents are no better or worse than placebo is fairly weak. The quality of the studies is generally good, as Dr Haas and co-workers showed in another recent publication, with the major exception that too many of them are too small, especially those comparing to placebo.

There has been a network meta-analysis in neonatology, only one that I am aware of, (Jones LJ, Craven PD, Attia J, Thakkinstian A, Wright I: Network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition 2011, 96(1):F45-F52). Published last year, and with a much simpler network, indomethacin and ibuprofen versus placebo. They seemed to demonstrate that both drugs are equally effective at closing the PDA, but that ibuprofen may lead to more BPD.

** Update ** I knew there was a recent article published about how to read and use a network meta-analysis, but my RAM failed me (my real actual memory) and my database search was fruitless, partly because the authors call this a multiple treatment comparison meta-analysis rather than ‘network’. Anyhow an addition to the JAMA series ‘A User’s Guide to the Medical Literature’ takes you through the topic in a very useful, usable, way.  (Mills EJ, Ioannidis JP, Thorlund K, Schunemann HJ, Puhan MA, Guyatt GH: How to use an article reporting a multiple treatment comparison meta-analysis. JAMA : the journal of the American Medical Association 2012, 308(12):1246-1253.)

 

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Weekly Updates #11

Posted on 21 October 2012 by Keith Barrington

Back to mostly actual neonatology this week

Kumral A, Tuzun F, Yesilirmak DC, Duman N, Ozkan H: Genetic basis of apnoea of prematurity and caffeine treatment response: Role of adenosine receptor polymorphisms. Acta Paediatrica 2012, 101(7):e299-e303. The paper suffers from a complete lack of detail about how apnea was ascertained. As it includes preterm babies some of whom were probably less than 30 weeks gestation who are noted to be “without apnea” this could be a problem. Having performed prolonged recordings of hundreds of preterm babies, I would say that the baby less than 30 weeks who goes 24 hours without an apnea is a very rare baby indeed. Also the division of babies with apnea into caffeine responsive and unresponsive is not explained, no definition is given and no details of how this was ascertained. So with all those important caveats, it seems that there are adenosine receptor polymorphisms which correlate with being in their “with apnea” group, and correlate with being in their “caffeine resistant” group. That being in their caffeine resistant group correlates with having more BPD, and that the adenosine receptor types therefore correlate with BPD. So it may be that the adenosine receptor subtypes are important in variations in breathing control, and that as caffeine works by blocking the receptors, variations in the receptor might affect caffeine responsiveness.

Larsen BMK, Goonewardene LA, Joffe AR, Van Aerde JE, Field CJ, Olstad DL, Clandinin MT: Pre-treatment with an intravenous lipid emulsion containing fish oil (eicosapentaenoic and docosahexaenoic acid) decreases inflammatory markers after open-heart surgery in infants: A randomized, controlled trial. Clinical Nutrition 2012, 31(3):322-329. This small single center RCT had physiologic rather than clinical end-points, the concentration of TNF-α. The report lacks a good description of the eligibility criteria, including for example how old the “infants” were and whether they were already hospitalized and already on TPN when randomized, or whether TPN was started in both groups for the study (even the results only give the gestational age at birth, the postnatal age is not mentioned). Anyway infants who got pre-operative omega3 fatty acids in their lipids had lower pro-inflammatory cytokines after surgery than the controls who received omega6 exclusive fat.

Hillman NH, Moss TJ, Nitsos I, Jobe AH. Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep. Pediatr Res. 2012. 15 minutes of positive pressure ventilation with 6 to 7 mL/kg tidal volumes compared to CPAP increased pro-inflammatory cytokines in partially exteriorized preterm fetal lambs. 15 minutes of oxygen had no effect. 6 to 7 mL/kg is not a very large tidal volume, but it was administered in this study without PEEP, in a previous study they showed that PEEP was partially protective .

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Early Detection of Sepsis in the NICU

Posted on 16 October 2012 by Keith Barrington

This came out before I started my blog, but think it is very important. I was reminded that I had never mentioned it on this blog when I met Joseph Randall Moorman at the airport on the way back from Istanbul. I think it is important because there is very little in recent years which has been shown in well-designed trials to reduce mortality in the NICU, but this innovative monitoring technique did.

I say innovative, but in fact people have been studying heart rate variability for years as an early indicator of various things, in this particular instance a reduction of baseline heart rate variability with an increase in transient decelerations as an early indicator of sepsis. Dr Moorman and his collaborators have been investigating this for years; they have developed ways of quantifying the changes which occur and expressing them as a relative increase in risk of developing sepsis in the next 24 hours.

In this study, (Moorman JR, Carlo WA, Kattwinkel J, Schelonka RL, Porcelli PJ, Navarrete CT, et al. Mortality Reduction by Heart Rate Characteristic Monitoring in Very Low Birth Weight Neonates: A Randomized Trial. The Journal of Pediatrics. 2011;159(6):900-6.e1) 3000 babies less than 1500 grams birth weight in 9 NICUs were put on a new monitor which records the index of heart rate characteristics (HRC). Half of the babies were randomized to have the information made available to the clinical staff, and the other half had the information hidden. The staff were trained to understand that when the HRC increased that was a potential indicator of early stages of sepsis. The use of an HRC index which is a relative risk, i.e. when the HRC is 2 the risk of sepsis is doubled, makes it very easy to understand and use as a part of clinical evaluation of the baby. A baby who otherwise looks perfectly fine and has a low pre-test probability of sepsis could just be evaluated and observed; for another baby at increased risk and some may-be signs of sepsis a full evaluation and starting antibiotics might well be appropriate.

The primary outcome variable for the trial was an increase in ventilator free days during the first 120 days of life. I am not sure why. The trial was powered for a 2 day difference in ventilator free days, they actually found a difference of 2.3 but it wasn’t “statistically significant” (see my previous post!)  I presume the variability in this outcome was greater than anticipated. There are a lot of things other than sepsis that affect ventilator free days, so choosing this for the primary outcome could really be questioned, it was probably a compromise between the statisticians, trialists and neonatologists. I would urge all of you to read the article, it is a model of a scientific report, concise, clear, with all the essentials, and a very nice discussion section of the pathophysiology. The one lack is that there is no discussion of why they chose this primary outcome.

In the control group 10.2% of the babies died. In the group with the HRC visible 8,1% died. This difference was statistically significant. The effect seemed more marked in the smaller babies.

The advantage of being in the HRC visible group was mostly among those who did indeed have an episode of culture proven sepsis. “The mortality rate in the 30 days after the first episode of proven sepsis was 10.0% in the infants whose HRC monitoring results were
displayed compared with 16.1% in the control infants,” the intervention group did get a few more sepsis work ups,  and a slight increase in antibiotic use.

Now what? I think this technology deserves to become widespread. I think that this particular algorithm is now better supported than any other monitoring technique in the NICU. I think that the company should licence the algorithm to other monitor manufacturers, who should buy the licence and make it available with software upgrades and new monitors at a reasonable price. I think that if anyone else wants to develop and try to sell their own algorithm, we should all be very wary, and recognize that this is the only HRC algorithm shown to reduce mortality, and anyone else needs to prove their own algorithms in a new large simple well-performed RCT. Like this one.

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