The modern NICU is one that is full of patients on CPAP these days. As I have mentioned before, the opportunity to intubate is therefore becoming more and more rare is non-invasive pressure support becomes the mainstay of therapy. Even for those with established skills in placing an endotracheal tube, the number of times one gets to do this per year is certainly becoming fewer and fewer. Coming to the rescue is the promise of easier intubations by being able to visualize an airway on a screen using a video laryngoscope. The advantage to the user is that anyone who is watching can give you some great tips and armed with this knowledge you may be better able to determine how to adjust your approach.
For those of you who have followed the blog for some time, you will recall this is not the first time video laryngoscopy has come up. I have spoken about this before in Can Video Laryngoscopy Improve Trainee Success in Intubation. In that piece, the case was made that training residents how to intubate using a video laryngoscope (VL) improves their success rate. An additional question that one might ask though has to do with the quality of the intubation. What if you can place a tube using a video laryngoscope but the patient suffers in some way from having that piece of equipment in the mouth? Lucky for us some researchers from the Children's Hospital of Philadelphia have completed a study that can help answer this additional question.
Video Laryngoscopy may work but does it cause more harm than good?
Using a video laryngoscope requires purchasing one first and they aren't necessarily cheap. If they were to provide a better patient experience though the added cost might well be worth it. Pouppirt NR et al published Association Between Video Laryngoscopy and Adverse Tracheal Intubation-Associated Events in the Neonatal Care Unit. This study was a retrospective comparison of two groups; one having an intubation performed with a VL (n=161 or 20% of the group) and the other with a standard laryngoscope (644 or 80% of the group). The study relied on the use of the National Emergency Airway Registry for Neonates (NEAR4NEOs), which records all intubations from a number of centres using an online database and allows for analysis of many different aspects of intubations in neonates. In this case the data utilized though was from their centre only to minimize variation in premedication and practitioner experience.
Tracheal intubation adverse events (TIAEs) were subdivided into severe (cardiac arrest, esophageal intubation with delayed recognition, emesis with witnessed aspiration, hypotension requiring intervention (fluid and/or vasopressors), laryngospasm, malignant hyperthermia, pneumothorax/pneumomediastinum, or direct airway injury) vs non-severe (mainstem bronchial intubation, esophageal intubation with immediate recognition, emesis without aspiration, hypertension requiring therapy, epistaxis, lip trauma, gum or oral trauma, dysrhythmia, and pain and/or agitation requiring additional medication and causing a delay in intubation.
Looking at the patient characteristics and outcomes, some interesting findings emerge.
Patients who had the use of the VL were older and weighed more. They were more likely to have the VL used for airway obstruction than respiratory failure and importantly were also more likely to receive sedation/analgesia and paralysis. These researchers have also recently shown that the use of paralysis is associated with less TIAEs so one needs to bear this in mind when looking at the rates of TIAEs. There were a statistically significant difference in TIAEs of any type of 6% in the VL group to 19% in the traditional laryngoscopy arm but severe TIAEs showed not difference.
Given that several of the baseline characteristics might play a role in explaining why VL seemed superior in terms of minimizing risk of TIAEs by two thirds, the authors performed a multivariable analysis in which they took all factors that were different into account and then looked to see if there was still an effect of the VL despite these seemingly important differences. Interestingly, us of VL showed an Odds ratio of 0.43 (0.21,0.87 95% CI) in spite of these differences.
What does it mean?
Video laryngoscopy appears to make a difference to reducing the risk on TIAEs as an independent factor. The most common TIAE was esophageal intubation at 10% and reducing that is a good thing as it leads to fewer intubation attempts. This was also sen as the first attempt success was 63% in the VL group vs 44% in the other.
Now we need to acknowledge that this was not a randomized controlled trial so it could indeed be that there are other factors that the authors have not identified that led to improvements in TIAEs as well. What makes this study so robust though is the rigour with which the centre documents all of their intubations using such a detailed registry. By using one centre much of the variability in practice between units is eliminated so perhaps these results can be trusted. Would your centre achieve these same results? Maybe not but it would certainly be interesting to test drive one of these for a period of time see how it performs.
It is hard to believe but it has been almost 3 years since I wrote a piece entitled A 200 year old invention that remains king of all tech in newborn resuscitation. In the post I shared a recent story of a situation in which the EKG leads told a different story that what our ears and fingers would want us to believe. The concept of the piece was that in the setting of pulseless electrical activity (where there is electrical conductance in the myocardium but lack of contraction leaves no blood flow to the body) one could pick up a signal from the EKG leads when there is in fact no pulse or perfusion to vital organs. This single experience led me to postulate that this situation may be more common than we think and the application of EKG leads routinely could lead to errors in decision making during resuscitation of the newborn. It is easy to see how that could occur when you think about the racing pulses of our own in such situations and once chest compressions start one might watch the monitor and forget when they see a heart rate of 70 BPM to check for a corresponding pulse or listen with the stethoscope. I could see for example someone stopping chest compressions and continuing to provide BVM ventilation despite no palpable pulse when they see the QRS complex clearly on the monitor. I didn’t really have much evidence to support this concern but perhaps there is a little more to present now.
A Crafty Animal Study Provides The Evidence
I haven’t presented many animal studies but this one is fairly simple and serves to illustrate the concern in a research model. For those of you who haven’t done animal research, my apologies in advance as you read what happened to this group of piglets. Although it may sound awful, the study has demonstrated that the concern I and others have has is real.
For this study 54 newborn piglets (equivalent to 36-38 weeks GA in humans) were anesthetized and had a flow sensor surgically placed around the carotid artery. ECG leads were placed as well and then after achieving stabilization, hypoxia was induced with an FiO2 of 0.1 and then asphyxia by disconnecting the ventilator and clamping the ETT. By having a flow probe around the carotid artery the researchers were able to determine the point of no cardiac output and simultaneously monitor for electrical activity via the EKG leads. Auscultation for heart sounds was performed as well.
The results essentially confirm why I have been concerned with an over reliance on EKG leads.
Of the 57 piglets, 14 had asystole and no carotid flow but in 23 there was still a heart rate present on the EKG with no detectable carotid flow. This yields a sensitivity of only 37%. Moreover, the overall accuracy of the ECG was only 56%.
Meanwhile the stethoscope which I have referred to previously as the “king” in these situations had 100% sensitivity so remains deserving of that title.
What do we do with such information?
I think the results give us reason to pause and remember that faster isn’t always better. Previous research has shown that signal acquisition with EKG leads is faster than with oximetry. While a low heart rate detected quickly is helpful to know what the state of the infant is and begin the NRP pathway, we simply can’t rely on the EKG to tell us the whole story. We work in interdisciplinary teams and need to support one another in resuscitations and provide the team with the necessary information to perform well. The next time you are in such a situation remember that the EKG is only one part of the story and that auscultation for heart sounds and palpation of the umbilical cord for pulsation are necessary steps to demonstrate conclusively that you don’t just have a rhythm but a perfusing one.
I would like to thank the Edmonton group for continuing to put out such important work in the field of resuscitation!
Alarms in NICU are part of the environment and with more advanced model appear to be more present. As one walks through the unit one is going off, creating annoyance to staff.Thus, raising the issue have reached a 'fatigue alarm'. Among I and some of the NICU professionals in my twitter Community belief. An article by Belteki and Morley give some answers.
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A few weeks back I wrote about the topic of intubations and whether premedication is really needed (Still performing awake intubations in newborns? Maybe this will change your mind.) I was clear in my belief that it is and offered reasons why. There is another group of practitioners though that generally agree that premedication is beneficial but have a different question. Many believe that analgesia or sedation is needed but question the need for paralysis. The usual argument is that if the intubation doesn’t go well and the patient can’t spontaneously ventilate could we be worse off if the patient loses their muscle tone.
Neonatal Intubation Registry
At the CPS meeting last month in Quebec City. I had the pleasure of listening to a talk by Dr. Elizabeth Foglia on the findings from a Neonatal intubation registry that many centres have been contributing to. The National Emergency Airway Registry for Neonates (NEAR4NEOs), records all intubations from a number of centres using an online database and allows for analysis of many different aspects of intubations in neonates.
This year, J. Krick et al published Premedication with paralysis improves intubation success and decreases adverse events in very low birth weight infants: a prospective cohort study. This study compared results from the registry of two centres, the University of Washington Medical Center (UWMC) and Seattle Children’s Hospital where the former rarely uses paralysis and the latter in almost all instances of non-emergent intubation. In all, 237 encounters were analyzed in the NICU for babies < 1500g with the majority of encounters (181) being from UWMC. The median PMA at intubation was 28 completed weeks (IQR: 27, 30), chronological age was 9 days (IQR: 2, 26) and weight was 953 g (IQR: 742,1200). The babies were compared based on the following groups. Premedication with a paralytic 21%, without a paralytic 46% and no premedication 31%.
This was an observational study that examined the rates of adverse events and subdivided into severe (cardiac arrest, esophageal intubation with delayed recognition, emesis with witnessed aspiration, hypotension requiring intervention (fluid and/or vasopressors), laryngospasm, malignant hyperthermia, pneumothorax/pneumomediastinum, or direct airway injury) vs non-severe (mainstem bronchial intuba- tion, esophageal intubation with immediate recognition, emesis without aspiration, hypertension requiring therapy, epistaxis, lip trauma, gum or oral trauma, dysrhythmia, and pain and/or agitation requiring additional medication and causing a delay in intubation.).
How did the groups compare?
It turns out paralysis seems to be a big deal (at least in this group of infants). Use of paralysis resulted in less attempts to intubate (median 1 attempt; IQR: 1, 2.25 vs. 2; IQR: 1, 3, p < 0.05)). In fact success was no different between the groups with no paralysis or no premedication at all! When it comes to tracheal intubation adverse events the impact of using paralysis becomes more evident. Paralysis does make a difference in reducing the incidence of such events and moreover when only looking at the rate of severe adverse events as defined above the finding was that none occurred when paralysis was used vs 9 when no paralysis was employed and 5 when no premedication was used at all. The rate of bradycardic events was less in the paralytic group but rates of oxygen desaturation between the three arms were no different.
How do we interpret the results?
Based on the results from the registry it looks like paralysis is a good thing here when electively intubating infants. If we try to determine the reason for it I suspect it may have much to do with the higher likelihood of success on the first attempt at placing an ETT. The longer it takes to place the ETT or the more number of attempts requiring intermittent PPV in a patient who truly needs a tube the greater the likelihood that you will see adverse events including bradycardia. It may simply be that a calm and still patient is an easier intubation and getting the tube in faster yields a more stable patient.
I am biased though and I think it is worth pointing out another possible reason for the differing results. One hospital in this study routinely used premedication and the other did not. Almost 3/4 of the patients came from one hospital which raises the possibility that skill set could be playing a role. If the skill of providers at the two hospitals differed, the results could reflect the variable skill in the practitioners versus the difference in the medications used themselves. What I don’t know though is whether the two share the same training program or not. Are the trainees the same at both sites (google maps says the two sites are 11 minutes away by car)? The difference still might be in local respiratory therapists or Neonatologists intubating as well. Regardless, the study provides evidence that paralysis makes a difference. To convince those out there though who remain skeptical I think we are going to need the registry to take part in a prospective trial using many centres. A format in which several centres that don’t use paralysis are compared to several who do routinely would help to sort out the concern in skill when looking only at two centres. This wouldn’t be randomized of course but I think it would be very difficult at this point to get a centre that strongly believes in using paralysis to randomize so a prospective study using groups chosen by the individual centre might be the next best thing. If anyone using the registry is reading this let me know what you think?
This post is very timely as the CPS Fetus and Newborn committee has just released a new practice point:
Managing infants born to mothers who have used opioids during pregnancy
Have a look at discharge considerations as that section in the statement speaks to this topic as well!
As bed pressures mount seemingly everywhere and “patient flow” becomes the catch-word of the day, wouldn’t it be nice to manage NAS patients in their homes? In many centres, such patients if hospitalized can take up to 3 weeks on average to discharge home off medications. Although done sporadically in our own centre, the question remains is one approach better than the another? Nothing is ever simple though and no doubt there are many factors to consider depending on where you live and what resources are available to you. Do you have outpatient follow-up at your disposal with practitioners well versed in the symptoms of NAS and moreover know what to do about them? Is there comfort in the first place with sending babies home on an opioid or phenobarbital with potential side effects of sedation and poor feeding? Nonetheless, the temptation to shift therapy from an inpatient to outpatient approach is very tempting.
The Tennessee Experience
Maalouf Fl et al have published an interesting account of the experience with outpatient therapy in their paper Outpatient Pharmacotherapy for Neonatal Abstinence Syndrome. The authors were able to take advantage of the Tennessee Medicaid program using administrative
and vital records data from 2009 to 2011 to capture a cohort of 736 patients who were treated for NAS. Forty five percent or 242 patients were treated as outpatients vs 290 cared for in hospital for the duration of treatment. It is worth mentioning at this point that when the authors say they were cared for as outpatients it really is a hybrid model as the duration of hospitalization for the inpatients was a median of 23 days (IQR 14-35) versus 11 days (IQR 7-18) for inpatients (P < .001). This practice isn’t much different than my own in which I start therapy in hospital and then discharge home with a period of home therapy.
The strength of the study is the volume of patients and the ability to follow-up with these babies for the first 6 months of life to determine what happened to them after discharge. In terms of duration of treatment, the differences are significant but perhaps not surprising. The median length of treatment for outpatients was 60 days (IQR 38-92) compared with 19 days (IQR 10-31) for inpatients (P < .001). What was interesting as well is that 82% of babies were discharged home on phenobarbital and 9.1% on methadone and 7.4% with both. A very small minority was discharged home on something else such as morphine or clonidine. That there was a tripling of medication wean is not surprising as once the patients are out of the watchful eye of the medical team in hospital it is likely that practitioners would use a very slow wean out of hospital to minimize the risk of withdrawal.
An Unintended Consequence
This study found a statistically significant increase in risk for presenting to the emergency department for those patients treated as outpatients.
What this graph demonstrates is that there was no increase risk in the first month but there was for the first 6 months. Despite the increased risk of presentation to the ED the rate of hospitalization was not different. Drilling down the data further, the reason for coming to the ED was not for withdrawal which was 10% in the outpatient and 11% in the inpatient group. The other major reason was The most common diagnoses were upper respiratory infections; 80% outpatient vs 71% inpatient. So while there was a significant difference (which was not by much) my take on it is that it was most likely by chance as I can’t think of how infections in the first 6 months could be linked to choice of medication wean.
What about phenobarbital?
Phenobarbital has been used for many years in Neonatology for control of seizures, sedation (taking advantage of a side effect) and management of NAS. The problem with a median use of phenobarbital for 2 months is its potential to affect development.
An animal study by Diaz in 1999 in which rat pups were given two weeks of phenobarbital starting on day 5 of life and then euthanized demonstrated the following weight reductions when high dose phenobarbital was utilized. In human data, children with febrile seizures treated with phenobarbital in the paper Late cognitive effects of early treatment with phenobarbital. had decreased intelligence than those not exposed to phenobarbital.
The issue here for me is not necessarily whether babies can be treated successfully as outpatients for NAS. The concern is at what cost if the choice of drug is phenobarbital. The reason phenobarbital was chosen is likely due to compliance. We know that the more frequently a drug is dose the less likely compliance will be achieved. Phenobarbital being dosed either q12h or q24h is an ideal drug from a compliance point of view but the ramifications of this treatment deserve reconsideration.
I look forward to seeing further studies on this topic and hope that we see the results of an opioid outpatient treatment program. I know these exist and would welcome any information you as the readers of this blog can offer. Treating patients in the home makes great sense to me but we need to do it with the right drugs!
Much has been written about methylxanthines over the years with the main questions initially being, “should we use them?”, “how big a dose should we use” and of course “theophylline vs caffeine”. At least in our units and in most others I know of caffeine seems to reign supreme and while there remains some discussion about whether dosing for maintenance of 2.5 -5 mg/kg/d of caffeine base or 5 – 10 mg/kg/d is the right way to go I think most favour the lower dose. We also know from the CAP study that not only does caffeine work to treat apnea of prematurity but it also appears to reduce the risk of BPD, PDA and duration of oxygen therapy to name a few benefits. Although initially promising as providing a benefit by improving neurodevelopmental outcomes in those who received it, by 5 and 11 years these benefits seem to disappear with only mild motor differences being seen.
Turning to a new question
The new query though is how long to treat? Many units will typically stop caffeine somewhere between 33-35 weeks PMA on the grounds that most babies by then should have outgrown their irregular respiration patterns and have enough pulmonary reserve to withstand a little periodic breathing. Certainly there are those who prove that they truly still need their caffeine and on occasion I have sent some babies home with caffeine when they are fully fed and otherwise able to go home but just can’t seem to stabilize their breathing enough to be off a monitor without caffeine. Then there is also more recent data suggesting that due to intermittent hypoxic episodes in the smallest of infants at term equivalent age, a longer duration of therapy might be advisable for these ELBWs. What really hasn’t been looked at well though is what duration of caffeine might be associated with the best neurodevelopmental outcomes. While I would love to see a prospective study to tackle this question for now we will have to do with one that while retrospective does an admirable job of searching for an answer.
The Calgary Neonatal Group May Have The Answer
Lodha A et al recently published the paper Does duration of caffeine therapy in preterm infants born ≤1250 g at birth influence neurodevelopmental (ND) outcomes at 3 years of
age? This retrospective study looked at infants under 1250g at birth who were treated within one week of age with caffeine and divided them into three categories based on duration of caffeine therapy. The groups were as follows, early cessation of caffeine ≤ 14 days (ECC), intermediate cessation of caffeine 15–30 days (ICC), and late cessation of
caffeine >30 days (LCC). In total there were 508 eligible infants with 448 (88%) seen at 3 years CA at follow-up. ECC (n = 139), ICC (n = 122) and LCC (n = 187). The primary outcome here was ND at 3 years of age while a host of secondary outcomes were also examined such as RDS, PDA, BPD, ROP as typical morbidities. It made sense to look at these since provision of caffeine had previously been shown to modify such outcomes.
Did they find a benefit?
Sadly there did not appear to be any benefit regardless of which group infants fell in with respect to duration of caffeine when it came to ND. When looking at secondary outcomes there were a few key differences found which favoured the ICC group. These infants had the lowest days of supplemental oxygen, hospital stay ROP and total days of ventilation. This middle group also had a median GA 1 week older at 27 weeks than the other two groups. The authors however did a logistic regression and ruled out the improvement based on the advanced GA. The group with the lowest use of caffeine had higher number of days on supplemental oxygen and higher days of ventilation on average than the middle but not the high caffeine group. It is tempting to blame the result for the longer caffeine group on these being babies that were just sicker and therefore needed caffeine longer. On the other hand the babies that were treated with caffeine for less than two weeks appear to have likely needed it longer as they needed longer durations of oxygen and were ventilated longer so perhaps were under treated. What is fair to say though is that the short and long groups having longer median days of ventilation were more likey to have morbidities associated with that being worse ROP and need for O2. In short they likely had more lung damage. What is really puzzling to me is that with a median GA of 27-28 weeks some of these kids were off caffeine before 30 weeks PMA and in the middle group for the most part before 32 weeks! If they were in need of O2 and ventilation for at least two weeks maybe they needed more caffeine or perhaps the babies in these groups were just less sick?
What is missing?
There is another potential answer to why the middle group did the best. In the methods section the authors acknowledge that for each infant caffeine was loaded at 10 mg/kg/d. What we don’t know though is what the cumulative dose was for the different groups. The range of dosing was from 2.5-5 mg/kg/d for maintenance. Lets say there was an over representation of babies on 2.5 mg/kg/d in the short and long duration groups compared to the middle group. Could this actually be the reason behind the difference in outcomes? If for example the dosing on average was lower in these two groups might it be that with less respiratory drive the babies in those groups needed faster ventilator rates with longer durations of support leading to more lung damage and with it the rest of the morbidities that followed?
It would be interesting to see such data to determine if the two groups were indeed dosed on average lower by looking at median doses and total cumulative doses including miniloads along the way. We know that duration may need to be prolonged in some patients but we also know that dose matters and without knowing this piece of information it is tough to come to a conclusion about how long exactly to treat.
What this study does though is beg for a prospective study to determine when one should stop caffeine as that answer eludes us!
When it comes to inserting tubes, NICU staff is probably the most experienced in the world. Intubation is one of the first procedures we learn as young doctors in NICU. Some of us perform it through nose, some through mouth. But who performs it on mother’s or father’s chest?
Well, I’ve seen it only once or twice, but that is a practice in Uppsala University Hospital.
What do you need to perform it? An intubation set. A baby, that actually needs that intubation. It can be a planned or an acute one. And then you need that special thing- a parent (or a caregiver), that is willing to help you with the procedure.
When I came back from Sweden, I shared this crazy idea with one neonatal nurse. She told me, that it must be extremely stressful for the parent and that she considers it inhumane to push parents to do that. Well, I can say that I partly agree with her, giving the specification of the unit she worked in at that time. It was a medium size NICU of the highest reference, where parents were welcome to visit the baby, but there were no beds for them, and the chairs for the kangaroo care were each time brought in for that short „session” of skin-to-skin care. LET’S TALK ABOUT SPONTANEITY THERE!
But in Uppsala University Hospital this procedure is possible, because you have parents there all the time. They basically never leave the unit. If they are not doing skin-to-skin with their baby (watching a movie on a little player approved by the unit or reading a book), they are cooking or eating in the parent’s area or taking shower in their bathroom. They are not patients there, but they are staying there overnight, so in the morning you can see some of them sneaking out to the bathroom in their pyjamas. So in that situation, you don’t just have a scared parent, who is there from time to time, smiling nervously to his or her child through the plastic incubator. You have a semi-professional companion, who knows his or her baby’s needs best and who is there to care for their own infant.
So back to the main topic. Intubation on parent’s chest. Ok, you may say- that sounds okay, but what are the benefits? Why should we risk intubating on an unstable ground? I asked Erik Normann, the Head of the Department of Neonatology in Akademiska Hospital in Uppsala the same question. His opinion is, that in that way child stays in it’s preferred care site during this stressful moment. And in case of spontaneous extubation during skin-to-skin care, you don’t have to move the child back to the incubator to place the tube, so this is quicker. And that skin-to-skin care just continues after the procedure. There’s no special technique or limitations for that procedure, but he admits, that it creates some logistic problems with the staff position around the bed. Also, bending over parent’s chest is not the most optimal working position (especially for taller doctors 😉). But what you get in return for that effort is a happier baby, supported and stabilized by their parents hands.
I’m not sure if all of us are „there yet”. What is the more important, is that we are heading in that direction- to this mental NICUland, where parents are there for the baby all the time, to offer warmth of their skin and delicacy of their touch, and where medical staff is ready to accept their help and presence. Together we can do more!
So hands up guys- who does that too in their unit? Who would like to try?✋✋✋
We are on important missions in the NICU. From time to time, we all sense the strong rewarding feeling that our work mattered a lot.
I love the hands-on work in the NICU, but I also believe strongly in pursuing work at the meta-level of things. That we can change care and improve outcomes through research, quality improvement, and taking our professionalism outside the box. And to the web! Naturally, the 99nicu “global village” is one of those meta-level journeys for me.
I have shared small bits of information previously about a new project with a really big scope.
Together with an EU-based group, I started Neobiomics, an academic startup project that will provide a super-high quality bifidobacterial product requested by neonatologists, “from the community, to the community”. The composition of the product is based on this RCT. Launch is planned in Europe mid-2019, and outside Europe during 2020.
Although the product itself is much requested, I personally think that this project has a much wider potential. With access to a highly advanced machinery (literally!) at the production facility, it should be possible to make other compositions (other sets of bacteria, other bacterial numbers, +/- other compounds etc) for some really cool comparative trials.
Manufacturing quality is key, but as important in this project is the not-for-profit business models. Naturally, we need to create something sustainable, but taking a perspective of social entrepreneurship enables the largest possible outreach.
We are still working mainly behind the scenes in the Neobiomics HQs, but relatively soon, we will step on stage and start creating buzz
As part of our communication strategy, we are now collecting Testimonials from neonatologists believing in bringing this product "from the community, to the community".
If you share the basic idea behind this project, please consider to click here and share a Testimonial for publication on neobiomics.org
And… stay tuned
PS. The project above has nothing and everything to do with the talk below. Creativity is the Power to Act.
If I look back on my career there have been many things I have been passionate about but the one that sticks out as the most longstanding is premedicating newborns prior to non-emergent intubation. The bolded words in the last sentence are meant to reinforce that in the setting of a newborn who is deteriorating rapidly it would be inappropriate to wait for medications to be drawn up if the infant is already experiencing severe oxygen desaturation and/or bradycardia. The CPS Fetus and Newborn committee of which I am a member has a statement on the use of premedication which seems as relevant today as when it was first developed. In this statement the suggested cocktail of atropine, fentanyl and succinylcholine is recommended and having used it in our centre I can confirm that it is effective. In spite of this recommendation by our national organization there remain those who are skeptical of the need for this altogether and then there are others who continue to search for a better cocktail. Since I am at the annual conference for the CPS in Quebec city I thought it would be appropriate to provide a few comments on this topic.
Three concerns with rapid sequence induction (RSI) for premedication before intubation
1. "I don't need it. I don't have any trouble intubating a newborn" - This is perhaps the most common reason I hear naysayers raise. There is no question that an 60-90 kg practitioner can overpower a < 5kg infant and in particular an ELBW infant weighing < 1 kg. This misses the point though. Premedicating has been shown to increase success on the first attempt and shorten times to intubation. Dempsey 2006, Roberts 2006, Carbajal 2007, Lemyre 2009
2. "I usually get in on the first attempt and am very slick so risk of injury is less." Not really true overall. No doubt there are those individuals who are highly successful but overall the risk of adverse events is reduced with premedication. (Marshall 1984, Lemyre 2009). I would also proudly add another Canadian study from Edmonton by Dr. Byrne and Dr. Barrington who performed 249 consecutive intubations with predication and noted minimal side effects but high success rates at first pass.
3. "Intubation is not a painful procedure". This one is somewhat tough to obtain a true answer for as the neonate of course cannot speak to this. There is evidence available again from Canadian colleagues in 1984 and 1989 that would suggest that infants at the very least experience discomfort or show physiologic signs of stress when intubated using an "awake" approach. In 1984 Kelly and Finer in Edmonton published Nasotracheal intubation in the neonate: physiologic responses and effects of atropine and pancuronium. This randomized study of atropine with or without pancuronium vs control demonstrated intracranial hypertension only in those infants in the control arm with premedication ameliorating this finding. Similarly, in 1989 Barrington, Finer and the late Phil Etches also in Edmonton published Succinylcholine and atropine for premedication of the newborn infant before nasotracheal intubation: a randomized, controlled trial. This small study of 20 infants demonstrated the same finding of elimination of intracranial hypertension with premedication. At the very least I would suggest that having a laryngoscope blade put in your oral cavity while awake must be uncomfortable. If you still doubt that statement ask yourself whether you would want sedation if you needed to be intubated? Still feel the same way about babies not needing any?
4. What if I sedate and paralyze and there is a critical airway? Well this one may be something to consider. If one knows there is a large mass such as a cystic hygroma it may be best to leave the sedation or at least the paralysis out. The concern though that there might be an internal mass or obstruction that we just don't know about seems a little unfounded as a justification for avoiding medications though.
Do we have the right cocktail?
The short answer is "I don't know". What I do know is that the use of atropine, an opioid and a muscle relaxant seems to provide good conditions for intubating newborns. We are in the era of refinement though and as a recent paper suggests, there could be alternatives to consider;Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency IntubationA Randomized Clinical Trial. I personally like the idea of a two drug combination for intubating vs.. three as it leaves one less drug to worry about a medication error with. There are many papers out there looking at different drug combinations. This one though didn't find a difference between the two combinations in terms of prolonged desaturations between the two groups which was the primary outcome. Interestingly though the process of intubating was longer with atropine and propofol. Given some peoples reluctance to use RSI at all, any drug combination which adds time to the the procedure is unlikely to go over well. Stay tuned though as I am sure there will be many other combinations over the next few years to try out!
I had an amazing opportunity to visit NICU in the Turku University Hospital in 2016. They admit around 550 problematic newborns per year. About 10% of them are born below 30 weeks of gestation. The whole unit is practically based on 11 family rooms (single family rooms when possible) and additionally one larger room for 4 patients. The larger room is usually used for babies who are admitted due to transient issues (tachypnea, hypoglycemia, hyperbilirubinemia etc). Single family rooms are equipped with an incubator/open warmer bed/cot, one adult bed, one reclining armchair and a nappy changing station. There is also a breast pump and a refrigerator for breast milk in the room. Parents are constantly involved in the care of their preterm baby and are welcome to stay and care for their child all day and night. That’s the theory. So what is the reality?
Entering the unit for the first time, the word that came to my mind was „serenity”.
The unit welcomes you with knitted octopuses and tiny socks everywhere. The whole design of the unit is somehow soft, warm and calming. Each family room is „protected” by a closed door with a window in them - and the window is also covered with a pastel-color quilt. If you want to enter the room, or you’re just looking for your co-worker, you can just „peek in” and check without disturbing the family much. Then you can knock on the door and enter the room. This way you are giving the family the maximum privacy we can offer in those special circumstances.
Well, you have those tiny, „problematic” children in those private family rooms, with their parents being their primary caretakers, guardians and gate-keepers. Yet, nobody feels that their access to the patient is limited. How is that even possible? Maybe this is what we call „the change of the caring culture”? When you’re „letting go” of some of your duties and delegating them to the parents, you also learn to trust them with your little patient. After all, we all have the same goal- and the parents are personally and emotionally interested in their own child’s well-being, so they have even stronger motivation to perform well.
Visiting you patient in the single family room feels like visiting your friends, who had just brought their newborn back from the hospital. Imagine the situation, that you’re paying them that first visit, with a little gift wrapped in a pink paper and a big pink balloon. What will you expect? I think it’s quite normal that their room will be a bit messy and everybody will be whispering around the sleeping baby. It’s normal that the mother will be breastfeeding (or pumping milk) in your presence. And again- it’s normal that parents will be touching and cuddling the baby.
I’ve visited several neonatal intensive care units around the Europe. They all announce proudly, that they are „family centered units”. They all know that skin-to-skin care is a recommended, good and beneficial procedure. Yet in the same time, they actually treat it like a medical procedure - which is time-limited and full of exclusion criteria. That procedure also seems to be quite stressful for the medical staff, because they feel like they can’t access their patient anymore. What if something happens, what if we need to react, how to save that baby when the baby is outside the cot? How can we be medical professionals, when the patient is out of reach?
It comes straight to the question: what exactly is skin-to-skin care for you? Is it a medical procedure, which is performed once or twice a week, for one hour, when the baby (and the parent!) is fully dressed? Or do you consider mother’s and father’s bare chest as a new space of care for your patient? A safe surrounding, stabilizing baby’s body temperature, breathing and heart rate? And what do you consider a contraindication for skin-to-skin care?
Recently I’ve heard from my friend that in their NICU (highest reference centre) kangaroo care is performed only after the baby reaches 1600g. In other place, I’ve seen a healthy 31-weeker in his second week of life, on full enteral feeds, happily kicking in a closed incubator, who couldn’t be kangarooed or even touched by his parents, just because there was a PICC-line placed in his arm. I still remember those sad parents, wearing plastic gowns, standing by that closed incubator, not being able to even touch their own baby, just because it was a preemie.
Prematurity is a diagnosis, but it’s not a sentence! If we are treating similar babies with similar equipment and similarly trained staff - why does our practice differ so much? Leave your comment and join the discussion!
One of the benefits of operating this site is that I often learn from the people reading these posts as they share their perspectives. On a recent trip I was reunited with Boubou Halberg a Neonatologist from Sweden whom I hadn’t seen in many years.
I missed him on my last trip to Stockholm as I couldn’t make it to Karolinska University but we managed to meet each other in the end. As we caught up and he learned that I operated this site he passed along a paper of his that left an impact on me and I thought I would share with you.
When we think about treating an infant with a medicinal product, we often think about getting the right drug, right dose and right administration (IV, IM or oral) for maximum benefit to the patient. When it comes to nutrition we have certainly come a long way and have come to rely on registered dieticians where I work to handle a lot of the planning when it comes to getting the right prescription for our patients. We seem comfortable though making some assumptions when it comes to nutrition that we would never make with respect to their drug counterparts. More on that later…
A Swedish Journey to Ponder
Westin R and colleagues (one of whom is my above acquaintance) published a seven year retrospective nutritional journey in 2017 from Stockholm entitled Improved nutrition for extremely preterm infants: A population based observational study. After recognizing that over this seven year period they had made some significant changes to the way they approached nutrition, they chose to see what effect this had on growth of their infants from 22 0/7 to 26 6/7 weeks over this time by examining four epochs (2004-5, 2006-7, 2008-9 and 2010-11. What were these changes? They are summarized beautifully in the following figure.
Not included in the figure was a progressive change as well to a more aggressive position of early nutrition in the first few days of life using higher protein, fat and calories as well as changes to the type of lipid provided being initially soy based and then changing to one primarily derived from olive oil. Protein targets in the first days to weeks climbed from the low 2s to the mid 3s in gram/kg/d while provision of lipid as an example doubled from the first epoch to the last ending with a median lipid provision in the first three days of just over 2 g/kg/d.
While figure 3 from the paper demonstrates that regardless of time period there were declines in growth across all three measurements compared to expected growth patterns, when one compares the first epoch in 2004-2005 with the last 2010-11 there were significant protective effects of the nutritional strategy in place. The anticipated growth used as a standard was based on the Fenton growth curves.
What this tells us of course is that we have improved but still have work to do. Some of the nutritional sources as well were donor breast milk and based on comments coming back from this years Pediatric Academic Society meeting we may need to improve how that is prepared as growth failure is being noted in babies who are receiving donated rather than fresh mother’s own milk. I suspect there will be more on that as time goes by.
Knowing where you started is likely critical!
One advantage they have in Sweden is that they know what is actually in the breast milk they provide. Since 1998 the babies represented in this paper have had their nutritional support directed by analyzing what is in the milk provided by an analyzer. Knowing the caloric density and content of protein, carbohydrates and fats goes a long way to providing a nutritional prescription for individual infants. This is very much personalized medicine and it would appear the Swedes are ahead of the curve when it comes to this. in our units we have long assumed a caloric density of about 68 cal/100mL. What if a mother is producing milk akin to “skim milk” while another is producing a “milkshake”. This likely explains why some babies despite us being told they should be getting enough calories just seem to fail to thrive. I can only speculate what the growth curves shown above would look like if we did the same study in units that actually take a best guess as to the nutritional content of the milk they provide.
This paper gives me hope that when it comes to nutrition we are indeed moving in the right direction as most units become more aggressive with time. What we need to do though is think about nutrition no different than writing prescriptions for the drugs we use and use as much information as we can to get the dosing right for the individual patient!
I must admit that it is a bit exciting to think about that 99nicu.org went live 12 years ago, at a time when Facebook and other “social media” web sites was yet to be invented.
(@Zuckerberg, no offense here. Obviously, you created something far greater than 99nicu, still a grass rot project. BTW – could we apply for funding from you Foundation?)
When starting 99nicu.org in 2006, we nourished an idea that experiences and expertise should not be hindered by geographical boundaries. In some sense, this was a statement, that we as medical professionals could help each other through other channels than journals and conferences, with inclusive and open mindsets, and new technologies.
Back then we knew little about the powerful potential of the Internet. Neither could we foresee how the Internet would change our private and professional lives. We were just a group of young staff in Sweden, wanting to create a web based platform for discussions within a global group of neonatal pro’s.
When I read this blog post by @AllThingsNeonatal (on his web site allthingsneonatal.com) where he reflects on how sharing and caring in social media has created a global village, I am struck by the thought - a global village was what we envisioned back in 2006. Coming from a small village myself, I think that also 99nicu.org parallells the village symbolism: a setting with small communication gaps (everyone knows everything about everyone, so we don't need formalities to get in touch and speak out), and where giving and taking advice is a bilateral process that may ultimately lead to “the best solution”. Or simply, that we find out that there are several good solutions for a given problem.
Has 99nicu become as global village for neonatal staff on the Internet? Although biased, I’d say YES . Data also supports that. During January through April, the web site had 18.000 visitors from all over the globe, making 45.200 pageviews. From the Google Analytics dashboard we can all see that 99nicu reaches almost every corner of the world!
Our principal idea has always been that the virtual space is where we operate. It is the Internet that creates the possibility to connect and exchange experience as expertise from where we are. However, meeting up IRL is also a powerful way to maintain sustainable networks and that idea is the driving force behind the “99nicu Meetups”.
For the 1st and 2nd Meetup conferences in Stockholm and Vienna (in June 2017 and in April 2018), delegates came from 17 and 33 countries, respectively. Let’s hope we can have even a larger geographical representation at our IRL Meetup next year. Stay tuned for dates and location
In the first part of this series of posts called Can prophylactic dextrose gel prevent babies from becoming hypoglycemic? the results appeared to be a little lackluster. The study that this blog post was based on was not perfect and the lack of a randomized design left the study open to criticism and an unbalancing of risks for hypoglycemia. Given these faults it is no doubt that you likely didn’t run anywhere to suggest we should start using this right away as a protocol in your unit.
Another Study Though May Raise Some Eyebrows
New Zealand researchers who have been at the forefront of publications on the use of dextrose gel recently published another article on the topic Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study). As the short study name suggests “Pre-hPOD” this was a preliminary study to determine which dosing of dextrose gel would provide the greatest benefit to prevent neonatal hypoglycemia. The study is a little complex in design in that there were eight groups (4 dextrose gel vs 4 placebo) with the following breakdown.
Dosing was given either once at 1 h of age (0.5 ml/kg or 1 ml/kg) or three more times (0.5 ml/kg) before feeds in the first 12 h, but not more frequently than every 3 h. Each dose of gel was followed by a breastfeed. The groups given prophylaxis fell into the following risk categories;
IDM (any type of diabetes), late preterm (35 or 36 wk gestation), SGA (BW < 10th centile or < 2.5 kg), LBW (birthweight > 90th centile or > 4.5 kg), maternal use of β-blockers.
Blood glucose was measured at 2 h of age and then AC feeds every 2 to 4 h for at least the first 12 h. This was continued until an infant had 3 consecutive blood glucose concentrations of 2.6 mmmol/L. With a primary outcome of hypoglycemia in the first 48 hours their power calculation dictated that a total sample size of 415 babies (66 in each treatment arm, 33 in each placebo arm) was needed which thankfully they achieved which means we can believe the results if they found no difference!
What did they find?
One might think that multiple doses and/or higher doses of glucose gel would be better than one dose but curiously they found that the tried and true single dose of 0.5 mL/kg X 1 offered the best result. “Babies randomised to any dose of dextrose gel were less likely to develop hypoglycaemia than those randomised to placebo (RR 0.79, 95% CI 0.64–0.98, p = 0.03; number needed to 10.”
Looking at the different cumulative doses, the only dosing with a 95% confidence interval that does not cross 1 was the single dosing. Higher and longer dosing showed no statistical difference in the likelihood of becoming hypoglycemic in the first 48 hours. As was found in the sugar babies study, admission to NICU was no different between groups and in this study as with the sugar baby study if one looked at hypoglycemia as a cause for admission there was a slight benefit. Curiously, while the previous study suggested a benefit to the rate of breastfeeding after discharge this was not noted here.
How might we interpret these results?
The randomized nature of this study compared to the one reviewed in part I leads me to trust these findings a little more than the previous paper. What this confirms in my mind is that giving glucose gel prophylaxis to at risk infants likely prevents hypoglycemia in some at risk infants and given that there were no significant adverse events (other than messiness of administration), this may be a strategy that some units wish to try out. When a low blood glucose did occur it was later in the group randomized to glucose gel at a little over 3 hours instead of 2 hours. The fact that higher or multiple dosing of glucose gel given prophylactically didn’t work leads me to speculate this may be due to a surge of insulin. Giving multiple doses or higher doses may trigger a normal response of insulin in a baby not at risk of hypoglycemia but in others who might already have a high baseline production of insulin such as in IDMs this surge might lead to hypoglycemia. This also reinforces the thought that multiple doses of glucose gel in babies with hypoglycemia should be avoided as one may just drive insulin production and the treatment may become counterproductive.
In the end, I think these two papers provide some food for thought. Does it make sense to provide glucose gel before a problem occurs? We already try and feed at risk babies before 2 hours so would the glucose gel provide an added kick or just delay the finding of hypoglycemia to a later point. One dose may do the trick though.
A reader of my Facebook page sent me a picture of the hPOD trial which is underway which I hope will definitively put this question to rest. For more on the trial you can watch Dr. Harding speak about the trial here.
I have written a number of times already on the topic of dextrose gels. Previous posts have largely focused on the positive impacts of reduction in NICU admissions, better breastfeeding rates and comparable outcomes for development into childhood when these gels are used. The papers thus far have looked at the effectiveness of gel in patients who have become hypoglycemic and are in need of treatment. The question then remains as to whether it would be possible to provide dextrose gel to infants who are deemed to be at risk of hypoglycemia to see if we could reduce the number of patients who ultimately do become so and require admission.
Answering that question
Recently, Coors et al published Prophylactic Dextrose Gel Does Not Prevent Neonatal Hypoglycemia: A Quasi-Experimental Pilot Study. What they mean by Quasi-Experimental is that due to availability of researchers at off hours to obtain consent they were unable to produce a randomized controlled trial. What they were able to do was compare a group that had the following risk factors (late preterm, birth weight <2500 or >4000 g, and infants of mothers with diabetes) that they obtained consent for giving dextrose gel following a feed to a control group that had the same risk factors but no consent for participation. The protocol was that each infant would be offered a breastfeed or formula feed after birth followed by 40% dextrose gel (instaglucose) and then get a POC glucose measurement 30 minutes later. A protocol was then used based on different glucose results to determine whether the next step would be a repeat attempt with feeding and gel or if an IV was needed to resolve the issue.
To be sure, there was big hope in this study as imagine if you could prevent a patient from becoming hypoglycemic and requiring IV dextrose followed by admission to a unit. Sadly though what they found was absolutely no impact of such a strategy. Compared with the control group there was no difference in capillary glucose after provision of dextrose gel (52.1 ± 17.1 vs 50.5 ± 15.3 mg/dL, P = .69). One might speculate that this is because there are differing driving forces for hypoglycemia and indeed that was the case here where there were more IDMs and earlier GA in the prophylactic group. On the other hand there were more LGA infants in the control group which might put them at higher risk. When these factors were analyzed though to determine whether they played a role in the lack of results they were found not to. Moreover, looking at rates of admission to the NICU for hypoglycemia there were also no benefits shown. Some benefits were seen in breastfeeding duration and a reduction in formula volumes consistent with previous studies examining the effect of glucose gel on both which is a win I suppose.
It may also be that when you take a large group of babies with risks for hypoglycemia but many were never going to become hypoglycemic, those who would have had a normal sugar anyway dilute out any effect. These infants have a retained ability to produce insulin in response to a rising blood glucose and to limit the upward movement of their glucose levels. As such what if the following example is at work? Let’s say there are 200 babies who have risk factors for hypoglycemia and half get glucose gel. Of the 100 about 20% will actually go on to have a low blood sugar after birth. What if there is a 50% reduction in this group of low blood sugars so that only 10 develop low blood glucose instead of 20. When you look at the results you would find in the prophylaxis group 10/100 babies have a low blood sugar vs 20/100. This might not be enough of a sample size to demonstrate a difference as the babies who were destined not to have hypoglycemia dilute out the effect. A crude example for sure but when the incidence of the problem is low, such effects may be lost.
A Tale of Two Papers
This post is actually part of a series with this being part 1. Part 2 will look at a study that came up with a different conclusion. How can two papers asking the same question come up with different answers? That is the story of medicine but in the next part we will look at a paper that suggests this strategy does work and look at possible reasons why.
In 2017 the Canadian Pediatric Society published the practice point Pulse oximetry screening in newborns to enhance detection of critical congenital heart disease. In this document we recommended universal screening for CCHDs but stressed the following:
“Recognizing that delivery and time of discharge practices vary across Canada, the timing of testing should be individualized for each centre and (ideally) occur after 24 hours postbirth to lower FP results. And because the intent is to screen newborns before they develop symptoms, the goal should be to perform screening before they reach 36 hours of age.”
This recommendation was put in place to minimize the number of false positive results and prevent Pediatricians and Cardiologists nationwide from being inundated with requests to rule out CCHD as earlier testing may pick up other causes for low oxygen saturation such as TTN. The issue remains though that many patients are indeed discharged before 24 hours and in the case of midwife deliveries either in centres or in the home what do we do?
A Population Study From the Netherlands May Be of Help Here
Researchers in the Netherlands had a golden opportunity to answer this question as a significant proportion of births occur there in the home under the care of a midwife. Accuracy of Pulse Oximetry Screening for Critical Congenital Heart Defects after Home Birth and Early Postnatal Discharge by Ilona C. Narayen et al was published this month in J Peds. About 30% of births are cared for by a midwife with about 20% occurring in the home. The authors chose to study this population of infants who were all above 35 weeks gestation and not admitted to an intensive care nor had suspicion of CCHD prior to delivery. The timing of the screening was altered from the typical 24-48 hours to be two time points to be more reflective of midwives practice. All patients were recruited after birth with the use of information pamphlets. The prospective protocol was screening on 2 separate moments: on day 1, at least 1 hour after birth, and on day 2 or 3 of life. The criteria for passing or failing the test are the same as those outlined in the CPS practice point. As part of the study, patients with known CCHDs were also screened separately as a different group to determine the accuracy of the screening test in patients with known CCHD.
There were nearly 24000 patients born during this period. Only 49 cases of CCHD were identified by screening and of these 36 had been picked up antenatally giving a detection rate of 73%. Out of 10 patients without prenatal diagnosis who also had saturation results available the detection rate was 50%. Three of the misses were coarctation of the aorta (most likely diagnosis to be missed in other studies), pulmonary stenosis (this one surprises me) and TGA (really surprises me). The false-positive rate of pulse oximetry screening (no CCHD) was 0.92%. The specificity was over 99% meaning that if you didn’t have CCHD you were very likely to have a negative test. Not surprisingly, most false- positives occurred on day 1 (190 on day 1 vs 31 infants on day 2 or 3). There were five patients missed who were not detected either by antenatal ultrasound. These 5 negatives ultimately presented with symptoms at later time points and all but one survived (TGA) so out of 24000 births the system for detecting CCHD did reasonably well in enhancing detection as they picked up another 5 babies that had been missed antenatally narrowing the undetected from 10 down to 5.
Perhaps the most interesting thing about the study though is what they also found. As the authors state: “Importantly, 61% (134/221) of the infants with false-positive screenings proved to have significant noncardiac illnesses re- quiring intervention and medical follow-up, including infection/ sepsis (n = 31) and PPHN or transient tachypnea of the newborn (n = 88)”
There are certainly detractors of this screening approach but remember these infants were all thought to be asymptomatic. By implementing the screening program there was opportunity to potentially address infants care needs before they went on to develop more significant illness. Under appreciated TTN could lead to hypoxia and worsen and PPHN could become significantly worse as well. I think it is time to think of screening in this way as being more general and not just about finding CCHD. It is a means to identify children with CCHD OR RESPIRATORY illnesses earlier in their course and do something about it!
I am a consultant neonatologist from Southampton United Kingdom.
We have run a quality improvement initiative with regards to thermal outcomes in in preterm neonates admitted to the NICU after birth called Project SHIP. This involves standardising management of preterm birth from before delivery to admission to the NICU. As part of this we are doing a short survey on practice in this regard world wide.
I would be grateful if you could answer a few questions in this regard.
Dr Alok Sharma
For almost a decade now confirmation of intubation is to be done using detection of exhaled CO2. The 7th Edition of NRP has the following to say about confirmation of ETT placement “The primary methods of confirming endotracheal tube placement within the trachea are detecting exhaled CO2 and a rapidly rising heart rate.” They further acknowledge that there are two options for determining the presence of CO2 “There are 2 types of CO2 detectors available. Colorimetric devices change color in the presence of CO2. These are the most commonly used devices in the delivery room. Capnographs are electronic monitors that display the CO2 concentration with each breath.” The NRP program stops short of recommending one versus the other. I don’t have access to the costs of the colorimetric detectors but I would imagine they are MUCH cheaper than the equipment and sensors required to perform capnography using the NM3 monitor as an example. The real question though is if capnography is truly better and might change practice and create a safer resuscitation, is it the way to go?
Fast but not fast enough?
So we have a direct comparison to look at. Hunt KA st al published Detection of exhaled carbon dioxide following intubation during resuscitation at delivery this month. They started from the standpoint of knowing from the manufacturer of the Pedicap that it takes a partial pressure of CO2 of 4 mm Hg to begin seeing a colour change from purple to yellow but only when the CO2 reaches 15 mm Hg do you see a consistent colour change with that device. The capnograph from the NM3 monitor on the other hand is quantitative so is able to accurately display when those two thresholds are reached. This allowed the group to compare how long it took to see the first colour change compared to any detection of CO2 and then at the 4 and 15 mm Hg levels to see which is the quicker method of detection. It is an interesting question as what would happen if you were in a resuscitation and the person intubates and swears that they are in but there is no colour change for 5, 10 or 15 seconds or longer? At what point do you pull the ETT? Compare that with a quantitative method in which there is CO2 present but it is lower than 4. Would you leave the tube in and use more pressure (either PIP/PEEP or both?)? Before looking at the results, it will not shock you that ANY CO2 should be detected faster than two thresholds but does it make a difference to your resuscitation?
The Head to Head Comparison
The study was done retrospectively for 64 infants with a confirmed intubation using the NM3 monitor and capnography. Notably the centre did not use a colorimetric detector as a comparison group but rather relied on the manufacturers data indicating the 4 and 15 mm Hg thresholds for colour changes. The mean age of patients intubated was 27 weeks with a range of 23 – 34 weeks. The results I believe show something quite interesting and informative.
Median time secs (range)
Earliest CO2 detection
3.7 (0 – 44s)
4 mm Hg
5.3 (0 – 727)
15 mm Hg
8.1 (0 – 727)
I wouldn’t worry too much about a difference of 1.6 seconds to start getting a colour change but it is the range that has me a little worried. The vast majority of the patients demonstrated a level of 4 or 15 mm Hg within 50 seconds although many were found to take 25-50 seconds. When compared to a highest level of 44 seconds in the first detection of CO2 group it leads one to scratch their head. How many times have you been in a resuscitation and with no CO2 change you keep the ETT in past 25 seconds? Looking closer at the patients, there were 12 patients that took more than 30 seconds to reach a threshold of 4 mm Hg. All but one of the patients had a heart rate in between 60-85. Additionally there was an inverse relationship found between gestational age and time to detection. In other words, the smallest of the babies in the study took the longest to establish the threshold of 4 and 15 mm Hg.
Putting it into context?
What this study tells me is that the most fragile of infants may take the longest time to register a colour change using the colorimetric devices. It may well be that these infants take longer to open up their pulmonary vasculature and deliver CO2 to the alveoli. As well these same infants may take longer to open the lung and exhale the CO2. I suppose I worry that when a resuscitation is not going well and an infant at 25 weeks is bradycardic and being given PPV through an ETT without colour change, are they really not intubated? In our own centre we use capnometry in these infants (looks for a wave form of CO2) which may be the best option if you are looking to avoid purchasing equipment for quantitative CO2 measurements. I do worry though that in places where the colorimetric devices are used for all there will be patients who are extubated due to the thought that they in fact have an esophageal intubation when the truth is they just need time to get the CO2 high enough to register a change in colour.
Anyways, this is food for thought and a chance to look at your own practice and see if it is in need of a tweak…
Hypoglycemia has to be one of the most common conditions that we screen for or treat in the NICU and moreover in newborn care in general. The Canadian Pediatric Society identifies small for gestational age infants (weight <10th percentile), large for gestational age (LGA; weight > 90th percentile) infants, infants of diabetic mothers (IDMs) and preterm infants as being high risk for hypoglycemia. It is advised then to screen such babies in the absence of symptoms for hypoglycemia 2 hours after birth after a feed has been provided (whether by breast or bottle). I am sure though if you ask just about any practitioner out there, they will tell you a story about a baby with “no risk factors” who had hypoglycemia. These one-off cases have the effect though of making us want to test everyone for fear that we will miss one. If that is the case though should we be recommending that all babies get at least one check?
The Canadian Pediatric Surveillance Program (CPSP)
The CPSP is a branch of the Canadian Pediatric Society that “provides an innovative means to undertake active paediatric surveillance and increase awareness of childhood disorders that are high in disability, morbidity, mortality and economic cost to society, despite their low frequency. I submit my surveys each month as i hope other Canadian Pediatricians do and help to determine the impact of these rare conditions in our Canadian population. Like with any survey we rely on people taking the time to submit but there is always the risk that what is being sent in under represents the true burden of illness as some cases may not be identified. Having said that, it is the best we have!
Turning our attention to hypoglycemia in low risk newborns
From April 2014 to March 2016 the CPSP searched for these types of patients and just published the results of their findings in Hypoglycemia in unmonitored full-term newborns—a surveillance study by Flavin MP et al. What I like about the study is that they have been able to look at a group of babies that fall outside those identified as being at risk in the CPS statement Screening guidelines for newborns at risk for low blood glucose. They were looking for severe hypoglycemia by using a threshold of < 2.0 mmol/L (36 mg/dl) and all infants must have received IV dextrose. In the end after excluding ineligible cases they had 93 babies who met criteria. Based on the Canadian birth rate this translates to an incidence of 1 in every 8378 births. These babies were all supposed to be low risk but there were in fact clues that while not strictly identified as risks in the CPS statement could have increased the likelihood of a low blood glucose. Twenty three percent of mothers had maternal hypertension and another 23% were obese while 47% had excessive weight gain during pregnancy. Furthermore, 8% of mothers were treated with a beta blocker (most likely labetalol I would think) during pregnancy which is a risk factor for hypoglycemia although not specifically cited in the current CPS statement.
A concerning finding as well was the likelihood of severe symptoms in this group on presentation. Twenty percent presented with major clinical signs (seizure, apnea or cyanosis). Median glucose levels at presentation were much lower than those without major signs (median = 0.8 mmol/L, interquartile range [IQR] = 0.5 versus 1.6 mmol/L, IQR = 0.7; P < 0.001). Lastly, providers were asked about neurodevelopmental concerns at discharge approximately 20% were thought to have issues.
Are these patients really low risk though?
Twenty five percent of the patients submitted had a birth weight less than the 10%ile for GA. These patients as per the CPS guideline recommendations are actually considered at risk and should have been screened. The second issue to address has to do with the way we diagnose diabetes in pregnancy. All women are provided with the oral glucose tolerance test around 28 weeks of pregnancy. No test is perfect but it is the best we have. Women who have excessive weight gain in pregnancy (almost 50% of the cohort) are at higher risk of developing diabetes or some degree of insulin resistance as are those who are classified as obese. I have long suspected and think it may be the case here that some babies who do not meet the criteria for screening as their mothers do not have a diagnosis of GDM actually are at risk due to some degree of insulin resistance or perhaps their mothers develop GDM later. The evidence for this are the occasional LGA babies who are born to mothers without a GDM diagnosis but who clearly have been exposed to high insulin levels as they behave like such affected infants with poor feeding and low sugars in the newborn period. The authors here comment on those that were SGA but how many in this cohort were LGA?
The effect of hypertension can also not be minimized which was present in about a quarter of patients. These babies while not being officially SGA may have experienced a deceleration in weight gain in the last few weeks but remained above the 10%ile. These infants would not have the glycogen stores to transition successfully but would not be targeted as being at risk by the current definitions.
Should we be screening everyone then?
If we acknowledge that about 25% were IUGR in this study (<10%ile) and should have been screened, the expected rate would be 1:1170 births alone. In Manitoba with our 17000 births a year we would capture about two extra babies a year which translates into a low of pokes for a lot of healthy babies. Given the further information that 1:5 babies who are identified may have neurodevelopmental concerns it would take about 2-3 years of testing to prevent one concern. That pick up rate for me is far too low to subject so many babies to testing. What this study though does highlight is the need to view risk factors a little less strictly. Babies who are almost meeting the criteria for being LGA or those whose mother’s have taken lebetalol should have a low threshold for screening. Should hypertension on medications, excessive maternal weight gain or obesity in the mother be considered a risk? What I didn’t see in the end of this study were patients who truly were AGA, being born to healthy non overweight mothers presenting as high risk.
Maybe what is really needed based on this study is to re-evaluate what we consider at risk. In the meantime, maybe we should be testing a few extra babies who fall into these “lesser” risk categories. Better yet a study isolating such patients and looking at the frequency of hypoglycemia in these patients is warranted to get a better idea of whether they are indeed risks.
Skin to skin care or kangaroo care is all the rage and I am the first one to offer my support for it. Questions persist though as to whether from a physiological standpoint, babies are more stable in an isolette in a quiet environment or out in the open on their mother or father’s chests. Bornhorst et al expressed caution in their study Skin-to-skin (kangaroo) care, respiratory control, and thermoregulation. In a surprising finding, babies with an average gestational age of 29 weeks were monitored for a number of physiological parameters and found to have more frequent apnea and higher heart rates than when in an isolette. The study was small though and while there were statistical differences in these parameters they may not have had much clinical significance (1.5 to 2.8 per hour for apnea, bradycardia or desaturation events). Furthermore, does an increase in such events translate into any changes in cerebral oxygenation that might in turn have implications for later development? Tough to say based on a study of this magnitude but it certainly does raise some eyebrows.
What if we could look at cerebral oxygenation?
As you might have guessed, that is exactly what has been done by Lorenz L et al in their recent paper Cerebral oxygenation during skin-to-skin care in preterm infants not receiving respiratory support.The goal of this study was to look at 40 preterm infants without any respiratory distress and determine whether cerebral oxygenation (rStO2)was better in their isolette or in skin to skin care (SSC). They allowed each infant to serve as their own control by have three 90 minute periods each including the first thirty minutes as a washout period. Each infant started their monitoring in the isolette then went to SSC then back to the isolette. The primary outcome the power calculation was based on was the difference in rStO2 between SSC and in the isolette. Secondary measures looked at such outcomes as HR, O2 sat, active and quiet sleep percentages, bradycardic events as lastly periods of cerebral hypoxia or hyperoxia. Normal cerebral oxygenation was defined as being between 55 to 85%.
Perhaps its the start of a trend but again the results were a bit surprising showing a better rStO2 when in the isolette (−1.3 (−2.2 to −0.4)%, p<0.01). Other results are summarized in the table below:
Mean difference in outcomes
Difference in mean
% time in quiet sleep
No differences were seen in bradycardic events, apnea, cerebral hypoexmia or hyperoxemia. The authors found that SSC periods in fact failed the “non-inferiority” testing indicating that from a rStO2 standpoint, babies were more stable when not doing SSC! Taking a closer look though one could argue that even if this is true does it really matter? What is the impact on a growing preterm infant if their cerebral oxygenation is 1.3 percentage points on average lower during SSC or if their HR is 5 beats per minute faster? I can’t help but think that this is an example of statistical significance without clinical significance. Nonetheless, if there isn’t a superiority of these parameters it does leave one asking “should we keep at it?”
Benefits of skin to skin care
Important outcomes such as reductions in mortality and improved breastfeeding rates cannot be ignored or the positive effects on family bonding that ensue. Some will argue though that the impacts on mortality certainly may be relevant in developing countries where resources are scarce but would we see the same benefits in developed nations. The authors did find a difference though in this study that I think benefits developing preterm infants across the board no matter which country you are in. That benefit is that of Quiet Sleep (QS). As preterm infants develop they tend to spend more time in QS compared to active sleep (AS). From Doussard- Roossevelt J, “Quiet sleep consists of periods of quiescence with regular respiration and heart rate, and synchronous EEG patterns. Active sleep consists of periods of movement with irregular respiration and heart rate, and desynchronous EEG patterns.” In the above table one sees that the percentage of time in QS was significantly increased compared to AS when in SSC. This is important as neurodevelopment is thought to advance during periods of QS as preterm infants age.
There may be little difference favouring less oxygen extraction during isolette times but maybe that isn’t such a good thing? Could it be that the small statistical difference in oxygen extraction is because the brain is more active in laying down tracks and making connections? Totally speculative on my part but all that extra quiet sleep has got to be good for something.
To answer the question of this post in the title I think the answer is a resounding yes for the more stable infant. What we don’t know at the moment except from anecdotal reports of babies doing better in SSC when really sick is whether on average critically ill babies will be better off in SSC. I suspect the answer is that some will and some won’t. While we like to keep things simple and have a one size fits all answer for most of our questions in the NICU, this one may not be so simple. For now I think we keep promoting SSC for even our sick patients but need to be honest with ourselves and when a patient just isn’t ready for the handling admit it and try again when more stable. For the more stable patient though I think giving more time for neurons to find other neurons and make new connections is a good thing to pursue!
Caffeine seems to be good for preterm infants. We know that it reduces the frequency of apnea in the this population and moreover facilitates weaning off the ventilator in a shorter time frame than if one never received it at all. The earlier you give it also seems to make a difference as shown in the Cochrane review on prophylactic caffeine. When given in such a fashion the chances of successful extubation increase. Less time on the ventilator not surprisingly leads to less chronic lung disease which is also a good thing.
I have written about caffeine more than once though so why is this post different? The question now seems to be how much caffeine is enough to get the best outcomes for our infants. Last month I wrote about the fact that as the half life of caffeine in the growing preterm infant shortens, our strategy in the NICU might be to change the dosing of caffeine as the patient ages. Some time ago though I wrote about the use of higher doses of caffeine and in the study analyzed warned that there had been a finding of increased cerebellar hemorrhage in the group randomized to receive the higher dosing. I don’t know about where you work but we are starting to see a trend towards using higher caffeine base dosing above 5 mg/kg/d. Essentially, we are at times “titrating to effect” with dosing being as high as 8-10 mg/kg/d of caffeine base.
Does it work to improve meaningful outcomes?
This month Vliegenthart R et al published a systematic review of all RCTs that compared a high vs low dosing strategy for caffeine in infants under 32 weeks at birth; High versus standard dose caffeine for apnoea: a systematic review. All told there were 6 studies that met the criteria for inclusion. Low dosing (all in caffeine base) was considered to be 5- 15 mg/kg with a maintenance dose of 2.5 mg/kg to 5 mg/kg. High dosing was a load of 5 mg/kg to 40 mg/kg with a maintenance of 2.5 mg/kg to 15 mg/kg. The variability in the dosing (some of which I would not consider high at all) makes the quality of the included studies questionable so a word of warning that the results may not truly be “high” vs “low” but rather “inconsistently high” vs. “inconsistently low”.
The results though may show some interesting findings that I think provide some reassurance that higher dosing can allow us to sleep at night.
On the positive front, while there was no benefit to BPD and mortality at 36 weeks PMA they did find if they looked only at those babies who were treated with caffeine greater than 14 days there was a statistically significant difference in both reduction of BPD and decreased risk of BPD and mortality. This makes quite a bit of sense if you think about it for a moment. If we know that caffeine improves the chances of successful extubation and we also know it reduces apnea, then who might be on caffeine for less than 2 weeks? The most stable of babies I would expect! These babies were all < 32 weeks at birth. What the review suggests is that those babies who needed caffeine for longer durations benefit the most from the higher dose. I think I can buy that.
On the adverse event side, I suppose it shouldn’t surprise many that the risk of tachycardia was statistically increased with an RR of 3.4. Anyone who has explored higher dosing would certainly buy that as a side effect that we probably didn’t need an RCT to prove to us. Never mind that, have you ever taken your own pulse after a couple strong coffees in the morning?
What did it not show?
It’s what the study didn’t show that is almost equally interesting. The cerebellar hemorrhages seen in the study I previously wrote about were not seen at all in the other studies. There could be a lesson in there about taking too much stock in secondary outcomes in small studies…
Also of note, looking at longer term outcome measures there appears to be no evidence of harm when the patients are all pooled together. The total number of patients in all of these studies was 620 which for a neonatal systematic review is not bad. A larger RCT may be needed to conclusively tell us what to do with a high and low dosing strategy that we can all agree on. What do we do though in the here and now? More specifically, if you are on call tomorrow and a baby is on 5 mg/kg/d of caffeine already, will you intubate them if they are having copious apneic events or give them a higher dose of caffeine when CPAP or NIPPV that they are already on isn’t cutting it? That is where the truth about how you feel about the evidence really comes out. These decisions are never easy but unfortunately you sometimes have to make a decision and the perfect study hasn’t been done yet. I am not sure where you sit on this but I think this study while certainly flawed gives me some comfort that nothing is truly standing out especially given the fact that some of the “high dose” studies were truly high. Will see what happens with my next patient!
The lungs of a preterm infant are so fragile that over time pressure limited time cycled ventilation has given way to volume guaranteed (VG) or at least measured breaths. It really hasn’t been that long that this has been in vogue. As a fellow I moved from one program that only used VG modes to another program where VG may as well have been a four letter word. With time and some good research it has become evident that minimizing excessive tidal volumes by controlling the volume provided with each breath is the way to go in the NICU and was the subject of a Cochrane review entitled Volume-targeted versus pressure-limited ventilation in neonates. In case you missed it, the highlights are that neonates ventilated with volume instead of pressure limits had reduced rates of:
death or BPD
severe cranial ultrasound pathologies
duration of ventilation
These are all outcomes that matter greatly but the question is would starting this approach earlier make an even bigger difference?
Volume Ventilation In The Delivery Room
I was taught a long time ago that overdistending the lungs of an ELBW in the first few breaths can make the difference between a baby who extubates quickly and one who goes onto have terribly scarred lungs and a reliance on ventilation for a protracted period of time. How do we ventilate the newborn though? Some use a self inflating bag, others an anaesthesia bag and still others a t-piece resuscitator. In each case one either attempts to deliver a PIP using the sensitivity of their hand or sets a pressure as with a t-piece resuscitator and hopes that the delivered volume gets into the lungs. The question though is how much are we giving when we do that?
High or Low – Does it make a difference to rates of IVH?
One of my favourite groups in Edmonton recently published the following paper; Impact of delivered tidal volume on the occurrence of intraventricular haemorrhage in preterm infants during positive pressure ventilation in the delivery room. This prospective study used a t-piece resuscitator with a flow sensor attached that was able to calculate the volume of each breath delivered over 120 seconds to babies born at < 29 weeks who required support for that duration. In each case the pressure was set at 24 for PIP and +6 for PEEP. The question on the authors’ minds was that all other things being equal (baseline characteristics of the two groups were the same) would 41 infants given a mean volume < 6 ml/kg have less IVH compared to the larger group of 124 with a mean Vt of > 6 ml/kg. Before getting into the results, the median numbers for each group were 5.3 and 8.7 mL/kg respectively for the low and high groups. The higher group having a median quite different than the mean suggests the distribution of values was skewed to the left meaning a greater number of babies were ventilated with lower values but that some ones with higher values dragged the median up.
< 6 mL/kg
> 6 ml/kg
Grade 3 or 4
Let’s be fair though and acknowledge that much can happen from the time a patient leaves the delivery room until the time of their head ultrasounds. The authors did a reasonable job though of accounting for these things by looking at such variables as NIRS cerebral oxygenation readings, blood pressures, rates of prophylactic indomethacin use all of which might be expected to influence rates of IVH and none were different. The message regardless from this study is that excessive tidal volume delivered after delivery is likely harmful. The problem now is what to do about it?
Unless I am mistaken there isn’t a volume regulated bag-mask device that we can turn to to control delivered tidal volume. Given that all the babies were treated the same with the same pressures I have to believe that the babies with stiffer lungs responded less in terms of lung expansion so in essence the worse the baby, the better they did in the long run at least from the IVH standpoint. The babies with the more compliant lungs may have suffered from being “too good”. Getting a good seal and providing good breaths with a BVM takes a lot of skill and practice. This is why the t-piece resuscitator grew in popularity so quickly. If you can turn a couple dials and place it over the mouth and nose of a baby you can ventilate a newborn. The challenge though is that there is no feedback. How much volume are you giving when you start with the same settings for everyone? What may seem easy is actually quite complicated in terms of knowing what we are truly delivering to the patient. I would put to you that someone far smarter than I needs to develop a commercially available BVM device with real time feedback on delivered volume rather than pressure. Being able to adjust our pressure settings whether they be manual or set on a device is needed and fast!
Perhaps someone reading this might whisper in the ear of an engineer somewhere and figure out how to do this in a device that is low enough cost for everyday use.
A common concern in the NICU these days is the lack of opportunity to intubate. A combination of an increasing pool of learners combined with a move towards a greater reliance on non-invasive means of respiratory support is to blame in large part. With this trend comes a declining opportunity to practice this important skill and with it a challenge to get a tube into the trachea when it really counts. One such situation is a baby with escalating FiO2 requirements who one wishes to provide surfactant to. Work continues to be done in the area of aerosolized surfactant but as of yet this is not quite ready for prime time. What if there was another way to get surfactant to where it was needed without having to instill it directly into the trachea whether through a catheter (using minimally invasive techniques) or through an endotracheal tube?
Installation of surfactant into the trachea
Lamberska T et al have published an interesting pilot study looking at this exact strategy. Their paper entitled Oropharyngeal surfactant can improve initial stabilisation and reduce rescue intubation in infants born below 25 weeks of gestation takes a look at a strategy of instilling 1.5 mL of curosurf directly into the pharynx for infants 22-24 weeks through a catheter inserted 3-4 cm past the lips as a rapid bolus concurrent with a sustained inflation maneuver (SIM) of 25 cm of H2O for 15 seconds. Two more SIMs were allowed of the heart rate remained < 100 after 15 seconds of SIM. The theory here was that the SIM would trigger an aspiration reflex as the pressure in the pharynx increased leading to distribution of surfactant to the lung. The study compared three epochs from January 2011 - December 2012 when SIM was not generally practiced to July 2014 - December 2015 when SIM was obligatory. The actual study group was the period in between when prophylactic surfactant with SIM was practiced for 19 infants.
A strength of the study was that resuscitation practices were fairly standard outside of these changes in practice immediately after delivery and the decision to intubate if the FiO2 was persistently above 30% for infants on CPAP. A weakness is the size of the study with only 19 patients receiving this technique being compared to 20 patients before and 20 after that period. Not very big and secondly no blinding was used so when looking at respiratory outcomes one has to be careful to ensure that no bias may have crept in. If the researchers were strongly hoping for an effect might they ignore some of the "rules around intubation" and allow FiO2 to creep a little higher on CPAP as an example? Hard to say but a risk with this type of study.
What did they find?
The patients in the three epochs were no different from one and other with one potentially important exception. There were higher rates of antenatal steroid use in the study group (95% vs 75 and 80% in the pre and post study epochs). Given the effect of antenatal steroids on reducing respiratory morbidity, this cannot be ignored and written off.
Despite this difference it is hard to ignore the difference in endotracheal intubation in the delivery room with only 16% needing this in the study group vs 75 and 55% in the other two time periods. Interestingly, all of the babies intubated in the delivery area received surfactant at the same percentages as above. The need for surfactant in the NICU however was much higher in the study period with 79% receiving a dose in the study group vs 20 and 35% in the pre and post study groups. Other outcomes such as IVH, severe ROP and BPD were looked at with no differences but the sample again was small.
What can we take from this?
Even taking into account the effect of antenatal steroids, I would surmise that some surfactant did indeed get into the trachea of the infants in the study group. This likely explains the temporary benefit the babies had in the delivery suite. I suspect that there simply was not a big enough dose to fully treat their RDS leading to eventual failure on CPAP and a requirement for intubation. Is all lost though? Not really I think. Imagine you are in a centre where the Neonatologist is not in house and while he/she is called to the delivery they just don't make it in time. The trainee tries to intubate but can't get the tube in. Rather than trying several times and causing significant amounts of airway trauma (as well as trauma to their own self confidence) they could abandon further attempts and try instilling some surfactant into the pharynx and proving a SIM. If it works at all the baby might improve enough to buy some time for them to be stabilized on CPAP allowing time for another intubater to arrive.
While I don't think there is enough here to recommend this as an everyday practice there just might be enough to use this when the going gets tough. No doubt a larger study will reveal whether there really is something here to incorporate into the tool chest that we use to save the lives of our smallest infants.
Hypoglycemia has to be one of the most common conditions that we treat in the newborn admitted to NICU. For many infants the transitional phase of hypoglycemia can be longer than a couple low blood sugars and as nurses commonly express, it doesn’t take long before the heels of these infants begin to resemble hamburger. For those of you who have used diazoxide in the treatment of hypoglycemia you know that it works and it works quickly to raise the blood sugar. It works by blocking the production of insulin from the pancreas, so particularly in the setting of an infant with detectable insulin levels while hypoglycemic (should be undetectable with a low blood sugar) it can be quite effective. In my own practice I have found that often within one or two doses of the medication with treatment being 5-15 mg/kg/d it can seem to work miracles. Years ago I heard rumours of a trial from birth of this medication in infants of diabetic mothers but saw nothing come to fruition. As someone though who really strives to critically look at every needle poke and strongly consider the need I have always leaned towards the use of this medication if only to reduce what I suspected would be a large number of heel lances.
A Study Comes Forward
Balachandran B et al published a paper on this topic this week in Acta Paediatrica entitled Randomised controlled trial of diazoxide for small for gestational age neonates with hyperinsulinaemic hypoglycaemia provided early hypoglycaemic control without adverse effects. To be clear this is a very small study with only 30 patients in total (15 in the diazoxide and 15 in the placebo arms) and as they had nothing to go on for determining a sample size needed there was no power calculation. The authors chose to look at a very specific group of neonates that were SGA and had hypoinsulinemic hypoglycemia so we need to resist extrapolating to other patient groups such as IDMs in case there is a positive effect here.
With those warnings though, what they did was devise a stepwise approach to initiating diazoxide at 8 mg/kg/d and escalating the dose to as much as 12 mg/kg/d followed by a standardized wean following blood glucose stability. The primary outcome in this case was the number of hours required to achieve a stable glucose with a glucose infusion rate of =< 4mg/kg/min. They examined a number of secondary outcomes as well including duration of IV fluids, episodes of sepsis and time to achieve full feeds as well as mortality. Given the small sample size though I would resist drawing too many conclusions about these secondary outcomes but they are reported nonetheless. From the paper the Kaplan Meier curve indicates a faster time to stability of blood sugars for 6 hours favouring the diazoxide group. Importantly there were no differences in baseline insulin or cortisol levels between the groups which might explain differing times to glycemic control. Intravenous reductions with feeding increments were also standardized for the study to ensure comparable treatment strategies aside from the provided diazoxide or placebo.
Claim of Safety
The authors note there were no differences in mortality or number of sepsis episodes between the groups. They did find a statistically significant reduction in duration of IV fluid requirements which is likely believable despite my earlier warning as the length of time to achieve control was significantly reduced. The fact remains though with such few patients I would take claims of safety with a grain of salt. You might think at this point though that I would be a champion for the therapy but despite my earlier enthusiasm I do have some reservations. The median time to achieve glycemic control was 40 vs 72.5 hours with a p value of 0.015 which is certainly significant but really we are talking about nearly 2 vs 3 days of management. Is diazoxide truly safe enough to warrant the 30 hour reduction in time to glycemic control? Assuming q3h point of care glucose checks this would be about 8-10 less pokes as a best case scenario but more likely 4-6 less as near the end of checking glucoses as the patient becomes more stable the number of pokes usually decreases. Is diazoxide worth it though?
Back in 2015 the FDA issued a warning that diazoxide can lead to pulmonary hypertension. In truth we have seen it in babies where I practice and as such now routinely have an ECHO done before starting the drug to determine if there is any pulmonary hypertension prior to starting the drug and if there is even a hint it is contraindicated. It isn’t too common a complication as in the FDA bulletin (read here) there have been only 11 cases reported since 1973 but it is a risk nonetheless.
Thirty patients sadly isn’t enough to rule out this complication and it is worth nothing that the authors did not look for this outcome so we don’t know if any patients suffered this.
Am I saying that one should never use diazoxide? Absolutely not but I am suggesting that if you use it then use it with great caution. Although I am delighted the authors chose to perform this study taking all risks into account and looking at the benefit in terms of time on IV and that needed to gain control of blood sugars I can’t say this should be standard of care.