A one size fits all approach to preterm ventilation may not have been right all this time.

A one size fits all approach to preterm ventilation may not have been right all this time.

I had the opportunity recently to give a talk on strategies to reduce BPD in our preemie population. For the talk, I used as a springboard the recommendations for reducing BPD as laid out by the Evidence Based Practice for Improving Quality (EPIQ) group. There are far too many recommendations for optimal care to go through but the point of this post is to highlight one strategy that I think is deserving of discussion.

That volume targeted ventilation is recommended is no surprise. Setting a desired volume and allowing pressures to fluctuate rather than fixing a pressure and allowing volumes to fluctuate reduces the risk of both atelectotrauma and volutrauma. A recent paper Early volume targeted ventilation in preterm infants born at 22-25 weeks of gestational age has added further arguments in those at the smallest gestational ages by reducing episodes of hypocapnia and increasing likelihood of extubation by 24 hours compared to those on pressure limited ventilation.

Are Bigger Volumes Better With Time?

It is the second highlighted piece above that has left me scratching my head. Going way back to my residency I was taught that the ideal tidal volume is somewhere between 3.5 – 4.5 mL/kg and we should try and keep PIPs less than 35 cm H2O as an absolute maximum. In reality we typically would switch to the high frequency jet ventilator if pressures were increasing above 25 cm H2O in an effort to avoid volutrauma by increasing volumes further or barotrauma from excessive pressure. The main thrust of the argument was that big volumes hurt the lung so one is better off being gentle and inflating the lung with PEEP and then using the more gentle pulse of the HFJV after that. To be sure in the early stages of the neonatal course excessive volumes and pressure can commit the patient to a significant risk of BPD and meticulous attention to respiratory care is needed. The question for today is whether after 2 or 3 weeks of age, babies with developing lung injury need more volume on conventional ventilation or whether continuing on the HFJV is the way to go. I will let you in on a secret right away though. There is a systematic review on the subject.

The problem is it only includes one study from 1991 which is before antenatal steroids and surfactant as standards of care so not much to take from this paper.

Evidence for Bigger Volumes

The first paper showing some evidence for this is by Kezler M et al from 2009 Evolution of tidal volume requirement during the first 3 weeks of life in infants <800 g ventilated with Volume Guarantee. The study examined 26 infants with blood gas and Vt sets (828 in total). The Vt measurements included in the analysis were only those that were used when the blood gas was within a normal range for age using permissive hypercapnia to guide treatment.

As shown in the table above the needed tidal volumes rise over time. The PIPs remain acceptable (below the set limits) but the volumes rise to close to 6 mL/kg by three weeks of age. If these results are generalizable to our own population this would mean that using our units current levels of 3.5 – 4.5 mL/kg would leave these older infants short. If so is it any wonder we see high pCO2 triggering a need for HFJV. The authors conclude here that the progressive dilation of the trachea and proximal bronchi over time from ventilation increase dead space and are responsible for the rise in needed Vt.

The next study Volume targeting levels and work of breathing in infants with evolving or established bronchopulmonary dysplasia was published in 2019 by Hunt et al. This study looked at 18 infants less than 32 weeks and randomly assigned them once older than one week of age and still ventilated to 20 minute periods on 4,5,6 and 7 mL/kg of Vt in random fashion. The median GA was 26 weeks and day of study 18 days. The outcome of interest was measurement of work of breathing using the Pressure-time product of the diaphragm (PTPdi). The findings are below.

One did not see a significant improvement in work of breathing until 7 mL/kg was reached and you can see a progressive rise in minute ventilation needed to maintain normocapnia over time. This study supports the previous one in suggesting that over time there is an increase in dead space and if we want to reduce air hunger which could be represented by work of breathing we need to consider higher volumes.

The Damage is Done

Its an imperfect science that we are looking at and there is no doubt there will be readers of this post that will cringe at the volumes being discussed. I think what this really comes down to is whether you think the damage is done by 2-3 weeks. We of course don’t officially classify babies as having BPD until 36 weeks but if we are being honest we often know or can predict which ones are destined to get it. Is it better for the babies to be put on high frequency ventilation for weeks or to be given some larger volumes on conventional ventilation? Hard to say based on the evidence as there really isn’t much to go by. One thing that does need to be considered is long term high frequency ventilation and the need for sedation. Many of our kids on weeks of such therapy need progressively more sedation and what effect does that have on the developing brain. On the other hand if excessive volumes even at 2-3 weeks lead to increased damage to the lungs are you risking a prolongation on the ventilator or increasing the need at some point for a tracheostomy?

In the end I don’t think at the moment anyone knows. If you move from one center to another though and see completely different approaches I hope that by reading this post you will at least understand where the differences in practice come from.

In the end we are all just trying to do what we believe is best for the baby.

Stop checking baseline cortisol levels for preemies with hypotension

Stop checking baseline cortisol levels for preemies with hypotension

As readers of this blog will know I am a big fan of anything that challenges my practice. It’s something that I think in general is a good practice to live by. For many years now when a preterm infant in particular is hypotensive it has been our practice to draw a serum cortisol level and then determine whether the stress response is adequate before starting hydrocortisone for blood pressure support. Having said that, sometimes we start the hydrocortisone and then use the level afterwards to determine if we need to continue. is this approach right though?

Evidence That Shakes Up Our Approach

It turns out the evidence that preterm infants may not be able to produce a robust cortisol response after birth has been around for sometime. In 1994 Hingre et al published Adrenal steroidogenesis in very low birth weight preterm infants. In this paper they documented the diminished ability of infants born < 30 weeks gestational age to produce cortisol finding preterm newborns had low basal cortisol levels “(mean +/- SEM, 207.4 +/- 23.5 nmol/L), and their levels were similar to basal levels reported for healthy full-term newborns (170.7 +/- 26.8 nmol/L; P = 0.31”. It is worth noting here that commonly held beliefs have been that an adequate adrenal response is in the range of 400 – 450 nmol/L or about 15 microgram/dL and these levels are lower than that. Moreover, when the authors measaured precursors of cortisol and found elevations consistent with a deficiency of decreased activity of 11 beta-hydroxylase (11 beta OH). Knowing this then, the use of a baseline cortisol to determine if an appropriate stress response is present before starting hydrocortisone is questionable. Having said that the practice has been that when it is low we assist with hydrocortisone and when it is high we can ease off the support. A new study that has just come out though I think may turn that thinking on its head!

High Cortisol Levels Are Concerning. Not the Lows!

Absence of relationship between serum cortisol and critical illness in premature infants by Prelipcean I et al was just published and looked at 224 infants at the University of Florida who were born under 30 weeks and had baseline cortisol levels drawn for clinical indications prior to 36 weeks PMA. Like many centres the baseline cortisol was done prior to starting hydrocortisone for hypotension. A baseline level under 15 mcg/dL was considered low which equates to about 413 nmol/L for those using those units (like my own hospital). The Simplified Score for Neonatal Acute Physiology II SNAP-II score , neonatal Sequential Organ Failure Assessment (nSOFA) and Vasoactive-Inotrope Score (VIS) were calculated and used as measures of illness severity against the the cortisol levels obtained in a retrospective fashion. Cortisol levels were taken at a median of 3.8 days with an IQR of 1.2 to 14 days). Hydrocortisone was givne to 71% of patients in the study as well.

What emerged from these results might be counterintuitive. From the figure below it was found that those infants with higher baseline cortisol levels were less likely to survive. This result just reached statistical significance. Thinking about this for a moment, we have traditionally worried about the infants with low cortisol and rushed to supplement them. The babies at real risk though here are the ones with a robust pituitary adrenal axis response. Notably another factor that leads to lower cortisol levels in the first few days of life is provision of antenatal steroids so it may be at least in part that the higher baseline levels might be seen in those without the benefit of antenatal steroids and therefore are at higher risk of adverse outcome. Bottom line though, a robust cortisol level would not necessarily appear to be marker of a good thing.

The second thing to be identified is the scatter of results for these infants across birth weight, day of life and gestational age. The authors discovered using a multivariable model that birth weight was the only statistically significant variable to explain cortisol variation. Interestingly for every 100g increase in birth weight cortisol increased an average of 10%.

Additionally, differences in average cortisol level were affected by chorioamnionitis and antenatal steroids. The presence of chorioamnionitis as a variable is not surprising I suppose given the results from the prophylactic steroid trials for BPD that have consistently found chorio predicts a higher rate of BPD.

Where things get really interesting is in the bottom half of the figure below. While weak linear associations with SNAP-II, nSOFA were found ,no correlation between serum cortisol concentration and concurrent critical illness severity objectively measured by SNAP-II and nSOFA scores at time points beyond the first day of life and prior to 36 weeks PMA in these infants were found. Most intriguing was the complete lack of relationship between the VIS and cortisol levels.

This presents a predicament about what to do with these levels. Based on this research the degree of illness and the amount of inotrope one is on (VIS takes into account doses of dopamine, dobutamine, vasopressin, milrinone, epinephrine and norepinephrine) has no relationship to cortisol level. If you are like our centre though you have been considering whether to use hydrocortisone based on the level of cortisol at baseline. Based on this research the message would be that if one wants to know a baseline cortisol it might be useful as a tool to determine how concerned one should be with an infant as risk of mortality is higher if baseline levels are above 413 nmol/L. In terms of determining whether one should support with hydrocortisone though in the face of a sick preterm infant and more specifically a hypotensive one the utility of the baseline measurement I would question. Adding to this the research from 1994 and one has to question if the level is low is that simply because the infant doesn’t have the metabolic machinery yet to produce enough rather than has an abnormal response to stress.

Some qualifiers as with any study like this need to be acknowledged. It is not a study of 1000 patients so the individual numbers of patients at different weight levels will be lower and therefore there could be unusual patients here influencing the results. Having said that, when you combine this information in this study with what is known from before about these preterm infants should we be surprised that there is no relationship between baseline cortisol and illness. If you don’t have the capacity to make it except when exceptionally stressed it would appear that all these baseline cortisols may in fact be good for telling ourselves how stressed we should be about the patient.