Even though the blog has been quiet recently, other academic output has continued…
In the NICU we are often faced with babies with late- or early- onset sepsis. The worst cases develop shock, which carries a significant mortality; they may survive if they receive intensive treatment. We have no idea really which treatments are helpful, and which are harmful. We try to follow physiologic principles but without much confidence that we are doing the right thing; we have been analyzing our treatments to try and figure out which interventions are helpful, and which might not work.
What often happens is that babies have standard interventions, (antibiotics, fluid boluses, dopamine or epinephrine infusions…) and when things are not going well we introduce other therapies, such as steroids or norepinephrine.
The first of these two studies looked at steroids: Altit G, et al. Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death? American journal of perinatology. 2017. We examined the responses to steroid, almost always hydrocortisone, therapy for babies in septic shock (i.e. hypotensive and not responding to first line inotropes). As this was not a research protocol, but just desperately trying to save babies who were in dire straits, the use of steroids was variable. But usually was after their response to either dopamine or epinephrine was inadequate. After starting hydrocortisone we were able, almost always, to reduce the doses of, or stop, other catecholamines. As time has progressed we have tended to use steroids earlier, sometimes before getting to high doses of catecholamines…
We compared episodes of septic shock among preterm babies who received steroids in addition to their inotrope, to those who did not receive hydrocortisone. We would expect the babies who received steroids to be more sick, and indeed their inotrope use index was higher, and they received inotropes for longer than the comparison group. Babies in both groups almost always had cultures that were positive, apart from a few cases of severe NEC with negative cultures. The babies receiving steroids were more immature. Mortality was significant 22% of those who did not get steroids, and 40% among those who did, reflecting their increased severity of illness (the difference may have been a chance difference by statistical testing). There were further deaths in both groups prior to discharge, and among survivors severe BPD was frequent. Because of the severe BPD we examined survival to follow-up at one year corrected age, in fact there were no more deaths after discharge. When we statistically corrected for gestational age and duration of inotrope use, there were more deaths among the babies who received hydrocortisone than those that did not.
We looked at the hemodynamic responses to the hydrocortisone and found a rapid improvement in blood pressure, starting within 6 hours, this was followed by a progressive reduction in inotrope requirements, mostly after the first 6 hours, and an improvement in urine output, starting after the blood pressure had increased. As you can see in table 4, these babies, who had a GA at birth on average of 26 weeks, and were about 2 weeks old, on average had mean blood pressures when we started the steroids of only 28 mmHg.
The second study examined our use of norepinephrine in another group of babies with septic shock. Before moving to Sainte Justine I don’t think I had ever used norepinephrine in a newborn infant, but the experience in adults, which shows a better hemodynamic profile in sepsis with norepinephrine compared to other catechols, led us to use norepinephrine in septic shock, mostly late-onset septic shock or NEC with shock.
Rizk MY, et al. Norepinephrine infusion improves haemodynamics in the preterm infants during septic shock. Acta Paediatr. 2017. We looked though our pharmacy database to find preterm babies who had received norepinephrine, all of whom were considered to be in septic shock. The 30 babies were already receiving either epinephrine or dopamine before we started norepinephrine, and nevertheless were very hypotensive, they were on average 26 weeks gestation, and 18 days old, but had a mean blood pressure of just over 20. We started the norepinephrine almost always at 0.1 microg/kg/min, and increased progressively, most babies not needing more than 0.2 microg/kg/min, but occasionally we went as high as 0.6. On average it took about 6 hours to achieve blood pressure and urine output within the normal range for each baby; they were oliguric when norepinephrine was started (mean urine output less than 2 mL/kg/h). We were able to commence reducing the other inotropes at that point, with all but 2 babies having reversal of their shock. Those 2 died, and one other for whom palliative care was started, for a mortality of 10% during the shock episode. There were 7 other deaths before discharge for an overall mortality of 33%. Long term outcomes were poor, with frequent disabling cerebral palsy and low Bayley scores.
Both of these studies have serious limitations of course, we don’t know if these babies would have done as well, or better, without these interventions, but there are very few studies examining therapies in septic shock, so we thought it worthwhile to examine our practice, to see how we can study this phenomenon for the future. A previous study on norepinephrine in preterm babies, who were mostly septic, showed a more rapid reversal of shock than our study, but started at a much higher dose (0.4 microg/kg/min) and took 24 hours to see improvement of oliguria. Their infants were also a little more mature (27 weeks), and had younger postnatal age (mean 1.5 days of age) and were sometimes being treated for PPHN, rather than sepsis.
What does this mean overall?
We desperately need prospectively controlled trials in infants with sepsis and hemodynamic compromise. In the meantime, use of steroids and/or use of norepinephrine are usually followed by hemodynamic improvement in babies who remain in hypotensive shock despite a single inotrope. That, I think is about all we can say, from these studies and others. Are such interventions much better than waiting or increasing the doses of the primary inotropes? Do they improve survival or other important outcomes?
As mortality is very high in these babies, RCTs of interventions would not need to be huge in order to have power to detect a clinically important difference in mortality; long-term adverse outcomes are also common, and moderately sized trials could also be informative for those outcomes.
I have some prior (not under any experimental protocol) experience in the NICU with colleagues using epinephrine for shock from sepsis and other causes. This was in babies of all gestations from 24 weeks through term. The experiences were not promising. There was frequent renal failure that could be attributed to the epinephrine, as well as evidence in some infants of other organ damage. Overall I haven’t had a high opinion of epinephrine as a beneficial treatment for shock despite the fact that it does increase blood pressure. What is the pharmacologic profile of norepinephrine that advances it as a useful medication in septic shock?
Norepinephrine is recommended as the first line inotrope in septic shock by the international consensus “surviving sepsis” campaign. Their rationale is