After my post on regression to the mean, and its importance in studies of apnoea therapy, I was thinking of other examples. Some which have been most evident to me are those which impact on areas of medicine that I have researched myself. One example, from many years ago now, looked at the haemodynamic effects of dopamine in sick preterm infants. Seri I, et al. Regional hemodynamic effects of dopamine in the sick preterm neonate. J Pediatr. 1998;133(6):728–34.

This study was performed during the 1st 2 days of life, a period when blood pressure normally gradually increases, and when renal vascular resistance falls dramatically. These known baseline changes are an additional confounder in the results of non-controlled studies. The subjects were preterm infants with what they termed “compensated shock”, that is they had a BP between the 10th and 90th percentiles, but were oliguric (<0.6 ml/kg/h of urine) and/or had slow capillary filling. They were all given dopamine, with echographic indices performed before and after.

What you can see is that overall mean BP increased, after doses of dopamine between 2.5 and 7.5 microg/kg/min

And an index of renal vascular resistance, the pulsatility index in the renal artery, decreased

These are actually changes that you would expect over time in the first hours of life. The time difference between the 2 measurement was relatively short, at about 30 minutes, one could argue, perhaps, that the changes are too quick to just be postnatal adjustment. Maybe they were caused by the dopamine?

Interestingly, the authors also presented results after, post hoc, dividing the infants into responders (who had a >10% increase in mean BP) and non-responders.

This shows that, the “responders”, panel A, had a lower mean BP before dopamine treatment, of about 35, and it increased to about 43 afterwards. The “non-responders”, panel D, had a mean BP, before and after dopamine, of just over 40 mmHg.

This is exactly what you would see if the results are entirely due to regression to the mean. Those with lower BP than average will tend to have an increase after any treatment, including placebo. It would be surprising, in an observational study such as this, for them to have given dopamine to babies with a higher BP than average.

Having said that, dopamine will in some circumstances, I think it is clear, increase BP, probably not by much at a dose of 2.5, but there is enormous variability in dopamine kinetics (and pharmacodynamics); some infants might have an increase in BP at low doses, and some have no effect at very high doses. Dopamine is, however, an effective vasoconstrictor, and any increase in BP is entirely due to vasoconstrition in the newborn. In this study, however, both “responders” and “non-responders” had a decrease in renal vascular resistance, why would this be? As I mentioned above, renal vascular resistance is known to decrease dramatically after birth; this study, for example shows an 88% decrease in RVR over the first 2 weeks of life, most of which is in the first 2 to 3 days.

Additionally, there is no newborn animal model in which dopamine causes renal vasodilatation; indeed the “dopaminergic effect” on renal blood flow has only really been shown in healthy adult dogs! In newborn mammals, in contrast, only renal vasoconstriction has been shown with dopamine. Here is one of my studies, from many years ago (Pearson RJ, et al. Dopaminergic receptor-mediated effects in the mesenteric vasculature and renal vasculature of the chronically instrumented newborn piglet. Crit Care Med. 1996;24(10):1706–12). The piglets I used were relatively insensitive to dopamine, requiring more than 16 microg/kg/min to have a BP increase, but there was no decrease in RVR at any dose.

I also subjected the animals to an infusion of Fenoldopam, as selective agonist of vascular dopamine receptors, which showed absolutely no renal vasodilatation.

These examples demonstrate, yet again, that one has to be very sceptical about the results of observational studies of the responses to an intervention. Whenever we treat a baby who has a problem which varies in intensity, be it apnoea, low blood pressure, oxygen requirements, oliguria, or anything else that you can think of, unless you randomize and treat only half of the infants, one can never know if any changes which are seen are due to the intervention, or just regression to the mean. Babies with BP lower than average will always tend to have higher BP the next time you measure it. Babies with low urine output will always tend to have higher urine output after an interval.

Controls, controls, controls. Preferably randomized controls. They are essential for determining the impacts, efficacy and safety of our interventions.