I often give talks where I present my ‘data’, (notice the quotation marks, what I actually present are my prejudices, and uncontrolled observational information, along with systematic reviews of other people’s data) which suggest strongly that there is no need to treat preterm infants with numerically low blood pressure whose perfusion is adequate.

The most common question I get asked after these talks is: how do you define and evaluate perfusion? I am currently on my way to the EAPS meeting in Istanbul (don’t cry for me!!!) where the talk I have to give is about exactly this issue. So, as I haven’t finished preparing the talk yet, I will write this post as I think about what I am going to say. ***Update, I just finished giving the talk and told the audience that I would post about this issue and put the pptx file on this blog, it is on the “presentations by our group” page, References are listed below this post.***

Definition: this is the easy bit. Adequate perfusion means that there is enough oxygen delivery to the tissues to maintain all of their vital functions and to avoid any long term adverse consequences. Actually, writing that definition is easy, but putting it into real-life practice is hellishly difficult.

Evaluation: this is still a work in progress. There are 3 potential categories of methods of evaluating perfusion. 1, clinical exam and history. 2 non-invasive monitoring. 3. invasive tests. Before I discuss each category, we should ask the question, how do we determine if a method of evaluating perfusion is accurate?

Now there’s the rub (as someone who could write fairly well once said). How do we determine if evaluation, for example, of capillary filling is an accurate representation of perfusion? Is there a gold standard to compare cap filling to?

I would say no, we have no gold standard that really tells me if the mitochondria are receiving enough oxygen. But I do think we have something that comes fairly close, and which for the moment is as good as we can get. The measure which I believe comes closest to a gold standard for perfusion is a shunt independent measure of systemic blood flow. Now we do have to remember that oxygen delivery depends on perfusion, but also on saturation and hemoglobin concentration. And adequacy of oxygen delivery depends on supply as well as on demand, but if we assume that we are only measuring these things in babies with a reasonably normal hemoglobin, and a reasonably normal saturation, and a reasonably normal oxygen consumption, then systemic blood flow will reflect whether supply is normal, and hopefully whether it is adequate.

What shunt independent measures of systemic blood flow exist? The best, in terms of being completely unaffected by the usual intra-and extra-cardiac shunts which are present in the preterm newborn, is flow in the superior vena cava. However, in terms of precision and reproducibility of measurement there are problems. Accurate measurement of the diameter of the SVC, and accurate doppler measurements of blood flow velocity in the vessel are both difficult, and there are some concerns about how reproducible the measures might be, especially in less experienced hands. The PA is easier to measure the diameter reproducibly, but if there is a significant inter-atrial shunt this measure is less helpful; however, for most purposes PA flow seems to be adequate.

A number of collaborators from Sydney, Australia (Martin Kluckow, Nick Evans, David Osborn and others) have shown that there appears to be a cutpoint of 40 mL/kg/min in the SVC below which there are adverse consequences, in particular an increase in the frequency of late onset intraventricular hemorrhage, they have also shown an association with poorer neurodevelopmental outcome. Other groups have confirmed this.

So do the measures of clinical perfusion correlate well with our imperfect gold standard?

1. Clinical evaluation of perfusion relies on what can be directly observed, and observations of the consequences of good or poor perfusion. Direct observations of perfusion are capillary filling time and warmth of the extremities. observations of consequences include urine output (renal perfusion), and level of activity/alertness. (CNS perfusion).

Capillary filling does have some correlation with SVC flow, but it is quite imperfect by itself. Even in order to achieve that degree of imperfection it needs to be done as objectively as possible, over the sternum with a standard methodology, and a stop watch to time the refill.

Toe temperature and central peripheral temperature difference are probably of limited value for babies who are in warm incubators. There is no good way of quantifying level of activity, so it is not clear whether this is useful. Urine output is low because of low renal blood flow and GFR immediately after birth, but seems to be more reliable after the first day or so (as renal vascular resistance falls by more than half), again little published data to confirm this.

2. Non-invasive measures. NIRS has great promise I think, but despite many years of investigation there remain a number of limitations to its use. It isn’t clear to me which parameter is most appropriate. Fractional oxygen extraction for example will be decreased if there is better oxygen supply, or if there is reduced consumption. It may be that simple is best and tissue oxygen saturation the preferred measure. Direct measures of tissue oxygenation correlate well with cranial NIRS, but there is a +/- 17% error, which is clearly substantial. In any case there is a correlation between tissue oxygenation and SVC flow. There is also a correlation between fractional oxygen extraction and the occurrence of cerebral injury.

You could be forgiven for thinking that NIRS should be the gold standard. Surely oxygenation of cerebral tissues is the most important function of the cardiovascular system from minute to minute? However there are numerous limitations, and its use has not become widespread clinically, at least not in North America, despite many publications (Gorm Griesen recently discussed why this should be, and how we should go about determining whether we should be using it routinely). I guess we need more evidence that low NIRS cerebral oxygenation correlates with poor outcomes, and then some evidence that therapy directed to improving NIRS improves outcomes. This may be asking a lot, as we don’t have such evidence for most of the things that we already treat (such as low blood pressure!) Newer devices which are simpler to use, and have probes designed for preterm infants might allow us to collect such evidence. We need to define a trigger level for intervention, or a set of circumstances which include a NIRS number.

How about perfusion index? The Masimo pulse oximeter displays a number called the perfusion index. This is of uncertain derivation (seems to be a trade secret) but has something to do with how much pulsation is going on in the signal that the pulse oximeter interprets. (Other pulse oximeters have numbers as well, but the further evaluation of PI has only been done with the Masimo). PI seems to correlate broadly with SVC flow, may correlate with poor outcomes, and may turn out to be an easily monitored indicator of peripheral perfusion. A number that the nurses can write down from a clinical monitor could perhaps be quite helpful to flag babies for further evaluation.

3. Invasive testing. Blood tests: serum lactates are the most studied for evaluating overall adequacy of oxygen delivery. Single measurements of lactate are correlated with mortality, but a single lactate taken shortly after birth is of more limited use, as lactates may be very high after a complicated delivery, and then fall if perfusion is adequate, so the trend in lactate values may be more useful. A lactate of 5 for example might mean something very different if the previous was 10 or if the previous one was 1!

Other lab tests such as pH or base excess seem to be of little value.

Combining indicators

Perhaps the best thing to do would be to combine indicators, to construct a perfusion scale with capillary filling, serum lactate and how much it has changed, urine output, etc. Some preliminary work in this has been published by my good friend and colleague Gene Dempsey, he showed that a combination of a capillary filling time of >4 secs and a lactate of more than 4 correlated well with an SVC flow of less than 40. As well as being significant it is easy to remember!

In Summary

An SVC flow below 40 mL/kg/min is associated with poorer outcomes, but –Using the same limit for everyone is a bit simplistic, it ignores variations in HgB, Saturation and O2 demand: but it is by far the best evaluated and supported measure we have

SVC flow <40 mL/kg/min has become relatively uncommon in the small preterms (<20%) probably in association with less aggressive intervention.

Other measures have often been evaluated for their correlation with SVC flow: They should also be evaluated independently for their association with clinical outcomes

Capillary filling has some correlation with SVC flow

An overall clinical estimation of poor perfusion is associated with poor outcomes

Cap filling <4 AND lactate >4 is associated with low SVC flow

NIRS of brain and other regions? The method of analysis, and best parameter to use are uncertain. The Big Question of NIRS that needs to be asked is: Is there a single cutoff that predicts poorer outcome, therefore could be used to instigate (or investigate) therapy?

Perfusion Index from the pulse oximeter? Much more work needed.

What we need are prospective cohort studies analyzing all of these factors in a group of preterm infants. They should be compared with echo indices of flow.and more importantly with short and long term complications.

The research questions to be asked are: •Does this measure correspond with outcomes? Does it correlate with flow •Is it an appropriate measure to guide treatment?

References

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