Assessing perfusion in the sick preterm baby

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

1. Greisen G, Leung T, Wolf M: Has the time come to use near-infrared spectroscopy as a routine clinical tool in preterm infants undergoing intensive care? Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 2011, 369(1955):4440-4451.
2. Wardle SP, Yoxall CW, Weindling AM: Determinants of Cerebral Fractional Oxygen Extraction Using Near Infrared Spectroscopy in Preterm Neonates. J Cereb Blood Flow Metab 2000, 20(2):272-279.
3. Victor S, Marson AG, Appleton RE, Beirne M, Weindling AM: Relationship Between Blood Pressure, Cerebral Electrical Activity, Cerebral Fractional Oxygen Extraction, and Peripheral Blood Flow in Very Low Birth Weight Newborn Infants. Pediatric Research 2006, 59(2):314-319.
4. Shah DM, Condò M, Bowen J, Kluckow M: Blood pressure or blood flow: Which is important in the preterm infant? A case report of twins. Journal of Paediatrics and Child Health 2011:no-no.
5. Kluckow M: Functional Echocardiography in Assessment of the Cardiovascular System in Asphyxiated Neonates. The Journal of Pediatrics 2011, 158(2, Supplement 1):e13-e18.
6. Groenendaal F, Lindemans C, Uiterwaal CSPM, de Vries LS: Early Arterial Lactate and Prediction of Outcome in Preterm Neonates Admitted to a Neonatal Intensive Care Unit. Neonatology 2003, 83(3):171-176.
7. Takahashi S, Kakiuchi S, Nanba Y, Tsukamoto K, Nakamura T, Ito Y: The perfusion index derived from a pulse oximeter for predicting low superior vena cava flow in very low birth weight infants. J Perinatol 2010, 30(4):265-269.
8. Moran M, Miletin J, Pichova K, Dempsey EM: Cerebral tissue oxygenation index and superior vena cava blood flow in the very low birth weight infant. Acta Pædiatrica 2009, 98(1):43-46.
9. Miletin J, Pichova K, Dempsey E: Bedside detection of low systemic flow in the very low birth weight infant on day 1 of life. European Journal of Pediatrics 2009, 168(7):809-813.
10. Miletin J, Dempsey EM: Low superior vena cava flow on day 1 and adverse outcome in the very low birthweight infant. Archives of Disease in Childhood – Fetal and Neonatal Edition 2008, 93(5):F368-F371.
11. Cresi F, Pelle E, Calabrese R, Costa L, Farinasso D, Silvestro L: Perfusion index variations in clinically and hemodynamically stable preterm newborns in the first week of life. Italian Journal of Pediatrics 2010, 36(1):6.
12. Weindling M, Paize F: Peripheral haemodynamics in newborns: Best practice guidelines. Early Human Development 2010, 86(3):159-165.
13. Miletin J, Pichova K, Doyle S, Dempsey EM: Serum cortisol values, superior vena cava flow and illness severity scores in very low birth weight infants. J Perinatol 2010.
14. Dempsey EM, Al Hazzani F, Barrington KJ: Permissive hypotension in the extremely low birthweight infant with signs of good perfusion. Arch Dis Child Fetal Neonatal Ed 2009, 94(4):F241-244.
15. Paradisis M, Evans N, Kluckow M, Osborn D: Randomized Trial of Milrinone Versus Placebo for Prevention of Low Systemic Blood Flow in Very Preterm Infants. The Journal of Pediatrics 2009, 154(2):189-195.
16. Dempsey EM, Barrington KJ: Evaluation and treatment of hypotension in the preterm infant. Clin Perinatol 2009, 36(1):75-85.
17. Dempsey EM, Barrington KJ: Treating hypotension in the preterm infant: when and with what: a critical and systematic review. J Perinatol 2007, 27(8):469-478.
18. Dempsey EM, Barrington KJ: Diagnostic criteria and therapeutic interventions for the hypotensive very low birth weight infant. J Perinatol 2006, 26(11):677-681.
19. Barrington KJ, Dempsey EM: Cardiovascular support in the preterm: treatments in search of indications. J Pediatr 2006, 148(3):289-291.
20. Osborn DA, Evans N, Kluckow M, Bowen JR, Rieger I: Low Superior Vena Cava Flow and Effect of Inotropes on Neurodevelopment to 3 Years in Preterm Infants. Pediatrics 2007, 120(2):372-380.
21. Hunt RW, Evans N, Rieger I, Kluckow M: Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants. The Journal of Pediatrics 2004, 145(5):588-592.
22. Weindling AM, Kissack CM: Blood pressure and tissue oxygenation in the newborn baby at risk of brain damage. Biol Neonate 2001, 79:341-245.
23. Kluckow M, Evans N: Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000, 82(3):F188-194.
24. Kluckow M, N. E: Superior vena cava flow in newborn infants:a novel marker of systemic blood flow. Arch Dis Child Fetal Neonatal Ed 2000, 82:F182-F187.
25. Deshpande SA, Platt MP: Association between blood lactate and acid-base status and mortality in ventilated babies. Arch Dis Child Fetal Neonatal Ed 1997, 76(1):F15-20.            26. de Boode W-P: Clinical monitoring of systemic hemodynamics in critically ill newborns. Early Human Development 2010, 86(3):137-141.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged . Bookmark the permalink.

One Response to Assessing perfusion in the sick preterm baby

  1. Denis Surkov says:

    1. The main goal of intensive care for neonates should be cerebral perfusion.
    2. Cerebral perfusion in neonates actually depends on CO not on BP.
    3. Monroe-Kelly hypothese doesn’t work in newborn, espesially in preterm. Equiation CPP=MBP-ICP is not useful for both term with HIE and preterm with IVH or PVL or any stroke.
    4. Oxygen delivery to brain tissue depends on cerebral blood flow.
    So, maybe it will be useful to study Doppler cerebral flow in ACA or MCA + NIRS for evaluation of cerebral hypoxia OR ischemia, or their combination.
    My point is that just NIRS isn’t enough. If you use 100% oxygen, you will see a pretty good rSO2, even in case of severe ischemia.

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