Brad Karon, M.D., Ph.D.
Professor of Laboratory Medicine and Pathology
Division Chair, Clinical Core Laboratory Services
Mayo Clinic, Rochester, Minnesota
Hello everyone. I'm Brad Karon. I am chair of the Division of Clinical Core Laboratory Services at Mayo Clinic in Rochester. Our division oversees our laboratory services or phlebotomy area, and we sponsor with Mayo Clinic Laboratories our annual Phlebotomy Conference. To those of you who have not previously been to a Phlebotomy Conference here in Rochester sponsored by Mayo Clinic Laboratories, the title of this topic today, "Top Gun Phlebotomy," may seem a little bit strange. Every year at the Phlebotomy Conference, those who attend are able, during the registration process, to submit a question or issue they would like to hear about at the conference. I take these ideas submitted by conference attendees and turn it into a presentation every year that is called “Top Gun Phlebotomy,” where I take these questions and issues that our audience wants to hear about and turn them into a case-based presentation. This Top Gun Phlebotomy "Hot Topic" is a case from last year's Phlebotomy Conference dealing with pediatric venipuncture volumes.
I have no disclosures related to today's presentation.
Prior to the Phlebotomy Conference, one conference attendee submitted this statement: "Pediatric venipuncture volumes is always a gray area." That's what I had to work with. That's what one of our conference attendees wanted to hear about during the conference. And so, I made it into the following case at last year's Phlebotomy Conference.
At the conference itself then, I used this question to make a case. This was the question or the case I came up with: "Based upon evidence from pediatric research studies, the maximum amount of blood that is safe to remove from a child is ..."
I won't read all the answers, but you can see I gave four different options for the maximum amount of blood that could be safely removed from a child. At the conference, in real-time, we used an audience polling application to see what our attendees of the conference believed to be the correct, or most correct, answer. For every Top Gun case, I then go through the data, evidence, and experience for Mayo Clinic and beyond Mayo Clinic that I can find related to the issue or topic. And then, at the end, you'll see we poll again and see if I've moved or convinced the audience of the correct answer.
Many cases do begin by reviewing CLSI guidelines on blood collections. The relevant CLSI guideline here is again the diagnostic venous blood specimen CLSI guideline. And there is information about pediatric collections. It states that the blood volume in children is higher in newborns in roughly 75 to 80 milliliters per kilogram of blood volume in a child. And it suggests limiting blood collection to 1% to 5% of total volume in a 24-hour period, or 10% of blood volume over eight weeks. That is one source of information you can use for pediatric blood volume guidelines, would be the CLSI guidelines.
Going beyond that, there are a number of guidelines and studies that deal with research studies. Research studies are a good way to address this question, because in participating in a research study, there's no direct benefit to the child. They're generally designed to say what safe amount of blood to remove from a child for the purposes of research that won't affect or harm the health of the child.
There's a European Commission guideline, you can see the link of reference here, on ethical conduct of pediatric studies. It recommends or suggests that you assume 80 to 90 milliliter per kilogram blood volume for a child. It suggests, similar to the CLSI guideline, that 1% of blood volume could be removed over 24 hours. That roughly comes out to about one milliliter per kilogram. It's also suggested about 3% blood volume over a one-month or four-week period, coming out to about 2.4 milliliters per kilogram. It does state that these are not necessarily based on a great deal of evidence — they're sort of expert consensus among the pediatric research community — and that each study should define the actual blood volumes and try to minimize them as much as possible.
Another source I found that addressed this question comes from the Hospital for Sick Children in Toronto, Canada. They have a large pediatric research center and their own internal guidelines. Again, they have similar assumptions about the blood volume of an infant or child being closer to that 85 to 90 milliliters per kilogram, or an infant or preterm infant closer to 75 to 80 after six months of age. It suggested about up to 5% of blood volume can be drawn over a three-month period. Either as a single blood draw in a day or dividing up that 5% blood volume over multiple draws in a three-month period.
As an example, a two-and-a-half kilogram infant has a 212-milliliter blood volume. Up to 10 milliliters, or a little over 10 milliliters, could be drawn over a three-month period of time.
The National Institutes of Health in the U.S. has a similar set of guidelines. They recommend no more than five milliliters per kilogram per day for pediatric patients at the NIH Clinical Center, and no more than 9.5 milligrams per kilogram over eight weeks for patients at the NIH Clinical Center. They state these are maximum amounts from healthy children. Again, individual study protocols should do whatever they can to consider risks and use less blood when possible.
These are some guidelines from CLSI, which I usually start with, and research institutes about safe amounts of blood to take out of a child without affecting their health for the purposes of research. But what about the underlying data from studies? This is a study not too old, 2019, you can see the reference here, that looked at 141 children at risk for diabetes who were enrolled in three different clinical trials. The median age of children in the trials was five years in one, one-year-old average age in the other, and five years on the third. The study protocols on these three studies differed, but patients in the studies had an average of 2.4 milligrams per kilogram, or about 3% total blood volume drawn over multiple occasions. In one study that was done monthly, it had 2.4 milligrams per kilogram monthly for three consecutive months. Another study designed had it twice in the first month, and then monthly thereafter for three months. These were several three to five consecutive draws over three months, spread out over a three-month period of time, each being about 3% total blood volume. No patient developed anemia or had an abnormal red blood cell index. The author suggests that 2.4 milligrams per kilogram in a single blood sampling or even repeated a few times over three months is safe for children and it would not then cause anemia.
Another study, a little older from 2009, looked at 34 female subjects ranging in age from two to nine, who were undergoing a study to look at gonadotropin-releasing hormone results. They needed more blood for these studies. The average phlebotomy loss was 9.6 milligrams per kilogram at the initial visit. Almost a 10% blood volume immediately on day one. Followed by subsequent six milliliters per kilogram blood volumes every six months. This amount of blood taken from these children did result in a drop in the average hemoglobin level by about 1.2 grams per deciliter after that initial 10% or 10 ml per kilogram blood sampling. With iron replacement, the hemoglobin of these children did normalize. They found they could keep the hemoglobin normal through the subsequent blood samplings, but only with continued iron supplementation. These authors concluded that these larger 10% blood volume draws are safe, but would require iron replacement to avoid a temporary drop in hemoglobin. Again, it may not be completely benign for a child to have a 10% blood volume blood draw in even one day.
Other studies out there have looked at repeated blood sampling of 3% to 5% of total blood volume in pediatric oncology patients. Again, these are not healthy children. These are children being treated with chemotherapy who may be at high risk for anemia. They found that the decrease in hemoglobin really did not correlate with the actual blood volume removed. Again, it may just reflect the fact that in inpatients, and we'll talk about this in a minute, you really have to tailor these to individual cases. Because inpatient sick children will tend to be anemic, and the blood volume taken may not correlate well with the incidence of anemia.
The final study I'll mention is The Environmental Determinants of Diabetes in the Young or the TEDDY study. It was a multi-center study of pediatric diabetes in the US, Germany, Finland, and Sweden. Studies started in 2004 and had a fairly conservative initial allowance for blood draws of 1.3 to 1.7 milliliters per kilogram monthly over three months. Many institutions, including ours, derived our initial pediatric blood volume rules based on what was defined in the TEDDY study. That 1.7 milligrams per kilogram limit is commonly seen across pediatric institutions. However, you should note this study found there were no safety issues documented and has now increased that limit closer to about 3% to 3.5% of blood volume allowed with local IRB approval.
The summary of pediatric blood draw volume studies, in terms of what is safe for a child, a healthy child, would be sort of benign, not cause anemia or problems for a healthy child. The guidelines that suggest a 1 milligram per kilogram or only 1% total blood volume do seem fairly conservative given the data that shows that a little bit higher didn't cause anemia or have issues. The 1.7 milligram per kilogram that has been used in places probably came from the TEDDY study, which now does allow more blood to be taken from healthy children. It seems reasonable that somewhere around a 3% blood volume blood draw, which is about 2.4 milligrams per kilogram for many children, is probably safe to do on a single occasion and even to have that repeated a small number of times over a three-month period. If you go over a 5% blood draw volume per day, that's where you would see, in a healthy child, risk of anemia and you may want to put limits on larger draws.
Again, these are guidelines developed from the best evidence in pediatric research studies. The fundamental question we're addressing is, if you have rules about the maximum amount of blood you take for an outpatient blood draw, based on the potential in a referral center or a children's hospital for multiple doctors to place orders for tests not knowing how much blood you might end up drawing, how much do you want to draw before you have a limit of contacting a physician to say, "Do we need to split up these orders or pare down what needs to be ordered on a given day?"
These guidelines, again, may work for general pediatric outpatient populations of that idea of around 3% blood volume per day. But again, you really can't apply this to inpatients, because they will be sick. They're often starting out anemic. Certainly, NICU, PICU, and inpatient rules need to be tailored with the clinical services to understand the risk of anemia, risk of transfusion, and the need for laboratory information to care for patients.
At this point in the conference, we would come back to the case, and we would put up the same question, "Based on the evidence from pediatric research studies, the maximum amount of blood that is safe to remove is ..." We would again poll the audience. We'd see if I convinced anybody that answer C seems like the best answer to give based on the evidence. And then, at the very end of the case, I would reveal the correct answer in my opinion to this case.
If you liked this presentation or this idea of case presentations, or even if you don't, I would like to encourage you to consider attending our Phlebotomy 2023: Empowering Our Employees During Challenging Times Phlebotomy Conference, which will take place as a live face-to-face event here in Rochester, Minnesota, on April 20 and 21. Thank you for your time and have a wonderful day.
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