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letter
. 2014 Mar;46(1):101–102.

Letters to the Editor

PMCID: PMC4557503  PMID: 24779128
letter J Extra Corpor Technol. 2014 Mar;46(1):101–102.

Going Beyond Manufacturers’ Limitations Is Not in the Best Interest of Our Patients

Gerard J Myers 1

To the Editor,

In your last issue, the Technique Article entitled “Prescriptive Patient Extracorporeal Circuit and Oxygenator Sizing Reduces Hemodilution and Allogeneic Blood Product Transfusion during Adult Cardiac Surgery: by Bronson et al. (JECT 2013;45:167–72), the authors and their cardiac program are to be congratulated on their quality initiative to address intraoperative hemodilution and their reduction in allogeneic blood transfusions over a 2-year period.

However, I have several concerns about this retrospective observation study. To start, the authors’ opening statement (also inferred in the title), “Decreased priming volumes led to increased hemoglobin nadir and decreases in allogeneic blood transfusion,” concerns me the most because it gives the impression that decreased prime volumes of approximately 100–200 mLs of crystalloid were causally related to the programs’ reduced transfusion statistics. Considering that only 30%of infused crystalloid contributes to intravascular hemodilution (1), the correlation between small decreases in prime volume and a programs’ reduction in allogeneic blood transfusion is confusing at best. Smaller prime volumes will contribute to the overall goal of reducing hemodilution during bypass, but it is only one small part of an entire team’s clinical practice that leads to reducing allogeneic blood transfusion statistics during cardiac surgery.

As the authors indicate in their conclusions, retrospective studies of this nature involve many confounders during the perioperative period (preoperative, intraoperative, postoperative), especially the fluid and pharmacological management practice of anesthesia, perfusion, and nursing, to name a few. Reinforcement of this fact is found in their methodology, where it is stated that “each perfusionist had the liberty to tailor their circuits to the patient needs” (arteriovenous loop reductions, antegrade and venous autologous prime [RAP, VAP], vacuum assist, 3/8” venous line, etc.), thereby stacking variable on variable in a broad retrospective analysis.

The authors did find statistical significance in nadir hemoglobin with a small mean increase of .38 g/dL over the 2-year period (8.76 vs. 8.38 g/dL, p < .01), but despite reaching good statistical validity, the poor internal validity relates to the many variables associated with perioperative transfusion and negates any direct relationship between their interpretation of “right size” circuits to the programs’ transfusion statistics or cost savings (2). However, the authors did acknowledge their poor internal validity in the last paragraph of the article with their singular statement: “The results observed here were not singularly the result of prescriptive patient circuit sizing, but rather contributed to in part by many other blood conservation efforts and transfusion reduction working concurrently.”

Another concern I have is in relation to the paper’s “flow chart.” This chart indicates that the authors would push a small adult oxygenator (FX15) beyond its manufacturer’s maximum rated flow of 5 LPM. If this was so, the authors would be using this device in an off-label manner. Unfortunately, this is not an uncommon practice with pediatric and small adult oxygenators such as the Terumo FX15, Sorin D905-EOS, and Maquet Quadrox i-sa. The truth of the matter is that all manufacturers set their maximum rated oxygenator flows based on the results of many forms of in vitro testing, including the standards set by the International Standards Organization (ISO). Based on a combination of the patients’ weight and height, and the target cardiac index of 2.4 L/min/m2 as suggested by the authors, the 5-LPM oxygenator is qualified to handle patients with a body surface area <2.08 m2 (3).

In the Journal of Medical Device Regulation, Klepinski (4) states that a physician’s use of a medical device offlabel is to be regulated by professional ethics, threat of a malpractice suit, Institutional Review Board or Ethics Committee policies, and insurance reimbursement rules. He also states that the manufacturer’s dissemination of information about using their device off-label is regulated by the Federal Drug Administration (FDA) and reimbursement laws as well. Federal regulatory agencies like the FDA and the Canadian Medical Protective Association state: “off label use of a medical device means any use that is not included in the printed, cleared indications for use” (5) and “off label refers to using a licensed medical device outside of the indication for which the license was issued, therefore it is recommended that the physician obtain and document the appropriate informed consent before using a device off-label” (6).

In addition to federal regulatory issues around intentionally using medical devices off-label (7), there is the potential for increasing patient morbidity associated with gaseous microemboli (GME) when intentionally pushing oxygenators beyond their manufacturers’ maximum rated flow. This morbidity can be associated with the increasing amounts of GME that are detected when pump flow rates approach or exceed the manufacturers’ maximum rated flow (8–10).

Excessive hemodilution during cardiac surgery may be an independent risk factor for transfusion (11), but it can be a manageable risk factor if addressed by reliable staff education, common sense, team work, and the cooperation of all professions involved in cardiac surgery (3).

My final concern is with the author’s use of the phrase “prescriptive” in this technique article. Considering the frequency of its use throughout the text and the devices the authors used, this phrase is too close to a manufacturer’s marketing concept and not to an individual program’s effort to reduce intraoperative hemodilution.

This article is a good indication of a department’s teamwork and effort to improve quality control, but it “does not” associate small prime volume reductions with improvements in allogeneic blood transfusion statistics nor does it qualify or quantify the use of small adult oxygenators in an off-label manner.

REFERENCES

  • 1.McIlroy DR, Kharasch ED.. Acute intravascular volume expansion with rapidly administered crystalloid or colloid in the setting of moderate hypovolemia. Anesth Analg. 2003;96:1572–1577. [DOI] [PubMed] [Google Scholar]
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J Extra Corpor Technol. 2014 Mar;46(1):103–104.

Response to Letter “Going beyond Manufacturers’ Limitations Is Not in the Best Interests of Our Patients” by Gerard J. Myers

Shahna L Bronson 1,2, Phillip D Scott 2, Joshua P Blessing 2, Jeffrey B Riley 2

To the Editor,

We appreciate Mr. Myers’ letter because it adds to the discussion of our article and is interesting. We respect his personal concerns regarding the publication.

Our article is not the first retrospective study to associate lower priming volumes with higher nadir hemoglobin levels and less allogeneic blood use. We cited and discussed those references in the article (1). It is true, in any institution, “excessive hemodilution can be a manageable risk factor if addressed by reliable staff education, common sense, team work and the cooperation of all professions involved in cardiac surgery.”

Regarding internal validity, multiple variables, and the weaknesses of retrospective studies, Mr. Myers restates in his letter what we admonished in the article. As months went by, our team was able to safely select the use of smaller circuits in a greater percentage of our patient population. In addition to the small significant increase in nadir hemoglobin, we reported a significant reduction in the percent of patients receiving allogeneic red blood cells. We also reported a significant reduction in median red blood cell use and direct costs in specific morphology patient subgroups.

Mr. Myers writes that it is common practice to use oxygenators outside of the manufacturer’s reported rated blood flow limits. His letter warns that there are ethical and federal regulatory issues associated with off-label use of medical devices. Is selecting an oxygenator with a maximum flow rate that more closely approximates a patient’s blood flow needs “off-label use” of a device? Modifying cardiopulmonary bypass circuits to reduce hemodilution was classified as a Class I Level of Evidence A recommendation in the guidelines published in 2006 (2). Manufacturers test oxygenators at normothermia with high hemoglobin levels, high blood flow rates, and low mixed venous hemoglobin oxygen saturations that are much more challenging to the device than the normal clinical values experienced during cardiopulmonary bypass. Regarding Mr. Myers’ statement “…the authors would push a small adult oxygenator, the RX15, beyond its manufacturer maximum rated flow of 5 L/min,” in reality, the RX/FX15 oxygenator was tested to an American Association for Medical Instrumentation standard of 7.0 LPM according to the manufacturer’s published instructions for use and specifications. Furthermore, blood flow calculations based on body surface area frequently overestimate flow requirements, particularly in patients with high body mass index (3,4).

Mr. Myers is an expert regarding gaseous microemboli behavior during cardiopulmonary bypass. His points about gaseous microemboli (GME) are difficult to argue, especially when using pediatric devices outside the rated blood flow limits as he cites. The W30 reservoir received its 4.0 LPM flow rating because it was associated with a prior SX oxygenator model and was not separately tested with the RX15 reservoir. Interestingly, the association with the SX model and its maximum flow of 4.0 LPM was before the use of vacuum-assisted venous drainage. The perfusion community uses a 3/8-inch venous line for flows up to 5.0 LPM without vacuum. Therefore, why would such a limitation be placed on the W30 reservoir? The oxygenators are the same. If a RX 15 oxygenator is placed with a W30 reservoir or a W40 oxygenator, it is still an opportunity to provide flow up to 7 L/min. Perfusionists using devices outside the manufacturer limits should study and understand the consequences for the patient in their own clinical setting, including GME creation and removal patterns.

Using our device selection chart, each perfusionist had the liberty to tailor their circuits to the patient needs including arteriovenous (A-V) loop reductions and oxygenator/ reservoir size selection. The goal behind creating the chart was to guide our teammates to consistently select the ideal minimum-sized oxygenator/reservoir/A-V loop combination to provide a circuit designed specifically based on the patient’s expected needs. These are steps toward standardization.

Ethically, a perfusionist should hold the patient’s best interests first and foremost. Albeit a small decrease in dynamic priming volume, the RX15 oxygenator it is still 115 mL less prime than the RX25 oxygenator. Add to that a decrease in all other components of our circuit that we improved, and you will find that the result is clinically significant, as reported in our experience. The recently updated AmSECT Standards and Guidelines for Perfusion Practice Standard 9 emphatically states perfusionists should expend efforts to minimize hemodilution, avoid unnecessary blood transfusions, and minimize the bypass circuit size (5).

The practice of perfusion has changed through the years in part because instructions for use (IFUs) are not held as iron-cast. Manufacturer IFUs are not just designed to direct safe medical practice but to protect the integrity of the product and the liability of the manufacturer. Off-label use of drugs and medical devices should be respected but not feared by perfusionists, because the practice is openly permitted through relevance to Continuing Medical Education (CME). According to The National Task Force on CME Provider/Industry Collaboration, the off-label use of medical devices is quite common and “…the patterns of off-label use are quite variable, with a range from single digits to up to 80% of use…” (6).

“A presentation of an off-label indication within the context of a continuing medical education activity is intended to provide healthcare providers with the most current clinical evidence for all available treatment options…” The National Task Force indicates that “…a discussion must be evidence-based, should be strictly limited to the discretion of the accredited provider within the activity, and cannot be positioned to encourage or promote off-label use for commercial purposes.”

The article being critiqued does meet these educational goals because it was presented to perfusionist peers in our professions educational journal, the Journal of Extracorporeal Technology, without promoting commercial gain. The sharing of that practice amidst peers in an educational journal is CME and is acknowledged as common practice.

The word “prescriptive” was used in a high frequency throughout the text because that is exactly what was done. Call it what you will, we are providing a customized circuit to decrease hemodilution, increase nadir hemoglobin, decrease blood transfusions, and decrease associated risks to the patient and costs to everyone.

The benefits of minimizing hemodilution of patients undergoing cardiopulmonary bypass are well proven and simply no longer just a consideration but an ethical obligation for perfusionists. Those willing to make progress and contribute to improvement will always be those taking on a challenge and testing the limits of success.

Operating a medical device outside of a manufacturer’s specification while using it within its designed indication and safely monitoring its performance is not off-label use, but progress.

REFERENCES

  • 1.McCusker K, Vijay V, DeBois W, Helm R, Sisto D.. MAST system: A new condensed cardiopulmonary bypass circuit for adult cardiac surgery. Perfusion. 2001;16:447–452. [DOI] [PubMed] [Google Scholar]
  • 2.Shann KG, Likosky DS, Murkin JM, et al. An evidence-based review of the practice of cardiopulmonary bypass in adults: A focus on neurologic injury, glycemic control, hemodilution, and the inflammatory response. J Thorac Cardiovasc Surg. 2006;132:283–290. [DOI] [PubMed] [Google Scholar]
  • 3.Alston RP, Anderson Anna A, Sanger K.. Is body surface area still the best way to determine pump flow rate during cardiopulmonary bypass? Perfusion. 2006;21:139–147. [DOI] [PubMed] [Google Scholar]
  • 4.Santambrogio L, Leva C, Musazzi G, et al. Determination of pump flow rate during cardiopulmonary bypass in obese patients avoiding hemodilution. J Card Surg. 2009;24:245–249. [DOI] [PubMed] [Google Scholar]
  • 5.AmSECT Standards and Guidelines for Perfusion Practice, July 2013, American Society of Extra-Corporeal Technology. Available at: www.amsect.org/documents/PDF/Final_ADOPTED_S_G_2013.pdf. Accessed February 24, 2014. [PMC free article] [PubMed]
  • 6.Fact Sheet, The National Task Force on CME Provider/Industry Collaboration, Volume 2, Issue 3; on-label and off-label usage of prescription medicines and devices, and the relationship to CME. Available at: www.ama-assn.org/resources/doc/cme/fact-sheet-4.pdf. Accessed February 24, 2014.

Articles from The Journal of Extra-corporeal Technology are provided here courtesy of EDP Sciences

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