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U.S. Department of Health and Human Services

MedSun: Newsletter #6, August 2006

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Newsletter #6, August 2006


Oxygen Delivery Device Can Also Deliver Infections

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This article appeared in Nursing2006: 36(7):18, July 2006.

By Robert A. Fischer, R.N., M.S.N.

A medical center reported that Ralstonia bacteria had been isolated from tracheal aspirates of seven patients. Six of them were receiving therapy with the Vapotherm 2000i Respiratory Gas Humidification Device, which is used to warm and humidify oxygen and other gases delivered by nasal cannula. Five of the affected patients were infants and one was a toddler. One of these patients died; he had sepsis associated with Ralstonia. Consequently, the manufacturer voluntarily issued an urgent nationwide recall for the Vapotherm 2000i humidification devices.

What went wrong?
Ralstonia organisms are Gramnegative bacteria found in the environment, primarily in water and soil and on plants. Occasionally they’re isolated from respiratory secretions of cystic fibrosis patients. In these cases of Ralstonia colonization or infection, the organism was cultured from the Vapotherm device’s waterside outlet port.
The patient who died had Down syndrome and had undergone surgery to repair cardiac birth defects. The Gram-negative sepsis was thought to have been a factor that contributed to his death. The medical center immediately discontinued use of the device pending further investigation.

Retrospective reviews of patient cultures have identified other cases of Ralstonia colonization associated with Vapotherm humidification devices. As of January, the Food and Drug Administration (FDA) had received reports of positive Ralstonia cultures from 26 hospitals in 16 states.

What actions were taken?
Issued in January 2006, the Class 1 recall of Vapotherm 2000i model is the most serious type of recall, signifying a situation with a high risk of serious injury or death. These devices are used in both acute care and home settings. The manufacturer and FDA advise health care providers to switch any patients using these devices to alternative equipment. Patients who’ve been exposed to the Vapotherm system should be monitored for signs and symptoms of infection, such as fever, poor feeding or irritability, and elevated white blood cell counts. The FDA recommends that clinicians consider Ralstonia infection in the differential diagnosis of symptomatic patients, even if Ralstonia hasn’t been isolated.

Additional Information:

Vapotherm, Inc.

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FDA Tissue and Cell Pilot Project: A Special Collaboration with the Medical Product Safety Network (MedSun) Project

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The FDA Tissue and Cell Pilot Project, a special collaboration between the Center for Biologics Evaluation and Research (CBER) and the Medical Product Safety Network (MedSun) Project, is open to all hospitals participating in the MedSun Project. This new initiative, which began in November 2005, is the first stimulated surveillance program for cell and tissue transplant adverse events. MedSun assists hospitals to fulfill the new Joint Commission on Accreditation of Healthcare Organizations (JCAHO) reporting requirement regarding cells and tissues, which in turn helps manufacturers with their FDA reporting.

Frequently Asked Questions
1. What standards and regulations currently exist with regard to reporting on Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)?

There are FDA regulations that apply to manufacturers and distributors of these products, and there are JCAHO standards that apply to reporting by hospitals and other health care facilities, as follows.

a)JCAHO Standards for Hospitals and Other Accredited Organizations

JCAHO revised its standards for the Laboratory Accreditation Program (revised standards QC.5.300, QC.5.310, and QC.5.320) and adopted these standards for the Ambulatory Care, Office-Based Surgery, Critical Access Hospital, and Hospital Accreditation programs (new standards PC.17.10, PC.17.20, and PC.17.30).

Effective July 1, 2005, these standards apply to accredited organizations that store or issue tissue. These new standards require that organizations assign oversight responsibility for a tissue program, use standardized procedures in all tissue handling, maintain traceability of all tissues, and have a process for investigating and reporting adverse events.

All adverse events involving tissues, including disease transmission or other complications suspected of being directly related to tissue use, are to be investigated and reported to the HCT/P establishment from which the tissue was received.

Per JCAHO standards, examples of tissue specimens include bone, cornea, skin, heart valves/conduits, tendons, fascia, dura, bone marrow, veins, arteries, cartilage, sperm, embryos, eggs, stem cells, cord blood, synthetic tissue (artificially prepared), and other cellular and tissue-based transplant or implant products.

b)FDA Regulations That Apply to Manufacturers (also known as Tissue Establishments) of HCT/Ps

The FDA regulation for “Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-based Products” (known as the CGTP regulation) went into effect May 28, 2005. The CGTP regulations require HCT/P establishments to recover, process, store, label, package, and distribute HCT/Ps in a way that prevents the introduction, transmission, or spread of communicable diseases. HCT/P establishments must also maintain complaint files and evaluate each complaint relating to core CGTP requirements.

Such establishments are also required to:
1. Investigate any adverse reaction involving a communicable disease related to an HCT/P they made available for distribution; and
2. Report to FDA any serious adverse reactions involving a communicable disease if it is: fatal; life-threatening; results in permanent impairment of a body function or permanent damage to body structure; or necessitates medical or surgical intervention, including hospitalization.

The establishments must use the FDA MedWatch mandatory reporting form (Form FDA-3500A) and submit each report to FDA within 15 days of initial receipt of the information. This is the first Federal requirement for reporting of adverse reactions from transplanted HCT/Ps.

2.What are some examples of HCT/Ps that are regulated by the FDA?

Examples include: dura mater, human heart valves or pericardium, ocular tissue (cornea), cell therapies, hematopoetic stem cells (peripheral, cord), combination tissue products, muscular skeletal tissue (bone, ligament), skin, eyes, and reproductive materials (semen, oocytes, embryos).

3. What about human organ transplants and blood and blood products?

Human organs are not considered HCT/Ps and are not regulated by the FDA. The Health Resources and Services Administration regulates human organs. For more information about regulations that apply to human organs, go to http://www.hrsa.gov. The FDA regulates blood and blood products, separately. For more information about reports on blood and blood products, go to http://www.fda.gov/cber/blood.htm.

4. What about xenograft transplants (such as porcine- or bovine-derived tissues)?

MedSun is interested in receiving reports about these products if they have reasonably caused or contributed to serious adverse events. The FDA regulates many of these products as devices; therefore, adverse event reports on deaths and serious injuries related to these products are required under the Safe Medical Devices Act. Sites that participate in the FDA Tissue and Cell Pilot Project should report on these products through MedSun.

5. If a hospital is part of the MedSun Project and agrees to participate in the FDA Tissue and Cell Pilot Project, what are some examples of problems with HCT/Ps that should be reported through MedSun?

For the FDA Tissue and Cell Pilot Project, the following are examples of events that should be reported. MedSun sites are asked to report not only on actual harm, but also on cases that show potential for harm, such as “close calls.”

a)Product Problems
Packaging: Incomplete seal on a bottle of bone chips
Labeling: Label indicated tendon to be one size, but the package contained a different size
Contamination: Product was found to have hair in the sterile package
Irregularity: Diameter of the vessel was larger on one end than the other, which was outside the specifications
Damage: Tissue sample had irregular cuts throughout
Sterility issues: Product was thought to have been prepared in a sterile manner, but was determined not to be sterile
Surgical difficulty with transplantation: Difficulty with the implantation of a tissue product, whether because of instructions for use, condition of the product, or any other reason.

b)Adverse Reaction, Infection-related
Clinical infection with no positive cultures: Patient exhibits sign of clinical infection with no positive cultures noted with the tissue implant
Infection with positive cultures: Patient exhibits sign of clinical infection with positive cultures noted with the tissue implant
Infections requiring further surgical intervention: Patient exhibits an infection requiring removal of the implant or other surgical intervention

c)Adverse Reaction, Non-infection-related
Transplant/graft malfunction: Transplant or graft did not function or operate in the manner expected
Destructive changes in the graft (stenosis, calcification, crumbling, etc.): Graft noted to have unexpected changes either prior to its implantation or with followup examinations
Immune response to transplant: Anaphylaxis, graft versus host disease

d)Other Problems
Positive cultures with no clinical infection: Implant is determined to have positive cultural growth either before or after its implantation, with no clinical infection noted by patient
Reasons tissues get discarded: Discarding of tissues for any reason should be reported, whether the reason is an unmet expectation of the product, wrong implant ordered, no longer needed, or other circumstance
Increase the risk of infection from implanted devices: Condition occurs in which an implant increases a patient’s risk of infection

6. What FDA resources are available for information about communicable diseases and problems with HCT/Ps?

There are two Web sites that provide information on new procedures:

For Procedures for Handling Adverse Reaction Reports Related to "361" Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), go to http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm073048.htm.

For tissue-related information, go to http://www.fda.gov/cber/tissue/docs.htm.

7. How are incidents reported?

While pilot sites are participating in the FDA Tissue and Cell Pilot Project with MedSun, they should report on problems with cells and tissues in the same way they report on device problems—using the secure MedSun online software or by phone or fax—and then supplement the report with details about the HCT/P, as requested on the list provided to the sites.

Sites that are not involved in the pilot project should send reports to the product distributor using the MedWatch FDA Form 3500A.

8. What are the benefits of this project?

There are benefits to the participating sites, to the FDA, and to distributors of cells and tissues as follows.
The benefits to the participating sites are similar to those for the MedSun Project in general: receipt of important feedback that constitutes an important contribution to public health. Pilot sites will generate information that will be available to the FDA (identified), shared with the distributors (identified), and among health care institutions throughout the country (de-identified).

The primary benefit of the pilot project to the FDA is the capacity to structure a larger project in the future to gain the information necessary to ensure the safety and effectiveness of cells and tissue products. In the long run, this should permit FDA to respond quickly when action is needed—such as product recalls or requests to distributors for specific types of user training. In addition, with the assistance of the pilot sites, FDA will have the advantage of MedSun participants, who are trained to be on the lookout for and to report in a timely manner relevant information on problems identified with cells and tissues.

The benefits to product distributors are that they will learn of problems with their products in a timely manner through the copy of the report sent from the MedSun Project and will have the opportunity to work on solutions so that the problems do not recur and/or cause unnecessary patient or health care provider injury or death. Because distributors will receive identified reports from MedSun Project staff, they will have the opportunity to get additional details for their product evaluations by directly contacting the reporters. Because MedSun sites tend to be better reporters than non-MedSun sites (at least that has been true for reporting medical devices), distributors may receive better reports—with more detail and better narrative descriptions of the problem—than they might expect from other sites.

Additional Information:

FDA Regulations That Apply to Manufacturers (also known as Tissue Establishments) of HCT/Ps:

For more information about regulations that apply to human organs, go to

For more information about reports on blood and blood products, go to

For Procedures for Handling Adverse Reaction Reports Related to "361" Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), go to

For tissue-related information, go to

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Updated August 1, 2006

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